An Investigation of the Hypoalgesic, Neurophysiological and Anti-Emetic

Effects of Transcutaneous Electrical Nerve Stimulation (TENS) and

Interferential Therapy (IFT)

Jos Alves-Guerreiro B.Sc. M.Med.Ed. MCSP S.R.P

Rehabilitation Sciences Research Group

Faculty of Life and Health Sciences
University of Ulster
Thesis submitted for Doctor of Philosophy (Ph.D.)

January 2004

Contents
Chapter 1. A History of Bioelectricity: Electroanalgesia and
1
Antiemetic Usage

1.1 Introduction

1.2 Physical principles of TENS

1.3 TENS modes available

1.4 TENS: clinical applications

11

1.5 IFT: physical principles

12

1.6 IFT: clinical applications

15

1.7 Action Potential Therapy (APS): a novel micro current device

15

1.8 Electroacupuncture: antiemetic usage

16

1.9 Summary

18

Chapter 2. Neurophysiological, Hypoalgesic and Antiemetic Effects

of Electrical Stimulation: Review of the Literature

2.1 Introduction

21

22

2.2 Electrical nerve stimulation: effects upon the RIII/Nociceptive

25

Flexion Reflex (NFR) and H-reflex

2.3 Electrical nerve stimulation: nerve conduction velocity (NCV),

38
microneurographic and somatosensory evoked potential (SEP) studies
2.4 Electrical stimulation and delayed onset muscle soreness

48

2.5 Sickness from anti-cancer therapy

58

ii

2.6 General mechanisms of nausea and emesis

59

2.7 Physiology of chemotherapy-induced nausea and vomiting: a brief

64

overview
2.8 Clinical care of patients receiving chemotherapy

67

2.9 Neiguan PC6 acupoint: antiemetic chemotherapy effects

69

2.10 Summary

78

Chapter 3. Effects of Interferential Therapy (IFT) upon Delayed

Onset Muscle Soreness (DOMS) in Humans

91

Abstract

92

3.1 Introduction

94

3.2 Aim

99

3.3 Methodology

99

3.4 Induction Protocol

100

3.5 Measurement of the Variables

101

3.6 Treatment Procedure

104

3.7 Data Analysis

106

3.8 Results

107

3.9 Discussion

120

3.10 Conclusion

126

iii

Chapter 4. The Effect of Three Electrotherapeutic Modalities upon

Mechanical Pain Threshold and Nerve Conduction in the Human

200

Median Nerve

Abstract

201

4.1 Introduction

203

4.2 Aim

205

4.3 Methodology

205

4.4 Recording Procedures

206

4.5 Data Analysis

210

4.6 Results

210

4.7 Discussion

218

4.8 Conclusion

223

Chapter 5. The Morrow Assessment of Nausea and Vomiting

(MANE): A Transcultural Adaptation for the Portuguese Language

264

of Portugal

Abstract

265

5.1 Introduction

266

5.2 Description of the Morrow Assessment of Nausea and Emesis

267

(MANE)
5.3 Psychometric Properties

268

5.4 The Development of a Portuguese Version of the MANE

270

iv

5.5 Aim

271

5.6 Methodology

271

5.7 Results

274

5.8 Discussion

276

5.9. Conclusion

277

Chapter 6. A Clinical Trial on the Hypoalgesic and Antiemetic

Effectiveness of Transcutaneous Electrical Nerve Stimulation and
Interferential Therapy in the Management of Cancer Patients

279

Receiving a High/Moderate Cytotoxic Chemotherapeutic Regimen

Abstract

280

6.1 Introduction

282

6.2 Methodology

287

6.3 Data Analysis

298

6.4 Results

300

6.5 Quality of Life Questionnaire C30 (QLQ-C30)

303

6.6 Discussion

312

6.7 Conclusion

321

Chapter 7. General Discussion and Conclusion

386

7.1 Introduction

387

7.2 Hyopalgesic effects of electrical stimulation (TENS and IFT)

391

7.3 Neurophysiological effects of electrical stimulation (TENS and IFT)

396

7. 4 Antiemetic effects of electrical stimulation (electroacupuncture) of

the acupoint PC-6 by TENS and IFT on the management of

397

chemotherapy-induced emesis.
7.5 Clinical Implications

400

7.6 Future Research

402

7.7 Summary/Conclusion

405

References

407

Appendices

467

vi

Acknowledgements
I would like to express my sincere thanks to the following:
Professor Deirdre Walsh and Dr Andrea Lowe-Strong for their helpful supervision
and valuable advice throughout the work of this thesis.

Dr Gareth Noble and Dr Patrick Minder for their assistance in data collection and
double-blinding procedures.

The medical and nursing stuff at the pain unit and oncology department (Hospital
Garcia de Orta, Portugal) for their willing participation in the clinical trial.

My postgraduate colleagues at the Rehabilitation Sciences Research Group for their

support and encouragement in the most difficult times.

The University of Ulster for the Vice Chancellors Research Scholarship throughout
my period of study.

Dr Garry Prentice for his friendship along these years and for his expert advice on
statistics and mathematical models.

vii

My colleagues at the Atlntica University, Lisbon, for the encouragement and

friendship. Special thanks to Artur Valentim for all the work done, the effort, and the
priceless help.

Mr Keith Tippey (Nidd Valley Medical Limited, North Yorkshire, UK) for providing
the TENS and IFT units for the clinical trial.

Most of all, I would like to thank my family for the support during all my academic
life. To my children and my wife, Joana, Miguel and Ftima for loving me so much.
To my father, thanks for giving me the research germ.

viii

Summary
Current literature reports that electrical stimulation is a popular modality that is used
by physiotherapists to treat a variety of clinical conditions. Although the rationale for
its use is well documented and its popularity is recognized, there is a debate about
the efficacy of this modality. The aim of the current thesis was to assess the
hypoalgesic, neurophysiological and antiemetic effects of TENS, IFT and APS. An
established laboratory pain model (delayed onset muscle soreness) was used to
investigate the hypolagesic effects of IFT. In addition, the neurophysiological effects
of TENS, IFT and APS were examined using neurophysiological techniques. Finally
an RCT investigated the hypoalgesic and antiemetic effectiveness of TENS and IFT
in the management of cancer patients undergoing an anti-neoplastic chemotherapy
regime. In the first study, a trend was observed over the duration of the study for
mechanical pain threshold in IFT 1 (10-20 Hz) group. The average decrease in pain
threshold along the length of the muscle at points 1-8 and over the muscle belly at
points 3-6 was noticeably less. However, differences between groups were not
statistically significant. The second study demonstrated that the application of the
IFT, TENS and APS over the human median nerve did not have a significant
hypoalgesic effect, although IFT (150 Hz, 125 s) produced a significant
neurophysiological effect compared to TENS and APS. Finally, the results obtained
from the RCT that investigated the effectiveness of IFT and TENS upon pain, nausea
and vomiting suggest that IFT (10 Hz, 200 s) and TENS (10 Hz, 200 s) did not

ix

have a hypoalgesic nor anti-emetic effect on sickness associated with cancer

chemotherapy. These findings, however, require further investigation.

The work presented in this thesis has resulted in the following publications and
presentations.

Publications in peer reviewed journals

J. Alves-Guerreiro, J.G. Noble, A.S. Lowe & D.M. Walsh. The effect of three
electrotherapeutic modalities upon peripheral nerve conduction and mechanical pain
threshold. Clinical Physiology, 21, 6, 704-711, 2001.

P.M. Minder, J.G. Noble, J. Alves-Guerreiro, I.D. Hill, A.S. Lowe, D.M. Walsh,
G.D. Baxter. Interferential therapy: lack of effect upon experimentally induced
delayed onset muscle soreness. Clinical Physiology and Functional Imaging, 22, 5,
339-347, 2002.

Published abstracts
J. G. Noble, J. Alves-Guerreiro, A. S. Lowe, D. M. Walsh. The Effects of three
electrotherapeutic modalities upon mechanical pain threshold and nerve conduction
in the human median nerve. Irish Journal of Medical Science, 169, (4), 273-274,
2000.

J. G. Noble, J. Alves-Guerreiro, I. Hill, P. Minder, A. S. Lowe & D. M. Walsh.

Effects of interferential therapy (IFT) upon delayed onset muscle soreness (DOMS)
in humans. Journal of Physiology, 515P, 87, 2000.

Alves-Guerreiro J, Lowe-Strong, AS, Walsh DM, Lopes BC, Costa R, Rosado R,

Monforte E, Rolo T, Projecto J, Ferreira M. Development of a Portuguese version of
the morrow assessment of nausea and emesis (MANE) questionnaire. Proceedings of
the 14th International WCPT Congress, RR-PO-2109, 2003.

Alves-Guerreiro J, Lowe-Strong AS, Walsh DM, Lopes BC, Costa R, Rosado R,

Monforte E, Rolo T, Projecto J, Ferreira M. Transcutaneous electrical nerve
stimulation versus interferential therapy: An investigation of the hypoalgesic and
anti-emetic effectiveness in the management of cancer patients undergoing antineoplastic chemotherapy regime. Proceedings of the 14th International WCPT
Congress, RR-PL-2110, 2003.

xi

Conference presentations
December 1999
Effects of interferential therapy (IFT) upon delayed onset muscle soreness (DOMS)
in humans.
J. G. Noble, J. Alves-Guerreiro, I. Hill, P. Minder, A. S. Lowe & D. M. Walsh.
Physiological Society Meeting, University of Birmingham, Birmingham.

January 2000
Effects of three different types of electrotherapeutic modalities upon mechanical pain
thresholds and nerve conduction in the human median nerve.
J. G. Noble, J. Alves-Guerreiro, A. S. Lowe, D. M. Walsh.
Royal Academy of Medicine in Ireland, Biomedical Section, Winter meeting,
Veterinary College, Dublin

June 2003
Development of a Portuguese version of the morrow assessment of nausea and
emesis (MANE) questionnaire.
Alves-Guerreiro J, Lowe-Strong AS, Walsh DM, Lopes BC, Costa R, Rosado R,
Monforte E, Rolo T, Projecto J, Ferreira M.
WCPT, 14th World Congress, Barcelona.

xii

Transcutaneous electrical nerve stimulation versus interferential therapy: An

investigation of the hypoalgesic and anti-emetic effectiveness in the management of
cancer patients undergoing anti-neoplastic chemotherapy regime.
Alves-Guerreiro J, Lowe-Strong AS, Walsh DM, Lopes BC, Costa R, Rosado R,
Monforte E, Rolo T, Projecto J, Ferreira M.
WCPT, 14th World Congress, Barcelona.

xiii

Abbreviations
ACTH

Adeno corticotropic hormone

AP

Appetite loss

AP

Area postrema

APS

Action potential stimulation

ASCO

American society of clinical oncology

CAP

Compound action potential

CDDP

Cis-dichloro-diammine-Pt(II)

CF

Cognitive functioning

CK

Creatine kinase

CNS

Central nervous system

CO

Constipation

CTZ

Chemo receptor trigger zone

DCS

Dorsal column stimulation

DI

Diarrhoea

DOMS

Delayed onset muscle soreness

DY

Dyspnoea

EF

Emotional functioning

EORTC

European organization for research and treatment of cancer

ES

Electrical stimulation

FA

Fatigue

FI

Financial difficulties

xiv

HT

High threshold neurons

HVPC

High-volt pulsed current

IFT

Interferential therapy

IPT

Isometric peak torque

IPT

Isometric peak torque

LT

Low threshold neurons

LVMAS

Low-volt microamperage stimulation

MANE

Morrow assessment of nausea and emesis

MENS

Microcurrent electrical neuromuscular stimulation

MET

Microcurrent electrical stimulation

MPQ

McGill pain questionnaire

MPT

Mechanical pain threshold

MVC

Maximum voluntary contraction

NCV

Nerve conduction velocity

NPL

Negative peak latency

NSAID

Non-steroidal anti-inflammatory drug

NTS

Nucleus tractus solitarius

NV

Nausea and vomiting

PA

Pain

PENS

Percutaneous electrical nerve stimulation

PF

Physical functioning

PPA

Peak to peak amplitude

xv

PPD

Peak to peak duration

PPL

Positive peak latency

QLQ-C30

Quality of life questionnaire

RANG

Resting angle

RCT

Randomised controlled clinical trial

RF

Role functioning

RM

1 repetition maximum

ROM

Range of motion

SEP

Somatosensory evoked potential

SF

Social functioning

SL

Insomnia

TENS

Transcutaneous electrical nerve stimulation

TT

Tactile threshold

VAS

Visual analogue scale

WDR

Wide dynamic range neurons

-EP

-endorphin

-LPH

-lipotropin

xvi

Declaration
I hereby declare that with effect from the date on which the thesis is deposited in
the Library of the University of Ulster, I permit the Librarian of the University to
allow the thesis to be copied in whole or part without reference to me on the
understanding that such authority applies provision of single copies made for study
purposes or for inclusion within the stock of another library. This restriction does not
apply to the British Library Thesis Service (which is permitted to copy the thesis on
demand for loan or sale under the terms of a separate agreement) not to the copying
or publication of the title and abstract of the thesis.

IT IS A CONDITION OF USE OF THIS THESIS THAT ANYONE WHO

CONSULTS IT MUST RECOGNISE THAT THE COPYRIGHT RESTS WITH
THE AUTHOR AND THAT NO QUOTATION FROM THE THESIS AND NO
INFORMATION DERIVED FROM IT MAY BE PUBLISHED UNLESS THE
SOURCE IS PROPERLY ACKNOWLEDGED.

xvii

Chapter 1

A History of Bioelectricity: Electroanalgesia and Antiemetic Usage

1.1 Introduction
The work presented in this thesis represents a series of studies on the hypoalgesic,
neurophysiologic

and

antiemetic

effects

of

electrical

stimulation,

namely

Transcutaneous Electrical Nerve Stimulation (TENS) and Interferential Therapy (IFT).

Electrical stimulation represents a popular form of therapeutic intervention used by
physiotherapists. However, it remains an area of substantial debate. As a background
to the literature review presented in Chapter 2, this chapter provides an historical
perspective of the use of the so-called medical electricity.

1.1.1 Early developments in electroanalgesia

The origins of electrical simulation for pain relief can be traced back to the dawn of
the astrological age of Pisces (Kane and Taub, 1975). Torpedo fish, amber and
magnetic rings were used by the ancient Egyptians for electrical treatment.
Undoubtedly, the first bioelectric phenomenon of which man became aware was the
electric discharge of certain types of fish. Throughout the ages, electric organs in
several species of fresh and salt water fish, notably the Torpedo marmorata,
Malopterurus electricus and Gymnotus electricus have reached a high degree of
development and are capable of delivering a very painful and paralysing shock
(Kellaway, 1946). The earliest man-made records in which electric fish are
represented are the fishing scenes portrayed on the walls of certain Egyptian tombs of
the Vth dynasty (ca. 2750 BC) (Kellaway, 1946; Kane and Taube, 1975; Wu, 1984).

The earliest written reference to an electric fish occurs in one of the books
Hippocratic Corpus (On Regimen) (Wu, 1984). The first person known to have been
cured by electricity was Anthero, a freed slave of the Emperor Tiberius Claudius Nero
Caesar who ruled ancient Rome from AD 14 to AD 37. Antheros enjoyment of
liberty was marred, however, by his suffering from gutta (probably gout). One day
whilst walking on the seashore, he stepped on a flat medium-sized fish called a
torpedo, which is known to be capable of delivering a substantial, sometimes lethal
electric shock of approximately 100-150 volts d.c. One effect of this shock on
Anthero, after the initial numbing had subsided, was to free him of his gout. Thus it
appears that the torpedo fish was the first electrotherapeutic agent (Cambridge, 1977).

The electrical discharge from fish was not the only electrical phenomenon in the
natural environment of the early civilizations to be exploited. Lightning was too
difficult to use, amber, which could be electrified by simple rubbing, was supplied in
the form of pills to combat haemorrhages, nausea and catarrh; it was even burnt to
prevent the spread of plague (Cartwright, 1977). Finally, magnetic rings were sold at a
higher price to those suffering from rheumatism (Cartwright, 1977).

It was not until the Renaissance period (16th Century) that an Italian physician and
mathematician, Girolamo Cardano (1501-1576) explained the behaviour of amber and
magnetic rings (static electricity) (Cambridge, 1977). Cardano in 1551 and Gilbert a

half century later, by clearly differentiating between magnetism and electricity, laid
the foundations for the production of man-made electricity.

In 1892, Hoorveg conducted the first quantitative studies with capacitor-discharge

shocks, but it was Lapicque (1905) who popularized their use and developed the
strength-duration curve which describes the requirements for stimulating excitable
tissue with different pulse durations (Geddes, 1984).

Discoveries in physics led physiologists to create stimulators, which were applied

immediately by physicians to treat a remarkable variety of afflictions. While physicists
concerned themselves with the laws that governed the flow of electric fluid, the
name used for current, physiologists sought to discover how current excited living
tissue. The history of electrical stimulation is therefore linked inextricably with
discoveries in physics. However, the therapeutic applications of electrical current
emerged well ahead of the necessary knowledge of the electrophysiology of excitation
(Geddes, 1984).

1.1.2 Mapping the pain pathways: neurophysiological theory and the development
of electrical stimulation
Throughout history, the relationship of pain to other sensory experiences within the
body has presented a major conceptual barrier in defining its underlying mechanisms.

The language of pain has been confounded by the use of the same words to describe
both the perceptual recognition of the experience and the unpleasantness or emotion
associated with it (Perl and Kruger, 1996). Pain has been a major concern of
humankind since our beginnings, and it has been the object of universal efforts to
understand and control it (Bonica and Loeser, 2001). Although the interest for the
understanding of pain can be traced back to Ancient Greece in writings such as the
Iliad and the Odyssey (Rey, 1995), it was not until several centuries later that Galen
(2nd Century A.D.) proposed the vital part played by the nervous system in the
perception and cognition of pain.

Physiological and medical concepts of pain had become mechanistic, localised and
empirical as part of the Cartesian theory of the body machine. Ren Descartes (15961650) cited the instinctive withdrawal of a foot from flame, to exemplify the
mechanical nature of the workings of the organism. Heat impacted upon the skin,
causing signals to be sent to the brain like a tug on a bell-rope (Porter, 2001). Pain was
the ringing of the bell, a signal to trigger self-preservative action.

In the 19th Century, physiology emerged as an experimental science. This

development led to the scientific study of sensation in general and pain in particular.
The work of Charles Bell (1774-1842) and Franois Magendie (1783-1855) showed
that the posterior roots of the spinal nerves responded to sensations whereas the
anterior roots appear to be associated with motor responses (Bonica and Loeser, 2001;

Porter, 2001). The works of Bell and Magendie laid the foundations for the idea of a
dedicated neural pathway of pain sensation. During the remainder of the 19th Century,
anatomical, physiological and histological studies were undertaken that prompted the
explicit formulation of two physiologic theories of pain; the specificity theory and the
intensive (summation) theory (Bonica and Loeser, 2001).

The specificity theory conceptualized pain as a specific sensation, with its own
sensory apparatus, independent of touch and other senses (Bonica and Loeser, 2001).
This theory was later supported by experimental work carried out by Max von Frey
(1896) who identified pain spots on the skin proclaiming that there was a unique
nerve type for each sensation (the specificity theory) (Rey, 1995; Bonica and
Loeser, 2001).

The intensive theory, which was implied in Aristotles concept that pain resulted from
excessive stimulation of the sense of touch, was fully developed in 1894 by
Goldscheider. According to this theory, pain results when the total output of cells
exceeds a critical level as a result either of excessive stimulation of receptors that are
normally fired by non-noxious thermal or tactile stimuli or of pathologic conditions
that enhance the summation of impulses produced by normally non-noxious stimuli
(Bonica and Loeser, 2001).

During the first half of the 20th Century, research on pain developed and the published
work was used in part to support either the specificity theory or the intensive theory or
a modification of these.

In 1965, the pain gate control theory, as proposed by Melzack and Wall (1965),
combined concepts from the two contradictory theories. The gate control theory
emphasized the mutually inhibiting interaction between nerve cell types. Thus, the
stimulation of A fibres inhibited afferent signals from A and C fibres. According to
this theory, afferent stimulation of the myelinated A fibres inhibited afferent pain
signals from A and C fibres from being relayed to higher centres in the central
nervous system.

1.1.3 Transcutaneous electrical nerve stimulation: from electrogenic fish to

electrodes
As previously stated, electricity has been used as therapeutic tool since Antiquity. In
the 1760s, John Wesley, a pioneer electrotherapist, identified fifty afflictions
supposedly cured by proper administration of electricity. These included: blindness,
blood extravasated, bronchocele, burns, rheumatism and painful states amongst others
(Rogal, 1989). With the introduction of the theory of faradism by Duchenne (1872) to
describe the use of a train of short-duration current pulses from the faradic (induction)
coil, further interest was directed towards the ability of electricity to relieve pain
(Geddes, 1984). The early 1900s saw a proliferation of questionable therapeutic

applications. In 1967, Wall and Sweet tested a hypothesis central to their gate control
theory of pain. They reported temporarily abolishing chronic pain by electrically
stimulating peripheral nerves via percutaneous electrical stimulation (Wall and Sweet,
1967). This technique soon became known as Transcutaneous Electrical Nerve
Stimulation (TENS) when applied via surface electrodes (Barr, 1999).

1.2 Physical principles of TENS

As Alon states, electrical stimulators have been recognized by the names of their
inventors or by inappropriate names promoted by commercial companies (Alon,
1999). Galvanic, faradic, diadynamic, high voltage, low voltage, low frequency,
medium frequency and TENS are several examples. This nomenclature has created a
considerable degree of confusion relative to the physiological effects and clinical
benefits (Alon, 1999). The simple fact is that the majority are Transcutaneous
Electrical Nerve Stimulators because they are applied transcutaneously with the
physiological objective of exciting peripheral nerves (Alon, 1999; Johnson, 2002). In
the early 1970s, small (approximately 2.5 x 4 x 1 inches), lightweight (<200 g),
portable stimulators became known as TENS units (Robinson, 1995).

1.2.1 Waveform
Common pulse waveforms used in TENS can be described as asymmetrical biphasic
rectangular or symmetrical biphasic rectangular with a zero net current to minimize
skin irritation (Walsh, 1997; Barr, 1999).

1.2.2 Frequency
The frequency of a current refers to the number of pulses delivered per second (Walsh,
1997). Usually, the frequency range of most TENS units is 0-250 Hz (Walsh, 1997;
Johnson, 2001).

1.2.3 Pulse duration

The elapsed time from the initiation of the phase until its termination is defined as
phase duration. The phase begins when the current departs from zero line and ends as
the current returns to the zero line. For the biphasic pulse, the pulse duration is
determined by adding the duration of the two phases (Alon 1999). TENS pulse
durations are expressed in microseconds (s), usually between 10 and 1000 s
(Johnson, 2001).

1.2.4 Intensity
Intensity refers to the magnitude of current or voltage applied and can be measured in
milliamps (mA) or volts (V) respectively (Walsh, 1997). The intensity of the
application depends on the subjective perception of the patient; usually the intensity is
set at a strong but comfortable sensation.

1.3 TENS modes available

The common modes of TENS that are discussed in the literature are: conventional
TENS (low intensity/high frequency); Acupuncture-like TENS (AL-TENS) (high

intensity/low frequency); Burst train TENS; and Brief intense TENS (high
intensity/high frequency) (Walsh, 1997; Johnson, 2001).

1.3.1 Conventional TENS (low intensity/high frequency)

Conventional TENS is the most commonly used mode of TENS. The stimulation
parameters are as follows: low intensity; a frequency usually above 100 Hz and a short
pulse duration (50-80 s) (Walsh, 1997). The aim of conventional TENS is to activate,
selectively, large diameter A fibres without concurrently activating small diameter
A and C fibres or muscle efferents (Johnson, 2001). The analgesia is of relatively
rapid onset, and it tends to be relatively short, typically lasting only for up to a few
hours post treatment (Ottoson and Lundeberg, 1988; Walsh, 1997).

1.3.2 Acupuncture-like TENS (high intensity/low frequency)

The aim of acupuncture-like TENS is to selectively activate small diameter A and C
fibres (Johnson, 2001). The stimulation parameters are: frequency usually 1-4 Hz;
high intensity (high enough to produce visible muscle contractions) and a pulse
duration of approximately 200 s (Walsh, 1997). Pain relief generally lasts longer than
that achieved with conventional TENS (Ottoson and Lundeberg, 1988; Walsh, 1995).

1.3.3 Burst train TENS

This type of stimulation was developed by applying the principles used in Chinese
electro-acupuncture. When first introduced by Eriksson and Sjlund in 1976, it was

10

called electro-acupuncture, but to avoid confusion with classical electrical

acupuncture stimulation, it was later known as low-frequency pulse train stimulation
or pulse-train burst stimulation (Ottoson and Lundeberg, 1988). Burst train TENS
represents a mixture of conventional and acupuncture-like TENS, and comprises a
baseline low frequency current together with high frequency trains (Walsh, 1995). The
frequency of the trains is typically 1-4 Hz with the internal frequency of the trains
around 100 Hz (Walsh, 1997).

1.3.4 Brief, intense TENS

Brief, intense mode uses a frequency of 100-150 Hz and long pulse duration (150-250
s) (Walsh, 1997). The aim of intense TENS is to activate small diameter A
cutaneous afferents by delivering TENS over peripheral nerves arising from the sites
of pain at a tolerable intensity to the patient. As intense TENS acts in part as a
counterirritant it can be delivered for only a short period of time (< 15 min) (Johnson,
2001).

1.4 TENS: clinical applications

The clinical uses of TENS can be separated into two major applications: analgesic and
non-analgesic. The common medical conditions in which TENS has been used can be
listed under: acute and chronic pain; labour pain; antiemetic effects (postoperative
nausea; motion/travel sickness; morning sickness; nausea and vomiting associated

11

with chemotherapy); improving blood flow and tissue healing (Puett and Griffin,
1994; Walsh, 1997; Caroll et al., 2002; Johnson, 2002; Roscoe et al., 2002).

1.5 IFT: physical principles

Interferential therapy has been available since the early 1950s. The concept was
developed by Dr Hans Nemec in Vienna, Austria, and has become increasingly
popular in the UK and USA over the last 20/30 years (Alon, 1999; Palmer and Martin,
2002). The term interferential therapy stems from the idea of two currents
interfering with each other (Domenico, 1982).

1.5.1 IFT: the problem of skin resistance

Skin impedance is one of the major obstacles to current penetration into the deeper
tissues (Alon, 1999). Skin impedance diminishes with increasing frequency according
to the formula:

Z =

1
2 FC

where Z = impedance in ohms; F = frequency in Hz and C = capacity of the skin in

microfarads. The above formula gives values for measurement of skin resistance at 50
Hz = 3200 ohms per 100 cm; at 4000 Hz = 40 ohms per 100 cm. Therefore, it
becomes evident that it should be possible to reach the tissues more deeply and
accurately without polar effects at the skin if medium frequency currents are used
(Wadsworth and Chanmugam, 1983). In the early 1950s, Hans Nemec overcame the

12

difficulty of applying low frequency alternating currents to deeper tissues by using

medium frequency currents around 4000 Hz to overcome skin resistance.

1.5.2 IFT: production of the interference effect

A typical IFT stimulator utilizes a medium frequency current (usually 4000 Hz) that
rhythmically oscillates in amplitude at low frequency (adjustable between 0 and 200250 Hz). IFT is the result of mixing two medium-frequency currents (e.g. 4000 Hz and
4100 Hz) that are slightly out of phase, either by applying them so that they interfere
within the tissues, or alternatively by mixing them within the stimulator prior to
application (premodulated). Theoretically, the two currents summate or cancel each
other producing the resultant amplitude-modulated interferential current. The
frequency of the resultant current will be equal to the mean of the two original
currents, and will vary in amplitude at a frequency equal to the difference between
these two currents. This latter frequency is known as the amplitude modulated
frequency (AMF) or beat frequency (Palmer and Martin, 2002). Figure 1.1
illustrates the production of the interference effect, where two currents of 4000 and
4100 Hz are mixed, resulting in a medium frequency current of 4050 Hz that is
amplitude modulated at a frequency of 100 Hz.

13

Fig. 1.1 Interference between two medium frequency currents. A: 4000 Hz

and B 4100 Hz produces an interferential current C: 4050 Hz and an
amplitude modulated frequency of 100 Hz. (From Robinson and SnyderMackler, 1995).

1.5.3 IFT: Constant versus beat frequencies

The amplitude modulated, beat frequency current that is produced endogenously by
IFT can be constant or variable. In the constant mode, there is a constant difference in
frequency between the two medium frequency circuits (e.g. if the difference in
frequency between the two circuits is 40 Hz, then the beat frequency will be constant
at 40 Hz). In the variable mode, the frequency between the two circuits varies within

14

preselectable ranges (e.g. 0.1 to 1 Hz; 1 to 10 Hz; 1 to 120 Hz; 90 to 120 Hz)
(Wadsworth and Chanmugam, 1983; Kloth, 1990). The pattern of change in frequency
can also be adjusted on most machines. It may be set to increase and decrease slowly
over a period of 6 seconds (depicted by 6^6) or to give a 1 second stimulation at one
frequency and then automatically switch to the other frequency (11) (Palmer and
Martin, 2002). A frequency sweep has been claimed to reduce adaptation and extend
the range of nerve types that can be stimulated (Low and Reed, 1995).

1.6 IFT: clinical applications

IFT is a widely used modality (Noble et al., 2000; Johnson and Tabasam, 2003).
During the past two decades, IFT has been reported to produce beneficial treatments in
a number of clinical conditions related to several painful states (Milanowska, 1987;
Schmitz et al., 1997), urinary incontinence (Dougal, 1985; Vahtera et al., 1997), bone
healing (Quirk et al., 1985; Fourie and Bowerbank, 1997) and vascular conditions
(Kloth, 1990).

1.7 Action Potential Therapy (APS): a novel micro current device

APS is a novel electrical stimulation device that was invented and developed by GA
Lube in 1991 in South Africa, and marketed in 1994 (Berger and Matzner, 1999). APS
Therapy falls under the broad definition of microcurrent electrical stimulation
(MET) and unlike most commercially available MET devices, utilizes a direct current.
According to the manufacturer (APS Technologies), APS uses a monophasic square

15

pulse exponential decaying wave form with a pulse rate of 150 Hz and a pulse
duration between 800 s and 6.6 ms. APS is claimed to be effective in pain relief,
cellular regeneration and increased protein synthesis (Berger and Matzner, 1999;
Odendaal and Joubert, 1999; van Papendorp et al., 2002).

1.8 Electroacupuncture: antiemetic usage

Acupuncture is a component of the healthcare system of China that can be traced back
for at least 2,500 years. The general theory of acupuncture is based on the premise that
there are patterns of energy flow (Qi) through the body that are essential for health.
Disruptions of this flow are believed to be responsible for disease. Acupuncture may
correct imbalances of flow at identifiable points close to the skin (NIH, 1997).
Acupuncture involves the stimulation of specific points (acupoints) on the skin,
usually by the insertion of needles. However, different methods such as non-invasive
transcutaneous electrical stimulation can be used (Pomeranz, 1995; Ulett et al., 1998).
Acupuncture appears to be effective for postoperative nausea and vomiting,
chemotherapy-related nausea and vomiting, motion sickness and hyperemesis
gravidarum (Hu et al., 1995; Vickers, 1996; Pearl et al., 1999; Carlsson et al., 2000;
NHS Centre for Reviews and Dissemination, 2001).

In 1958 when the Chinese were developing methods of acupuncture for surgical
anesthesia, they found it inconvenient to have several acupuncturists twirling the
needles continuously for several hours. Instead they attached flexible wires (via small

16

alligator

clips)

to

the

needles

and

stimulated

them

electrically.

Thus

electroacupuncture (EA) was born (Pomeranz, 1995). EA involves a current applied to

the needle or to skin surface electrodes from a battery-operated stimulator with a
frequency set at 10-15 Hz (McMillan, 1998). Professor John Dundee was one of the
first medical practitioners to become involved in the scientific evaluation of the
antiemetic effects of acupuncture. He initiated a series of studies that investigated the
antiemetic effect of acupuncture in a number of clinical situations and his work led to
the development and evaluation of the non-invasive technique using electrical
stimulation (McMillan, 1998).

1.8.1 Electroacupuncture: the PC-6 acupuncture point

The Neiguan (PC-6) point is the most commonly referred point for antiemetic effects
(Pomeranz, 1995; Vickers, 1996; Roscoe et al., 2002). It is located on the pericardial
meridian 2 Cun (approximately 2 inches) proximal to the distal wrist crease
between the tendons of palmaris longus and flexor carpi radialis muscles of the
forearm (see Chapter 2, Fig 2.3). A number of other points are also referred to in
textbooks in relation to the treatment of nausea and vomiting (ST-21; ST-25; ST-36;
CV-12; LR-3; LI-4), although the clinical efficacy of these has not been scientifically
evaluated (McMillan, 1998).

17

1.9 Summary
This chapter provided a short history of the interaction of electricity and medicine,
which can be traced back to the Egyptian era. Modern stimulators for exciting nerve
and muscle date from the 1940s (Geddes, 1994) and their use has been closely
associated with the development of the physiotherapy profession (Granger, 1976). As
stated by Watson (2000), electrotherapy is one of the fundamental elements of
physiotherapy practice, yet despite its widespread use from the early professional
times, it is often poorly understood, sometimes inappropriately used and the topic of
substantial debate.

The modern era of electrical stimulation of the skin for pain relief has an ancient
heritage. Although a number of acute and chronic painful conditions have been
reported to respond favourably to electrical stimulation, a substantial fraction of
reports suffer from serious methodological shortcomings (Chakour et al., 2000).
Studies of optimal stimulation parameters, including pulse pattern characteristics, site
of electrode placement, duration of treatment as well as number of treatments per day
should be carried out (Hansson and Lundeberg, 2002). TENS and IFT are analgesic
techniques used by health professionals world-wide namely by physiotherapists
(Johnson, 2000). However, the clinical effectiveness of TENS is in doubt, as a number
of investigators have systematically reviewed TENS literature and have concluded that
TENS limited pain relief in several clinical conditions (Johnson, 2000). IFT is also
poorly understood and its associated physiological effects are not clearly defined.

18

Moreover, investigations concerning the clinical effectiveness of this form of electrical

stimulation are limited (Noble et al., 2000). The continuous usage of TENS and IFT
remains controversial, since clinical protocols are governed by evidence-based
practice, it is essential that laboratory studies and clinical research is carried out to
justify the use of these two electrical modalities within the clinical setting. Therefore
the aims of this thesis are:

i). To determine the effectiveness of electrical stimulation (IFT and TENS) using a
validated pain model (delayed onset muscle soreness).

ii). To investigate any neurophysiological changes induced by electrical stimulation

(IFT, TENS and APS).

iii). To investigate the clinical effectiveness of electrical stimulation in the

management of pain, nausea and vomiting in cancer patients receiving antitumor chemotherapy.

iv). To investigate a possible relationship between parameter manipulation and

observed outcomes.

v). To compare the effects of these three forms of electrical stimulation (IFT, TENS,
APS).

19

In order to accomplish these aims, two laboratory studies and one randomised
controlled clinical trial (RCT) were conducted. These studies are detailed in the
following chapters.

20

Chapter 2
Neurophysiological, Hypoalgesic and Antiemetic Effects of Electrical
Stimulation: Review of the Literature

21

2.1 Introduction

False facts are highly injurious to the progress of science, for

they often endure long; but false views, if supported by some
evidence, do little harm, for every one takes a salutary pleasure
in proving their falseness; and when this is done, one path
towards error is often closed and the road to truth is often at the
same time opened
Darwin, The Descent of Man. (Devinsky, 1993)

The aim of this chapter was to review the literature that relates to the use of electrical
stimulation (namely Interferential Therapy and Transcutaneous Electrical Nerve
Stimulation) concerning its neurophysiological, hypoalgesic and antiemetic effects.

At beginning of the 1960s, Mazars et al. (1960) stated that stimulation of the human
spinothalamic tract could reduce pain. However, it was the pain gate control theory
by Melzack and Wall (1965) that acted as a catalyst for the therapeutic development of
electrical stimulation (ES) of the spinal cord, as the assumption was that pain input
carried by small fibres was modulated at the dorsal horn by large myelinated fibres.
Wall and Sweet first reported stimulation of peripheral nerves for control of pain in
1967, and ever since then the interest and research on electroanalgesic mechanisms
has been growing exponentionally. However, despite the amount of research produced
in the field, the mechanisms that underpin electroanalgesia remain unclear.

22

Electrical stimulation (ES) is a non-pharmacological form of clinical intervention that

has been used to decrease the pain associated with delayed onset muscle soreness
(DOMS). However, the lack of understanding of the pathophysiological mechanisms
underlying DOMS, the absence of common investigational protocols, the wide array
of measurement tools and formats used to assess the outcomes, as well as a paucity of
studies involving the use of ES in this specific clinical condition have rendered the
comparison and conclusions on the effectiveness of the use of the ES almost
impossible.

Although the use of ES has been primarily associated with the management of painful
conditions, a number of non-analgesic effects have also been reported namely the
antiemetic effect of ES over the Neiguan PC6 acupoint (PC6) in chemotherapy
induced emesis (Walsh, 1997; Gadsby et al., 1997; Shen et al., 2000).

Chemotherapy-induced nausea and vomiting is consistently ranked amongst the most

frequent and feared side effects of the anti tumor treatment, and has been associated
with poor quality of life and patient distress both physically and emotionally (Dundee
and Yang 1990; Dibble et al., 2000; Tan et al., 2001). Although several advances have
been made in the control of nausea and vomiting, namely with the introduction of the
new classes of antiemetic agents (5-HT3 receptor antagonists), the situation remains
far from optimal. Post-chemotherapy nausea and emesis continue to be reported by
close to half of all patients receiving chemotherapy for the first time and by the

23

majority of patients by the end of their treatment. A significant effort and interest
continues to be focused on developing better control of this symptomatology (Hickok
et al., 1999; Roscoe et al., 2002). A considerably unexplored but potentially useful
adjunct to the pharmacological control of nausea and vomiting is the use of electrical
stimulation to PC6 acupoint (Vickers, 1996; NHI, 1997; McMillan, 1998; Roscoe et
al., 2002).

The literature review that follows reviews studies that have investigated the effects of
electrical stimulation upon the gating mechanisms and spinal reflexes, and the
effectiveness of ES upon DOMS and chemotherapy-induced nausea and vomiting.

An electronic search of studies on the effects of electrical stimulation upon gating

mechanisms, spinal reflexes, DOMS, and nausea and vomiting was carried out
covering the years from 1980 until January 2004. MEDLINE, AMED, CINAHL,
PEDro, Proquest and Cochrane Library databases were searched using the following
keywords: transcutaneous electrical nerve stimulation, interferential therapy, medium
frequency currents, RIII-reflex, H-reflex, peripheral nerve compound action potential,
electroanalgesia, nerve conduction velocity, delayed onset muscle soreness, DOMS,
treatment,

double-blind

method,

nausea,

vomiting,

cancer,

acupuncture,

electroacupuncture and acupuncture points. In addition, a manual search of the

bibliographies of the identified papers was carried out to ensure that all appropriate

24

articles concerning the treatment using electrical stimulation were reviewed. A

summary of the most relevant studies is presented in Tables 2.2, 2.3, 2.4 and 2.5.

2.2 Electrical nerve stimulation: effects upon the RIII/Nociceptive flexion reflex
(NFR) and H-reflex
In the early years of the 20th Century, Sherrington (1910) ascertained that painful
electrical stimulation of the limb in experimental animal studies caused an ipsilateral
hip, knee and ankle withdrawal reflex that he named nociceptive flexion reflex
(Roby-Brami and Bussel, 1987; Skljarevski and Ramadan, 2002). The nociceptive
flexion reflex (NFR), also known as RIII-reflex, is a polysynaptic exteroceptive reflex
subserving withdrawal from noxious stimuli that is correlated with the activity in the
A and C fibres, and has been reported to have the same threshold as that of pain
sensation (Chan and Tsang, 1987; Garcia-Larrea et al., 1989; Schomburg et al., 2000).
The RIII-reflex has been described as an electromyographic response recorded in
flexor muscles with a latency of less than 110 ms after cutaneous stimulation or
electrical stimulation of a peripheral nerve (Roby-Brami and Bussel, 1987). Based on
evidence that the reflex cannot be elicited without activation of nociceptive fibres, the
RIII-reflex is considered a reliable and objective tool in pain assessment, and the
method became an established tool in the research of pain (Willer, 1977; Skljarevski
and Ramadan, 2002).

25

The following studies concerning the effects upon RIII/NFR and H-reflex are
presented in Table 2.2.

In 1987, Roby-Bramy and Bussel conducted an electromyographic (EMG) study on

flexor muscle responses (RIII-reflex) on 16 patients with clinically completed spinal
cord transection. Stimulation was applied either to a cutaneous (sural) or to a mixed
(tibial) nerve and muscle response was recorded from tibialis anterior, biceps femoris
and rectus femoris. EMG recordings showed that a distinct early and late ipsilateral
flexor muscle response could be elicited. The fact that the reflex was present in this
specific population, demonstrates that the RIII-reflex is mainly a spinal reflex. Further,
the averaged values concerning early responses were similar to the latency of the
flexion withdrawal reflex previously described in normal man.

Sjlund (1985) undertook a study in order to investigate the most suitable parameters
for conditioning stimulation of a skin nerve to elicit maximal suppression of C-fibreevoked flexion reflex. Eight-two rats were used in the study, seven stimulation
frequencies (10, 40, 60, 80, 100, 120, and 160 Hz), and a stimulation time of 30 min
were investigated. Results showed that 80 and 100 Hz frequencies caused a marked
long-lasting depression of C-fibre-evoked reflex at a weak intensity (twice threshold).
With higher intensities (10 times threshold), stimulation using 40 to 80 Hz had a more
marked effect. In this particular experiment, it seems that fibre conditioning was
frequency and intensity dependent. This postulate was confirmed by the same author

26

in a study that extended the former investigation of the most suitable parameters of
fibre conditioning to the low-frequency range, employing short trains as in
acupuncture-like (burst) TENS (Sjlund, 1988). An interesting aspect subjacent to
both studies was the introduction of the paradigm of parameter manipulation, or
parameter specificity.

Chang and Tsang (1987), in an attempt to gain insight into the underlying mechanisms
of the effects of electrical stimulation upon the RIII-reflex, conducted a nonrandomized, non-blinded controlled study that examined the inhibitory effect of
segmentally applied TENS on the nociceptive component of the flexion reflex. The
RIII-reflex from 11 healthy subjects was recorded from the biceps femoris (BF),
tibialis anterior (TA) and the hip flexor (HF) muscles. Amplitude and area values of
the flexion reflex of each muscle were recorded prior to, during and 50 min after the
application paraspinally (L4-S1) of placebo or low intensity TENS (100 Hz, 1 ms
square pulses) for 30 min. The results showed that low intensity TENS caused a
significant inhibition of the flexion reflex in both BF and HF. The time to peak
maximum inhibitory effect took 30 and 20 min respectively after the onset of TENS,
and the flexion reflex often did not return to control values even at 40-50 min post
TENS. The TENS placebo application showed no significant changes of the RIIIreflex in all the muscles examined. The authors concluded that conventional TENS
exerted a progressive and long-lasting inhibitory action on a large number of flexor
motoneurons in man. This effect was more prominent on the proximal than distal

27

lower limb muscles. Commenting on the pattern of the onset and offset of the
inhibitory influence, the authors suggested the involvement of an endogenous opioid
mechanism.

The release of endogenous opioids has been used to explain the effects of TENS by
several authors (Johnson et al., 1992; Ishimaru et al., 1995; Sluka and Walsh, 2003).
The endogenous opiates are derived from polipeptides, a string of large amino acid
molecules. Two of these opiate acting polypeptides are short strings, five amino acids
long, called the enkephalins. The longer chains are 16 to 30 amino acids long and are
referred to as endorphins. All of these strings of amino acids have been identified as a
segment of a large molecule called -lipotropin (-LPH), 91 amino acids long, which
is secreted by the pituitary gland (Szkely and Rnay, 1982; McKim, 1996; Brody et
al., 1998).

In line with the possible involvement of an opioid mechanism is the work of

Facchinetti et al. (1984) who evaluated the role of endogenous opioids in sustaining
analgesia induced by TENS. Twelve healthy volunteers (males) divided in two groups
of six received TENS for 30 min. Group 1 received a frequency of 85 Hz, a pulse
duration of 80 s and the intensity increased to induce a tingling sensation. Group 2
received a frequency of 0.5 Hz, pulse duration of 80 s and very low intensity (lower
than the muscle twitch threshold), although the sensation was always perceived. In the
latter group, TENS was considered as placebo. The RIII-reflex from the BP (capitis

28

brevis) was recorded as well as plasma levels of -LPH, -endorphin (-EP) and
adeno corticotropic hormone (ACTH). The results showed that in group 1 the RIIIreflex threshold increased progressively in magnitude during the application of the
TENS, reaching its peak 30 min post stimulation, whereas no significant changes were
recorded in group 2. -LPH plasma levels increased significantly at the end of TENS
treatment in group 1, remained high up to the 40th min, and then decreased to basal
values after 70th min; -EP levels increased significantly at the 40th min only
decreasing subsequently to basal values. In group 2, none of the peptides showed any
significant change in their plasma content in response to placebo stimulation. ACTH
plasma levels varied randomly after TENS in both group 1 and group 2. The findings
of this study are in agreement with the existence of a specific pain modulatory system
for descending control of nociception, and supported by the work of Wall (1967) who
demonstrated that structures in the brain stem tonically inhibit nociresponsive neurons
in the spinal cord (Fields and Basbaum, 1999).

Garcia-Larrea et al. (1989) conducted a study on 21 patients undergoing either

epidural dorsal column stimulation (DCS) (n=16) or TENS (n=5) for chronic
intractable pain. This study investigated the effects of electrical stimulation upon RIIIreflex changes. RIII-reflex activity was recorded from the biceps femoris. A train
stimulus of 1 ms duration and 500 Hz was used to generate the RIII-reflex. Responses
were analysed using a 150 ms window (either within 80-230 ms or 50-200 ms
window) and the results showed a depression of RIII-reflexes during neurostimulation

29

in 11/21 patients, 9 who received DCS and 2 who received TENS. Nine other patients
did not exhibit any significant modification of the RIII-reflex.

In 1990, Garcia-Larrea and Mauguiere investigated the RIII-reflexes of the lower

limbs in a series of 45 patients undergoing ES, either epidural (SCS, n=38),
transcutaneous (TENS, n=6) or thalamic (n=1) for chronic intractable pain. The results
showed that the analgesic neurostimulation changed significantly in 62% of cases
(28/45). In 23 patients, 51% showed a decrease or even an abolished flexion response,
17% of the cases did not entail any significant change of the RIII-reflex and in 5% of
the patients the RIII-reflex was enhanced by neurostimulation. This study is in
agreement with the previous study carried out by the same group; however, studies
were not randomised, nor blinded, did not have a control or placebo group, and the
sample size was very small.

Piezo-Electric Current (PEC) is a new form of electrical therapeutic current that is

generated by mechanical deformation of piezo-electric ceramic rod (motorized
device). In this device, an electric motor is used to set the precise PEC generation rate.
One revolution of the motor produces mechanical compression, then relaxation of the
piezo-electric ceramic rod. Each compression or relaxation of the rod produces a burst
of 10 electric pulses (2 to 3 ms duration each) that are positive during compression
and negative during relaxation. Each burst lasts 50 to 250 ms, depending on the motor
speed. The amount of electricity carried out by each pulse is always of the same

30

magnitude, between 0.3 and 0.7 micro-Coulomb, such that each total charge provided
by a complete burst is between 0.3 and 0.6 micro-Coulomb. The current peak value
measured in a stimulated skin model is about 900 volts and the intensity is 25 A
(Danzinger et al., 1998). According to the authors, the application of PEC to the skin
for 2 minutes produces a tolerable pricking and bitting pain associated with a long
lasting (3 to 4 hours) neurogenic inflammation indicating that nociceptors of various
types (A and C) might be activated (Danziger, 1998).

In a study conducted by Danziger et al. (1998), the authors compared the effects of
TENS and PEC on lower limb NFR in human subjects. Twenty-four healthy subjects
(14F, 10M) participated in the study and received 8 different procedures (4 TENS and
4 PEC) in random order. The RIII-reflex elicited in the lower limb by electrical
stimulation of the sural nerve at the ankle was studied before, during and after the
application of the following conditioning stimulus: TENS1 (non-noxious): 100 Hz, 0.1
ms, 2 mA, applied segmentally and heterotopically; TENS2 (noxious): 3 Hz, 2 ms, 20
mA, applied segmentally and heterotopically; PEC1 (noxious): 3 Hz applied
segmentally and heterotopically; and Sham PEC: applied segmentally and
heterotopically. Electrical stimulation was applied for 2 minutes. The value of the
RIII-reflex was recorded before, during and after the application of the electrical
stimulation. The results showed that non-noxious TENS1 stimulation produced
inhibitions of the RIII-reflex only during the 2 min conditioning period; the noxious
TENS2 when applied segmentally produced a facilitatory effect during the application,

31

followed by a significant inhibitory after-effect; however the application of the TENS2

heterotopically resulted in inhibition of the RIII-reflex both during and after the 2minute conditioning period; application of PEC1, whether segmentally or
heterotopically induced powerful long-lasting inhibitory after-effect; sham PEC did
not result in significant change of the RIII-reflex. The authors suggested that the
inhibitory mechanisms observed could be explained in terms of a counterirritation
process, which is in disagreement with previous studies that explained the reflex
inhibition in the light of the gating mechanisms or opioid induced analgesia system.
Another interesting feature of this study is the stimulation time used (2 minutes) which
is much different than the duration of stimulation used in clinical practice (20-30 min).

Gregori (1998) carried out an investigation on the effect of TENS (100 Hz, 200 s,
30 min, intensity below threshold for the evoked visible muscle contraction) applied to
the area of sural nerve on the early and late electromyographic component of the RIIIreflex. Twenty patients with complete (n=12) and incomplete (n=8) transversal spinal
cord injuries (SCI) participated in the study. Results demonstrated that the early
component of the RIII-reflex decreased immediately after TENS in all patients with
incomplete SCI, while it was decreased in some patients with complete SCI (5 out of
12). Furthermore, patients in the placebo group showed no decrease in the reflex
response. The author suggested that the inhibitory effects induced by TENS are
probably confined to the segmental interneuronal system of the spinal cord. The
results are also suggestive that suprasegmental mechanisms may play an important

32

role in analgesia. This hypothesis has been also validated by the work of Noordenboos
and Wall (1976) who observed that contralateral pain sensation and some touch
sensibility was preserved in a patient who suffered a nearly complete spinal
transection. There is also ample evidence from cordotomies, suggesting that if
performed, cordotomies should be made through the entire anterolateral quadrant and
only for terminal cancer patients because even if initially successful, the pain can
return or a central pain can develop (Craig and Dostrovsky, 1999).

The history of the H-reflex begins with the early studies by Piper (1912) followed by
the work of Hoffman (1918), that clearly described a reflex response in calf muscles
that followed electrical stimulation of the posterior tibial nerve and was comparable in
latency to the Achilles reflex (Schieppati, 1987; Fisher, 1999). H-reflex involves the
conduction from the periphery to and from the spinal cord and they take place at
latencies considerably longer than the latency of a direct motor response (Fisher,
1999). They are reflexes that involve afferent conduction by large afferent fibres and
efferent conduction via alpha motoneurons (Schieppati, 1987; Fischer, 1999). Fwaves, by contrast, are produced by antidromic activation of the same motoneurons
(Shahani, 1985; Fischer, 1999).

H-reflexes and F-waves are recorded by well-established neurophysiologic techniques

(Shahani, 1985; Schieppati, 1987; DeLisa et al., 1994; Fisher, 1999), and despite their
differences they are commonly discussed together. H-reflexes and F-waves are

33

frequently used as a diagnostic tool, and at comparable latencies, reflect conduction to

and from the spinal cord involving motoneuron activation (Schieppati, 1987; DeLisa
et al., 1994; Fischer, 1999). In addition, the H-reflex has been used to assess disorders
of the peripheral and central nervous system, and has also been used to assess the
effects of electrical stimulation upon cutaneous stimulation on motoneural excitability
in man (Francini, 1981; Goulet, 1997).

Bureau et al. (1981) studied the effects of dorsal cord spinal stimulation (DCS) on
human lower limb spinal reflexes. Eight patients with intractable pain were treated
with DCS. H-reflex was evoked by tibial nerve stimulation (1 ms, 0.2 Hz), and
recordings from the RIII-reflex were taken from the soleus muscle (90-150 ms).
Results showed a significant inhibition of the H-reflex in 34% of the subjects, and an
inhibition of the RIII-reflex that began and ended with the DCS. The authors
underlined the role of segmental relation for DCS effects and suggest a close
association with segmental mechanisms. These results contradict the findings of
Danziger et al. (1998), however, the Bureau et al. (1981) study did not include a
control group to validate the findings, and the sample was very small.

In order to determine which combination of TENS parameters would be more

effective in decreasing H-reflex amplitude, Goulet et al. (1994) conducted a study in
11 healthy subjects (5M, 6F). The subjects in the TENS1 group received a frequency
of 50 Hz and a pulse duration of 250 s, whilst subjects in the TENS2 group received

34

a frequency of 99 Hz and a pulse duration of 250 s. The intensity was set at the
slightest sensation perceived by the subject and the stimulation time lasted for 30
minutes. H-reflex recordings from the stimulation of the sural (SN) and common
peroneal nerve (CPN) were taken every 30 sec during a 45 min period. Control values
were measured for a 5 min period before TENS application. H-reflexes were then
recorded for the next 30 min. Once TENS was discontinued, reflex responses were
again measured. Skin temperature was also monitored. The study revealed differential
effects of repetitive cutaneous stimulation in normal subjects. The authors stated that
neither the frequency, nor the type of nerve stimulated increased or decreased the
amplitude of the soleus H-reflex. However, a trend towards inhibition was observed in
63% of the subjects during TENS applied over the CPN at 99 Hz, and in 50% of the
subjects during TENS over the SN at 99 Hz. This work was extended (Goulet et al.,
1997) to investigate the differential effect of 30 minutes of TENS (99 Hz, 250 s,
twice the perceptual threshold) on the H-reflex amplitude of the soleus (SO),
gastrocnemius lateralis (GL), and gastrocnemius medialis (GM). Control values of Hreflex amplitudes were measured for 5 min before the application of TENS. After the
cutaneous stimulation started, H-reflexes were recorded for 30 min. Reflex responses
were also recorded for 10 min post TENS stimulation in order to monitor any
persistent effects. Skin temperature was also monitored. The authors concluded that no
differential effects of TENS on the H-reflex amplitude of muscle of different fibre
type content were observed. However, a significant inhibition of the H-reflex was
observed on both the SO and GL during TENS application over the CPN or SN. Also,

35

this study failed to replicate the associated increase in the GL H-reflex amplitude
previously observed during TENS over the CPN (Goulet et al., 1994).

In order to extend the knowledge of the neurophysiological and hypoalgesic effects of

different combinations of TENS parameters developed previously at this centre, Walsh
et al. (2000) investigated the effect of various TENS parameters upon the RIII and Hreflex on 50 healthy subjects (25M, 25F). Subjects were randomly allocated to a
control group or one of four TENS groups (TENS1: 110 Hz, 200 s; TENS2: 110 Hz,
50 s; TENS3: 4 Hz, 50 s; TENS4: 4 Hz, 200 s); stimulation was applied for a total
of 15 min. Ipsilateral RIII and H-reflexes were recorded five times during the
experimental time: before TENS; immediately after the application of TENS (i.e. at
15th min); at 25th, 35th, and 45th minutes. Skin and ambient temperature were
concomitantly recorded. The electrical stimulation used to evoke the RIII-reflex
consisted of a train of stimuli of five rectangular 1 ms duration pulses delivered over
25 ms. The results showed a decrease in H-reflex peak-to-peak amplitude (PPA) in all
groups immediately after the application of TENS that continued throughout the rest
of the experimental period, with the exception of TENS1, which continued to present a
decrease in PPA below baseline. The authors speculated that the observed effect may
have been associated with changes in skin temperature. In fact, the computation of the
correlation coefficients (r) confirmed a high correlation between skin temperature and
PPA for the control and all the TENS groups (r= 0.5-0.9) except for TENS1 (r=0.08).
Negative peak latency (NPL) showed an increase over the experimental period.

36

According to the authors this fact cannot be explained by the increase in

gastrocnemius skin temperature, once an increase in skin temperature is associated
with a decrease in latency. However, this observation is probably linked to a direct
neurophysiological effect of TENS upon the nerve fibres mediating the H-reflex. The
authors concluded that the combinations of TENS parameters employed in the study
had no significant effect upon the RIII/H-reflexes.

A recent double blind randomised controlled study carried out by this research group
(Cramp et al., 2000) compared the effects of TENS and interferential therapy (IFT)
upon the RIII and H-reflex. Seventy healthy subjects were randomly allocated in equal
numbers to one of seven groups: TENS1 5 Hz; TENS2 100 Hz; TENS3 200 Hz; IFT1
5 Hz; IFT2 100 Hz; IFT3 200 Hz and Control. For all groups, the pulse duration was
125 s, and intensity was set at a strong but comfortable sensation. Stimulation was
applied over the right sural nerve for 15 min. Ipsilateral RIII and H-reflexes from the
biceps femoris were recorded before treatment, immediately after treatment, and
subsequently at 25, 35 and 45 minutes. The results showed no statistically significant
differences between baseline and post-treatment measurement for RIII and H-reflex,
suggesting that neither TENS nor IFT significantly affects the RIII and H-reflex at
least at the parameters used. The novelty of this study is that it was the first study to
investigate the neurophysiological effect of the IFT.

37

2.3

Electrical

nerve

stimulation:

nerve

conduction

velocity

(NCV),

microneurographic and somatosensory evoked potential (SEP) studies

Nerve conduction studies assess peripheral motor and sensory functions by recording
the evoked response to stimulation of peripheral nerves (Daube, 1999). The study of
nerve conduction assumes that when a nerve is stimulated electrically, a reaction
should occur somewhere along the nerve. The reaction of the nerve to stimulation can
be monitored with appropriate recording electrodes (DeLisa, 1994). Nerve conduction
studies have been used to show the effects of several therapeutic interventions such as
electrical stimulation (Walsh et al., 1995, 1998; Levin and Hui-Chan, 1993; Cox et al.,
1993); cryotherapy (Rutkove, 2001; Chesterton et al., 2002); Laser therapy (Opsomer
et al., 1999); ultrasound (Oztas et al., 1998; Moore et al., 2000; Paik et al., 2002) and
different types of pharmacological agents (Cornefjord et al., 2002; Mert et al., 2002).

The following studies concerning NCV, microneurographic and SEP are presented in
Table 2.3.

Ignelzi et al. (1981) investigated the effects of peripheral repetitive electrical

stimulation and spinal cord activity in 17 cats, in a total of 80 neurons and dorsal
column fibres. Recordings of the cellular activity in dorsal neural horns were taken at
L5-L7 level. The stimulation parameters used were 6-200 Hz, 200 s, the intensity
values ranging from 0-12 mA, and a time duration between 5-30 min. The results
showed that 5% of the spinal cord units underwent transient facilitatory changes, 46%

38

showed suppressive effects, and 36% showed no influence. In all cases, the discharge
alterations remained beyond the period of stimulation. These results are in accordance
with previous work carried out at the same laboratory (Ignelzi and Nyquist, 1979).
Thus, the authors concluded that both studies indicate that repetitive electrical
stimulation produces a predominantly suppressive effect either on nociceptive or nonnociceptive neural elements. This statement is in disagreement with the axiomatics of
the gate control theory by Melzack and Wall (1965) in which suppression of small
fibre nociceptive input is mediated by large fibre activity.

Garrison and Foreman (1994) investigated the effects of TENS application to somatic
receptive fields on spontaneous and noxiously evoked dorsal horn cell activity in
anaesthetized cats. The authors recorded the action potentials from 83 spontaneously
discharging cells in 14 cats (wide dynamic range and high threshold neurons). TENS
parameters were as follows: 5-125 Hz, 100 s, 20-30 sec, intensity between 5 and 60
mA. The results showed that spontaneous cell activity was decreased in 65% of the
cells, 30% did not respond, and 5% showed an increase in activity. This study is in
accordance with previous work by Ignelzi and collaborators (1979, 1981). These
findings are also consistent with the axiomatics of the gate control theory (Melzack
and Wall, 1965), in that less noxious information would be involved in the pain
perception process. These results were also confirmed by the same investigators in a
study designed to show if TENS maintained a decrease in spontaneous and noxiously
evoked cell activity for a prolonged time (Garrison and Foreman, 1997). Interestingly

39

the results indicate a possible relationship between the parameters used in this study
and inhibition achieved, namely that the use of high frequency/low intensity (HF/LI)
(5-125 Hz and 5-40 mA) reduced spontaneous cell activity while low frequency/high
intensity (LF/HI) (5-45 Hz and 50-60 mA) had no effect on the same cell. An
explanation for this fact can also be given by biophysical principles in that HF/LI
parameters recruit A, A fibres more efficiently than LF/HI.

Recently Ma and Sluka (2001) examined the effects of TENS on dorsal horn neurons
sensitised by acute inflammation. Extracellular recordings from wide dynamic range
neurons (WDR), high threshold neurons (HT) and low threshold neurons (LT)
comprising a total of 83 cells of the dorsal horn neurons in anaesthetized rats were
assessed for spontaneous activity, innocuous and noxious mechanical stimulation and
receptive field size. Responses were measured before and 3 hours after induction of
inflammation, and immediately after application of either TENS 100 Hz, 100 s or
TENS 4 Hz 100 s, for 20 min. Results demonstrated that TENS reduced both
innocuous and noxious evoked responses of WDR and HT, and had no effect on LT
neurons. Also, there was no reduction in spontaneous activity or receptive field size of
dorsal horn neurons by TENS. These findings contradict previous studies by Garrison
and Foreman (1994, 1997). The authors explain the conflicting results in relation to
the different methodologies used; previous studies applied TENS up to 5 min as
compared to a 20 min application in this study.

40

Lee et al. (1985) used an experimental animal model to investigate the underlying
mechanisms of TENS using the evoked responses of C-fibres. Recordings were made
from identified spinotalamic tract (STT) neurons in the lumbosacral spinal cord of
seven anaesthetized monkeys. The STT cells were activated by stimulating the
common peroneal nerve at suprathreshold intensity for C-fibres. Responses of C-fibres
were compared before, during, and after application of TENS for 5 min. In 14 STT
cells, some degree of inhibition of C-fibre responses occurred only when the intensity
of TENS exceeded the threshold of A fibres. At a given stimulus intensity, bursts of
pulses repeated at a low-rate were more effective than high-rate pulses. When TENS
was applied to an area of the skin within a cells receptive field, it was more effective
than when it was applied outside the receptive field. The C-fibre volley recorded from
a peripheral nerve was not reduced in size, and there were no substantial changes in its
latency due to TENS. Furthermore, the inhibition of the activity of STT cells was not
altered significantly after intravenous injection of naloxone hydrochloride. The
authors concluded that the inhibitory effect of TENS seems to be due to a mechanism
that does not involve release of opioid substances.

Microneurography was devised for, and applied almost exclusively to, the
investigation of the normal physiological parameters of nerve impulse activity of
human peripheral nerves. Microneurographic recording involve the use of tungsten
needle microelectrodes with a diameter of 200 m and a gradually tapered tip of a few
micrometers. A recording electrode is inserted through the skin into an underlying

41

nerve trunk. A reference electrode is placed subcutaneously 1 to 2 cm away. Multiunit or single-unit afferent activity is then discriminated from the skin or muscle nerve
fascicles (Ochoa and Bell, 1999).

Janko and Trontelj (1980) carried out a microneurographic and perceptual study on 8
healthy volunteers that investigated the peripheral physiological mechanisms involved
in TENS for the suppression of pain. The TENS parameters used were as follows:
frequencies between 0.2-1 Hz, 1 to 50 Hz or 100 Hz; pulse duration between 100 and
300 s and a stimulation period of 30 min. Results showed that the shape of the pulse
was irrelevant in terms of fibre recruitment or sequence of recruitment. Also there was
no difference between the responses obtained by pulses of different durations. An
increase in stimulus frequency usually resulted in increased jitter (the variation of time
interval between two consecutive action potentials) and intermittent blocking. The
authors suggested that the increased jitter of individual spikes resulted in artificially
decreased amplitude and the appearance of false spikes in the averaged recording. The
authors concluded that a peripheral contribution of TENS, if any, seems to be
unimportant. These findings contradict the findings by Garrison and Foreman (1994)
namely in respect to fibre recruitment (parameter specificity), however, this may be
related to different methodologies used.

Walmsley et al. (1986) investigated the effects of TENS upon median nerve sensory
nerve conduction velocity. Twelve nave healthy volunteers were exposed to TENS

42

100 Hz, 100 s for 30 min at a mild tingling sensation. Median nerve conduction
velocities were recorded prior to the application of TENS and at 30 and 60 min
subsequently. Skin temperature was also monitored. Results showed a significant
decrease in NCV post-TENS (p=0.003) as well as a significant reduction in skin
temperature (p<0.001). The authors concluded that although the application of TENS
did cause a significant decrease in nerve conduction velocity, the decrease of skin
temperature may have influenced the conduction velocity. However, this study did not
have a control group that could validate the findings, and it remains unclear as to
whether NCV decreases over time were as a result of TENS, or because the subjects
were inactive during the treatment period.

A similar study by Levin and Hui-Chan (1993) investigated whether conventional

TENS (100 s, intensity three times threshold) and acupuncture-like TENS (internal
frequency of 100 Hz delivered at 4 Hz, 700 s, intensity greater than three times
threshold) application excite similar afferent nerve fibres. TENS was delivered over
the median nerve of 17 healthy subjects. Compound action potentials of the median
nerve were recorded. Results showed that both conventional and acupuncture-like
TENS resulted in recruitment of large-diameter A, A fibres. These findings
contradict the axiomatic of the pain gate control theory (Melzack, 1965) as well as the
findings of Garrison and Foreman (1994, 1997). Fibre recruitment depends not only
on the intrinsic excitability of the type of tissue (nerve or muscle) but also on their
location with respect to the electrodes used to transfer the current. Generally, the

43

closer the excitable tissue to the electrodes, the more likely is to be activated by the
current (Benton et al., 1981; Robinson and Snyder-Mackler, 1995). Thus, at a fixed
intensity of stimulation, small-diameter axons close to the stimulating electrodes may
be activated before a large-diameter fibres located away (Robinson and SnyderMackler, 1995). Therefore, A touch-pressure sensory nerve fibres are commonly
recruited before the more inherently excitable A motor fibres (Robinson and SnyderMackler, 1995). Concomitantly, an increase in the amplitude of the current results in
the excitation of additional nerve fibres, including both smaller fibres near the
electrodes and larger fibres farther from the stimulating electrodes (Benton et al.,
1981; Robinson and Snyder-Mackler, 1995). In this study it seemed to be the case, as
the intensity used for the conventional TENS was three times the sensory threshold,
while for the acupuncture TENS the intensity was greater than three times the sensory
threshold. Another aspect that deserves some consideration was the use of frequency
modulation for the acupuncture TENS groups as opposed to a fixed frequency and the
hypothetical influences of that upon fibre recruitment. Comments on the pulse train
stimulation mode are interesting. Vaarwerk et al. (1995) on commenting the pulsetrain (burst) stimulation mode states that: Burst parameters can also be delivered at
low intensity similar to the conventional mode. When used in this manner, amplitude
and pulse width may be in the range of the conventional mode, and the sensation
consists of mild parasthesia plus a rhythmic background pulsing (Vaarwerk et al.,
1995). The sensory description presented by Vaarwerk is consistent with the
information transmitted by fibres A, A.

44

A further study by Cox et al. (1993) investigated the effect of acupuncture-like and
conventional TENS on motor nerve conduction velocity. Thirty-one female volunteers
participated in the study; TENS application lasted for 20 min and the parameters used
were as follows: Acupuncture-like TENS 2 Hz, 250 s, 24.4 mA; Conventional TENS
100 Hz, 85 s, 26.7 mA; Placebo TENS (no current delivered). The results showed no
significant differences between groups. Thus, it would appear that pain relief
associated with TENS may occur either by a peripheral mechanism that does not
involve the motor nerves, or by a spinal/central mechanism as suggested by various
investigators (Woolf et al., 1980; Chan and Tsang, 1987; Hansson and Lundeberg,
2002).

Walsh et al. (1995) investigated the effects of four combinations of TENS pulse
durations (50 s and 200 s) and frequencies (4 Hz and 110 Hz) in two separate
double-blinded studies that included a total of 88 subjects. Action potential,
mechanical pain threshold (MPT) and ambient and skin temperature recordings were
taken. The authors concluded that the observed decrease in nerve conduction was
parameter-dependent. In this study, the greatest effect shown was associated with 110
Hz, 200 s when compared to the other parameter combinations as well as the control
group. To further investigate the neurophysiological effects of TENS, Walsh et al.
(1998) extended the previous study to investigate the effects of these parameters on
nerve conduction in the human superficial radial nerve and on MPT and tactile
threshold (TT). Using a similar methodology to that used in Walsh et al. (1995), the

45

authors studied 50 healthy subjects (25M, 25F) that were randomly allocated to five
groups consisting of four TENS groups and a control group. The authors confirmed
the results found in the previous study. Results clearly showed that only one
combination of TENS (110 Hz, 200 s) effected obvious and statistically significant
changes in MPT and TT. The authors also stated that notwithstanding the
contradictions found in the literature, the findings from their study suggest some
peripheral component to TENS mediated hypoalgesia.

Somatosensory evoked potentials provide the means for safely and noninvasively
studying segments of the peripheral and central nervous system. Evoked potentials are
electrical signals generated by the nervous system in response to sensory stimuli.
Surface electrical excitation of large myelinated fibres in peripheral nerves produces
afferent volleys that ascend in the posterior columns to the primary somatosensory
cortex. Electrical stimulation of a mixed nerve initiates a relatively synchronous volley
that elicits a sizeable somatosensory evoked potential (SEP) (DeLisa, 1994; Aminoff
and Eisen, 1999). This type of stimulus activates predominantly, if not entirely, the
large diameter, fast conducting group Ia muscle and II cutaneous afferent fibres
(Aminoff and Eisen, 1999). Amongst other uses, evoked potentials have been used in
neuropharmacological research, physiological research on pain and to evaluate the
effects of analgesics, anaesthetics, acupuncture and TENS, cryotherapy and Laser
(Panjwani et al., 1991; Umino et al., 1996; Kanda et al., 2002; Restuccia et al., 2002).

46

Ashton et al. (1984) investigated the effects of TENS and aspirin on late SEPs
compared with placebo (aspirin placebo). Thirty-two healthy volunteers (17M, 15F)
were studied. TENS was applied unilaterally over the median nerve at the wrist via
two carbon electrodes. Stimulation frequency was 100 Hz, pulse duration 200 s over
a period of 15 minutes. Intensity was set at a strong but comfortable level.
Components of the SEP were identified as a sequence of positive and negative troughs
and peaks utilising latency criterion windows of: P 1 60-100 msec; N 1 : 100-160 ms;
P 2 : 160-260 ms; N 2 and P 3 : 260-360 ms. Recordings were taken 15 min prior to the
treatment, immediately after treatment and 15, 30 and 45 min post-treatment. Results
showed a reduction in peak-to-peak amplitude of the late components N 1 , P 2 of the
SEP in all groups over time. TENS produced further significant changes compared
with placebo and aspirin, including a fall in N 1 , P 2 amplitude; increase in N 1 latency
and a decrease in the total excursion of the SEP between 25 and 450 ms after stimulus
onset. The same team of investigators (Golding et al., 1986), using a similar
methodology, investigated the effect of TENS on both early and late SEP components
in 26 health volunteers. Subjective assessment of stimulus intensity, sensory detection
threshold, and pain threshold were recorded and analysed. The results demonstrated
that TENS decreased early and late SEP amplitudes and stimulus intensity ratings, and
elevated sensory detection threshold. However, this study did not include a control
group that could be used to validate the findings. Another aspect open to debate is the
fact that the authors used the contralateral side as a control yet there is a possibility of
a generalized effect.

47

2.4 Electrical stimulation and delayed onset muscle soreness

Prolonged or strenuous exercise can lead to several types of muscle pain. Delayed
onset muscle soreness (DOMS), is the soreness experienced 24 to 48 hours after
overexertion or strenuous muscular exercise that gradually subsides after 4 to 6 days
(Fitzgerald, 1993; Bougie, 1997).

Although several theories have been developed to explain DOMS such as muscle
spasm theory, connective tissue damage theory, muscle damage theory, and
inflammation theory, the exact mechanisms of DOMS are unclear (Craig et al., 1999).
However, despite the fact that the underlying causes of DOMS remain unknown,
several treatments have been proposed to minimize the effects of DOMS. These can
be classified as pharmacological and non-pharmacological. Electrical stimulation is a
non-pharmacological form of intervention which has been investigated for the
management of DOMS.

Pain is one of the cardinal signs and symptoms associated with DOMS (Armstrong,
1984; Smith, 1991; Br, 1997). Skeletal muscle is innervated by specialised small
myelinated or unmyelinated nociceptive afferent fibres. The generation of painful
sensations involves the activation of small-diameter afferent sensory fibres A or C,
which in this type of tissue are often designated as group III and IV. Muscle
nociceptors are activated by chemical stimuli of algesic substances, such as
bradykinin, prostaglandins, serotonin, and high concentrations of potassium ions

48

(Smith, 1991; Bruce and Perl, 1996). Nociceptors may exhibit a preferential
sensitisation to mechanical stimuli such as contractions, elevated pressure and
mechanical distortion of the tissue which are associated with inflammatory-like
processes and that could activate the nociceptors in the muscles and elicit the sensation
of DOMS (Armstrong, 1984). The fact that DOMS is associated with signs and
symptoms such as pain as well as cellular changes consistent with an inflammatory
process (Smith, 1991; Hasson et al., 1993; OGrady et al., 2000) makes it a suitable
model to study the hypoalgesic and anti-inflammatory effectiveness of electrical
stimulation.

The following studies concerning the effects of ES upon DOMS are presented in
Table 2.4.

Denegar and Huff (1988) conducted a study that compared the efficacy of high TENS
(80 Hz, 90 s) and low TENS (2 Hz, 200 s). Twenty-four female subjects were
recruited and randomly assigned to one of four groups (group 1: high TENS treatment
of the dominant arm, 2: high TENS treatment of the non-dominant arm, 3: low TENS
treatment of the dominant arm, 4: low TENS treatment of the non-dominant arm).
DOMS was induced in the flexors through repeated eccentric muscle contractions.
Upon completion of the exercise, each subject was assessed for range of motion
(ROM) and pain (Talags scale). At 48 hours after exercise, subjects received
treatment which lasted for 30 min. The results showed that the two forms of TENS

49

were equally effective in treating pain associated with DOMS. No control or placebo
group was included in the study. The same authors (1992) compared the changes in
pain, elbow ROM and strength loss in subjects experiencing DOMS. DOMS was
induced in the non-dominant arm in 40 females. Subjects were randomly assigned to
treatment with either TENS (90 Hz, 90 s), Cold, TENS+Cold (combined treatment),
Sham TENS, 20 min of rest. Treatments were followed by a static stretch. Results
showed that perceived pain decreased following treatment with Cold, TENS, the
combined treatment, and the Sham treatment, as well as following stretch (p<0.001).
However, not all groups experienced an identical response to treatment (p<0.05).
Static stretching resulted in decreased perceived pain in all groups (p<0.001).
However, subjects who received Cold, TENS, or the combined treatment plus
stretching had greater decreases in perceived pain than those who received Sham
TENS or no treatment prior to stretching (p<0.05).

Extending the previous investigations, Denegar et al. (1989) carried out a study that
tried to determine the potential application and mechanisms of TENS as an antiinflammatory agent upon DOMS. The authors investigated the influence of TENS on
pain, ROM and serum cortisol. They postulated that TENS would increase the anterior
pituitary to release -endorphins. These molecules would cause a cascade of hormone
stimulation that would lead to the synthesis and release of cortisol and would therefore
produce an anti-inflammatory response. Eight females received TENS (2 Hz, 300 s)
for 30 min at four sites associated with the relief of upper arm pain. Blood samples

50

were taken 15 and 1 min before, and 1, 20 and 40 min after treatment. The authors
concluded that there were no significant differences in pre and post-treatment cortisol
concentrations. However, there was a significant increase in elbow ROM after TENS.
The study did not include a control and a placebo group, the number of subjects
included was very small and all the subjects were female, which can be a biasing
factor considering that the difference in creatine kinase (CK) release between the
sexes is significant; females have a lower CK activity than man at rest (Meltzer, 1971)
and show less CK efflux after bicycle exercice (Shumate et al., 1979).

Microcurrent electrical neuromuscular stimulation (MENS) is another form of

electrical stimulation that has been investigated. Denegar et al. (1992) used DOMS as
a model for skeletal injury to compare daily treatments with low-volt microamperage
stimulation (LVMAS) and static stretching to a placebo treatment and static stretching.
DOMS was induced in the elbow flexor muscle group in 16 subjects (3M, 13F), who
were evaluated for pain, elbow flexor strength, and elbow extension range of motion.
Data were collected before eccentric exercise bout, before and after treatment 24, 48,
72, 96 and 196 hours following the exercise bout. LVMS was delivered at an intensity
of 100 mA, 0.3 Hz, and an alternating polarity for 20 minutes. The results showed no
significant differences between LVMAS and placebo treatments on any of the
variables across the duration of the study, but the LVMAS did provide a transient
analgesic effect 24 and 48 hours following the eccentric exercise.

51

A further study by Weber et al. (1994) compared the effect of massage, NMES or
upper body ergometry upon DOMS. Forty female volunteers were randomly assigned
to one of three treatment groups or to a control group. Group 1 received massage,
group 2 received MENS (0.3 Hz, 0.5 sec slope, 30 A for 8 min), group 3 received
upper body ergometry, and group 4 was the control. Soreness, maximum voluntary
contraction (MVC) and peak torque (PT) were measured. The results showed no
significant differences between the treatments and the control groups. Once again the
sample used in this study only included females, and the treatment time was 8
minutes, which is significantly lower than the time used in current clinical practice.
Allen et al. (1999) also investigated the effects of MENS treatment on pain and loss of
ROM associated with DOMS. Eighteen subjects (3M, 15F) were assigned to one of
two groups. Group 1 received MENS (30 Hz, 200 A for 10 min, followed by 0.3 Hz,
100 A for 10 min) and group 2 served as a sham group. ROM and pain (graphic
rating scale) were measured. The authors found no significant differences between
groups concerning pain and ROM.

Acustat (TC Corporation, CA) is a membrane that provides microcurrent

stimulation. It comprises a nonwoven, self-adhesive, microporous polymer membrane
measuring approximately 8.5 cm by 15 cm. The polymer is an electret (a solid
dielectric that exhibits persistent dielectric polarization) that stores a strong negative
electrostatic charge, produced during manufacture. When placed in contact with the
skin, it discharges over a 48-h period, inducing a flow of electrons into the skin and

52

subcutaneous tissues. The total current flow over this period has been measured at 20
A. The patient feels no sensation during treatment (Lambert et al., 2002).

Recently, Lambert et al. (2002) evaluated the effect of Acustat using DOMS as a
model of acute soft tissue inflammation. Thirty healthy male were recruited for a
double-blinded, placebo-controlled trial. Subjects were randomly assigned either to a
placebo or experimental group (active Acustat). DOMS was induced in the nondominant arm by eccentric exercise and the membrane (either active Acustat or
placebo) was applied immediately after the exercise protocol and stayed in place for
96 hours and monitored for a total of 168 hours. Muscle soreness (MPT) was
measured at 9 fixed sites on the biceps by measuring the force required to cause pain.
Resting angle (RANG); maximum voluntary contraction (MVC); biceps girth
measurements and CK activity was also measured. Results demonstrated that subjects
in both groups experienced severe pain and swelling of the elbow flexors after
eccentric exercise. After 24 hours, the elbow joint angle in the placebo group had
increased significantly more than in the active Acustat group (p<0.05). For the first
48 hours, MVC was significantly impaired in the placebo group by up to 25%
(p<0.05), whereas MVC was unchanged in the active Acustat group. Plasma CK
was also lower in the active Acustat group (p<0.05). The authors concluded that the
data showed that Acustat electro-membrane microcurrent therapy reduces some of
the clinical features of DOMS. However, the study did not include a true control

53

group (the investigators used the contralateral arm as a control) and the sample only
included males.

Similarly, Craig et al. (1996) used DOMS as a model to study the effectiveness of
TENS as a hypoalgesic agent. Forty-eight TENS nave subjects (24F, 24M) were
randomly allocated under double-blinded conditions to one of four groups: TENS1 (4
Hz, 200 s), TENS2 (110 Hz, 200 s), control, placebo. DOMS was induced by
eccentric exercise. Mechanical pain threshold, pain (VAS; McGill pain questionnaire)
and RANG were measured before and after treatment under controlled double-blinded
conditions. The researchers reported no significant differences between groups for any
of the variables. This study contradicts the results by Denegar and Huff (1988) and
Denegar et al. (1989) but may be explained in part due to differences in experimental
protocols and the fact that the Denegar and Huff study (1988) did not include blinded
controls.

The effects of interferential current therapy (IFT) upon DOMS have also been
investigated. In 1997, Schmitz et al. hypothesized that IFT would be able to produce
analgesia via activation of the hypothalamic-pituitary-adrenal axis. Using DOMS as a
model of injury, the authors compared the ability of IFT high (100 Hz, 100 s) and
low (10 Hz, 100 s) frequency to control musculoskeletal pain as measured by
perceived pain scales (Talags) and serum cortisol levels. Ten subjects were randomly
assigned to one of two groups (high and low IFT). Measurements were taken pre and

54

post-treatment (immediately after 15 and 30 min following treatment). The results

showed a significant decrease in perceived pain scores across time (p=0.0001) but no
significant difference in serum cortisol for the two groups. However, these findings
may be questionable due to the small sample size included.

After the introduction of TENS devices in the mid 1970s, a second class of constant
voltage stimulators become available. The so called high-voltage pulsed galvanic
stimulators or high-volt pulsed current (HVPC) generate a twin-spike, monophasic
pulsed current wave form with peak spike amplitudes of up to 500 V and pulse
durations of about 50-200 s at frequencies ranging from 1 to approximately 120 twinspike pulses per second (Alon, 1991; Robinson and Snyder-Mackler, 1995).

Walcot et al. (1991) compared the effects of HVPC and micro current stimulation
(MS) on DOMS. Fifty females performed eccentric exercise of the hamstring muscle
group and were randomly assigned to one of four groups: control group (n=12); MS
group (n=13); a HVPC group in which current was delivered at subsensory level
(n=14) and a HVPC group where current was delivered at submotor level (n=11).
Soreness perception, hamstring flexibility and plasma CK were evaluated prior to and
twice following the soreness inducing exercise. Hamstring flexibility and soreness
were monitored for one week. The authors concluded that the measurements of the
three outcomes indicated that HVPC delivered at the submotor level was most
effective in reducing DOMS.

55

A further study by Butterfield et al. (1997) investigated the effects of high-volt pulsed
current on DOMS. Twenty-eight subjects (17F and 11M) were randomly assigned to
one of two groups, HPVC or sham. Subjects in the HPVC treatment group were given
a high-volt, twin-peak, pulsed electrical current at a rate of 125 Hz for 30 min.
Subjects performed concentric and eccentric knee extensions with the right leg to
induce muscle soreness. Assessments were taken before and after the exercise bout
and each treatment at 24, 48 and 72 hours post-exercise. The results showed no
significant reduction in pain perception or improvement in loss of function at 24, 48
and 72 hours post exercise. Therefore, HPVC at the parameters used in this
investigation were ineffective in providing lasting pain reduction and at reducing
ROM and strength loss associated with DOMS. This is in disagreement with the
results of Wolcot et al. (1991). However, the differences may be the result of the
different methodologies employed.

Rebox-Physio is a novel form of current developed in the Czech Republic by Petr

Slovak in 1980. According to the manufacturer, it is a portable device delivering direct
rectangular current, with a frequency between 2 to 4 kHz, pulse duration between 100
and 300 s, and amplitude between 0 and 20 V. This form of current can be classified
as a medium frequency current (Low and Reed, 1994). There are few clinical studies
involving Rebox-Physio and according to the Rebox Company, the treatment
method of the Rebox-Physio device is based on transcutaneous correction of local

56

acidosis (TCLA). Rebox-Physio application is indicated for the treatment of pain,

oedema, acute inflammation and microtrauma.

Nussbaum and Gabison (1998) considered DOMS to be an appropriate model for

evaluating the effectiveness of this form of electrical stimulation. Therefore, they
carried out an investigation to evaluate the effectiveness of Rebox-Physio on an
experimental model of soft tissue inflammation. Thirty healthy subjects (15M, 15F)
were randomly allocated to: Rebox-Physio (3000 Hz, 100 s, 160 A duration
between 10 and 15 min depending on the number of points being treated), sham
Rebox-Physio, or control group. Treatments were applied for 3 days. DOMS was
induced in the biceps brachii by eccentric exercise. The outcome measures comprised
the daily ratings of pain (VAS), mechanical pain threshold (MPT) and pressure-pain
tolerance (PT). The results showed significant increases in VAS (p=0.0001) and
decreases in PPT and PT were found at 24 and 48 hours. There was no difference
between groups. Thus, Rebox-Physio had no effect on this experimental model of
soft tissue injury.

The use of electricity as an analgesic and anesthetic was reported in the mid-1800s and
early 1900s by a number of physicians and dentists (Sluka and Walsh, 2003).
However, electrical stimulation for pain relief was not fully accepted by the medical
field until the publication by Wall and Sweet (Sluka and Walsh, 2003). Every since
then a growing number of non-analgesic effects have also been reported, these include

57

antiemetic effects. The next section will review the studies on the effects of
stimulation of the PC6 acupoint in the management of nausea and emesis induced by
chemotherapy.

2.5 Sickness from anti-cancer therapy

At some pointsI imagined that if you felt this horrible for a

long time you wouldnt care if you lived or died. (2001)

The previous quote represents a description of the emetic experience by one patient
who participated in the clinical trial described in Chapter 6. Nausea and vomiting are
perhaps the best-known adverse effects of chemotherapy, and have consistently ranked
high on the list of factors most feared by patients undertaking chemotherapy regimens
(King, 1997; Hesketh, 1999; Tonato and Roila, 1999).

When cancer chemotherapy was introduced in 1942, it soon became evident that
nitrogen mustard (mechlorethamine hydrochloride), the first effective drug, was a
highly emetic compound (Dundee and Yang, 1990; Seymour, 1993). Inadequately
controlled emesis can lead to substantial physiologic complications such as:
esophageal tears, bone fractures, metabolic alkalosis and dehydration, significantly
reducing quality of life and increasing the risk of patient non-compliance with
treatments (Dundee and Yang, 1990; Axelrod, 1997; King, 1997; Cunningham, 1997,
Suzanne et al., 2000).

58

A brief review of some of the cancer statistics from the United Kingdom (UK) can
provide some insight into the magnitude of the problem of nausea and emesis in anticancer therapy. Cancer is a major cause of morbidity in the UK with more than
262,000 new cases diagnosed in 1998. Overall it is estimated that 1 in 3 people will
develop some form of cancer during their lifetime (Cancer Research, 2003). The UKs
2000 estimates of total prevalence from the EUROPREVAL study (2002) indicate that
approximately 2% of the population of the UK are alive having received a diagnosis of
cancer, that is, around 1.2 million people (Micheli et al., 2002). It is clear from the
above that it is likely that a relatively large number of patients will at some point in
their treatment, receive cytotoxic chemotherapy.

Although the pharmacological control of chemotherapy-induced nausea and emesis

has improved with the widespread use of the new 5-HT3 antiemetic agents, such as
ondansetron hydrochloride (Zofran, Glaxo Wellcome Inc., Research Triangle Park,
NC), approximately 40% of patients still develop emesis following chemotherapy, and
over 75% report nausea. Thus, the control of nausea has become a compelling issue in
cancer therapy (Goldspiel and Curt, 1996; Cunningham, 1997).

2.6 General Mechanisms of Nausea and Emesis

The main central nervous system (CNS) structures considered to be involved in the
mediation of nausea and vomiting are grouped in the caudal brainstem and the central
grey matter of the spinal cord. They include: the chemo receptor trigger zone (CTZ)

59

for vomiting area postrema (AP); the principal visceral sensory nucleus of the vagus
nerve nucleus tractus solitarius (NTS); the dorsal motor nucleus of the vagus nerve
which sends parasympathetic efferents to the abdominal viscera; a vomiting centre
which has been considered to act as an integrating motor centre or a central pattern
generator for the emetic response lying in the dorsomedial medulla oblongata; and the
anterior horn of the spinal cord which contains lower motor neurons responsible for
activating the somatic muscles which help to expel the gastric content (Leslie and
Reynolds, 1993; Hogan and Grant, 1997).

The vomiting centre, located in the dorsal portion of the lateral reticular formation
controls vomiting. It is strategically situated to perform its role of coordinating the
processes that result in vomiting via somatic and visceral efferents (Veyrat-Follet et
al., 1997). It lies in the proximity of the following regulatory centres: respiratory,
inspiratory and expiratory centre, vasomotor centre, salivatory and vestibular nuclei,
and the bulbofacilitatory and inhibitory systems (Borison and McCarthy, 1983;
Dundee and Yang, 1990; Veyrat-Follet et al., 1997). Thus, the vomiting centre by
itself coordinates the activities of other neural structures in its immediate surrounding
areas to originate an intricate pattern response. Stimuli pass via the vasomotor,
respiratory, and salivary centres and from the brain stem to the gastrointestinal tract to
initiate vomiting.

60

The CTZ is a highly vascularised (blood and cerebrospinal fluid) structure located in
the floor of the fourth ventricle (AP). It possesses different types of receptors that can
respond to a variety of endogenous agents that can provoke vomiting when present in
the blood or cerebrospinal fluid. A number of neurotransmitters have been postulated
(e.g. dopamine, substance P, enkephalin, etc) (Dundee and Yang, 1990; Veyrat-Follet
et al., 1997). Although the CTZ is an important chemo sensor for vomiting, vomiting
can be induced by substances acting on other chemosensory inputs to the emetic centre
(Veyrat-Follet et al., 1997).

Abdominal visceral afferents in particular the vagi are involved in prompting the
emetic response to a variety of agents (Veyrat-Follet et al., 1997). The NTS, closely
associated to the AP, is the main local for termination of visceral vagal afferents. It is
also an integrating area of the visceral information processing, and is involved in
transmitting emetic signals from the viscera to the CNS (Andrews and Davis, 1993;
Veyrat-Follet et al., 1997) (See Fig. 2.1).

The main function of the vomiting reflex is to protect against the accidental ingestion
of toxins. It is consequently not surprising that the gut should have recognition
systems capable of activating the reflex - the enterochromaffin cell has been proposed
as the detector cell (Cubeddu, 1992; Andrews and Davis, 1993; Andrews et al.,
1998). Electrical stimulation of the abdominal vagal afferents can induce emesis

61

within 20 seconds, illustrating therefore the aptitude of the pathway for rapid ejection
of gastric contents (Andrews and Davis, 1993).

Fig 2.1: Schema representing the pathways involved in nausea and vomiting. (from
Bountra et al., 1986).

Vomiting occurs in three phases: pre-ejection, ejection and post-ejection (Andrews

and Davis, 1993). The pre-ejection, also called prodromal phase, is usually
accompanied by the sensation of nausea, tachycardia and increased salivation. Its
physiology is poorly understood. The proximal stomach relaxes and a powerful

62

contraction (the retro giant contraction) begins in the small intestine and it propagates
in a retrograde fashion towards the stomach (Andrews and Davis, 1993; Hogan and
Grant, 1997; Veyrat-Follet et al., 1997). This mechanism is mediated by the vagus
nerve and the neurotransmitter is acetylcholine.

The ejection phase consists of retching and vomiting both of which are under control
of the somatic division of the nervous system. Retching and vomiting are produced
primarily by changes in thoracic and abdominal pressures that are generated by the
coordinated action of the major respiratory muscles (diaphragm, abdominal and intercostal). During retching, the diaphragm forcefully contracts with the abdominal
musculature, but gastric contents are not expelled. The contraction is much more
powerful during vomiting, when the periesophageal diaphragm relaxes, thus allowing
contents from the stomach and proximal small intestine to enter the esophagus.
Finally, the post-ejection phase occurs after a vomiting episode when nausea is often
relieved and the individual reports feeling better. The mechanism is unknown, but
according to Andrews and Davis (1993), this might be due to the release of
endorphins.

Nausea is a subjective, unobservable phenomenon of an unpleasant sensation

experienced in the back of the throat and the epigastrium that may or may not
culminate in vomiting (Tonato et al., 1993; Rhodes, 1997; Hogan and Grant, 1997).
The word nausea comes from the Greek naus or ship for seasickness, obviously

63

recognizing that motion is an inducer of this symptom (Axelrod, 1997). Nausea can be
the product of a wide variety of organic and psychogenic disorders, and in cancer
patients receiving chemotherapy, is perceived as one of the most distressing side
effects of anti-neoplastic treatment (Tonato et al., 1993; Rhodes, 1997; Hesketh,
1999).

The unpleasantness of nausea is seen as a protective mechanism that reduces the

chances that an animal or human will choose to ingest the same toxin again (Andrews
and Davis 1993). Very little is known about the physiology of nausea (Tonato et al.,
1983; Veyrat-Follet et al., 1997). The manifestation of nausea occurs as previously
described on the pre-ejection phase of vomiting, meaning that stimuli, which evoke
vomiting, usually evoke nausea prior to vomiting.

2.7 Physiology of chemotherapy-induced nausea and vomiting: a brief overview

Nausea and vomiting can be encountered in a variety of clinical contexts either
associated with pathological factors (brain injury, intracranial pressure, inflammatory
bowel disease, visceral pain); physiological factors (unnatural motion, endocrine
disturbances, pregnancy); as a product of certain types of therapeutic interventions
(anaesthesia, ionising radiation exposure, chemotherapeutic agents) (Andrews and
Sanger, 1993; Veyrat-Follet et al., 1997). (See Fig. 2.2).

64

Chemotherapy induced-emesis represents a particular case, and it is understood as a

protective reflex by the body to get rid of a noxious substance (Andrews and Sanger,
1993; Veyrat-Follet et al., 1997).

Fig 2.2: A diagram showing the major visceral and somatic motor nuclei
involved in emesis. (from Andrews and Davis, 1993).

As previously stated, cancer chemotherapy is often accompanied by severe nausea and

vomiting, and this is due to several factors such as: emetogenic potential of the drugs
used, time of onset and duration of action (Borison, 1983; Judson, 1993). Anti-cancer
cytotoxic drugs constitute a broad collection of cellular poisons that aim to damage
cancer cells in preference to the normal tissue. The most emetic drug is cis-dichloro-

65

diammine-Pt(II) (cisplatin or CDDP) followed by mustine (mechlorethamine

hydrochloride),

dacarbazine,

actinomycin

D,

doxorubicin,

carboplatin

and

cyclophosphamide (Seymour, 1993; Veyrat-Follet et al., 1997). When used in

combination the emetogenic potential of each agent is additive, and combinations of
highly emetogenic drugs are commonly employed in various anticancer treatments
(Hesketh, 1999).

Patterns of nausea and vomiting include: acute, delayed and anticipatory nausea and
vomiting. Acute nausea and vomiting occurs in the first 24 hours after chemotherapy
administration; delayed nausea and vomiting has been arbitrarily defined as beginning
24 hours after chemotherapy administration and can persist up to 6 or 7 days.
Anticipatory nausea and vomiting can occur before a subsequent cycle of
chemotherapy in patients with a previous history of acute and delayed nausea and
vomiting (Hogan and Grant, 1997; Kris et al., 1988; Morrow et al., 1988; Tonato and
Roila, 1999).

Although several models of emesis have been proposed and they have been described
elsewhere (Andrews and Davis, 1993; Veyrat-Follet et al., 1997; Andrews et al.,
1998), the identification of the precise mechanisms by which anti-cancer therapies
activate delayed emesis, and the neuropharmacology of the sensation of nausea, are
yet to be clarified.

66

2.8 Clinical care of patients receiving chemotherapy

The side effects of chemotherapy are variable and depend on the drug or combination
regime that is used. However, most cytotoxic drugs cause emesis (Jones and
Cunningham, 1993; Tonato and Roila, 1999). The goal of the antiemetic therapy is to
prevent nausea and vomiting completely. The treatment consists of: minimizing
factors that predispose to sickness, such as motion or anxiety; giving cytotoxic drugs
over a period of time rather than a single, high-dose bolus whenever possible; using
drugs that block one or more of the emetic mechanisms; and using adjuvant drugs
such as benzodiazepines that will reduce the psychological problems (anticipatory
nausea and/or anxiety) associated with treatment. The benefit of a multiple drug
regimen, attacking different parts of the emetic process, has previously been
demonstrated (Dundee and Yang, 1990; Jones and Cunningham, 1993; Gralla et al.,
1999). Such regimens may include sedation, corticosteroids and acupuncture (neiguan
PC6), as well as specific antiemetics (Dundee and Yang, 1990).

67

Classification of Antiemetics

Metoclopramide hydrochloride
Dopamine-receptor antagonist

Domperidone
Phenotiazines
Butyrophenones

Some phenotiazines
Antihistamines

Cyclizine hydrochloride
Dimenhydrinate

Ondansetron hydrochloride
5-HT3 antagonists
Graniseteron

Anticholinergic agents

Scopolamine hydrobromide

Benzodiazepines
Agents with no specific action
Corticosteroids

Cannabinoids
Agents with unknown site of action
Neiguan PC6 acupuncture

Table 2.1: Classification of antiemetics (from Dundee and Yang, 1990).

68

2.9 Neiguan PC6 acupoint: antiemetic chemotherapy effects

Acupuncture is believed to have originated in China around 2500 years ago (NIH,
1997; Birch and Kaptchuk, 1999), and it has been practised in a number of Asian
countries for centuries.

The term acupuncture comes from late seventeenth Europe and describes a variety of
procedures involving the stimulation of anatomical locations on the skin by a variety
of techniques (Mao-Liang, 1993; Birch and Kaptchuk, 1999). The most studied
mechanism of stimulation of acupuncture points located over meridians employs the
penetration of the skin by thin, solid, metallic needles, which are manipulated
manually or by electrical stimulation (NIH, 1997; Effective Health Care, 2001).
Acupuncture appears to be effective for postoperative nausea and vomiting in adults,
chemotherapy-related nausea and vomiting (McMillan and Dundee, 1991; Sanger,
1993; NIH, 1997; Effective Health Care, 2001).

Neiguan (inner pass, PC6) is the point most commonly described for its antiemetic
effect (Fig 2.3). It is located on the pericardial meridian 2 Cun or Chinese inches
(a Cun is equivalent to the distance between the creases of the flexed index finger,
or approximately the width of the thumb across the interphalangeal joint 2.5 cm)
proximal to the distal wrist crease between the tendons of palmaris longus and flexor
carpi radialis muscles of the forearm (McMillan, 1991; Mao-Liang, 1993).

69

Fig 2.3: Location of Neiguan PC6 acupoint (from McMillan, 1998).

The following studies concerning the effects of the stimulation of the PC6 acupoint in
the management of nausea and emesis are presented in Table 2.5.

In the 1990s, Professor Dundee carried out several studies on the antiemetic action of
PC6 acupuncture in patients receiving cancer chemotherapy. A preliminary study
performed by Dundee et al. (1987) investigated 10 patients receiving 30 mg of CDDP.
Patients received acupuncture to the PC6 neiguan point or a dummy point in a
random order. Electroacupuncture (10 Hz, 250 s) for 5 minutes was applied
immediately before or soon after the start of the CDDP infusion. The effects were
monitored over 8 hours using a 4-point scale graded as: very good, some benefit,
no change or worse. The results showed that there was significantly less sickness
when PC6 was stimulated than when the dummy point was used (p<0.001).

70

For cytotoxic therapy induced emesis, electroacupuncture at the PC6 point

considerably reduced CDDP-induced emesis in patients receiving metoclopramide and
prednisolone and who had previously experienced a severe and persistent emetic
response with CDDP. By contrast, a randomised cross-over study with a placebo
treatment showed no effect (Dundee et al., 1989). This study involved 130 patients (15
in an open pilot study, 10 in a randomised placebo controlled cross-over study and 105
in a definitive study), and followed the same methodology as the preliminary study
carried out by the same authors in 1987. The results showed that sickness was
completely absent or reduced in 97% of patients and no side effects were encountered,
agreeing with the preliminary pilot study. Extending the previous work, Dundee and
Yang (1990) carried out a study where they investigated if acupressure at the PC6
would increase the antiemetic effect of electroacupuncture on patients receiving
chemotherapy. Using the same methodology as stated previously, 40 patients (20
inpatients and 20 outpatients) were recruited. Following the protocol used in previous
studies, patients received electroacupuncture, and immediately after they were given
an elasticated band with a plastic stud (Sea Band) and they were instructed to press the
stud (at the PC6) for 5 min every 2 waking hours over 24 hours. The results showed a
beneficial effect at 8 and 24 hours after chemotherapy in 95% of the patients.
However, none of these studies were blinded. In addition, inpatients follow-up
measurements of sickness were carried out on the evening of treatment or the next
morning. It is known that nausea and vomiting peaks after 24 hours and it is relatively
well controlled in this period of time (du Bois et al., 1992; Cunningham, 1997; Kris et

71

al., 1998; Andrews et al., 1998) therefore, the results may be questionable. In addition,
inpatients and outpatients were included in the sample which my act as a source of
bias.

More recently, Shen et al. (2000) assessed a standardized electroacupuncture protocol

as an adjunct to antiemetic pharmacotherapy for controlling emesis associated with
intensive, multiple drug, combination myeloablative chemotherapy compared to
minimal needling (stimulation of sites that are not indicated for nausea and emesis
control - placebo group) or antiemetic pharmacotherapy alone. One hundred and four
females receiving CDDP, cyclophosphamide and carmustine, were randomly assigned
to receive either low frequency electroacupuncture (2-10 Hz, 0.5-0.7 ms, 26 mA, 20
min), once daily for 5 days (n=37), minimal needling at control points with sham
stimulation on the same schedule (n=33) or pharmacotherapy (n=34). The
investigators included the recording of the total number of emetic episodes occurring
during the 5-day study period and the proportion of emesis-free days, compared
among the three groups. The results showed that the number of episodes occurring
during the 5 days was lower for patients in the electroacupuncture group compared to
minimal needling and the pharmacotherapy groups (p<0.001; median number of
episodes 5, 10 and 15 respectively). The electroacupunture group had fewer episodes
of emesis than the minimal needling group (p<0.001), whereas the minimal needling
group had fewer episodes of emesis than the antiemetic pharmacotherapy group
(p=0.18). The differences among groups were not significant during the 9-day follow-

72

up period (p=0.18). However, this study was not performed under double-blinded
conditions.

Stannard (1989) conducted a 3 month study that recruited 18 patients receiving

chemotherapy. Each chemotherapy course took place over a one to four-day period
occurring every two weeks, depending on the regime prescribed. Each patient in the
study received between one and four courses. Acupressure bands were worn by all
patients during some courses and were not worn during others and comparisons were
made between the times when the patients wore the acupressure bands and the times
when they were unable to wear them, or where the bands were incorrectly positioned.
Two methods of data collection were used: a record of each patients progress, which
included the feelings of both patients and staff; and a chart kept on each patients bed
for recording the number of times the patient vomited and the amount of antiemetic
drugs administered. The author concluded that although nausea still remained, in most
cases it was greatly reduced. Vomiting was reduced both in number of episodes, and
amount of vomit; some patients did not vomit at all. The amount of antiemetic drugs
used was also greatly reduced. However, the results were not validated by the
inclusion of a control group, and the sample size was very small.

In 1991, Price et al. compared the effect of PC6 acupressure (Sea Band) to that of a
Sea Band applied to a dummy point at the ankle. This single-blinded, randomised,
crossover study included 38 patients that received chemotherapy considered highly

73

emetogenic. Patients were told to use the bands for 7 days applying pressure for 1 min
every waking hour. Assessment was by means of a daily dairy card and a single
questionnaire at the end of treatment. Both were completed by the patient alone, and
evaluated nausea, sickness, mood, anxiety and overall condition. The authors
concluded that those patients receiving wrist acupressure had significantly less
sickness and nausea, and their overall mood and condition was better than those
treated at the placebo ankle point. Although this study was carefully controlled, a
larger sample would have provided a more reliable conclusion.

Dibble et al. (2000) compared the differences in nausea experience and intensity in 17
women undergoing chemotherapy (a combination of cyclophosphamide metotrexate
and fluorouracil) between those receiving usual antiemetic therapy plus acupressure
training treatment and those receiving only usual antiemetic therapy. This randomised
trial included finger acupressure bilaterally at PC6 and ST36. The experiment lasted
for 21 days. Baseline and post-study questionnaires were used to collect data. The
findings showed significant differences between the two groups regarding the nausea
experience (p<0.01) and nausea intensity (p<0.04) during the first 10 days of the
chemotherapy cycle, with the acupressure group reporting less intensity and
experience of nausea. The small sample size used may render the results questionable.

Recently Roscoe et al. (2002) investigated the efficacy of an acupressure wrist band
for the relief of chemotherapy-induced nausea. They compared the effect of active

74

acupressure at PC6 with sham acupressure and a control group in a randomised study
that included 25 women and 2 men who experienced moderate or severe nausea
following their first chemotherapy treatment. Results showed no statistically
significant differences in average severity of nausea between the three interventions.
However, the data showed a difference close to statistical significance in the severity
of delayed nausea reported during active acupressure stimulation compared to nonacupressure stimulation (p<0.06). In addition, patients on the active group took less
medication as compared to other groups (p<0.05). The sample used in this study was
asymmetric in terms of gender, which may also be a source of potential bias.

Aglietti et al. (1990) carried out a pilot study where metoclopramide, dexametasone,
and diphenhydramine were compared to manual acupuncture. Twenty-six women
receiving an infusion of CDDP as well as the same antiemetic treatment:
metoclopramide (3 mg/Kg i.v. 30 min before CDDP, and 1.5 h afterward),
dexamethasone (20 mg i.v.) and diphenhydramine (50 mg i.v.), both given 30 min
before CDDP. Manual acupuncture was also carried out at the PC6 point during the
infusion (20 min) and then replaced by a needle for permanent use, which was
removed 24 h after CDDP administration. Efficacy of the antiemetic treatment was
based on the overall count of the vomiting episodes, the intensity of nausea and its
duration. Complete protection was defined as the absence of nausea, vomiting or both.
The results obtained in patients treated with acupuncture were compared with those
obtained in a similar group. The results demonstrated that there was no difference

75

between the two groups in complete protection from both nausea and vomiting and
from vomiting alone. However, complete protection from nausea, the mean number of
vomiting episodes, the mean maximal score of nausea and the duration of nausea and
vomiting were significantly reduced by the addition of acupuncture. Nevertheless this
study did not include a control group.

McMillan et al. (1991) compared the effect of electroacupuncture as an adjunctive

therapy to ondansetron. Sixteen patients on a CDDP regime were recruited and
received non-invasive electroacupunture (10-15 Hz) for 5 min every 2 h when awake
during 5 consecutive days. Nausea and vomiting were assessed using a 4-point scale.
Results showed that 12 patients had a preference in favour of the electroacupuncture.
This represented a statistically significant difference (p=0.0005). Once again a small
sample was used, and the results represent only the frequency of episodes of nausea
and vomiting, not reporting on the severity and duration of each episode.

More recently, Tan et al. (2001) in a blinded randomised study compared the effects
of TENS to ondansetron and to a combination of ondansetron and TENS. Fourteen
testis and eleven bladder cancer patients were included in the study. The frequency
and severity of nausea and vomiting were assessed during cisplatin administration.
Low-frequency TENS (4 Hz) was delivered one hour prior to the administration of
cisplatin and continued throughout the infusion (8-hour duration). The results showed
a statistically significant difference between the number of emetic episodes observed

76

with the TENS+ondansetron combination and TENS alone (p=0.000) or ondansetron

alone (p=0.001). Ondansetron was better than TENS in preventing emetic attacks
(p=0.001). However, the results could not be compared to similar controls.

Shaoxiang et al. (1991) compared the effectiveness of a magnetic disk applied on the
PC6 point versus a non-magnetic disk and compression. Two hundred and six patients
receiving CDDP (20 mg/day over 5 days) and a combination that include other drugs
such as fluorouracil, mytomicyn C, cyclophosphamide, etc. If nausea and vomiting
were present after the administration of CDDP, paspertin 20 to 40 mg was injected
intramuscularly. Patients who could not be relieved of nausea and vomiting were
divided into 3 groups: magnetotherapy (161), non-magnetotherapy (23) and point
compression (22). In the magnetotherapy group, a flat 5 mm thick and 20 mm
diameter strontium and calcium-containing ferrite magnet of 60 mT intensity was
sewn to a cotton band. The band was fastened to the wrist with the N pole of the
magnet on the PC6 and removed 2 hours after the CDDP administration. In the nonmagnetotherapy group a similar cotton band with a disk of the same size but made of
ordinary iron was applied. In the point compression group, a 0.5 cm diameter steel ball
was used instead of a disk. Nausea and vomiting were assessed using a 3 point scale:
markedly effective when the administration of CDDP did not induce nausea and
vomiting; effective when nausea and vomiting were mild and ineffective when nausea
and vomiting remained unmitigated. Results showed that of 161 cases in the magnetic
group, the treatment was markedly effective in 61.4%, effective in 28%, and

77

ineffective in 10.6%. Of 23 cases in the non-magnetic group, 21.7% were effective

and 78.3% ineffective. All cases in the pressure group were ineffective. Comparison
between the groups was statistically significant (p<0.001). However, the authors did
not mention which kind of outcome measure was used to assess nausea and vomiting,
the study was not randomised double blinded and the sample distribution across
experimental groups was skewed (161 cases in the magnetotherapy group, 23 cases in
the non-magnetotherapy group and 22 cases in the point compression group).

2.10 Summary
This chapter reviewed the literature related to the use of TENS, APS and IFT
concerning their hypoalgesic, neurophysiological and antiemetic effects. However,
despite the popularity of such modalities, there is ongoing debate regarding their
clinical effectiveness. Based on the literature review, it was decided to investigate the
effectiveness of IFT using a validated pain model (delayed onset muscle soreness), to
examine whether any observed hypoalgesic effects were a result of neurophysiological
changes induced by IFT, TENS and APS in the human radial nerve and to investigate
the clinical effectiveness of electrical stimulation on the management of pain, nausea
and vomiting in cancer patients receiving anti-tumor chemotherapy.

The next Chapter will investigate the effects of IFT upon an experimental pain model
(DOMS) in Humans.

78

Chang et al.,
2001

Walsh et al.,
2000

Cramp et al.,
2000

Danziger et al.,
1998

Human

Human

Human

Human

Human

Group/Stimulation
Parameters

Results

H-reflex recorded before stimulation,

during stimulation (4-5, 9-10 and
14-15 min respectively), and after
stimulation (4-5 and 9-10 min
respectively)

TENS 2 Hz and 100 Hz increased the amplitude of

the H-reflex, TENS 100 Hz had a greater effect
than TENS 2 HZ, MA didnt increase the
amplitude of the H-reflex

50

Duration=15 min. TENS1: 110 Hz,

200 s, TENS2: 100 Hz, 50s
TENS3 4 Hz, 50 s, TENS4: 4 HZ,
200 s Control, (n=10 per group)

Ipsilateral RIII and H-reflexes were

recorded 5 times during the 45 min
experimental period. Concomitantly,
-motoneuron excitability was
monitored

No significant effect upon RIII/H-reflexes

70

Duration=15 min. TENS1: 5 Hz

TENS2: 100 HZ, TENS3: 200 HZ
IFT1: 5 HZ, IFT2: 100 Hz
IFT3: 200 Hz; Control
(n=10 per group)

Ipsilateral RIII and H-reflex recorded

before treatment, immediately after and
at 25, 35, and 45 min

No significant effect upon RIII/H-reflexes

13

Duration=15 min
TENS1: 2 Hz, 40 mA, TENS2: 100
Hz, 20 mA, Manual Acupuncture
(MA): 15 min, Control

Record

24

TENS1: 100 Hz, 0.1 msec, 2 mA

TENS2 3 Hz, 2 msec, 20 mA
PEC, Sham PEC

RIII-reflex recorded at biceps femoris

(90-180 ms)

TENS1: short term inhibition of RIII (p<0.0001)

TENS2: facilitatory effect (p<0.0001) followed by
inhibition (p<0.0001), application of PEC
produced long-lasting effects. Application of sham
PEC did not result in any significant change on the
RIII-reflex

20

Duration=30 min. TENS: 100 Hz,

0.2 ms, intensity below visible muscle
contraction.
Complete SCI (n=12). Incomplete SCI
(n=8)

RIII-reflex (early and late components)

from tibialis anterior was recorded
during treatment, and 30 minutes post

Early component decreased in all incomplete SCI

(8/8), and on 5 complete SCI (5/12). Late
component decreased more rapidly and
significantly immediately (p<0.01) and 30 minutes
after (p<0.01)

79

Table 2.1

Gregoric, 1998

Species

Chapter 2: Summary of the effects of electrical stimulation upon the H-reflex, RIII-reflex

References

References

Goulet et al., 1994

Sandrini, et al., 1992

Species

Human

Human

Group/Stimulation
Parameters

Record

Results

11

Duration=30 min
TENS1: 99 Hz, 250 s; TENS2: 50
Hz, 250 s intensity @ slightest
perceived sensation

H-reflex of SN, CPN, pre, during

and post TENS

Tendency towards inhibition of the H-reflex in

63% of the subjects after TENS1 over the
CPN, and in 50% after TENS 2 over SN

Duration=20 min, n=5, TENS: 100

Hz, 125 s, intensity equals 2 x
sensory threshold
Stimulation of the tibialis nerve was
applied using a rectangular pulses
of 1ms duration, and a frequency of
0.2 Hz

RIII and H-reflex over soleus

muscle and biceps femoris. Records
were taken prior to TENS, at the 10th
and 20th minute of TENS, and 10
min after TENS

Significant increase in vibratory inhibition of

Hmax/2, no significant change for
Hmax/Mmax, and reduction in RIII-reflex area
during and after TENS

RIII-reflex over the short head of the

ipsilateral biceps femoris. Responses
were analysed over 150 msec
(either, within a 80-230 msec or a
50-200 msec window)

RIII-reflex suppressed or depressed in 52.4%

(11/21); 9/DCS and 2/TENS; 9 did not exhibit
any significant modification, in 1 showed an
increase of RIII-reflex

As Garcia-Larrea et al., 1989

Garcia-Larrea et al.,
1989

Human

21

Bipolar Dorsal Column Stimulation

n=16, TENS n=5
Neurostimulation time ??
Sural nerve stim: 1ms, square
pulses at 500 Hz, 3/5 pulses per
train, 1.5 x T (up to 60 mA)

Garcia-Larrea et al.,
1990

Human

45

As Garcia-Larrea et al., 1989.

Groups: Epidural SCS n=38,
TENS n=6; Thalamic n=1

80

52% significant decrease or abolished flexion

response. 5% RIII increased response. In 17
cases no changes

Table 2.1 (continued)

References

Sjlund, 1988

Chan and
Tsang, 1987

Species

Rat

Human

Group/Stimulation
Parameters

114

Duration=30 min
TENS: 100 Hz (internal frequency) of 8 and
16 pulse duration, train repetition rates of 1
and 5 Hz Intensities=2xT and 10xT
Plantar and Sural nerves were stimulated with
monophasic square pulses of 150 500 msec
duration and an intensity less than 20 A

RIII-reflex of sciatic and

common peroneal nerve

11

Duration=30 min
TENS: 100 Hz, 1 ms, n=9
intensity developed a subjective tingling
sensation. Placebo group n=2
Stimulation electrodes placed over the
median arch of foot, proximal to the ankle,
200 Hz train, 6 x 1msec, 30msec

RIII-reflex (Flexion Reflex)

@motor points of biceps
femoris, tibialis anterior and hip
flexors prior to, during and 50
min after the application of
TENS
RIII and H-reflex over soleus
muscle and biceps femoris.
Records were taken prior to
TENS, at the 10th and 20th
minute of TENS, and 10 min
after TENS

STT cells activity, peripheral

nerve conduction

Sandrini et al.,
1992

Human

Duration=20 min, n=5, TENS: 100 Hz, 125

s, intensity equals 2 x sensory threshold
Stimulation of the tibialis nerve was applied
using a rectangular pulses of
1 ms duration, and a frequency of
0.2 Hz

Lee et al., 1985

Monkey

Duration=5 min, TENS: 85 Hz and low-rate

comfort bursts (3 burst/sec, 7 pulses/burst,
internal frequency 85 Hz), 80 s

Record

81

Results
A long-latency discharge was evoked in the common
peroneal nerve at a stimulation strength recruiting Cfibres in the ispsilateral plantar nerve. Skin-nerve
stimulation produced little or no suppression of the
nociceptor reflex, whereas muscle nerve at identical
parameters produced a clear suppression reflex

TENS caused a significant inhibition on the RIII-reflex.

Placebo TENS showed no significant effect on
RIII-reflex

Significant increase in vibratory inhibition of Hmax/2, no

significant change for Hmax/Mmax, and reduction in
RIII-reflex area, during and after TENS

Some degree of inhibition of C-fibre response, only when

intensity exceeded the threshold of A fibres. No changes
in latencies or amplitudes of the C-fibres volleys

Table 2.1 (continued)

References

Sjlund, 1985

Species

Rat

Group/Stimulation
Parameters

82

Duration=30 min
TENS: 10, 40, 60, 80, 100, 120
and 160 Hz
Plantar and Sural nerves were stimulated
with monophasic square pulses of 150500 msec duration and an intensity less
than 20 A

RIII-reflex on sciatic and common

peroneal nerve

RIII-reflex and plasma -lipotropin,

-endorphin, Adeno corticotropic
hormone

TENS 85 Hz: RIII threshold peaked @ 30 min, plasma lipotropin peaked @ 20min (r=0.856, p<0.001)
TENS 0.5 Hz: no changes were recorded, less positive
correlation between RIII and -endorphin (r=0.574,
p<0.05)

Record

Results
C-fiber-evoked flexion reflex is susceptible to a 30min
conditioning, The reflex depression elicited as a pattern
similar to pain relief seen after TENS in man. It indicates
a temporary decrease of the transmission from C-fibres to
second-order neurons in the spinal cord

Human

12

Boureau et al.,
1981

Human

DCS (??), n=8, sural nerve was

stimulated with 300 Hz and a 20 ms
trains

RII, RIII and H-reflex were recorded

from biceps femoris (RII 50-70 msec
latency; RIII 90-150 msec latency)

Significant inhibition of H-reflex (34%), inhibition of

RIII, facilitation of RII reflex, only during DCS
stimulation

Duration=40 min
TENS: 50 Hz, 100 s, n=65
(40 healthy subjects and 25 patients
suffering from chronic myofascial pain)

Group 1 (n=7), every 5 min a

recruitment curve of the H-reflex was
obtained. Tests were carried out 20
min before TENS, during TENS, and
35 min after TENS.
Group2 (n=58), sequential T and Hreflexes and cutaneous pain threshold
were studied, measurements taken 10
min before TENS, during TENS (24
min) and 25 min after TENS

In the healthy subjects group, no significant differences

were observed. In the pathological subjects group, when
the pain threshold before TENS was low, TENS induced
an inhibition both on afferent and efferent side. When the
pain threshold was high before TENS, the main effect
was a facilitation on both sides

Francini et al.,
1981

Human

65

82

Table 2.1 (continued)

Facchinetti et al.,
1984

Duration=30 min
TENS1: 85 Hz, 80 s, n=6
TENS2: 0.5 Hz, 80 s, n=6
intensity induced a well tolerated
tingling sensation
Sural nerve was stimulated with 10 x T
1 ms, 20 ms train, 300 Hz

References

Walsh et al.,
1998

Garrison and
Foreman, 1997

Human

Cat

Human

Group/Stimulation Parameters

Record

Results

83

Duration=20 min
TENS1: 100 Hz, 100 s
TENS2: 4 Hz, 100 s
Intensity between 15 and 25 mA

Activity on LT, HT and WDR of

dorsal horn neurons. Recordings were
taken before and 3 hours after
induction of inflammation, and
immediately, and 1 hour after TENS

TENS (either100 Hz or 4 Hz) reduced both

innocuous and noxious responses of WDR
and HT dorsal horn neurons immediately and
1 hour after the application of TENS

50

Duration=15 min
TENS1: 110 Hz, 200 s, n=10
TENS2: 110 Hz, 50 s, n=10
TENS3: 4 Hz, 50 s, n=10
TENS4: 4 Hz, 200 s, n=10
Control n=10
Intensity strong but comfortable

CAPs in the SRN (before TENS, and

after each of the three consecutive
5 min TENS applications, and then at
25, 45 and 60 min), and MPT

TENS at 110 Hz and 200 s increased NPL

and TT (p=0.01)

16

Duration=5-8.5 min
TENS: 5-125 Hz, 100 s
intensity 5-60 mA

Spontaneous and noxiously evoked

dorsal horn cell activity. Action
potentials were averaged before,
during and immediately after TENS

TENS application decreased spontaneous or

noxious evoked activity for a prolonged
time(p0.05). Post-Tens application cell
activity was not statistically different from
pre-TENS (p0.05)

48

Duration=15 min
TENS1: 110 Hz, 200 s, n=8
TENS2: 110 Hz, 50 s, n=8
TENS3: 4 Hz, 50 s, n=8
TENS4: 4 Hz, 200 s, n=8
Control n=8
Placebo n=8
Intensity strong but comfortable

MPT on the first dorsal web space

Control values showed a decrease in MPT

over time (p=0.0001) and a significant
interactive effect (p=0.0333). Significant
differences between groups at the 15 min
point (one factor ANOVA, p=0.042)

Table 2.2

83

Microneurographic and SEPs

Walsh et al.,
1995

Rat

Chapter 2: Summary of the effects of electrical stimulation upon the NCV,

Ma and Sluka,
2001

Species

References

Walsh et al.,
1995

Garrison, 1994

Levin and HuiChan, 1993

Species

Human

Cat

Human

Group/Stimulation
Parameters

Record

40

Duration=15 min
TENS1: 110 Hz, 200 s, n=8
TENS2: 110 Hz, 50 s, n=8
TENS3: 4 Hz, 50 s, n=8
TENS4: 4 Hz, 20 s, n=8
Control n=8
Intensity strong but comfortable

CAP of SRN, taken before TENS, and

immediately after each period of
stimulation (i.e., 5, 10 and 15 min)

TENS1 showed the greatest increase in latency.

Post hoc Scheff and Fishers test showed a
significant increase in NPL in the TENS1 group
compared with others at the 10 and 15 min point

14

Duration=20-30 sec
TENS1: 5-45 Hz, 100 s,
intensity=50-60 mA
TENS2: 50-125 Hz, 100 s,
intensity=5-40 mA

Extracelular recordings from 83

spontaneously discharging neurons
WDR and HT. Recordings were taken
prior to TENS (baseline), and during
the application of TENS

Spontaneous cell activity decreased in 65% of the

cells, 30% did not respond, and 5% increased
activity

17

Duration=??
conventional TENS and acupuncturelike TENS (internal freq.=100 Hz and
delivery freq.=4 Hz), intensity
@maximal pain tolerance (3xT)

CAP of median nerve

No significant differences in NCV between groups.

The results showed that both conventional and
acupuncture resulted in the excitation of mainly
large-diameter A, A fibres

Ulnar motor nerve conduction. Records

taken 1 min before treatment, and
immediately 1, 3 and 5min posttreatment

No significant differences between groups

Median sensory NCV

Significant decrease in NCV post-TENS

(p=0.003), as well as on skin temperature
(p<0.001)

Cox et al., 1993

Human

31

Duration=20 min
TENS1: 2 Hz, 250 s,
intensity=24.4 mA
TENS2: 100 Hz, 85 s,
intensity=26.7 mA, Placebo

Walmsley et al.,
1986

Human

12

Duration=30 min
TENS: 100 Hz, 100 s, intensity mild
tingling sensation

84

Results

Table 2.2 (continued)

References

Ashton et al.,
1984

Ignelzi et al.,
1981

Species

Human

Cat

Group/Stimulation
Parameters

Record

Results

32

Duration=15 min
TENS: 100 Hz, 200 s,
intensity strong but comfortable

SEPs

TENS showed a significant effect on the

amplitude (p<0.0001), latency and total
excursion of the late components of SEP
(p<0.001)

17

Duration=5-30 min
Frequency: 6-200 Hz, 200 s
intensity=0-12 mA

Activity of neurons of the spinal cord

dorsal horn and single fibres of the dorsal
column

5% of the spinal cord units showed

facilitated discharge, 46% inhibited or
depressed discharge, 36% no change, and
13% showed equivocal responses

Action potentials from median, ulnar and

radial nerves.

Peripheral contribution to the analgesic

effects of TENS seems to be unimportant.

SEPs

TENS decreased early and late components

of SEPs

Janko and
Trontelj, 1980

Human

Duration=??
Frequency: 0.2-100 Hz, 3-30 ms
triangular and rectangular pulses
motor intensity

Golding et al.,
1986

Human

26

Duration=15 min
TENS: 100 Hz, 200 s
intensity strong but comfortable

Table 2.3 (continued)

85

Species

Group/Stimulation
Parameters

Outcome Measures

Record

Lambert et al.,
2002

Human

30

Active and Placebo Acustat. Strong

negative electrostatic, 20 A

MPT, IPT, biceps diameter, RANG,

CK activity

Acustat group: Decreased pain, muscle function

unchanged, Plasma CK lower compared to
placebo group

Allen et al.,
1999

Human

18

MENS: 30 Hz, 200 A for 10 min,

then 0.3 Hz, 100 A for 10 min
Placebo group

VAS, MPT, ROM

No significant differences between groups

Nussbaum and
Gabison, 1998

Human

30

300 Hz, 100 s, 160 A, 15 min

placebo group

VAS, PPT, PT

No significant differences between groups

Pain, Serum Cortisol

Decrease of pain in both groups, no changes in

cortisol release in both groups

Schmitz et al.,
1997

Human

10

IFT1: 10 Hz, 10 s
IFT2: 100 s
Duration=30 min,
Carrier Frequency 5000 Hz

Butterfield et
al., 1997

Human

28

HVPC: 125 Hz, Duration=30 min,

Placebo group

VAS, ROM

No significant differences between groups

VAS, MPQ, MPT, RANG, FANG,

EANG

No significant differences between groups

Pain, IPT

No significant differences between groups

Craig et al.,
1996

Human

48

TENS1: 4 Hz, 200 s

TENS2: 110 Hz, 200 s
Control, Placebo
Duration=20 min.

Weber et al.,
1994

Human

40

MENS: 0.3 Hz, 0.5 sec slope, 30 A

Duration=8 min, Massage, UBE,
Control

Table 2.4

DOMS

86

Chapter 2: Summary of studies investigating the effects of electrical stimulation upon

References

References
Species

Group/Stimulation
Parameters

Outcome Measures

Record

Pain; ROM; Concentric and Eccentric

Peak Torque

Ice treatments increased significantly ROM

(p<0.05); Stretching treatments decreased pain
significantly (p<0.05)

Human

40

Denegar et al.,
1989

Human

TENS: 2 Hz, 300 s

Duration=30 min

Pain, ROM, Serum Cortisol

Decreased pain (p<0.05); Increased ROM

(p<0.05); No changes on cortisol concentrations

Denegar et al.,
1992

Human

16

LVMAS: 3 Hz, 100 A

VAS, ROM, Muscle Strenght

No significan t differences between groups.

LVMAS provided a transient analgesic effect 24
and 48 hours following exercise

Nussbaum and
Gabison, 1998

Human

30

Rebox: 300 Hz, 100 s, 160 A, 15

min, placebo group.

VAS, PPT, PT

No significant differences between groups

Denegar and
Huff, 1988

Human

24

TENS1: 80 Hz, 90 s
TENS2: 2 Hz, 200 s
Duration=30 min.

Pain, ROM

No significant differences between groups

87

Table 2.4 (continued)

Denegar and
Perrin, 1992

TENS: 90 Hz, 90 s, 20 min, tingling

sensation
Sham TENS: 2 Hz, 20 s, 20 min, 110
mA, 99sec On/1sec Off; TENS+ICE;
ICE; Control

Group/Stimulation
Parameters

Outcome Measures

Results

Roscoe et al.,
2002

Human

27

Active acustimulation of the PC6 point

Vs Sham acustimulation

Severity of nausea, quantity of

antiemetic medication used

The efficacy of the acustimulation for the

control of chemotherapy-induced nausea and
vomiting are positive but not conclusive

Tan et al., 2001

Human

25

PC6 stimulation with TENS at 4 Hz;

TENS+Ondansetron; Ondansetron

Patient self report of nausea and

vomiting.

TENS plus ondansetron provided significant

benefit in preventing nausea and emetic
attacks caused by cisplatin.

Number of emesis episodes

Electroacupuncture group performed better

(p<0.001); differences among groups were not
significant during the 9-day follow-up period
(p=0.18)

Human

104

ES: 2-10 Hz, 0.5-0.7 ms, 26 mA

Duration=20 min

Dibble et al.,
2000

Human

17

Usual care, Usual care+Finger

acupressure at PC6 and ST36 acupoints
Duration=3 min each morning.

Nausea, vomiting and retching

Significant differences between the groups for

the occurrence of nausea (p<0.01) and nausea
intensity (p<0.04)

McMillan et al.,
1991

Human

16

Electroacupunture PC6: 10-15 Hz

Duration=5 min

Nausea and Vomiting

Electroacupuncture enhanced the antiemetic

effect of ondansetron (p=0.0005)

Price et al.,
1991

Human

38

Acupressure PC6; Acupressure

dummy point

Nausea, sickness, mood, overall

condition
Self-completion questionnaires

Acupressure at PC6 was significantly better in

all the variables measured (p<0.02) when
compared to other group

88

Table 2.5

Shen et al.,
2000

Chapter 2: Summary of the studies on the effects of stimulation of the PC6 acupoint in the

Species

management of nausea and emesis induced by chemotherapy

References

References

Species

Group/Stimulation
Parameters

Outcome Measures

Record

Shaoxiang et
al., 1991

Human

206

Magnetotherapy n=161
Non-magnetotherapy n=23
Compression n=22

Three point scale: markedly effective,

effective, ineffective

Magneto-therapy group was more effective

compared to other groups (p<0.001)

26

Manual acupuncture +
Metoclopramide + Dexamethasone +
Dyphenhydramine

Number and duration of vomiting

episodes + intensity and duration of
nausea
Time points: 2, 4, 6, 8 and 24 h after
chemotherapy

No difference between groups in concerning

the complete protection of nausea and
vomiting. Duration of nausea and vomiting
were reduced by the addition of acupuncture

4 point Likert-type scale

97% of the Inpatients referred benefit; 90%

of the Outpatients referred benefit. In 95%
of the patients the antiemetic action was
maintained for 24 hours

Aglietti et al.,
1990

Human

Human

40

Stannard, 1989

Human

18

Acupressure PC6 acupoint.

Number of episodes of vomiting,

usage of antiemetic drugs

Vomiting was reduced as well as the amount

of antiemetic drugs used.

130

Shackman JS863-4 ACP: 10 Hz

Duration=5 min
Placebo n=10
Open Pilot (ES) n=15
Active ES=105

4 point Likert-type scale

Sickness completely absent or reduced in

97% of patients

Dundee et al.,
1989

Human

89

Table 2.5 (continued)

Dundee and
Yang, 1990

Electro acupuncture: 10 Hz, 250 s

Duration=5 min every 2 hours
Sea Band=5 min every 2 hours
Inpatients n=20
Outpatients n=20

References

Dundee et al.,
1987

Species

Human

Group/Stimulation
Parameters

Outcome Measures

Record

10

DC stimulator
10 Hz, 250 s, Duration=5 min
P6 group n=5
Dummy point n=5

4 point Likert-type scale

P6 group significantly better (p<0.001) than

Dummy point

Table 2.5 (continued)

90

Chapter 3
Effects of Interferential Therapy (IFT) upon Delayed Onset Muscle
Soreness (DOMS) in Humans

91

Abstract
Interferential therapy (IFT) is a popular modality used primarily for the management
of pain. IFT comprises the application of two medium frequency currents in the
kilohertz range to produce a low frequency current (<250 Hz) within the tissues.
However, to date there is a lack of published research which has examined the
analgesic mechanism(s) of IFT or indeed its effectiveness. The current study therefore,
was designed to compare the hypoalgesic effects of IFT upon an experimental pain
model: Delayed Onset Muscle Soreness (DOMS). DOMS is a common form of
myogenic pain that occurs after eccentric or novel exercise. Following ethical
approval, forty healthy IFT naive subjects (20M:20F) were recruited and randomly
allocated in equal numbers to the following groups: Control, Placebo, IFT1 (10-20
Hz), IFT2 (80-100 Hz). The induction protocol for DOMS involved the non-dominant
arm. Each subjects concentric 1 Repetition Maximum (RM) was determined for the
elbow flexors using free weights. DOMS was induced by a series of eccentric
contractions using the subjects 1 RM until there was no voluntary control of descent
of the free weight. This was completed only on day one. Measurements of Peak
Torque (90 and 60), Resting Angle, Mechanical Pain Threshold, Visual Analogue
Scale and McGill Pain Questionnaire were taken at set time points (i.e. pre-induction
on day one, pre- and post-treatment on each subsequent day). Treatment was applied
for 30 minutes each day for a period of 5 days, using two electrodes attached to the
skin overlying the biceps muscle. Pulse duration was standardised at 125 s in all
treatment groups. Data were statistically analysed using parametric and non-

92

parametric tests where appropriate. Statistical analysis of difference scores (i.e. the
difference from pre-induction baseline values) demonstrated that there was no
significant variation between groups for any of the measurements, with the exception
of a significant interactive effect (ANOVA: p=0.02) for Resting Angle. One factor
analysis of variance failed to demonstrate significance at any of the time points. The
Kruskal-Wallis test for daily analysis of the treatment, showed a significant difference
between groups for Peak Torque at 60 (Day 1, p=0.04; Day 2, p=0.003) and 90 (Day
1, p=0.01), and VAS measurements at extension (Day 2, p=0.04), and point 2 (Day 3,
p=0.01). A trend was identified over the duration of the study for MPT in the IFT1
(10-10 Hz) group. However, these results suggest that the application of interferential
therapy at the parameters used in this study had no overall beneficial effect upon the
physiological correlates of delayed onset muscle soreness.

93

3.1 Introduction
Muscle soreness that has a delayed onset is a common feature among both athletes and
untrained individuals who engage in unusual exercise (Fridn et al., 1983; Armstrong
et al., 1991; Craig et al., 1996, Nosaka and Newtown, 2002). Prolonged or vigorous
forms of exercise can act as a source of several types of muscle pain.

Delayed onset muscle soreness (DOMS) is a peculiar type of pain that is characterised
as a dull aching pain combined with tenderness and stiffness (Armstrong, 1984; Jones
et al., 1986).

DOMS is experienced as a response to motion or palpation, presenting a gradual onset

in the first 24 to 48 hours after exercise, reaching a maximum intensity between 24
and 72 hours and then subsiding; usually it is no longer felt after 5-7 days (Hasson et
al., 1990; Br et al., 1997). The tenderness is often localised in the region of the distal
myotendinous junction, but it can also be generalised throughout the muscle
(Armstrong, 1984). It is well reported that DOMS is particularly severe when induced
by eccentric exercise, also known as negative work (Armstrong, 1990; Armstrong et
al., 1991; Miles and Clarkson, 1994; Schmitz et al., 1997).

Several different theories have been proposed to explain DOMS, although, despite the
amount of research, the underlying mechanisms of this phenomenon are not fully
understood (Jones et al., 1986; Ciccone et al., 1991; Craig et al., 1999). Irrespective of

94

the aetiology, damage to any type of tissue results in some form of inflammatory
response, with the resulting cascade of events that are associated with it (Craig et al.,
1999). Therefore DOMS, with all the cytoskeletal structural changes as well as
changes in the transport characteristics of the sarcolema, fits into an inflammatory
frame as evidenced by the infiltration of monocytes to macrophages, and an increasing
number of mast cells and histocytes within and around the muscle cell (Armstrong et
al., 1983; Jones et al., 1986; Hasson et al., 1990; Br et al., 1997). This inflammatory
response promotes the formation of oedema leading to the production and release of
algogen substances such as kinins, histamine, serotonin, prostaglandins and substance
P (Armstrong, 1984; Mannheimer and Lampe, 1984) that will trigger a painful
response by sensitising type III and IV pain afferents (Br et al. 1997).

Exercise for which a skeletal muscle is not adequately conditioned results in

significant injury spread within and among the fibers (Armstrong et al., 1991). Two
hypotheses (metabolic or physical) have been proposed to describe damage to skeletal
muscle as a consequence of exercise (Ebbeling and Clarkson, 1989; Armstrong et al.,
1991). The first hypothesis relates to a metabolic overload, in which the demand for
ATP exceeds its production, originating a vicious cycle of Ca+ overloading of the cell
and a further decrease in ATP production (Br et al. 1997). Some experiments
maintain the metabolic hypothesis, such as the similarity of exercise-induced muscle
damage to ischaemic damage (Armstrong, 1986; Hoppeler, 1986).

95

The fact that strenuous eccentric exercise causes an alteration of the muscles
homeostasis, inducing wide morphological damage and a great increase in creatine
kinase (CK) activity, concurrently with pain, stiffness and weakness (Jones et al.,
1986; Cleak and Eston, 1992; Fridn and Lieber, 1992; Br et al., 1997) offers support
to the second hypothesis that mechanical factors are a cause of exercise-induced
damage (Newham, 1988; Armstrong et al., 1991). Although the metabolic cost is low
in eccentric contractions, the mechanical strain per muscle fibre is high as few fibers
are recruited (Br et al., 1997). Also disorganization of the myofibrillar material,
particularly that of the Z bands as well as the sarcolemma, have been observed after
eccentric exercise (Fridn et al., 1983; Armstrong et al., 1983; Armstrong et al., 1991;
Fridn and Lieber, 1992) and may be a sign of mechanical damage resulting from
excessive forces on muscle fibres.

Various researchers have investigated a multitude of treatments in an effort to

decrease the consequences of DOMS. The approaches used range from
pharmacological to non-pharmacological interventions, and have been focused into
two main vectors that seem to be closely related to DOMS: the inflammatory process
or oedema resultant from tissue damage; and/or breaking up the pain-spasm cycle.
Headley et al. (1985) investigated the effects of prednisolone (a steroidal antiinflammatory agent) in human subjects using a double-blind crossover methodology
and found no significant differences in either pain scores or creatine kinase (CK)
levels between the experimental and placebo groups. In contrast, Hill and Richardson

96

(1989) conducted a double-blind trial that investigated the effect of a non-steroidal

anti-inflammatory drug (NSAID); a 10% triethanolamine salycilate cream. The
authors found a significant difference in DOMS on days 3, 4 and 5 following exercise
that produced soreness. This double blind trial included a placebo group and was
carried out on a large number of subjects. More recently a randomised, double-blind,
placebo-controlled trial, investigated the effects of Naproxen, an NSAID drug on
muscle soreness, plasma CK activity and muscle strength (Lecomte et al., 1998). The
authors concluded that Naproxen did not prevent the CK release into the plasma, but
diminished the feeling of muscle soreness and increased quadriceps peak torque.

Although the pathophysiology of DOMS remains unknown, several clinical

approaches have been proposed. The effect of non-pharmacological interventions
upon the signs and symptoms of DOMS namely those that include electrotherapeutic
modalities have been investigated. However, the results seem to be contradictory
raising doubts towards the effectiveness of such modalities (Cleak and Eston, 1992;
Craig et al., 1999).

IFT is a form of electrical stimulation that was developed in Europe during the 1950s.
A typical IFT unit is characterised as a two-channel stimulator delivering sinusoidal,
symmetrical, alternating currents. It comprises the application of two medium
frequency currents in the kilohertz range to produce a low frequency current (<250
Hz) within the tissues (Ganne, 1976; Griffin and Karselis, 1988; Nelson and Courrier,

97

1987). Proponents of this form of electrical stimulation claim that the current delivered
by one channel interacts with the current produced by the second channel, originating
a net ionic movement different from that produced by either channel alone (Robinson
and Snyder-Mackler, 1995).

Schmitz et al. (1997) investigated the effect of IFT on perceived pain and serum
cortisol associated with DOMS in 10 healthy subjects. Current was delivered using a
carrier frequency of 5 kHz, with a beat frequency of 10 Hz or 100 Hz and pulse
duration of 100 s. Four electrodes were used to deliver the current, and treatment
lasted for 30 minutes. The results showed a decrease on pain scores across time in
both treatment protocols, but perceived pain levels did not differ significantly between
treatment groups. The authors also found no significant difference in serum cortisol
for the two groups and concluded that pain control was accomplished regardless of the
IFT protocol.

Although IFT is a popular modality amongst clinicians in the management of painful

conditions (Stephenson and Johnson, 1995; Robertson and Spurrit, 1998), there is a
lack of published research which has examined the analgesic mechanism(s) of IFT or
indeed its effectiveness (Stephenson and Johnson, 1995; Johnson and Wilson, 1997;
Ward and Robertson, 1998). The use of IFT in clinical practice has been justified by
the physiological rationale which underpins its proposed action. Physiotherapists
believe that the amplitude modulated frequency is the principal actor of IFT and

98

they argue that the amplitude wave mediates physiological effects by selectively
activating excitable tissue in deep-located structures. The mechanisms by which this
takes place are doubtful (Johnson, 1999).

This investigation represents an attempt to contribute to the clarification of the role of

the relative analgesic effects across two different frequencies in the management of
DOMS.

3.2 Aim
The aim of this investigation was to compare the analgesic effects of IFT at two
different frequencies using delayed onset muscle soreness as an experimental pain
model.

3.3 Methodology
Following approval from the University of Ulsters Research Ethical Committee, forty
healthy IFT nave volunteers (n=40; 20 male and 20 female; average age 240.74
years) were recruited from staff and students of the University, and screened for
medical history or current signs/symptoms, including current pain and trauma, current
medication, cardiovascular problems or diabetes mellitus. Anyone who participated in
weight or upper body training was also excluded from the study.

99

The experimental procedure and purpose of the experiment was explained to subjects,
who were then asked to sign a consent form (Appendix I) and were randomly assigned
in equal numbers to one of four experimental groups: Control; Placebo; IFT1 (10 to 20
Hz) or IFT2 (80 to 100 Hz). Subjects were required to attend on a daily basis over five
days at the same time every day. On day one, delayed onset muscle soreness was
induced via a series of eccentric exercises. On days one to five, subjects were assessed
and treatment was applied.

3.4 Induction Protocol

The non-dominant arm of each subject was used in this study. Subjects in all groups
were seated at a preachers bench to ensure their shoulder was flexed to a 45 angle
(see Fig. 3.1). Once comfortably seated, the subjects concentric 1 repetition
maximum (RM) was determined for the elbow flexors using weights placed on a
dumb bell in increments of 0.5 Kg. The subjects 1 RM free weight was then lifted by
the experimenter and the subject slowly lowered the weight to a count of three until
the elbow was fully extended. The experimenter then returned the weight back to the
vertical position to ensure that the subject did not perform any concentric contractions
using their biceps. Each subject then completed a series of eccentric exercises until
there was no voluntary control of the descent of the free weight throughout their full
range of movement. The average weight was 8.250.49 Kg and the average repetitions
were 38.081.35 (n=40 subjects).

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3.5 Measurement of the Variables

Resting Angle (RANG); Mechanical Pain Threshold (MPT); Isometric Peak Torque
(IPT) and Pain, were used as a correlate of DOMS and were measured at the same
time points. Baseline measurements were established on day 1 where pre-/postinduction and post treatment measures were taken. On subsequent days (day 2, 3, 4
and 5) pre-/post treatment measures were recorded. To ensure double blinding, three
separate investigators carried out assessment, induction of DOMS, and treatments.

3.5.1 Resting Angle

Any increase in resting angle provides a correlate of muscle shortening due to muscle
damage as a result of eccentric exercise induction procedures (Clarkson et al., 1992;
Rodenburg et al., 1993). Resting angle was measured using a universal goniometer
(Zimmer, Bridgend, Mid Glam, United Kingdom). In order to perform the
measurements, subjects were asked to stand with their hands in a supinated position
with their shoulders in 0 flexion. To standardise measurement procedures, points
were marked on the lateral epicondyle of the humerus, greater tubercule of the
humerus and on the mid point of the lateral border of the distal radius. Resting angle
was measured with the subjects standing with their forearm supinated and their arm
resting by their side.

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3.5.2 Mechanical Pain Threshold (MPT)

Mechanical pain threshold (MPT) was measured for the same time points as resting
angle and was used as a correlate of tenderness. Measurements were taken over the
length of the biceps brachii. In order to standardise measurements, the insertion of the
biceps brachii into the radius and the intertubercular groove of the humerus were
marked. Using a ruler, 8 points were marked on the biceps brachii at 3 cm intervals
beginning at the insertion of the biceps (see Fig. 3.2). An electronic pressure
algometer with a 0.9 cm diameter head (Electronic Force Gauge, Salter, West
Bromwich, England) (see Fig 3.3) was used to apply a compressive force to each of
these points. This procedure was performed with the subjects instructed to say stop or
pain at the precise moment they felt the pressure turn into a painful sensation, i.e. the
mechanical pain threshold. If no pain was reported at 40 Newtons (N), this figure was
recorded and considered to be the maximal limit. To account for tenderness of the
musculotendinous area, the first four points were averaged. The mean of the recorded
MPT scores for all the 8 points was calculated to examine tenderness within the whole
muscle. Also an average of MPT scores recorded from points 3-6 was analysed to
examine the level of tenderness specifically in the muscle belly.

3.5.3 Isometric Peak Torque (IPT)

Measurements were obtained using a Biodex Isokinetic Dynamometer (Shirley,
New York, USA) (Fig. 3.4). At the beginning of each week the dynamometer was
calibrated before each measurement was recorded; in addition it was further calibrated

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for the effects of gravity upon the limb. The dynamometer was adjusted for each
subject with the backrest positioned at 15 from the vertical. Restraining straps around
the shoulders and waist secured the subjects in order to inhibit any accessory
movements that would interfere with the accuracy of the muscle strength movements.
Subjects shoulders were kept in 45 flexion by the positioning of the upper arm in the
support provided. The axis of the dynamometer was aligned using the lateral
epicondyle of the humerus, with the hand positioned according to comfort on the
handgrip. Measurements were obtained with the elbow flexed at 90 and 60 with a
rest period of 30 sec between each recording.

3.5.4 Visual Analogue Scale (VAS)

Visual analogue scale (VAS) measurements were obtained to assess the subjects level
of pain. The validity and reliability of this tool in measuring experimentally induced
pain have been established (Price et al., 1983), and it has been previously used to
measure exercise-induced muscle soreness by several authors (Ciccone et al., 1991;
Fitzgerald et al., 1991; Hill et al., 1998; Craig et al., 1999).

Measurements were taken pre and post treatment at 24-hour intervals over the 5 days
of the investigation. A computerised 10 cm line VAS was used1 with the anchors no
pain and max pain at either end. These scales were displayed randomly on the
screen at 30 sec intervals. Subjects used a mouse control attached to a computer (Atari
1

This software was written by Mr A. Gilmore, Technician, Faculty of Life and Health Sciences, University of Ulster at
Jordanstown

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1040 ST, Atari Corporation, Digital Research Inc.) to mark a point between the two
anchors that best reproduce the current pain intensity they felt. Each time the VAS was
displayed on the screen, the orientation of the marker and the position of the scale
were randomly allocated. Each presentation lasted for 30 seconds on the screen, or
until the subject had selected a point on the scale. At the end, VAS recordings were
digitally stored for subsequent measurement and analysis. Four separate aspects were
measured, with the average of 2 VAS calculated for each, i.e. VAS at rest, extension,
MPT point 2 and point 5. To obtain VAS at points 2 and 5, a force of 15 N was
applied for a total of 10 seconds.

3.5.5 McGill Pain Questionnaire (MPQ)

On days 1, 3 and 5, subjects were asked to complete the McGill Pain Questionnaire
(Melzack, 1975) (See Fig. 3.5). For this pain rating measurement, a collection of
descriptive words was orally presented to the subject. Subjects were instructed to
select one word (or more) from each group which best described the pain they felt.

3.6 Treatment Procedure

The treatment procedures were double-blinded; subjects did not know the type of
treatment they were receiving and a second investigator that was not involved in
obtaining measurements or DOMS induction applied the treatment. Once subjects

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were included in the investigation, they were randomly allocated in the following four
experimental groups:

(1) Control group no treatment applied.

(2) Placebo group no treatment applied (no current flowing through the output
leads).
(3) IFT1 group - Variable beat frequency between 10 and 20 Hz. Fixed pulse
duration of 125 s and a carrier frequency of 4000 Hz. Sweep duration ratio of
1:1
(4) IFT2 group - Variable beat frequency between 80 and 100 Hz. Fixed pulse
duration of 125 s and a carrier frequency of 4000 Hz. Sweep duration ratio of
1:1.

Subjects were also given a demonstration of the treatment they would receive. An
Endomed 582 interferential unit (Enraf Nonius, Netherlands) (see Fig 3.6) was used
in this study. Prior to the beginning of the investigation, the accuracy of the IFT unit
was verified using an oscilloscope (Gould Electronics, Essex, United Kingdom) (see
Fig 3.7). The interferential current was applied for 30 min via two-carbon rubber
electrodes (6 cm by 4 cm; Enraf Nonius, Netherlands) soaked in a saline solution and
positioned over the anterior aspect of the biceps brachii (see Fig. 3.8). The intensity of
the current applied to each subject was increased until they reported a strong but
comfortable sensation. To prevent the so called accommodation effect induced by

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electrical stimulation delivered at a constant rate, all subjects were asked to report if
the level of sensation decreased at set time intervals; if sensation had decreased, the
intensity was increased to return it to the original sensation. Subjects in the Control
group received no interferential current. For the Placebo condition, the IFT procedure
was identical to that in the active groups. However, no interferential current was
delivered via the two electrodes. Treatment was applied once a day over five
consecutive days.

3.7 Data Analysis

For the purpose of statistical analysis, difference scores (i.e. variation from the
baseline values) were calculated using pre-induction measurements as baseline for
Resting Angle, MPT, and IPT. Difference scores were calculated for VAS scores
using post-induction values as baseline; raw scores were used for analysis of MPQ
data. In addition, daily scores were computed to explore any transitory effect of IFT
upon the correlates of DOMS.

In order to select the appropriate statistical analysis (i.e. parametric or nonparametric), a Shapiro-Wilk test was performed. This statistic is calculated if the
sample size does not exceed 50, and indicates whether the raw data (pre-induction
only) is normally distributed or not (SPSS 9.0, l998). If data were normally distributed
parametric analysis were performed (ANOVA, Repeated Measures). If not, nonparametric analysis (Kruskal-Wallis and Mann-Whitney U tests) were carried out. For

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subjective data, such as VAS, MPT, MPQ and daily treatment difference scores, only
non-parametric analysis were performed.

3.8 Results
3.8.1 McGill Pain Questionnaire - Sensory Dimension
Raw data for the McGill Pain Questionnaire - Sensory Dimension, comprise items 1 to
10 that describe the sensory qualities of the experience in terms of temporal, spatial,
pressure, thermal and other properties. Data are presented in Appendix II and
summarised in Table 3.1. The sensory scores showed that there was a distinct increase
on day 3 for the Control group (8.52.01, means.e.m) followed by a decrease
towards baseline. The same pattern was observed for the IFT2 group (80-100 Hz)
(15.62.51, means.e.m), as well as for the Placebo group (12.22.19 means.e.m). In
the IFT1 group, a constant fall in scores was recorded from day 1 to day 3.

Figure 3.9 summarises the sensory rating of the MPQ expressed as difference scores
(means.e.m.) plotted against time in days for all experimental groups. The KruskalWallis test showed no significant differences between groups at any time points
(p0.06) (Table 3.2).

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3.8.2 McGill Pain Questionnaire - Affective Dimension

Raw data for McGill Pain Questionnaire - Affective Dimension (items 11 to 15), are
presented in Appendix III and summarised in Table 3.3. These items encompass words
that describe affective qualities in terms of tension, fear, and autonomic properties that
are part of the pain experience. Results show an increase in the scores for the IFT1
(10-20 Hz) on day 3 (1.10.48, means.e.m), decreasing slightly on day 5. For the
IFT2 group (80-100 Hz), a sharp increase on the values was recorded on day 3
(2.21.14, means.e.m) declining on day 5. A similar pattern was observed in the
Placebo group. This increase reached a peak on the 3rd day, (1.20.59, means.e.m)
and on the 5th day decreased close to the baseline values. The values for the Control
group remained reasonably constant for the first three days, falling significantly by the
5th day (0.20.13, means.e.m). Figure 3.10 summarises the affective rating of the
MPQ expressed as difference scores (means.e.m.) plotted against time in days for all
experimental groups. Kruskal-Wallis test also demonstrated no significant differences
between groups at any of the time points (p0.53) (Table 3.4).

3.8.3 McGill Pain Questionnaire - Evaluative Dimension

Raw data for the McGill Pain Questionnaire - Evaluative Dimension (item 16), is
presented in Appendix IV and summarised in Table 3.5. This section includes words
that describe the overall subjective intensity of the total pain experience. The results
revealed a notable rise in the IFT1 (10-20 Hz) group scores on day 3 (1.30.4,
means.e.m); by the 5th day the scores dropped substantially towards the baseline

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values (0.50.17, means.e.m). A similar scenario was observed in the Placebo group.
In the Control group, a steady increase was observed throughout the three days, and in
the IFT2 (80-100 Hz) group a slight increase was observed on day 3 (0.90.28,
means.e.m), with a small decrease recorded on the 5th day. Figure 3.11 summarises
the evaluative rating of the MPQ expressed as difference scores (means.e.m.) plotted
against time in days for all experimental groups. The Kruskal-Wallis test also
demonstrated no significant differences between groups at any of the time points
(p0.45) (Table 3.6).

3.8.4 McGill Pain Questionnaire - Miscellaneous Dimension

Raw data for the McGill Pain Questionnaire - Miscellaneous (items 17 to 20), are
presented in Appendix V and summarised in Table 3.7. The results showed a sharp
rise on day 3 for the Control group (2.80.77, means.e.m), decreasing substantially
by day 5 (1.20.57, means.e.m). The IFT1 (10-20 Hz) group showed a small
variation from baseline on day 3, decreasing substantially on day 5 (1.70.52,
means.e.m). A constant decrease throughout the experiment was recorded for the
IFT2 (80-100 Hz) group. Figure 3.12 summarises the miscellaneous rating of the MPQ
expressed as difference scores (means.e.m.) plotted against time in days for all
experimental groups. The Kruskal-Wallis test showed no significant differences
between groups at any of the time points (p0.06) (Table 3.8).

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3.8.5 McGill Pain Questionnaire - Pain Rating Index

Raw data for the McGill Pain Questionnaire - Pain Rating Index - are presented in
Appendix VI and summarised in Table 3.9. The Pain Rating Index showed a vast
increase on day 3 for all the groups, followed by a decrease that reached levels close to
the baseline values with the exception for IFT2 group values that remained stable.
Figure 3.13 summarises the pain rating index of the MPQ expressed as difference
scores (means.e.m.) plotted against time in days for all experimental groups. The
Kruskal-Wallis test showed no significant differences between groups at any of the
time points (p0.7) (Table 3.10).

3.8.6 McGill Pain Questionnaire - Present Pain Index

Raw data for the McGill Pain Questionnaire - Present Pain Index - are presented in
Appendix VII and summarised in Table 3.11. The Present Pain Index scores showed a
similar pattern for groups; IFT1, IFT2 and Placebo. In these groups a similar rise in
scores were recorded for the same time points (days 1, 3 and 5). In the Control group a
notable increase was recorded on day 3 (12.52.33, means.e.m) followed by a sharp
decrease that reached values below the baseline. Figure 3.14 summarises the present
pain index of the MPQ expressed as difference scores (means.e.m.) plotted against
time in days for all experimental groups. The Kruskal-Wallis test showed no
significant differences between groups at any of the time points (p0.2) (Table 3.12).

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3.8.7 Mechanical Pain Threshold - Points 1 to 8

Raw data for MPT points 1 to 8 are presented in Appendix VIII and summarised in
Table 3.13. MPT average values for points 1 to 8 represent the difference scores from
the baseline (pre-induction) and time points for each day. All the groups showed a
similar pattern, where a decrease in values was recorded until day 3 post-treatment,
followed by an increase towards baseline levels. Figure 3.15 summarises mean
mechanical pain threshold at points 1-8 expressed as difference scores (means.e.m.).
The positive values represent an increase in mechanical pain threshold, i.e. a
hypoalgesic effect.

The Kruskal-Wallis test demonstrated that there were no significant differences

between groups at any of the time points (p0.15) (Table 3.14). The daily differences
for treatment using the Kruskal-Wallis test also showed no significant differences
between groups (p0.07) (Table 3.15).

3.8.8 Mechanical Pain Threshold - Points 3 to 6

Raw data for the MPT points 3 to 6 are presented in Appendix IX and summarised in
Table 3.16. MPT average values for points 3 to 6 represent the difference scores
(means.e.m.) from the baseline (pre-induction) and time points for each day. Fig 3.16
summarises mean mechanical pain thresholds at points 3-6. The positive values
represent an increase in the mechanical pain threshold, i.e. a hypoalgesic effect. Again,
all the groups showed a similar pattern, where the values recorded decreased until day

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3 followed by an increase towards the baseline. However, the treatment groups

preformed better than the Placebo and the Control group.

The Kruskal-Wallis test demonstrated that there were no significant differences

between groups at any of the time points (p0.19) (Table 3.17). The daily differences
for treatment using the Kruskal-Wallis test also showed that there were no significant
differences between groups at any of the time points (p0.4) (Table 3.18).

3.8.9 Visual Analogue Scales (VAS)

Measurements were taken pre and post treatment and difference scores were
calculated using post-induction scores as baseline. The positive values represent an
increase in VAS, i.e. a hyperalgesic effect. Due to the subjective nature of the data
non-parametric analysis were performed on all sets.

3.8.10 VAS at Rest

Raw data for VAS at rest are presented in Appendix X and summarised in Table 3.19.
Statistical analysis of this data is provided in Tables 3.20 and 3.21. Fig 3.17
summarises VAS measurements with the arm at rest expressed as differences scores
(means.e.m.) plotted against time in days for all experimental groups.

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The values obtained for the Control group illustrated a decrease immediately after
treatment on day 1, followed by a subsequent increase until day 3 pre-treatment
followed by a decrease towards the baseline during the rest of the experimental period.
In the IFT1 group (10-20 Hz), a sharp increased was observed on day 2 pre-treatment,
followed by a decrease until day 3 post-treatment. On day 4 pre-treatment a sharp
increase in VAS was recorded followed by a decline towards the baseline for the
remainder of the experiment. The values for the IFT2 (80-100 Hz) showed a steady
increase until day 4 pre-treatment, which decreased until day 5 pre-treatment, rising
again on day 5 post-treatment. Placebo values showed several fluctuations, and then
decrease on day 3 pre-treatment throughout the rest of the experimental period.

The Kruskal-Wallis test demonstrated that there were no significant differences

between groups at any of the time points investigated (p0.36). The Kruskal-Wallis
test of daily treatments showed no significant differences between groups on any of
the days (p0.28).

3.8.11 VAS at Extension

Raw data for VAS at rest are presented in Appendix XI and summarised in Table 3.22.
Statistical analysis of these data is provided in Tables 3.23 and 3.24.

Fig 3.18 summarises VAS measurements, which were taken after the subject extended
their non-dominant arm for 10 seconds. Results are expressed as differences scores

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(means.e.m.) plotted against time in days for all experimental groups. Values
recorded for the Control group showed a decrease post-treatment on day 1. Values
increased significantly until day 3 pre-treatment, followed by a constant decrease
towards the baseline throughout the experimental period. The IFT1 group (10-20 Hz)
also showed a decrease after treatment on day 1. On day 2 pre-treatment, values
increased sharply, decreasing after treatment. This pattern was observed during the
whole course of the experiment, i.e. an increase of the pre-treatment values, and a
decrease post-treatment. In the IFT2 group (80-100 Hz), a steady increase of the
values was recorded until day 2 post-treatment followed by a fluctuation until the
remaining of the experiment. The values recorded for the Placebo group demonstrated
an increase until day 2 pre-treatment, followed by a subsequent oscillation throughout
the rest of the experimental period.

The Kruskal-Wallis test showed that there were no significant differences between
groups at any of the time points. However, daily difference scores using the KruskalWallis test demonstrated that there was a significant difference on day 2 (p=0.04).
Mann-Whitney U tests showed that the significant difference was between the IFT1
versus Control group (p=0.02) and IFT2 (p=0.01). Figure 3.19 and Table 3.25
summarise these results as box plots illustrating medians, interquartile ranges and 95%
confidence intervals.

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3.8.12 Visual Analogue Scale - Point 2

Raw data for VAS at point 2 are presented in appendix XII and summarized in Table
3.26. Figure 3.20 summarises VAS recorded with compression force of 15 N applied
for 10 seconds to MPT point 2. Results are expressed as difference scores
(means.e.m.) plotted against time in days for all experimental groups. The results
showed a similar pattern for all the groups, i.e. an increase pre-treatment followed by a
decrease post-treatment were observed. The results for the Control values show a
decrease post-treatment on day 1, followed by an abrupt increase on day 2 pretreatment, reaching its highest value on day 3 pre-treatment progressively decreasing
towards the baseline value until day 5 pre-treatment.

The Kruskal-Wallis test showed no significant differences between groups at any of

the time points (p0.18). The daily difference scores for treatment using the KruskalWallis test showed a significant difference between groups on day 3 (p=0.01). MannWhitney U test showed a significant difference between Control versus IFT2
(p=0.001) and Placebo (p=0.002). Figure 3.21 and Tables 3.27, 3.28 and 3.29
summarise these results as box plots illustrating medians, interquartile ranges and 95%
confidence intervals.

3.8.13 Visual Analogue Scale - Point 5

Raw data for VAS at rest are presented in appendix XIII and summarized in Table
3.30. Statistical analysis of this data is provided in Tables 3.31 and 3.32. Figure 3.22

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Summarises VAS recorded with compression force of 15 N applied for 10 seconds to

MPT point 5. Results are expressed as difference scores (means.e.m.) plotted against
time in days for all experimental groups. Control values showed a decrease on day 1
post-treatment, followed by a sharp rise on day 2 pre-treatment. Values slightly
decrease until day 3 post-treatment where a sharp rise was recorded, followed by a
constant decrease throughout the remainder of the experimental period. The IFT1 (1020 Hz) group showed an increase of the values until day 2 pre-treatment, with a fall on
day 2 post-treatment, followed by a steady increase that peaked on day 4 pretreatment. The values recorded then declined substantially for the rest of the
experimental period. For the IFT2 (80-100 Hz) a steady increase was observed until
day 2 post-treatment followed by a decrease on day 3 pre-treatment, and an increase
that peaked at day 4 post-treatment, followed by a decrease until the end of the
experimental period. The Placebo group showed a consistent increase in the values
until day 3 pre-treatment, which was accompanied by a continual decrease until the
end of the experimental period.

The Kruskal-Wallis test illustrated that there were no significant differences between
groups at any of the time points investigated (p0.44). The daily differences scores for
treatment using Kruskal-Wallis test also illustrated that there were no significant
differences between groups (p0.18).

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3.8.14 Resting Angle (RANG)

Raw data for RANG are presented in Appendix XIV and summarised in Table 3.33.
Statistical analysis of this data is detailed in Table 3.34 and 3.35. The values for
RANG represent the difference scores (means.e.m.) taken at pre-induction and post
treatment on days 2, 3, 4 and 5, and they are summarised in Figure 3.23. Positive
values indicate an increase in RANG and serve as an indicator of the extent of DOMS.
Values for the Control group showed an increase that peaked on day 3 pre-treatment
indicating a loss of function, followed by a decrease towards the baseline that
remained until the end of the experiment. In the IFT1 (10-20 Hz) group, a sharp
increase was recorded at post induction, followed by a decrease until day 2 posttreatment. Again, a rise in the values was observed which peaked on day 4 postreatment, decreasing on day 5 pre-treatment, rising again on day 5 post-treatment. In
the IFT2 (80-100 Hz) group, a similar trend to the IFT1 group was observed. The
values peaked at day 2 pre-treatment, showing a decrease until day 5 pre-treatment to
increase again on day 5 post-treatment. The values for the Placebo group showed a
similar oscillating pattern.

The Shapiro-Wilk test indicated that data were normally distributed, therefore
parametric tests were performed. Repeated measures analysis of variance (ANOVA)
demonstrated a significant interactive effect (p=0.02), and a significant difference over
time (p<0.0001), but no significant difference between groups (p=0.29). Further

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analysis using the Kruskal-Wallis test on daily treatment differences showed no

significant differences between groups (p0.08).

3.8.15 Isometric Peak Torque (IPT) at 60

Raw data for IPT at 60 are presented in Appendix XV and summarised in Table 3.36.
Statistical analysis of these data is provided in detail in Table 3.37. Figure 3.24
summarises IPT at 60 of flexion expressed as differences scores (means.e.m.)
plotted against time in days for all the experimental groups.

Isometric peak torque is a marker of muscle power. Any positive values in Figure 3.24
are representative of an increase in muscle power. There was a general trend observed
in all the groups that consisted in a fluctuation of scores. However, the IFT 1 group
and IFT2 group performed better than the Control and Placebo groups.

The Shapiro-Wilk test indicated that data were normally distributed, therefore
parametric analysis were performed. Repeated measures analysis of variance
(ANOVA) demonstrated no significant differences between groups (p=0.66) nor any
significant interactive effect (p=0.09). However, a significant effect over time
(p<0.0001) was observed. The daily difference scores for treatment using KruskalWallis test showed a significant difference on day 1 (p=0.04) and day 2 (p=0.003).
Mann-Whitney U test revealed a significant difference on day 1 between Control and
IFT1 (p=0.02) and IFT2 (p=0.01). Mann-Whitney U tests on data from day 2 showed

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a significant difference between the Placebo and all the other groups (p0.05). These
analyses are summarised as box plots illustrating median, interquartile ranges and 95%
confident intervals in Figures 3.25 and 3.26, and Tables 3.38, 3.39 and 3.40.

3.8.16 Isometric Peak Torque (IPT) at 90

Raw data for IPT at 90 are presented in Appendix XVI and summarised in Table
3.41. Statistical analysis of these data is provided in detail in Table 3.42, 3.43. Figure
3.27 summarises IPT at 90 of flexion expressed as differences scores (means.e.m.)
plotted against time in days for all the experimental groups.
IPT is a correlate of muscle power (Weber et al., 1994, Br et al., 1997). Any positive
value in Figure 3.27 denotes an increase in muscle strength. All the groups showed a
marked decrease for IPT following induction. The values for the Control group
increased from post-induction until day 2 pre-treatment, which decreased post
treatment, augmenting again on day 3 pre-treatment. This oscillating pattern
(increasing pre treatment and decreasing post-treatment) was maintained throughout
the experimental period. The values for the IFT1 (10-20 Hz) group showed a dramatic
decrease on day 1 post-induction until day 2 post-treatment. On day 3 pre-treatment a
sharp increase in values was recorded, with subsequent fluctuations until the end of
the experimental period. A similar pattern was recorded for the IFT2 (80-100 Hz)
group. The values for the Placebo group showed a constant decrease until day 2 posttreatment. On day 3 pre-treatment an increase in values was recorded, followed by a
decrease on day 3 post-treatment. On day 4 pre-treatment another increase in the

119

values was recorded. The values observed on subsequent days and until the end of the
experimental period increased towards the baseline values.

Repeated measures analysis of variance (ANOVA) showed a significant effect over

time (p<0.0001), but no significant difference between groups (p=0.87) nor an
interactive effect (p=0.91). The Kruskal-Wallis analysis of daily treatment differences
showed a significant difference in day 1 (p=0.01). Mann-Whitney U test revealed a
significant difference on day 1 between the Control and all the experimental groups
(p=0.006). This analysis is summarised as box plots illustrating medians, interquartile
ranges and 95% confidence intervals (Table 3.44, Fig 3.28).

3.9 Discussion
Exercise for which a skeletal muscle is not accustomed results in focal sites of injury
distributed within and among the fibres (Armstrong et al., 1991, Nosaka and Newton,
2002), particularly exercises with an eccentric component (OGrady et al., 1999,
Beaton et al., 2002). Evidence of damage after this type of exercise includes a decline
in performance, morphological/structural changes, elevation of molecular enzymes in
circulation namely creatine kinase (CK) and extensive inflammatory activity (Cleak
and Eston, 1992, Dolezal et al., 2000, OGrady et al., 2000).

As stated previously, DOMS has been described as a dull, aching pain combined with
tenderness, stiffness, and is by nature a multidimensional phenomenon where several

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physiological correlates such as range of motion (ROM), isometric peak torque (IPT)
muscle damage (biochemical markers), and pain measures have been used to assess
the aforementioned clinical condition (Br et al., 1997).

The present investigation used subjective pain assessment, mechanical pain threshold,
ROM and MVC, as indicators of the effectiveness of IFT upon functional impairment
and pain on experimentally induced DOMS in humans. Analysis of the results showed
that the application of IFT at the parameters used in this study had no overall
beneficial effect upon the physiological correlates of DOMS.

The results of the present investigation are in conflict with those of Denegar et al.
(1989), who reported that TENS treatment decreased perceived pain and increased
ROM at the elbow. Differences in the results reported may be explained however by
the different methodologies used in both studies. The Denegar study (1989), did not
include a control or placebo group, the sample size was very small (n=8) as well as the
probability of bias introduced by gender (females subjects only) since it is known that
the difference in Creatine Kinase (CK) release between sexes is remarkable; women
have a lower CK activity then man at rest (Meltzer, 1971) and show less CK efflux
after bicycle exercise (Shumate et al., 1979).

A reduction in the ability of muscle to generate force has been equated with the degree
of exercise-induced muscle damage (Warren et al., 1993). Maximal muscle power can

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be reduced by 50 per cent or more after damaging exercise (Br et al., 1997). It has
previously been reported that muscle strength reaches its lowest value immediately
after eccentric exercise and gradually recovers over 10 days (Clarkson et al., 1992).
This appears to be a consequence of a reduction in voluntary effort due to pain,
together with a decreased ability to generate intrinsic force (Byrd, 1992). These
findings are in agreement with the results of the current study; it can be seen that in the
data concerning daily treatment effect, there are significant differences between
groups for Peak Torque at 60 (Day 1, p=0.04; Day 2, p<0.003) and 90 (Day 1,
p=0.01) (see Tables 3.38 and 3.43), and VAS measurements at extension (Day 2,
p=0.04), and point 2 (Day 3, p=0.01) (see Tables 3.24 and 3.28).

Muscle shortening has been observed following eccentric exercise (Rodenburg et al.,
1993), suggesting an inverse relationship between pain and ROM. In an investigation
carried out by Denegar and Huff (1988), the authors compared two different
frequencies of TENS (80-100 Hz/High Frequency vs. 1-5 Hz/Low Frequency) in the
treatment of DOMS using ROM as a physiological correlate. The authors concluded
that the results of the study did not support the prediction that if pain perception
decreases, a concomitant increase in ROM would follow. In the current investigation,
the results also showed that that there were no significant differences between groups
concerning the hypothetical correlation between pain and ROM (see Fig 3.23).

122

As previously stated, two of the core signs and symptoms of DOMS are pain and
tenderness. The pain associated with DOMS is perhaps the most frequently described
phenomena, and has been investigated by several researchers since the beginning of
the century (Cleak and Eston, 1992). Pain related to DOMS is believed to be
associated with the stimulation of the small diameter A myelinated and C
unmyelinated nerve endings that supply specific as well as polymodal receptors found
in muscle tissue, namely in the musculotendinous junctions and fascial sheets (Casey
1982; Armstrong, 1984; Mense and Simons, 2001). Several noxious stimuli such as
chemical, thermal and mechanical mediators may induce pain. Although the specific
mediators involved in DOMS have not yet been identified, studies using electrical
stimulation have suggested at least some temporary decrease in pain and soreness
(Denegar et al., 1989; Denegar and Perrin, 1992; Weber et al., 1994; Schmitz et al.,
1997).

The relevance of parameter manipulation on pain thresholds has been acknowledged

in the literature (Walsh et al., 1995; Chakour et al., 2000; Chesterton et al., 2002). In
the present study two different frequencies were used (IFT1 10-20 Hz; IFT2 80-100
Hz). However, none proved to be effective in achieving hypoalgesic effect. These
contrast the results published by Denegar et al. (1989), Denegar and Perrin (1992),
and Schmitz et al. (1997). However, these studies did not include a placebo or a
control group and therefore the results are questionable. The findings of the present
study are compatible with previous research conducted at this centre, Craig et al

123

(1996) reported that neither low frequency TENS (200 s, 4 Hz) nor high frequency
TENS (200 s, 110 Hz) produced any significant hypoalgesic effect.

The beliefs that justify the use of IFT in clinical practice stemmed on the idea that the
amplitude modulated waves mediate physiological effects by selectively activating
excitable tissue located deep within the human body (Johnson, 1997), however, the
mechanism by which this occurs is a matter of debate, and there is a lack of
experimental evidence to support these claims (Alon, 1992; Johnson and Wilson,
1997, Johnson,1999).

Electrical current applied to the body through surface electrodes encounters resistance
of two types at the electrode-skin interface. The first is known as ohmic resistance and
depends on the morphologic characteristics of the skin as well as on electrode surface
area. The second is called capacitive resistance and represents a force created on
electrically charged ions present at interfaces between different types of tissues and in
cell membranes (Kloth, 1987; Green and Laycock, 1990). This bioelectrical
phenomena can be described by the following equation Z=1/2C, where Z = skin
resistance (), = current frequency (Hz), and C = skin capacitance (F). Thus, two
high-frequency signals can be used to decrease skin impedance. For constant current
drive, less voltage is dropped across the skin at higher frequencies, and so there is less
skin discomfort at the higher current levels (Green and Laycock, 1990). This axiom is
based on the assumption that the body would behave as a perfectly homogeneous

124

conductor (electrically isotropic medium), although the human body, particularly

muscle tissue, is electrically anisotropic (Green and Laycock, 1990).

Timing and dosage seems to play a role on the effectiveness of electrical stimulation.
Pilot studies suggest that the analgesic effects of IFT and other forms of electrical
stimulation namely TENS occur only when the stimulator is switched on, and there is
limited pain relief once the stimulator is turned off (Johnson, 1999). It is therefore
possible that the results obtained in the present study may reflect an under dosage.

Knowledge of the electrical interferential pathways is crucial in the mode of

production and delivery of the interferential pattern (electrodes positioning). The
generation of a true interferential current is achieved by a tetrapolar technique where
two orthogonal current pathways are introduced within the region to be treated,
originating the interferential pattern (Green and Laycock, 1990; Martin, 1998, Palmer
et al., 1999). In the present study an alternative technique was utilized (bipolar) using
two electrodes, where the two currents are added before the output stage of the current
generator, rather than in the tissues. Although this may not be considered a truly
interferential technique (Green and Laycock, 1990), with certain electrode positions,
this seems equally effective (Green and Laycock, 1990; Martin, 1998; Palmer et al.,
1999). Another point open to speculation is the duration of the swing pattern. In the
present study a 1:1 swing pattern was used. Whether different IFT swing patterns have
differential hypoalgesic effects remains to be determined.

125

3.10 Conclusion
It is well established that unaccustomed eccentric muscular activity produces a
phenomenon called DOMS (Smith, 1991; Beaton, 2002), that usually occurs 8-10
hours after exercise and peaks between 24 and 72 hours post exercise (Lee et al.,
2002). Such exercise-induced muscle injury is very common occurring both in normal
daily life as well as in high intensity training (Br et al., 1997). The precise
mechanism underlying the changes to muscle structure and function following
exercise is not known (Belcastro, 1998).

Irrespective of the fact that the explanatory theories of DOMS are inconclusive,
studies aimed at decreasing the soreness have been attempted (Fitzgerald, 1993;
Bougie, 1997). Some studies have used DOMS as a human model to study different
types of clinical interventions such as: exercise, stretching, massage, ultrasound,
electrical stimulation (TENS), iontophoresis, nonsteroidal anti-inflamatory drugs,
topical analgesics and cryotherapy.
However, some irregular, yet significant differences in daily treatment effects and
interactive effects over time were identified. The results of the present investigation do
not provide support for the use of interferential therapy applied at two different
frequencies (10-20 Hz and 80-100 Hz, with a 1:1 swing pattern) in the management of
pain as a result of DOMS. However, further research is required, namely the
development of bioelectrical models that can provide an insight into the behaviour of

126

the interferential pattern within, and across, the biological tissues as well as further
investigation on the manipulation of the parameters, and how they affect physiological
responses induced by IFT.

The next Chapter will assess the effects of three electrotherapeutic modalities (TENS;
IFT and APS) upon mechanical pain threshold and nerve conduction in the human
median nerve.

127

Figure 3.1
Picture of the preachers bench used in induction protocol

128

Figure 3.2
Picture of the measurement of mechanical pain threshold

129

Figure 3.3
Picture of the pressure algometer (Salter Abbey Weighing Machines Ltd., UK)

130

Figure 3.4
Picture of the Biodex Isokinetic Dynamometer (Shirley, New York, USA)

131

Figure 3.5
Picture of McGill pain questionnaire

132

Fig 3.6
Picture of the IFT unit Endomed 982 (Enraf Nonius, Netherlands)

133

Fig 3.7
Picture of the Oscilloscope (Gould Electronics, Essex, UK)

134

Figure 3.8
Treatment set-up

135

Figure 3.9
Summary of MPQ sensory rating difference scores plotted against time (days)

IFT 2 (80-100Hz)

IFT 1 (10-20Hz)

Day 1
-5

10

Placebo

MPQ Sensory Rating Difference Scores

Control

136

Day 3

Day 5

(means.e.m.; n=10 for each group)

Figure 3.10
Summary of MPQ affective rating difference scores plotted against time (days)

Day 1
-1,5

-1

-0,5

0,5

1,5

IFT 2 (80-100Hz)
Placebo

MPQ Affective Difference Scores

Control
IFT 1 (10-20Hz)

137

Day 3

Day 5

(means.e.m.; n=10 for each group)

Figure 3.11
Summary of MPQ evaluative rating difference scores plotted against time (days)

Day 1
-0,5

0,5

IFT 1 (10-20Hz)

Placebo

1,5

IFT 2 (80-100Hz)

MPQ Evaluative Rating Differences Scores

Control

138

Day 3

Day 5

(means.e.m.; n=10 for each group)

Figure 3.12
Summary of MPQ miscellaneous difference scores plotted against time (days)

Day 1
-2

-1

IFT 2 (80-100Hz)
Placebo

MPQ Miscellaneous Rating Difference Scores

Control
IFT 1 (10-20Hz)

139

Day 3

Day 5

(means.e.m.; n=10 for each group)

Figure 3.13
Summary of MPQ pain rating index difference scores plotted against time (days)

Day 1
-5

MPQ Pain Rating Index Difference Scores

10

Control
IFT 1 (10-20Hz)
IFT 2 (80-100Hz)
Placebo

140

Day 3

Day 5

(means.e.m.; n=10 for each group)

Figure 3.14
Summary of MPQ present pain index index difference scores plotted against time (days)

Day 1
-1,5

-1

-0,5

0,5

1,5

IFT 1 (10-20Hz)
IFT 2 (80-100Hz)
Placebo

MPQ Present Pain Index Difference Scores

Control

141

Day 3

Day 5

(means.e.m.; n=10 for each group)

d
in
e
Pr

-15

-10

-5

n
ti
s
Po

n
tio
c
u

s
Po

n
tio
c
du
tt

t
en
m
at
re
D

ay

e
pr
D

ay

ay

142

st
po

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po

Placebo

IFT 2 (80-100Hz)

IFT 1 (10-20Hz)

Control

Figure 3.15

Summary of mean mechanical pain thresholds points 1-8 difference scores (N) plotted against time
(days) (means.e.m.; n=10 for each group)

Mean Mechanical Pain Threshold Difference Scores for Points 1-8 (N)

i
re

nd

-20

-15

-10

-5

i
st
o
P

tio
uc

143

t
t
t
t
t
re
re
re
re
os
os
os
os
en
p
p
p
p
p
p
p
p
2
3
4
5
tm
2
3
4
5
y
y
y
ea
ay
ay
ay
ay
a
a
a
ay
r
D
D
D
D
t
D
D
D
D
st
Po

n
tio
c
du

Placebo

IFT 1 (10-20Hz)
IFT 2 (80-100Hz)

Control

Figure 3.16

Summary of mean mechanical pain thresholds points 3-6 difference scores (N) plotted against
time (days) (means.e.m.; n=10 for each group)

Mean Mechanical Pain Threshold Difference Scores for Points 3-6 (N)

Visual Analogue Scale at Rest Difference Scores (%)

st
Po

in

-10

-5

10

15

20

25

st
Po

n
tio
c
du
ea
tr

t
en
tm
D

ay

e
pr
D

ay

144

st
po

ay

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po

Control
IFT 1 (10-20Hz)
IFT 2 (80-100Hz)
Placebo

Figure 3.17

Summary of visual analogue scale at rest difference scores (%) plotted against time
(days) (means.e.m.; n=10 for each group)

Visual Analogue Scale at Extension Difference Scores (%)

i
st
o
P

-15

-10

-5

10

15

20

25

30

145

t
e
e
e
e
st
st
st
st
en
pr
pr
pr
pr
po
po
po
po
m
5
4
3
2
4
2
5
3
at
ay
ay
ay
ay
ay
ay
ay
ay
re
D
D
D
D
t
D
D
D
D
st
o
P

n
tio
c
du

Placebo

Control
IFT 1 (10-20Hz)
IFT 2 (80-100Hz)

Figure 3.18

Summary of visual analogue scale at extension difference scores (%) plotted against time
(days) (means.e.m.; n=10 for each group)

Figure 3.19
The box plots illustrating the interquartile ranges, medians and 95%
confidence levels for visual analogue scale at extension on day 2

30
20
10
0
-10
-20
-30
-40
-50
N=

10

10

10

10

Control

IFT1

IFT2

Placebo

146

147

Visual Analogue Scale at point 2 Difference Scores (%)

st
Po

a
re
t
st
Po

n
tio
c
du
in

-10

-5

10

15

20

25

30

t
en
tm
ay
D

e
pr
ay
D

Control
IFT 1 (10-20Hz)
IFT 2 (80-100Hz)
Placebo

147

st
po

ay
D

e
pr
ay
D

st
po

ay
D

e
pr
ay
D

st
po

ay
D

e
pr
ay
D

st
po

Figure 3.20

Summary of visual analogue scale at point 2 difference scores (%) plotted against time
(days) (means.e.m.; n=10 for each group)

Figure 3.21
The box plots illustrating the interquartile ranges, medians and 95%
confidence levels for visual analogue scale at point 2 on day 3
60

40

20

-20

-40
N=

10

10

10

10

Control

IFT1

IFT2

Placebo

148

149

st
Po

in

-10

10

20

30

149

t
e
e
e
e
st
st
st
st
en
pr
pr
pr
pr
po
po
po
po
m
4
5
2
3
4
5
3
2
at
ay
ay
ay
ay
ay
ay
ay
ay
re
D
D
D
D
t
D
D
D
D
t
os

n
tio
c
du

IFT 1 (10-20Hz)
IFT 2 (80-100Hz)
Placebo

Control

Figure 3.22

Summary of visual analogue scale at point 5 difference scores (%) plotted against time
(days) (means.e.m.; n=10 for each group)

Visual Analogue Scale at Point 5 Difference Scores (%)

Resting Angle Difference Scores ()

Pr

nd
ei

10

12

14

16

18

20

n
ti
s
Po

n
t io
c
u
st
Po

n
tio
c
du
m
at
e
tr

Placebo

en

t
D

ay

IFT 2 (80-100Hz)

IFT 1 (10-20Hz)

Control

e
pr
D

ay

150

s
po

t
D

ay

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po
D

ay

e
pr
D

ay

st
po

Figure 3.23

Summary of resting angle difference scores (%) plotted against time

(days) (means.e.m.; n=10 for each group)

Isometric Peak Torque at 60 Difference Scores (N)

n
ei
r
P

-25

-20

-15

-10

-5

s
Po

n
tio
c
u

n
ti
st
Po

n
tio
c
du

Placebo

t
en
m
t
ea
tr

IFT 2 (80-100Hz)

IFT 1 (10-20Hz)

Control

ay

e
pr
2

151

ay
D

po

st
D

ay

e
pr
D

ay

st
po

ay
D

pr

e
D

ay

st
po
D

ay

e
pr
D

ay

st
po

Figure 3.24

Summary of isometric peak torque at 60 flexion difference scores plotted against time
(days) (means.e.m.; n=10 for each group)

152

Figure 3.25
The box plots illustrating the interquartile ranges, medians and 95%
confidence levels for isometric peak torque at 60 flexion on day 1

20

10

-10

-20
N=

10

10

10

10

Control

IFT1

IFT2

Placebo

152

Figure 3.26
The box plots illustrating the interquartile ranges, medians and 95%
confidence levels for isometric peak torque at 60 flexion on day 2

10

-10

-20

Control

IFT1

IFT2

153

Placebo

Isometric Peak Torque at 90 Difference Score (N)

154

t
n
n
t
t
t
t
e
e
e
e
en
os
os
os
os
tio
tio
pr
pr
pr
pr
p
p
p
p
c
c
m
2
3
4
5
u
u
t
2
3
4
5
y
y
y
y
ea
ay
ay
ay
ay
nd
nd
i
a
a
a
r
a
i
t
D
D
D
D
e
D
D
D
D
st
st
Pr
o
Po
P

-30

-25

-20

-15

-10

-5

Placebo

IFT 2 (80-100Hz)

IFT 1 (10-20Hz)

Control

Figure 3.27

Summary of isometric peak torque at 90 flexion difference scores plotted against time
(days) (means.e.m.; n=10 for each group)

155

Figure 3.28
The box plots illustrating the interquartile ranges, medians and 95%
confidence levels for isometric peak torque at 90 flexion on day 1

20

10

-10

-20
N=

10

10

10

10

Control

IFT1

IFT2

Placebo

155

Table 3.1
DOMS study MPQ sensory dimension
(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

Day1

5.51.78

10.31.5

10.62.77

5.61.45

Day3

8.52.01

9.81.46

15.62.51

12.22.19

Day5

4.61.72

81.61

11.72.13

8.52.52

156

Table 3.2
Summary of statistical analysis for MPQ sensory rating data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.06

0.2

157

Table 3.3
Summary of raw data for MPQ affective rating data
(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

Day1

0.50.22

0.70.26

1.50.79

0.80.25

Day3

0.60.27

1.10.48

2.21.14

1.20.59

Day5

0.20.13

0.80.33

10.49

0.50.4

158

Table 3.4
Summary of statistical analysis for MPQ affective rating data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.75

0.53

159

Table 3.5
Summary of raw data for MPQ evaluative rating data
(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

Day1

0.30.15

0.30.15

0.70.26

0.60.22

Day3

0.60.22

1.30.4

0.90.28

10.3

Day5

0.80.29

0.50.17

0.80.13

0.90.28

160

Table 3.6
Summary of statistical analysis for MPQ evaluative rating data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.45

0.88

161

Table 3.7
Summary of raw data for MPQ miscellaneous rating data
(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

Day1

0.90.28

2.40.79

3.31.06

3.10.84

Day3

2.80.77

2.60.75

2.81.13

2.60.67

Day5

1.20.57

1.70.52

2.30.56

2.61.17

162

Table 3.8
Summary of statistical analysis for MPQ evaluative rating data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.06

0.65

163

Table 3.9
Summary of raw data for MPQ pain rating index data
(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

10.3

0.90.28

0.60.22

0.90.23

Day3

1.50.22

1.60.27

1.50.31

1.60.31

Day5

0.90.1

1.40.22

1.50.17

10.26

Day1

164

Table 3.10
Summary of statistical analysis for MPQ pain rating index data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.7

0.11

165

Table 3.11

Summary of raw data for MPQ present pain index data

(means.e.m.; n=10 for each group)

Time (Days)

Control

IFT1

IFT2

Placebo

Day1

7.22.23

14.22.25

15.54.41

9.12.58

Day3

12.52.33

15.62.34

20.14.04

14.33.81

Day5

6.72.1

12.32.18

15.83.09

10.44.24

166

Table 3.12
Summary of statistical analysis for MPQ present pain index data

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Day 1

Day 3

Day 5

KW p value

0.8

0.2

167

Table 3.13
Summary of raw data for mean mechanical pain threshold points 1-8
(means.e.m.; n=10 for each group) (N)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

37.440.81

38.21.07

37.561.74

37.051.33

Post-induction

36.710.22

38.40.75

36.562.06

35.931.94

Post-treatment

34.011.93

37.940.92

36.361.92

34.652.16

Day 2 Pre-treatment

29.952.44

34.931.46

31.982.53

30.752.73

Day 2 Post-treatment

28.332.8

35.091.36

32.412.51

30.532.92

Day 3 Pre-treatment

27.282.79

34.811.37

29.593.16

29.663.14

Day 3 Post-treatment

25.983.27

33.861.56

32.482.72

29.882.87

Day 4 Pre-treatment

27.852.89

34.81.75

32.742.75

31.092.89

Day 4 Post-treatment

28.232.92

34.891.71

33.412.8

32.242.76

Day 5 Pre-treatment

31.612.33

36.490.9

35.162.17

34.492.34

Day 5 Post-treatment

31.442.64

36.261.04

35.162.38

33.653.01

168

Table 3.14
Summary of statistical analysis for mean mechanical pain threshold points 1-8

(a) Data distribution:

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

KW p value

Pre-ind

Post-ind

Day 2

Day 2

Day 3

Pre

Post

Pre
0.15

Post-Rx

0.63

0.33

0.5

0.41

Day 3

Day 4

Day 4

Day 5

Day 5

Post

Pre

Post

Pre

Post

0.32

0.28

0.37

0.76

0.63

Time (minutes)

KW p value

169

Table 3.15
Summary of statistical analysis for mean mechanical pain threshold points 1-8

(a) Kruskall-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

Day 1

Day 2

Day 3

Day 4

Day 5

KW p value

0.37

0.73

0.07

0.51

0.92

170

Table 3.16
Summary of raw data for mean mechanical pain threshold points 3-6
(means.e.m.; n=10 for each group) (N)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

37.631.01

38.450.89

37.131.91

36.81.52

Post-induction

36.551.43

38.60.75

35.932.23

36.081.94

Post-treatment

33.252.2

37.481.28

35.452.14

34.452.3

Day 2 Pre-treatment

29.492.45

33.81.83

30.712.76

29.883.05

Day 2 Post-treatment

28.73.03

34.081.74

30.232.83

29.33.3

Day 3 Pre-treatment

26.183.08

34.51.76

27.33.46

28.353.29

Day 3 Post-treatment

25.383.65

32.981.9

31.382.95

28.433.13

Day 4 Pre-treatment

26.983.22

34.431.96

31.652.89

29.753.01

Day 4 Post-treatment

27.383.22

34.481.93

32.852.93

30.982.79

Day 5 Pre-treatment

30.32.64

35.651.06

34.852.11

34.182.52

Day 5 Post-treatment

312.84

35.12.38

35.12.38

33.983.06

171

Table 3.17
Summary of statistical analysis for mean mechanical pain threshold points 3-6

(a) Data distribution

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

KW p value

Pre-ind

Post-ind

Day 2

Day 2

Day 3

Pre

Post

Pre
0.19

Post-Rx

0.45

0.37

0.54

0.82

Day 3

Day 4

Day 4

Day 5

Day 5

Post

Pre

Post

Pre

Post

0.46

0.36

0.04

0.44

0.48

Time (minutes)

KW p value

172

Table 3.18
Summary of statistical analysis for mean mechanical pain threshold points 3-6

(a) Kruskall-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

Day 1

Day 2

Day 3

Day 4

Day 5

KW p value

0.53

0.95

0.4

0.85

0.82

173

Table 3.19
Summary of raw data for visual analogue scale at rest
(means.e.m.; n=10 for each group) (%)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

11.94.1

7.42.63

8.352.26

5.951.82

Post-induction

10.85.05

12.93.36

10.12.98

7.752.5

Post-treatment

19.455.25

17.655.44

15.354.25

19.158.45

Day 2 Pre-treatment

18.054.51

17.554.91

17.754.88

14.85.84

Day 2 Post-treatment

23.76.99

15.96.74

184.57

19.99.14

Day 3 Pre-treatment

17.74.59

14.555.05

175.65

16.857.77

Day 3 Post-treatment

16.057.52

165.82

18.555.06

11.76.01

Day 4 Pre-treatment

13.76.45

14.95.21

17.756.3

12.27.28

Day 4 Post-treatment

12.055.26

12.24.72

12.954.76

10.256.43

Day 5 Pre-treatment

10.95.15

9.653.94

15.356.33

8.856.25

Day 5 Post-treatment

11.94.1

7.42.63

8.352.26

5.951.82

174

Table 3.20
Summary of statistical analysis for visual analogue scale at rest

(a) Data distribution

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

KW p value

Post-ind

Day 2

Day 2

Day 3

Pre

Post

Pre

Post-Rx

0.36

0.91

0.7

0.66

Day 3

Day 4

Day 4

Day 5

Day 5

Post

Pre

Post

Pre

Post

0.97

0.54

0.44

0.92

0.57

Time (minutes)

KW p value

175

Table 3.21
Summary of statistical analysis for visual analogue scale at rest

(a) Kruskal-Wallis/Mann-Whitney U test on daily treatment differences

Time (Days)

Day 1

Day 2

Day 3

Day 4

Day 5

KW p value

0.36

0.59

0.56

0.79

0.28

176

Table 3.22
Summary of raw data for visual analogue scale at extension
(means.e.m.; n=10 for each group) (%)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

12.855.42

15.65.59

11.052.96

10.13.28

Post-induction

7.852.37

11.54.36

12.43.83

10.654.23

Post-treatment

23.95.51

24.357.07

15.84.16

21.46.67

Day 2 Pre-treatment

23.855.05

22.16.38

21.055.80

17.456.47

Day 2 Post-treatment

33.657.6

29.357.08

215.64

21.959.14

Day 3 Pre-treatment

274.99

22.654.65

20.085.87

20.057.4

Day 3 Post-treatment

20.57.21

34.156.7

22.254.65

16.157.4

Day 4 Pre-treatment

21.057.25

32.355.69

17.45.34

14.357.26

Day 4 Post-treatment

15.45.1

24.95.73

16.154.77

16.357.53

Day 5 Pre-treatment

13.55.33

19.855.44

17.95.93

14.757.81

Day 5 Post-treatment

12.855.42

15.65.59

11.052.96

10.13.28

177

Table 3.23
Summary of statistical analysis for visual analogue scale at extension

(a) Data distribution

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Day 2
Time (minutes)

Post-ind

Post-Rx

Day 2 Pre

Day 3 Pre
Post

KW p value

Time (minutes)

Day 3

0.82

0.51

Day 4
Day 4 Pre

Post
KW p value

0.5

0.34

Day 5
Day 5 Pre

Post
0.19

178

0.16

0.14

Post
0.81

0.86

Table 3.24
Summary of statistical analysis for visual analogue scale at extension

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

p value

Day 2

0.04

Significant paired comparisons

Control Vs IFT1 (p=0.02)
IFT1 Vs IFT2 (p=0.01)

179

Table 3.25
Summary of median and interquartile ranges for visual analogue scale at
extension on day 2

Group

Median

Interquartile Range

Control

1.25

4.12

IFT1

-1.75

5.75

IFT2

3.25

11.62

Placebo

10.75

180

Table 3.26
Summary of raw data for visual analogue scale at point 2
(means.e.m.; n=10 for each group) (%)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

10.553.63

62.01

8.152.74

5.33.19

Post-induction

8.33.15

7.12.62

9.653.35

9.854.24

Post-treatment

22.755.01

15.154.47

12.654.58

17.55.87

Day 2 Pre-treatment

205.87

16.154.54

13.44.18

18.257.22

Day 2 Post-treatment

307.7

20.155.83

13.94.89

186.66

Day 3 Pre-treatment

20.86.81

154.91

15.355.55

23.58.32

Day 3 Post-treatment

177.01

24.257.93

18.255.48

13.96.93

Day 4 Pre-treatment

16.756.76

20.65.77

18.556.19

15.38.1

Day 4 Post-treatment

12.854.78

124.74

15.056.13

12.67.89

Day 5 Pre-treatment

13.65.39

11.44.91

16.056.04

13.958.52

Day 5 Post-treatment

10.553.63

62.01

8.152.74

5.33.19

181

Table 3.27
Summary of raw data for visual analogue scale at point 2 on day 3
(a) Data distribution

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Post-

Post-

Day 2

Day 2

Day 3

ind

Rx

Pre

Post

Pre

0.89

0.18

0.76

0.28

Day 3

Day 4

Day 4

Day 5

Day 5

Post

Pre

Post

Pre

Post

0.55

0.74

0.81

0.98

0.88

Time (minutes)

KW p value

Time (minutes)

KW p value

182

Table 3.28
Summary of raw data for visual analogue scale at point 2 on day 3

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

p value

Significant paired comparisons

Control Vs IFT2 (p=0.001)

Day 3

0.01
Control Vs Placebo (p=0.002)

183

Table 3.29
Summary of median and interquartile ranges for visual analogue scale at
point 2 on day 3

Group

Median

Interquartile Range

Control

-8.5

11.37

IFT1

-4.25

14.75

IFT2

-0.25

4.25

Placebo

-0.50

12.5

184

Table 3.30
Summary of raw data for visual analogue scale at point 5
(means.e.m.; n=10 for each group) (%)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

15.554.44

9.84.22

10.253.51

7.653.44

Post-induction

14.65.42

14.25.08

10.53.44

12.955.5

Post-treatment

27.16.05

22.25.4

16.654.7

17.66.28

Day 2 Pre-treatment

26.96.7

195.31

21.44.5

20.657.7

Day 2 Post-treatment

23.856.77

23.955.21

17.155.63

23.69.08

Day 3 Pre-treatment

24.25.16

26.645.68

17.85.87

21.28.55

Day 3 Post-treatment

25.18.74

287.4

19.755.79

17.88.15

Day 4 Pre-treatment

20.356.91

22.755.51

206.78

17.858.56

Day 4 Post-treatment

15.554.94

14.654.77

15.455.99

13.657.25

Day 5 Pre-treatment

13.95.99

13.94.34

16.76.44

12.758.34

Day 5 Post-treatment

15.554.44

9.84.22

10.253.51

7.653.44

185

Table 3.31
Summary of statistical analysis for visual analogue scale at point 5

(a) Data distribution

These data were treated as non-parametric as the data set was subjective

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

KW p value

Post-ind

Day 2

Day 2

Day 3

Pre

Post

Pre

Post-Rx

0.64

0.69

0.91

0.5

Day 3

Day 4

Day 4

Day 5

Day 5

Post

Pre

Post

Pre

Post

0.44

0.72

0.62

0.91

0.7

Time (minutes)

KW p value

186

Table 3.32
Summary of statistical analysis for visual analogue scale at point 5

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

Day 1

Day 2

Day 3

Day 4

Day 5

KW p value

0.64

0.18

0.86

0.93

0.61

187

Table 3.33
Summary of raw data for resting angle data
(means.e.m.; n=10 for each group) ()

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

29.60.98

30.61.7

29.81.71

31.11.8

Post-induction

38.21.45

42.82.83

37.91.97

40.12.95

Post-treatment

39.82.57

38.82.73

36.52.1

38.12.73

Day 2 Pre-treatment

38.21.48

39.82.34

392.63

37.82.82

Day 2 Post-treatment

38.41.91

37.52

38.32.96

38.73.29

Day 3 Pre-treatment

39.32.16

43.72.12

44.62.69

39.52.65

Day 3 Post-treatment

39.11.91

42.62.02

42.62.93

40.32.94

Day 4 Pre-treatment

34.12.56

44.23.4

42.32.86

38.23.58

Day 4 Post-treatment

34.92.59

44.43.54

40.62.85

38.93.31

Day 5 Pre-treatment

331.73

38.42.38

39.64.37

36.92.78

Day 5 Post-treatment

30.90.9

40.63.18

40.33.96

36.93.14

188

Table 3.34
Summary of statistical analysis for resting angle data

(a) Shapiro-Wilk Test

Group

p value
0.18

Control

0.59

IFT1

0.98

IFT2

0.73

Placebo

(b) Repeated measures analysis of variance (ANOVA)

df

Mean Square

F-test

p value

336.527

1.311

0.29

Repeated Measure (B)

10

375.167

13.655

<0.0001

Interaction AB

30

44.746

1.629

0.02

Source
Condition (A)

189

Table 3.35
Summary of statistical analysis for resting angle data

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

Day 1

Day 2

Day 3

Day 4

Day 5

KW p value

0.23

0.46

0.14

0.18

0.08

190

Table 3.36
Summary of raw data for isometric peak torque at 60 flexion
(means.e.m.; n=10 for each group) (N)

Time (Days)

Control

IFT1

IFT2

Placebo

Pre-induction

35.234.48

32.554.06

32.183.68

30.495.12

Post-induction

25.863.44

23.792.98

21.932.8

23.033.99

Post-treatment

28.483.45

21.82.81

19.532.92

21.663.66

Day 2 Pre-treatment

28.724.84

21.212.47

20.413.72

18.663.97

Day 2 Post-treatment

26.874.67

18.943.08

15.8830.7

20.673.95

Day 3 Pre-treatment

28.84.13

23.392.7

22.493.97

19.93.54

Day 3 Post-treatment

26.944.25

19.992.51

18.923.34

20.483.85

Day 4 Pre-treatment

28.664.22

23.512.67

22.224.81

22.63.22

Day 4 Post-treatment

28.84.03

22.592.42

21.684.67

25.113.57

Day 5 Pre-treatment

30.724.11

28.524.41

22.543.55

21.783.57

Day 5 Post-treatment

30.894.44

29.024.24

19.662.52

21.422.75

191

Table 3.37
Summary of statistical analysis for isometric peak torque at 60 flexion

(a) Data distribution: Shapiro-Wilk test

p value

Group

0.88

Control

0.58

IFT1

0.55

IFT2

0.14

Placebo

Data normally distributed, therefore non-parametric analysis was carried out

(b) Repeated measures analysis of variance (ANOVA)

Source
Condition (A)
Repeated Measure (B)
Interaction AB

df

Mean Square

F-test

p value

365.232

0.541

0.66

10

403.342

16.335

<0001

30

34.037

1.378

0.09

192

Table 3.38
Summary of statistical analysis for isometric peak torque at 60 flexion data

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

p value

Significant paired comparisons

Control Vs IFT1 (p=0.02)

Day 1

0.04
Control Vs IFT2 (p=0.01)
Placebo Vs Control (p=0.001

Day 2

0.003

Placebo Vs IFT1 (p=0.01)

Placebo Vs IFT2 (p=0.003)

193

Table 3.39
Summary of median and interquartile ranges for isometric peak torque at
60 flexion on day 1

Group

Median

Interquartile Range

Control

1.5

6.8

IFT1

-1.8

4.8

IFT2

-3

3.3

Placebo

-0.4

4.5

194

Table 3.40
Summary of median and interquartile ranges for isometric peak torque at
60 flexion on day 2

Group

Median

Interquartile Range

Control

-1.95

1.8

IFT1

-2.15

3.9

IFT2

-4.25

9.3

Placebo

1.5

1.8

195

Table 3.41
Summary of raw data for isometric peak torque at 90 flexion data
(means.e.m.; n=10 for each group) (N)

Time (Days)
Pre-induction
Post-induction
Post-treatment
Day 2 Pre-treatment
Day 2 Post-treatment
Day 3 Pre-treatment
Day 3 Post-treatment
Day 4 Pre-treatment
Day 4 Post-treatment
Day 5 Pre-treatment
Day 5 Post-treatment

Control

IFT1

IFT2

Placebo

44.974.76

44.264.47

41.554.59

38.396.35

28.893.15

29.952.76

27.264.67

25.43.91

31.483.45

24.983.55

24.964.07

24.533.33

33.945.96

25.833.23

23.694.28

23.044.28

28.445.14

21.92.97

20.823.77

21.073.89

34.45.17

28.682.59

27.45.7

23.934.44

33.065.67

26.492.47

25.255.07

21.833.55

35.195.08

31.342.94

27.265.11

27.334.04

32.144.27

27.862.69

25.684.77

27.313.71

37.375.15

35.364.46

31.365.83

31.644.66

33.73.94

32.663.98

27.284.06

30.434.11

196

Table 3.42
Summary of statistical analysis for isometric peak torque at 90 flexion data

(a) Shapiro-Wilk Test

p value

Group

0.62

Control

0.34

IFT1

0.9

IFT2

0.23

Placebo

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

348.095

0.234

0.872

Repeated Measures (B)

10

1044.509

26.961

<0.0001

Interaction AB

30

25.795

0.666

0.912

197

Table 3.43
Summary of statistical analysis for isometric peak torque at 90 flexion data

(a) Kruskal-Wallis/Mann-Whitney U tests on daily treatment differences

Time (Days)

p value

Significant paired comparisons

Control Vs IFT1 (p=0.02)

Day 1

0.01

Control Vs IFT2 (p=0.006)

Control Vs Placebo (p=0.006)

198

Table 3.44
Summary of median and interquartile ranges for isometric peak torque at
90 flexion on day 1

Group

Median

Interquartile Range

Control

2.8

2.3

IFT1

-2.25

6.8

IFT2

-2.65

6.3

Placebo

-0.7

4.7

199

Chapter 4
The Effect of Three Electrotherapeutic Modalities upon Mechanical
Pain Threshold and Nerve Conduction in the Human Median Nerve

200

Abstract
Recent surveys have indicated the popularity of electrotherapeutic modalities in the
treatment of various pathological conditions. However, there is ongoing
controversy regarding the hypoalgesic and neurophysiological effects of such
modalities. The aim of the current study was to investigate the effect of 3 different
electrotherapeutic modalities upon mechanical pain threshold and peripheral nerve
conduction.

The modalities examined in this study were Interferential Therapy (IFT),

Transcutaneous Electrical Nerve Stimulation (TENS) and a novel device, Action
Potential Stimulation (APS) therapy. Following approval by the University of
Ulsters Research Ethical Committee, healthy volunteers (n=40; 20M: 20F; age 2040yrs; mean age 26.18yrs) were recruited and screened for contraindications.
Subjects were randomly allocated in equal numbers to the following groups:
Control, TENS (asymmetrical byphasic waveform, 150 Hz, 125 s), IFT
(sinusoidal waveform, 150 Hz, 125 s) or APS (monophasic exponential decaying
waveform, 153 Hz, 6.4 ms). Antidromic compound action potentials were recorded
from the right median nerve pre-treatment, immediately post treatment (i.e. at 15
minutes) and then at 25, 35 and 45 minutes. Immediately following nerve
conduction recordings, mechanical pain threshold recordings were obtained from
two recording sites (proximal and distal) on the palmar surface of the right hand.
Concomitantly, ambient and skin temperature data were also recorded. Appropriate
statistical analysis of difference scores (i.e. the difference from baseline values)

201

only showed significant differences between groups for peak to peak amplitude.
Mann-Whitney U test indicated a significant increase in peak to peak amplitude in
the IFT group compared to all other groups at 25 minutes (p0.02), 35 minutes
(p0.04) and 45 minutes (p0.01). At the 35-minute point, there was an increase in
peak to peak amplitude of 4.561.62 V (means.e.m.) in the IFT group compared
to a decrease of 2.171.33 V (means.e.m.) in the APS group. No significant
differences were found for mechanical pain threshold recorded from either site or
for the overall mean scores.

This study has therefore demonstrated that none of the aforementioned modalities
produced a significant hypoalgesic effect; however, the application of IFT
produced a significant neurophysiological effect compared to TENS and APS.

202

4.1 Introduction
Compound Action Potential (CAP) recordings are a simple non-invasive technique
that has been used to examine potential neurophysiological effects induced by
electrical stimulation (Cox et al., 1993; Palmer et al., 1999). Peripheral
neurophysiologic effects have typically been investigated by observing alterations in
CAPs (Cox et al., 1993; Walsh et al., 1998). Alterations in A and C fibres CAPs
(namely a decline), are consistent with the model of the gate control theory of pain
in that less noxious information would be involved in the pain perception process
(Ignelzi and Nyquist, 1976; Sjlund, 1988).

TENS has been extensively used in the management of pain for a wide variety of
clinical conditions (Sjlund, 1988; Akyz et al., 1995; Walsh et al., 1995;
McDowell et al., 1999); even though the clinical success of TENS is established, the
neural mechanisms that modulate pain are not well understood (Walsh et al., 1998,
McDowell, 1999). It is not surprising therefore that research findings on the
neurophysiological effects of TENS reported contradictory results; some authors
concluded that TENS induced alterations in nerve conduction velocity (NCV)
(Campbell and Taub, 1973; Torebrk and Hallin, 1974; Ignelzi et al., 1981; Sjlund,
1988), while others did not report any such significant changes (Golding et al.,
1986; Cox et al., 1993).

IFT can be described as a medium frequency current (usually 4000 Hz) amplitude
modulated at low frequency (0 to 250 Hz) created by the mixing of two slightly out-

203

of-phase medium frequency currents (e.g. 4000 Hz and 4100 Hz). Theoretically this
form of current has the advantage of reducing skin resistance normally associated
with the low frequency currents (such as TENS) while still producing low frequency
effects within the tissues (Kloth, 1991; Martin, 1998). Despite the increasing
acceptance of this electrotherapeutic modality amongst clinicians (Lindsay et al.,
1995; Pope, 1995; Robertson and Spurrit, 1998), the claims of IFT effectiveness are
based on anecdotal evidence in the form of descriptive studies or from the personal
experience of experts in the field (Taylor et al., 1987; Christie and Willoughby,
1990; Johnson and Wilson, 1997; Johnson, 1999); moreover, the literature reporting
the efficacy of IFT is deficient, with several authors pointing to the scarcity of
empirical evidence for this modality (Stephenson and Johnson, 1995; Schmitz et al.,
1997; Palmer et al., 1999; Noble et al., 2000). However, Belcher (1974) carried out
a study to assess the effect of the IFT upon nerve conduction velocity of the human
median and ulnar nerves. The author used a variable frequency (0-100 Hz) with a
suction cup set at 0.1 kp/cm over 15 minutes. The results showed that at the
parameters used, IFT did not produce any significant effect in either nerve.

As previously stated, APS therapy is a new form of electrical stimulation (MET)

wich produces a current that is claimed to stimulate an action potential in the
neurone. This current is supposed to mimic the bodys natural electrical impulse,
which then causes cycle synchronous depolarisation (Berger and Matzner, 1999).
Thus, it is claimed that electrolysis may occur within the cell (Berger and Matzner,
1999). Depending on the frequency of the current, different mechanisms and areas of
the central nervous system will be activated. In the spinal cord, non-endophinergic

204

substances such as dynorphin and enkephalin are released. In the brain, endorphin
and serotonin, among other neuro chemicals, are also released (Berger and Matzner,
1999). At the present time, there is an obvious scarcity of published literature on
APS therapy (Berger and Matzner, 1999).

Despite the advances made in the electroanalgesia field, particularly pertaining to the
physiological underlying mechanisms, there is still debate over the inherent
neurophysiologic effects of electrical stimulation. It would therefore appear that
controversy still exists concerning the precise hypoalgesic effects of electrical
stimulation, thus the physiological intention of the present study is to assess the
possible peripheral mechanism(s) of action of TENS, IFT and this novel form of
stimulation named APS therapy in a human mixed nerve (median nerve).

4.2 Aim
The aim of this investigation was to compare the effects of three electrotherapeutic
modalities: Transcutaneous Electrical Nerve Stimulation (TENS); Interferential
Therapy (IFT) and Action Potential Stimulation (APS) upon mechanical pain
threshold (MPT), and peripheral nerve conduction velocity (NCV) in the human
median nerve.

4.3 Methodology
The University of Ulster's Research Ethical Committee approved this study. Forty
healthy nave volunteers (n=40; 20 male and 20 female; mean age 26.18yrs) were

205

recruited from the staff and students of the University, and screened for medical
history and for current signs/symptoms of neuromuscular disorders including
peripheral neuropathy (Appendix XVII). The experimental procedure was explained
to subjects who were then asked to sign a consent form (Appendix XVIII) and
randomly assigned in equal numbers to one of four experimental groups: Control;
TENS (150 Hz); IFT (150 Hz); APS (153 Hz) under double blind conditions.
Subjects remained supine for the duration of the experiment. The anterior surface of
the right forearm and hand was prepared using alcohol, and the stimulation and
recording sites at the elbow and second digit respectively, were cleaned with a
colloidal abrasive (Omniprep, Weaver & Co. Aurora, CO, USA) in order to
decrease skin resistance.

4.4 Recording Procedures

4.4.1 Compound Action Potentials (CAPs)
In order to record Compound Action Potentials, a bipolar muscle stimulator
(Mystro+, Medelec, Woking, UK) was used to identify the median nerve at the
elbow. A monopolar muscle stimulator was further used to map the course of the
nerve along the right forearm to the palmar surface of the hand. A surface bar
stimulation electrode was attached at the right elbow and two digital ring electrodes
were attached to the second digit, with the active electrode on the proximal phalanx,
and the reference electrode 3 cm distally on the middle phalanx. Both sets of
electrodes were coated with gel. An earth electrode was also attached approximately
2 cm distal to the first treatment electrode on the medial aspect of the right forearm,

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and all electrodes were connected to an electrophysiological stimulation and

recording system (Mystro+, Medelec, Woking, UK) (Fig 4.1). Standard settings
were used to record CAPs on this system: 100 Hz-2 kHz bandwidth; 50-100
V/division sensitivity and sweep duration of 10 ms. The median nerve was
stimulated supramaximally using 100 s pulses, delivered at a frequency of 1 Hz.
Averaged responses to a train of 16 pulses were recorded and stored digitally for
subsequent analysis. Recordings were taken at 2-minute intervals until three
consecutive readings showed constant negative peak latencies (NPL variation
<0.01 ms). Once stabilised in this way, antidromic CAPs were recorded at 0, 15,
25, 35, 45 minutes.

4.4.2 Mechanical Pain Threshold (MPT)

In order to measure MPT, two recording points (proximal and distal to the wrist
crease) were marked on the palmar surface of the right hand. A ruler was placed
over the anterior aspect of the right forearm from the wrist crease along the middle
of the second digit, and the recording points were marked at 3 cm and 4.5 cm distal
to the wrist crease. MPT was measured using a handheld pressure algometer (Salter
Abbey Weighing Machines Ltd, UK) (see Chapter 3, Fig 3.3). The probe head
measured 0.9 cm in diameter. The head probe of the algometer was slowly lowered
until it made contact with the skin at the recording site. Once in place, the pressure
was further increased at a slow steady rate of ~5 N/s until pain threshold was
reached (see details of experimental procedure; Fig 4.2). Subjects were instructed to
give a response of "pain or stop" at the precise moment when the pressure sensation

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changed into a painful sensation, i.e. Mechanical Pain Threshold. Two MPT
measurements were obtained for each recording site at the same time points as the
nerve conduction recordings. The MPT measurements always followed the same
order, with the proximal point recorded first and the distal one recorded after. The
mean score was used for the purpose of statistical analysis.

4.4.3 Temperature
Ambient and skin temperature was recorded concomitantly throughout the procedure
at 1-minute intervals. For this, one ambient probe and one skin thermistor (Grant
Instruments, Cambridge, UK) were used. The latter was placed on the anterior
aspect of the right forearm, attached directly to the skin overlying the mid-point
between the elbow and the wrist (see Fig 4.2). Both thermistors were connected to a
Squirrel data logger (1250 series, Grant Instruments, Cambridge, UK) (Fig 4.3)
connected to a microcomputer (Personal System 12, Model 50, IBM). The
thermistors were sensitive to temperature changes of 0.05C; any recordings
showing a variation of 0.5C were excluded from the study.

4.4.4 Treatment parameters

An Endomed 982 (Enraf Nonius, Netherlands) (see Chapter 3, Fig 3.6), a TENS
120Z unit, (ITO, Tokyo, Japan) (Fig 4.4) and an APS unit, (APS Therapy,
Dublin, Ireland) (Fig 4.5) were used to deliver the three electrotherapeutic currents.
In each case, the treatment currents were applied through two pre-gelled selfadhesive PALS UltraFlex, neurostimulation electrodes (5 x 5 cm), (Nidd Valley

208

Medical Ltd, North Yorkshire, UK), placed directly over the course of the median
nerve with a 10 cm gap between electrodes. Prior to the commencement of the study,
the parameters of the TENS unit were calibrated and the accuracy of the IFT and
APS units were also checked using an oscilloscope (Gould Electronics, Sussex,
UK) (see Chapter 3, Fig 3.7). Subjects were given a brief demonstration of the
treatment they were randomly assigned to on their left forearm prior to the
experiment. In addition, peripheral sensation was verified using a sharp/blunt test
over the dermatome of the median nerve.

Four experimental groups were included in this investigation:

1. Control group;
2. TENS group: asymmetrical biphasic waveform, with a fixed frequency of 150
Hz, and a pulse duration of 125 s;
3. IFT group: sinusoidal waveform, with a carrier frequency set at 4000 Hz, a
"beat" frequency of 150 Hz, and a pulse duration of 125 s;
4. APS group: monophasic square pulse exponential decaying waveform, with a
fixed frequency of 153 Hz and a pulse duration of 6.4 ms.

Subjects in the control group received no active form of treatment, although the
electrodes were attached. Treatment was applied double blind for 15 minutes (i.e. by
a second investigator who was not involved in data collection, and subjects also did
not know what kind of electrical stimulation was given to them), at an intensity that
the subjects described as a "strong but comfortable" sensation. To counteract the
accommodation effect induced by a constant form of electrical stimulation, all

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subjects were asked to report if the level of sensation had decreased at set time
intervals (i.e. every 2 minutes); if sensation had decreased, the intensity was
increased to return it to the original level.

4.5 Data Analysis

For the purpose of statistical analysis, difference scores were calculated (i.e. the
variation from baseline). These difference scores were calculated by taking the
initial value as baseline and expressing subsequent values as difference from this.
The Shapiro-Wilk test was performed on raw data in order to check for normal
distribution. For normally distributed data, repeated measures analysis of variance
(ANOVA) and post hoc tests were performed. When data were not normally
distributed, non-parametric analysis was used (Kruskal-Wallis and Mann-Whitney U
tests). All statistical analysis was carried out using the SPSS 9.0 software for
IBM compatible PC.

4.6 Results
4.6.1 Negative Peak Latency (NPL)
Raw data for NPL are presented in Appendix XIX and summarised in Table 4.1.
Statistical analysis of these data is provided in Table 4.2. The NPL is measured in
milliseconds (ms) from the stimulus artefact to the peak of the first negative
deflection. The values recorded represent the maximum point of negative peak
amplitude. Figure 4.6 shows NPL difference scores (means.e.m.) plotted against

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time in minutes for the groups. The values obtained for the Control group show a
fall until 35 minutes (-0.072.28ms, means.e.m) followed by an increase at 45
minutes (-0.062.28ms, means.e.m). The values for TENS and APS groups showed
a consistent decrease over time. The scenario for the IFT group was different,
showing an overall increase that peaked at 25 minutes (0.050.03ms, means.e.m).
The Shapiro-Wilk test showed that data were normally distributed for all groups.
Repeated measures analysis of variance (ANOVA) did not demonstrate any
significant difference between groups (p=0.102) or an interactive effect (p=0.41).
However there was a significant difference over time (p=0.001).

4.6.2 Positive Peak Latency (PPL)

Raw data for PPL are presented in detail in Appendix XX and summarised in Table
4.3. Statistical analysis of these data is provided in Table 4.4. PPL is measured in
milliseconds (ms) and it represents the distance between the point of maximum
positive peak amplitude and the stimulus artefact. Figure 4.7 shows PPL difference
scores (means.e.m) plotted against time in minutes for all groups. The Control,
TENS and APS groups showed a reduction in the PPL values throughout the
experimental procedure. In the IFT group, a rise in PPL values was observed. This
elevation reached its maximum value at 35 minutes (0.240.2ms means.e.m),
followed by an abrupt decrease at 45 minutes to values close to baseline (0.067.72ms means.e.m).

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The Shapiro-Wilk test showed that data were normally distributed. Repeated
measures of variance (ANOVA) showed that the differences over time were not
significant (p=0.260), nor between groups (p=0.131), or interactive effect (p=0.268).

4.6.3 Peak to Peak Duration (PPD)

Raw data for PPD are presented in detail in Appendix XXI and summarised in Table
4.5. Statistical analysis of this data is provided in Table 4.6. PPD is measured in
milliseconds (ms) and represents the duration from the point of maximum negative
peak amplitude to the point of maximum peak amplitude on the CAP. Figure 5.1
shows PPD difference scores (means.e.m) plotted against time in minutes for all
the groups. The results show a small variation between groups. However, at 35
minutes there was a sharp increase in the values for the IFT group (0.210.19ms,
means.e.m), which dropped substantially at 45 minutes (-0.034.25ms,
means.e.m) in close proximity to the baseline values.

The Shapiro-Wilk test showed that the Control group data were not normally
distributed. The Kruskal-Wallis test showed no significant differences between
groups at any of the time points (p 0.43).

4.6.4 Peak to Peak Amplitude (PPA)

Raw data for PPA are presented in detail in Appendix XXII and summarised in
Table 4.7. Statistical analysis of these data is provided in Table 4.8. The values for
PPA represent the amplitude in microvolts (V) of the sensory response measured

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from the peak of the negative phase to the peak of the positive phase of the CAP.
Figure 4.9 shows PPA amplitude difference scores (means.e.m), plotted versus
time in minutes for all the groups. Control values showed and increase at 15 minutes
(0.150.93V, means.e.m) followed by a decrease until 35 minutes (-1.62.36V,
means.e.m), and a rise at 45 minutes (-0.071.26V, means.e.m). In the APS
group, a decrease in the PPA values was observed at 15th minute (-1.951.77V,
means.e.m), which remained fairly constant until the 45th minute. The values for
the TENS group showed a sharp increased at the 15th minute (4.834.25V,
means.e.m) followed by a significant decrease that remained throughout the
experimental period. The values recorded for the IFT group showed a steady rise
that peaked at 35th minute (4.561.62V, means.e.m). The Shapiro-Wilk test
demonstrated that data were not normally distributed. The Kruskal-Wallis test
showed that there were significant differences between groups at 25 minutes
(p=0.01), 35 minutes (p=0.01) and 45 minutes (p=0.02). Mann-Whitney U tests
showed that the IFT group was significantly different from all other experimental
groups at 25 and 35 minutes, and at 45 minutes the IFT group was significantly
different from APS and TENS groups but not to Control group. These analyses are
summarised as box plots representing medians, interquartile ranges and 95%
confidence intervals in Figures 4.10, 4.11 and 4.12 respectively and Tables 4.9, 4.10
and 4.11 respectively.

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4.6.5 Proximal Mechanical Pain Threshold

Raw data for proximal mechanical pain threshold are presented in detail in Appendix
XXIII and summarised in Table 4.12. Statistical analyses of these data are provided
in Table 4.13. Figure 4.13 illustrates proximal mechanical pain threshold differences
scores (means.em.) plotted against time in minutes for all groups. All values above
baseline correspond to an increase in mechanical pain threshold, i.e. a hypoalgesic
effect. The Control group showed a significant decrease in proximal mechanical pain
threshold for the first 35 minutes (-10.191.86N, means.em.) followed by a slight
increase at the 45th minute (-9.911.98N, means.em.). The values recorded for the
APS group showed a steady decline throughout the experimental period. The
recording values for the TENS group showed a similar pattern. IFT values
demonstrated a significant decrease during the first 35 minutes, (-7.841.69N,
means.em.) followed by a sudden increase at the 45th minute (-4.521.31N,
means.em.). Due to the subjective nature of this data, non-parametric analysis was
performed. The Kruskal-Wallis test did not show significant differences between
groups at any of the time points (p0.29).

4.6.6 Distal Mechanical Pain Threshold

Raw data for distal mechanical pain threshold are presented in detail in Appendix
XXIV and summarised in Table 4.14. Statistical analysis of these data is provided in
Table 4.15. Figure 4.14 illustrates distal mechanical pain threshold difference scores
(means.e.m.) plotted against time in minutes for all groups. All values above
baseline correspond to an increase in mechanical pain threshold, i.e. a hypoalgesic

214

effect. The Control values showed a minor deviation from the baseline values at 15
minutes followed by a decrease until the 35th minute (-5.792N, means.em.) and a
minor rise in the values was recorded at the 45th minute (-5.271.85N, means.em.).
The values recorded for the APS group showed a small decrease throughout the
experimental period. The IFT values showed an immediate rise at 15 minutes
(3.971.78N, means.em.) pointing out a hypoalgesic effect. However, IFT values
then decreased throughout the experimental period. In the TENS group, a consistent
decrease throughout the experimental time was observed. Due to the subjective
nature of this data, non-parametric test was performed. The Kruskal-Wallis test
showed that there were no significant differences between groups at any of the time
points (p0.28).

4.6.7 Overall Mechanical Pain Threshold

Raw data for overall mechanical pain threshold are presented in detail in Appendix
XXV and summarised in Table 4.16. Statistical analyses of these data are provided
in Table 4.17 and correspond to the mean scores of all recorded mechanical pain
threshold values from both sites (proximal and distal). Figure 4.15 illustrates overall
mechanical pain threshold difference scores (means.e.m.) plotted against time in
minutes for all groups. All values above baseline represent an increase in mechanical
pain threshold, i.e. a hypoalgesic effect. The Control values demonstrated a sudden
decline at 15 minutes (-3.211.24N, means.em.) that remained until the 35th
minute, followed by a minor rise towards the baseline value was recorded (i.e. 45th
minute). In the APS group, the recordings showed a consistent decrease over the

215

experimental period. The values recorded for the IFT group demonstrated a rise
immediately after treatment (i.e. 15th minute). However, the values dropped off
below baseline for the rest of the experimental period. The TENS group showed a
consistent decrease in the values recorded throughout the experimental period. The
Kruskal-Wallis test showed no significant differences between groups at any of the
time points (p0.33).
4.6.8 Ambient Temperature
Raw data for ambient temperature are presented in detail in Appendix XXVI and
summarised in Table 4.18. Statistical analyses of these data are provided in Table
4.19. Figure 4.16 illustrates ambient temperature differences scores (means.em.)
plotted against time in minutes for all groups. The mean ambient temperature
recorded at 0 minutes was 25.860.38C (means.em.). The values for the Control
group showed an increase during the first 25 minutes with a slight decrease at 35
minutes followed by an increase at 45 minutes. The APS group showed an increase
in ambient temperature recorded at 15th minute followed by a decrease at 25th
minute, again followed by an increase at 35th minute followed by a small drop on the
values recorded at 45th minute. The values for the IFT group showed a rise for the 25
minutes with a subsequent decrease until 45 minutes. The TENS group showed a
small rise in ambient temperature values after treatment that peaked at 35 minutes
and then decreased by the 45th minute.

The Shapiro-Wilk test confirmed that data were normally distributed. Repeated
analysis of variance (ANOVA) demonstrated no significant differences between

216

groups (p=0.068) nor an interactive effect (p=0.592) or a significant effect over time
(p=0.834).

4.6.9 Skin Temperature

Raw data for skin temperature are presented in detail in Appendix XXVII and
summarised in Table 4.20. Statistical analysis of these data is provided in Table
4.21. Figure 4.17 illustrates skin temperature differences scores (means.e.m.)
plotted against time in minutes for all groups. All the groups showed an increase in
the values recorded for the skin temperature during the first 25 minutes. The TENS
and the APS groups showed a consistent rise in the values recoded throughout the
experimental period. The IFT group showed a decrease in the values recorded at 45
minutes (0.280.15C, means.em.). The TENS group showed a constant rise in the
values until the 45th minute (0.360.15 C, means.em.). The Shapiro-Wilk test
indicated that data were normally distributed. Repeated measures analysis of
variance (ANOVA) showed no significant differences between groups (p=0.190) or
an interactive effect (p=0.108). However, there was a significant effect over time
(p=0.012).

217

4.7 Discussion
One possible mechanism for electrical stimulation-mediated analgesia is through
peripheral electrogenic blockade or fatigue occurrence in nociceptive afferent axons
(Campbell and Taub, 1973; Ignelzi et al., 1981; Cox et al., 1993). Several authors
have suggested that peripheral stimulation originates a peripheral blocking of
nociceptive input before the first synapse at substantia gelatinosa of the dorsal horn.
This assumption has been corroborated by reports of increases in peripheral nerve
conduction latency (Ignelzi and Nyquist, 1979; Ignelzi et al., 1981; Walsh et al.,
1998; Mc Dowell et al., 1999). In the present study only one form of electrical
stimulation showed statistical significant differences in peak to peak amplitude (IFT
group). These findings contradict the results obtained by Belcher (1974) who carried
out an uncontrolled study to assess the effects of IFT (0-100Hz; suction at
0.1kp/cm; 15 minutes) upon nerve conduction velocities of the human median and
ulnar nerves. The authors reported that at the parameters used in their investigation
there were no significant changes in nerve conduction velocities. A possible
explanation for the contradiction between the Belcher (1974) study and the present
investigation may be associated with the utilization of different experimental
methodologies such as the use of suction cups with mechanical effects as well as the
inclusion of controls.

Peak to peak duration reflects the synchrony of individual muscle fibre discharges. If
there is a significant difference in the conduction velocity among nerve fibres, the
duration will be prolonged. This is mainly related to the range of conduction
velocities of the large myelinated fibres (Oh, 1984; Stalberg and Erbem, 2000).

218

Interestingly in the present study, although there was no significant difference

between groups according to peak to peak duration, the IFT group showed a sharp
rise at 35 minutes. An aspect that is open to debate is the role of the carrier
frequency opposed to the role of amplitude modulated frequency as well as the
possible interaction between the carrier frequency and the amplitude modulation
frequency in explaining the pattern of fibre recruitment.

Ward and Robertson (1998) showed that manipulating the frequency of alternating
currents over a wide range of 1 to 35 kHz (amplitude modulated at 50Hz) produced
clear separation of sensory, motor and pain thresholds. They found that the three
thresholds decreased as frequency increased. Contradictory findings however, were
reported by Palmer et al. (1999) who used similar methods and concluded that
alteration of the amplitude modulated frequency of IFT did not produce a clear and
predictable change in the threshold of sensory, motor and pain pathways. Along the
same lines of thought is the discussion of the findings for peak to peak amplitude
where the values for the IFT group revealed significant differences from all other
experimental groups at any of the time points (25, 35 and 45 minutes). The values
obtained for the TENS group reached the peak at 15 minutes decreasing immediately
after showing a temporal pattern opposite to the IFT group.

The findings obtained for the TENS group are in accordance with previous work
carried out by this research group and others (Ashton et al., 1984; Walsh et al.,
1995; Mc Dowell et al., 1996); Johnson et al. (1991) also showed that the
hypoalgesic effect of TENS only occurred during treatment rather then after, as

219

described by chronic pain patients receiving TENS for pain relief. Another study
that investigated the effects of TENS and aspirin on late somatosensory potentials by
Ashton et al. (1984) reported that the maximum effect of TENS on somatosensory
evoked potentials amplitude and latency also occurred immediately after TENS was
first applied, and that the effect tended to fade as TENS continued.

As peak to peak amplitude is an expression of the estimate of the number of fibres

recruited (Ma and Liveson, 1983; Oh, 1993; Stalberg and Erbem, 2000), the results
for the IFT group may be related to the characteristics of this type of current, namely
the ability to recruit and excite certain nerve fibre populations, as well as the
timing for the occurrence of this phenomena (during treatment or immediately
after) and wave form.

MPT recordings provide objective data on sensory effects (Walsh et al., 1998).
Findings from this study showed a marginal hypoalgesic effect in the IFT group,
(values raised immediately after treatment, i.e. 15 minutes) associated to an increase
of NPL, which is an indicator of a decrease in the nerve conduction velocity and
correlates highly with changes in MPT (Walsh et al., 1995; McDowell et al., 1996;
Walsh et al., 1998). These findings are also in accordance with previous studies
conducted by Johnson and Wilson (1997) and Tabasam and Johnson (1999) who
reported significant increases in ice pain thresholds after the application of IFT. The
MPT values obtained for the TENS group showed a decrease throughout the 45
minute period, indicating a non-hypoalgesic effect, which agreed with the results of
Golding et al., (1986); Cox et al., (1993), but contradicts previous work carried out

220

by this research group (Walsh et al., 1995; Walsh et al., 1998). However, the
frequency and pulse duration used in the present study were slightly different than
the parameters used in previous studies, which may account for the difference of the
results recorded. This idea is also reinforced by Walsh et al. (1995; 1998), who
showed in previous studies, that only one combination of TENS parameters (110 Hz,
200 s) effected a significant change in measured conduction latency and MPT.

Recently, Cheing and Hui-Chan (2003) investigated whether TENS or IFT was more
effective in reducing experimentally induced heat pain. Forty-eight healthy subjects
were randomly allocated in equal numbers assigned into three experimental groups:
TENS (100 Hz, 120 s) group; IFT (100 Hz) and Control. A thermal sensory
analyser was used to record the heat pain threshold. The stimulation lasted for 30
minutes and the heat pain thresholds were measured before, during and after the
stimulation. The results showed that TENS (p=0.003) and IFT (p=0.004)
significantly elevated the heat pain threshold, but the Control group did not. The
heat pain threshold for the TENS and IFT groups was significantly higher than that
of the Control group 30 minutes into the stimulation (p=0.017). Both TENS and IFT
increased the heat pain threshold to a similar extent during the stimulation period.
However, the post-stimulation effect of IFT lasted longer than that of TENS. These
results contradict the findings of the present investigation. However, the recording
procedures and the parameters used in the study by Cheing and Hui-Chan (2003)
were different than the recording procedures and parameters used in the present
study, which may account for the difference in the results.

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Although the exact mechanisms of action are uncertain, the most direct effect of
electrical stimulation is an alteration in the frequency and pattern of nerve impulses
propagated along the nerve fibres stimulated. In the present study, electrical
stimulation was applied over the median nerve in the forearm. Any effects caused by
electrical stimulation would therefore be expected in the distribution of the median
nerve. The results of the present study showed no significant differences between
groups. These results agreed with the findings of Nolan et al. (1993) who reported
that neither TENS in the burst mode nor the conventional mode influenced skin
temperature, suggesting that the application of TENS at the parameters used did not
affect physiological mechanisms responsible for regulating temperature. However,
the values recorded for the APS group showed an overall intensification in skin
temperature that peaked at the 45th minute. This is in agreement with the findings
reported by Kaada et al. (1984) who found an increase in temperature maintained
stimulation for 45 minutes using TENS. However, Janko and Trontelj (1980) applied
TENS in the conventional mode and found skin temperature to be decreased. A
factor that might be worth some attention in interpreting these findings is the
stimulation parameters used in this investigation (150 Hz, 125 s and 153 Hz, 6.4
ms). The parameters used stand for what has been called the "brief intense mode"
(Mannheimer & Lampe, 1984; Walsh, 1997). This stimulation mode produces nonrhythmic muscle contractions that are either fasciculatory or tetanic in nature
(Mannheimer & Lampe, 1984); this fact might account for a rise in temperature due
to mechanical work inducing circulatory changes and heat dissipation. Furthermore,
the results for the APS group may be associated with the physical characteristics of
the current format (monophasic exponentially decaying waveform) that could induce

222

metabolic and vascular changes that may lead to a rise in tissue temperature and
consequent changes in nerve conduction velocity. An increase in nerve temperature
(as a result of electrical stimulation) is typically associated with decreases in
conduction latency (Buchthal and Rosenfalck, 1966). It is interesting that Walsh et
al. (1995) reported small variations in skin temperature as well as a rise in NPL
values, when investigating the effects of TENS (110 Hz, 200 s) upon the human
superficial radial nerve. The authors explained the inconsistencies found in the
pattern of change in recorded skin temperature and NPL as not being the result of
indirect thermal mechanisms.

Stimulation parameters (pulse duration; frequency; stimulus intensity; waveform and

stimulation time) represent a fundamental aspect that stipulates the observed effects
(Tulgar et al., 1991; Johnson et al., 1991; Walsh, 1995; Foster et al., 1996). The
apparent contradiction of the findings reported in the literature related to the effects
of electrical stimulation on skin temperature may be associated with differences in
procedures and methods used (Nolan et al., 1993). Therefore, it is no surprise that
study results differ and that questions regarding the effects of electrical stimulation
on skin temperature might remain unanswered.

4.8 Conclusion
The current study has demonstrated that according to the parameters used in this
investigation TENS, IFT and APS did not show a significant hypoalgesic effect.
However, IFT produced a significant change in PPA compared with TENS and APS.

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Investigations of the peripheral mechanism(s) of action of TENS have produced

variable results (McDowell et al., 1995: Walsh, 1995). Different methodologies
employed, controversy around the model of experimental pain most appropriate to
investigate the potential hypoalgesic effect of the electrical stimulation, the
parameters used (i.e. frequency; pulse duration; intensity), lack of standardized
outcome measures and insufficient reporting of treatment techniques have rendered
it impossible to directly compare previous pain threshold studies on electrical
stimulation (McDowell et al., 1999). According to Walsh et al. (1998) despite more
than 30 years of clinical applications there is still controversy over the possible
neurophysiological effects of TENS. Therefore, further laboratory and clinical
studies are needed in order to clarify the role of electrical stimulation on pain
modulation.

In assessing the efficacy of a pharmacological or non-pharmacological

interventions ability to produce a hypoalgesic effect, the use of established
laboratory base pain models is of vital importance (Tabasam and Johnson, 1999;
Noble et al., 2001). However, there are substantial differences between
experimentally induced pain and clinical pain. Experimentaly inducing pain has
been criticized because it elicits one type of pain sensation, whereas a patients pain
often is more complex (Johnson and Tabasam, 2003). Therefore, further clinical
studies are needed in order to clarify the role of electrical stimulation on pain
modulation.

224

The following chapters will investigate the clinical effectiveness of TENS and IFT
on the management of pain, nausea and vomiting on cancer patients receiving
antitumor chemotherapy.

225

Figure 4.1
The stimulation and recording system Mystro+ (Medelec, Woking, UK)

226

Figure 4.2
Details of experimental procedure

Treatment
Electrodes

Temperature
Probe
Stimulation
Electrode

Earth
MPT
Recording
Electrodes

227

Figure 4.3
Squirrel data logger 1250 series (Grant Instruments, Cambridge, UK)

228

Figure 4.4
TENS 120Z unit (ITO, Tokyo, Japan)

229

Figure 4.5
APS unit (APS Therapy, Dublin, Ireland)

Stimulation
Electrode
Recording
Electrodes

230

Stimulation
Electrode
Recording
Electrodes

231

Figure 4.6
Summary of negative peak latency difference scores (ms) plotted against time

-0,25

TENS

IFT

APS

-0,2

-0,15

-0,1

-0,05

0,05

Negative Peak Latency Difference Scores (ms)

0,1

Control

231

15

25
Time (minutes)

35

45

(minutes) (means.e.m.; n=10 for each group)

Figure 4.7
Summary of positive peak latency difference scores (ms) plotted against time

0
-0,4

-0,3

-0,2

-0,1

0,1

0,2

0,3

0,5

0,4

Positive Peak Latency Difference Scores (ms)

0,6

Control
APS
IFT
TENS

15

232

Time (minutes)

25

35

45

(minutes) (means.e.m.; n=10 for each group)

Figure 4.8
Summary of peak to peak duration difference scores (ms) plotted against time

0
-0,2

-0,1

0,1

0,2

0,3

0,4

0,5

TENS

Peak to Peak Duration Difference Scores (ms)

Control
APS
IFT

15

233

Time (minutes)

25

35

45

(minutes) (means.e.m.; n=10 for each group)

Figure 4.9
Summary of peak to peak amplitude difference scores (V) plotted against time

-5

-3

-1

TENS

IFT

APS

Peak to Peak Amplitude Difference Scores (V)

Control

15

234

Time (minutes)

25

35

45

(minutes) (means.e.m.; n=10 for each group)

235

Figure 4.10
Box plots illustrating the interquartile ranges, medians and 95% confidence
levels for peak to peak amplitude data at 25 minutes

20

25 minutes

10

-10

-20
N=

10
Control

10
APS

10
IFT

235

10
TENS

Figure 4.11
Box plots illustrating the interquartile ranges, medians and 95% confidence
levels for peak to peak amplitude data at 35 minutes

30

35 minutes

20

10

-10

-20
-30
N=

10
Control

10
IFT

10
APS

236

10
TENS

Figure 4.12
Box plots illustrating the interquartile ranges, medians and 95% confidence
levels for peak to peak amplitude data at 45 minutes

45 minutes

10

-10

-20
N=

10
Control

10

10

APS

IFT

237

10
TENS

238

Figure 4.13
Summary of proximal mechanical pain threshold difference scores (N) plotted

0
-15

IFT

TENS

-13

APS

-11

-9

-7

-5

-3

-1

Proximal Mechanical Pain Threshold Difference Scores (N)

Control

15

238

Time (minutes)

25

35

45

against time (minutes) (means.e.m.; n=10 for each group)

Figure 4.14
Summary of distal mechanical pain threshold difference scores (N) plotted

-10

TENS

IFT

-8

APS

-6

-4

-2

Distal Mechanical Pain Threshold Difference Scores (N)

10

Control

15

239

Time (minutes)

25

35

45

against time (minutes) (means.e.m.; n=10 for each group)

Figure 4.15
Summary of overall mechanical pain threshold difference scores (N) plotted against

-10

TENS

IFT

APS

-5

Overall Mechanical Pain Threshold Difference Scores (N)

Control

Time (minutes)

240

15

25

35

45

time (minutes) (means.e.m.; n=10 for each group)

Figure 4.16
Summary of ambient temperature difference scores (C) plotted against time

0
-0,05

0,05

0,1

0,15

IFT

APS

TENS

0,2

0,3

0,25

Ambient Temperature Difference Scores (C)

Control

15

241

Time (minutes)

25

35

45

(minutes) (means.e.m.; n=10 for each group)

Figure 4.17
Summary of skin temperature difference scores (C) plotted against time (minutes)

IFT

APS

0
-0,25

0,25

0,5

0,75

TENS

Skin Temperature Difference Scores (C)

Control

15

242

Time (minutes)

25

35

45

(means.e.m.; n=10 for each group)

Table 4.1
Summary of raw data for negative peak latency
(means.e.m.; n=10 for each group) (ms)

Time

Control

APS

IFT

TENS

6.850.23

6.490.22

6.460.19

6.590.24

15

6.820.23

6.440.23

6.50.18

6.570.24

25

6.810.23

6.440.23

6.510.2

6.50.25

35

6.770.24

6.420.23

6.480.2

6.490.25

45

6.790.23

6.390.23

6.490.21

6.460.25

243

Table 4.2
Summary of statistical analysis for negative peak latency data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.5

APS

0.44

IFT

0.6

TENS

0.81

Not significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Repeated measures analysis of variance

Source

df

Mean Square

F-test

p value

Condition (A)

0.111

2.221

0.102

Repeated Measure (B)

0.193

5.509

0.001

Interaction AB

0.0365

1.045

0.41

244

Table 4.3
Summary of raw data for positive peak latency
(means.e.m.; n=10 for each group) (ms)

Time

Control

APS

IFT

TENS

7.880.28

7.470.26

7.330.22

7.660.31

15

7.870.27

7.450.25

7.370.22

7.640.35

25

7.820.27

7.40.27

7.40.23

7.580.37

35

7.810.31

7.340.26

7.560.29

7.460.3

45

7.790.27

7.350.25

7.390.25

7.460.33

245

Table 4.4
Summary of statistical analysis for positive peak latency data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.56

APS

0.6

IFT

0.3

TENS

0.91

Not significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Repeated measures analysis of variance

Source

df

Mean Square

F-test

p value

Condition (A)

0.402

2.002

0.131

Repeated Measure (B)

0.0537

1.357

0.26

Interaction AB

0.0498

1.259

0.268

246

Table 4.5
Summary of raw data for peak to peak duration
(means.e.m.; n=10 for each group) (ms)

Time

Control

APS

IFT

TENS

1.040.09

0.970.06

0.870.05

1.070.07

15

1.050.11

1.010.05

0.880.05

1.080.12

25

1.010.06

0.970.06

0.90.08

1.080.14

35

1.040.1

0.920.6

1.080.21

0.980.06

45

1.020.1

0.960.04

0.90.07

0.970.09

247

Table 4.6
Summary of statistical analysis for peak to peak duration data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.03*

APS

0.27

IFT

0.7

TENS

0.55

* Significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Kruskal-Wallis/Mann-WhitneyU tests

Time (minutes)

15

25

35

45

KW p value

0.78

0.96

0.43

0.56

248

Table 4.7
Summary of raw data for peak to peak amplitude
(means.e.m.; n=10 for each group) (V)

Time

Control

APS

IFT

TENS

17.682.39

14.852.3

12.471.5

16.042.4

15

17.832.42

12.892.62

14.951.91

20.876.26

25

16.341.88

13.282.75

16.162.28

16.692.69

35

16.081.7

12.682.31

17.032.24

16.892.56

45

17.762.93

12.752.39

15.842.15

16.012.24

249

Table 4.8
Summary of statistical analysis for peak to peak amplitude data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.02*

APS

0.04 *

IFT

0.25

TENS

0.02 *

* Significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

p value

Significant paired comparisons

0.01

IFT Vs Control (p=.003)

IFT Vs APS (p=0.005)
IFT Vs TENS (p=0.02)

35

0.01

IFT Vs Control (p=0.02)

IFT Vs APS (p=0.02)
IFT Vs TENS (p=0.04)

45

0.02

IFT Vs APS (p=0.03)

IFT Vs TENS (p=0.004)

25

250

Table 4.9
Summary of median and interquartile ranges for peak to peak
amplitude data at 25 minutes (V)

Group

Median

Interquartile Range

Control

-0.9

4.5

APS

-0.25

4.6

IFT

3.17

5.2

TENS

0.05

3.3

251

Table 4.10
Summary of median and interquartile ranges for peak to peak
amplitude data at 35 minutes (V)

Group

Median

Interquartile Range

Control

-0.55

6.07

APS

-2.75

5.8

IFT

3.87

4.77

TENS

0.75

3.24

252

Table 4.11
Summary of median and interquartile ranges for peak to peak
amplitude data at 45 minutes (V)

Group

Median

Interquartile Range

Control

-0.1

7.48

APS

-0.5

8.34

IFT

3.62

3.84

TENS

-0.07

3.68

253

Table 4.12
Summary of raw data for proximal mechanical pain threshold
(means.e.m.; n=10 for each group) (N)

Time
0
15
25
35
45

Control

APS

IFT

TENS

46.134.57

37.193.19

41.863.17

42.074.32

39.854.57

35.713.14

38.693.78

39.863.64

35.954.71

32.593.03

36.073.38

37.964.13

35.934.01

31.432.68

34.023.59

37.664.21

36.214.57

31.392.42

37.343.68

35.844.45

254

Table 4.13
Summary of statistical analysis for proximal mechanical pain threshold data

(a) Normal distribution:

This data was treated as non-parametric due to its subjective and nominal data set.

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)

15

25

35

45

KW p value

0.4

0.4

0.3

0.29

Demonstrated no significant difference between groups at any time point

255

Table 4.14
Summary of raw data for distal mechanical pain threshold
(means.e.m.; n=10 for each group) (N)

Time
0
15
25
35
45

Control

APS

IFT

TENS

39.844.02

33.684.14

34.52.95

35.774.5

39.684.39

33.193.5

38.473.76

36.163.72

37.063.94

32.162.49

35.924.05

35.664.48

34.053.44

31.62.95

34.254.29

32.523.58

34.573.75

31.323.58

33.284.12

32.144.43

256

Table 4.15
Summary of statistical analysis for distal mechanical pain threshold data

(a) Normal distribution:

This data was treated as non-parametric due to its subjective and nominal data set.

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)
KW p value

15

25

35

45

0.4

0.77

0.28

0.58

Demonstrated no significant difference between groups at any time point

257

Table 4.16
Summary of raw data for overall mechanical pain threshold
(means.e.m.; n=10 for each group) (N)

Time
0
15
25
35
45

Control

APS

IFT

TENS

42.984.02

35.433.52

38.183.01

38.924.32

39.774.35

34.453.21

38.583.63

38.013.64

36.54.24

32.372.63

363.63

36.824.27

34.983.63

31.512.78

34.133.9

34.843.77

35.394.03

31.363.83

35.213.83

34.14.43

258

Table 4.17
Summary of statistical analysis for overall mechanical pain threshold data

(a) Normal distribution:

This data was treated as non-parametric due to its subjective and nominal data set.

(b) Kruskal-Wallis/Mann-Whitney U tests

Time (minutes)
KW p value

15

25

35

45

0.51

0.4

0.33

0.32

Demonstrated no significant difference between groups at any time point

259

Table 4.18
Summary of raw data for ambient temperature (means.e.m.;
n=10 for each group) (C)

Time
0
15
25
35
45

Control

APS

IFT

TENS

24.580.35

26.540.38

260.55

26.340.26

24.720.35

26.590.39

26.120.54

26.420.26

24.740.33

26.570.36

26.130.54

26.420.25

24.730.33

26.630.36

26.10.52

26.430.25

24.780.32

26.590.37

26.090.52

26.430.25

260

Table 4.19
Summary of statistical analysis for skin temperature data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.78

APS

0.7

IFT

0.35

TENS

0.35

Not significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Repeated measures analysis of variance

Source

df

Mean Square

F-test

p value

Condition (A)

0.0185

0.288

0.834

Repeated Measure (B)

0.0534

0.828

0.592

Interaction AB

0.0746

2.593

0.068

261

Table 4.20
Summary of raw data for skin temperature (means.e.m.;
n=10 for each group) (C)

Time
0
15
25
35
45

Control

APS

IFT

TENS

31.950.3

32.850.3

32.550.34

32.280.28

31.970.3

33.120.35

32.670.38

32.480.27

32.160.26

33.150.36

32.710.36

32.60.27

32.050.28

33.320.35

32.710.4

32.650.29

32.240.25

33.340.37

32.590.42

32.630.31

262

Table 4.21
Summary of statistical analysis for skin temperature data

(a) Normal distribution: Shapiro-Wilk test

Group

p value

Control

0.7

APS

0.53

IFT

0.16

TENS

0.37

Not significantly different from a normal distribution, therefore parametric analysis

was performed

(b) Repeated measures analysis of variance

Source

df

Mean Square

F-test

p value

Condition (A)

0.158

3.849

0.012

Repeated Measure (B)

0.0681

1.660

0.108

Interaction AB

0.611

1.676

0.19

263

Chapter 5
The Morrow Assessment of Nausea and Vomiting (MANE): A
Transcultural Adaptation for the Portuguese Language of Portugal

264

Abstract
Despite the advances in the development of antiemetic medication, nausea and
vomiting remain a prevalent side effect of chemotherapy. The rigorous assessment of
antiemetic effectiveness is related to the reliability and validity of the outcome
measures used. The Morrow Assessment of Nausea and Emesis (MANE)
questionnaire is the most comprehensive and widely used measure of treatmentrelated nausea and vomiting. A cross-cultural adaptation of the MANE questionnaire
to the Portuguese language (of Portugal) was carried out in this study. Results
showed a high degree of validity (content validity) as well as a high degree of
reliability (standardized alpha item coefficient of 0.83). These findings are in
accordance with previous studies carried out in the MANEs original language. This
preliminary study has provided an assessment tool for measuring nausea and
vomiting that may be useful for Portuguese speaking clinicians. The adapted
questionnaire was used as an outcome measure in the RCT detailed in Chapter 6.

265

5.1 Introduction
Nausea and vomiting are signs and symptoms that can result from antineoplastic
drugs, making patients feel uncomfortable and promoting other treatment
complications; for example, psychological depression, anxiety, helplessness as well
as medical complications such as fractures, oesophageal tearing and wound
dehiscence (Whitehead, 1975; Andrews and Sanger, 1993).

Regardless of efforts being made in the control of post chemotherapy nausea and
vomiting since the introduction of 5-hydroxytryptamine (5HT3) receptor antagonists
and their combinations with dexamethasone, a significant proportion of patients still
experience this problem; therefore, adequate control of nausea and vomiting is an
important problem in the management of the cancer patients undergoing
chemotherapy (Morrow, 1992; Rhodes, 1997; Kobayashi et al., 1999). Nausea is a
subjective, non-observable phenomenon, and has been described as an unpleasant
sensation of discomfort referred to the upper gut that may or may not end up in
vomiting (Del Favero et al., 1992; Tonato et al., 1993; Rhodes, 1997). Vomiting is
the forceful expulsion of the contents of the stomach, duodenum, or jejunum through
the oral/nasal cavity (Rhodes, 1997).

Although the scrupulous measurement of nausea and vomiting has been understood
as a key element in the evaluation of side effects induced by cancer chemotherapy as
well as the efficacy of any anti-emetic therapy (Morrow, 1992; Tonato et al., 1993),

266

assessment procedures are far from being standardized and the psychometric
properties of the measurement instruments are frequently not reported (Tonato et al.,
1993; Rhodes, 1997); thus, the assessment of chemotherapy related side effects
remains a critical and important part of clinical care.

5.2 Description of the Morrow Assessment of Nausea and Emesis (MANE)

The MANE was originally developed at the University of Rochester (Cancer
Centre), United States, and it was first reported in Cancer in 1984. It is a 17-item
self-report instrument, which assesses the following: anticipatory nausea;
anticipatory vomiting; post-treatment nausea and post-treatment vomiting (see
Appendix XXVIII). The rationale behind the development of this assessment
instrument is firmly rooted on the fact that nausea and vomiting are made of an
intricate series of neurological, physiologic and psychological events (Borison,
1953), and while a subjective phenomena, patient self-reports of the side effects may
be more accurate and clinically more relevant than other approaches.

The dimensions assessed by the MANE questionnaire have been shown to represent
distinct responses to chemotherapy treatments (Morrow, 1982). Nausea and vomiting
are likely to have a separate classification based on types or categories that can be
identified such as: frequency, severity and duration. These different categories may
give rise to different clinical concerns and call for different antiemetic approaches
(Morrow, 1984). The frequencies of anticipatory nausea, post-treatment nausea,

267

vomiting and post treatment vomiting are assessed by a 4-point scale from during or
after treatment to never. Duration of each response (nausea and vomiting) is
quantified by the number of hours. Severity is assessed by a 6-point scale from very
mild to intolerable, and the time when nausea and vomiting was worst is assessed
by a 7-point scale from during treatment to no time more severe than any other.

5.3 Psychometric Properties

The psychometric properties of the original version of the MANE were studied in
500 oncology patients receiving chemotherapy (Morrow, 1984). Various aspects of
validity were assessed. Content validity is the degree to which the content of a
particular assessment instrument measures what it is supposed to measure. If
anticipatory and post-treatment side effects are sensibly distinct phenomena, they
should not be highly correlated. Morrow (1984) found that none of the 36 pair wise
correlations between the frequency, severity, and duration of anticipatory nausea, or
the frequency, severity and duration of post-treatment nausea and post-treatment
vomiting was greater than 0.50 (25% shared variance). Thus, the content validity of
the instrument was corroborated by the findings of a non-significant relationship
between patient-reported anticipatory side effects and patient-reported post-treatment
side effects. Also the archetype of an independent status between frequency, severity
and duration of nausea sustained their inclusion in the scale as separate dimensions
of nausea and vomiting. Construct validity was also assessed. Construct validity
focuses on the assessment of whether a particular measure relates to other measures

268

consistent with theoretical derived hypotheses concerning the relationships among

the concepts convergent or divergent validity (Zeller, 1990). The MANE was
shown to be more highly correlated with independent measures related to nausea and
vomiting than with measures of other chemotherapy side effects (convergent
validity). Results have also shown non-significant correlations between the MANE
and patients self-report of other chemotherapy-induced side effects (divergent
validity). Thus, results showing convergent as well as divergent validity provide
support to the construct validity (Morrow, 1984). The MANE correlation coefficients
concerning validity ranged from 0.72 to 0.96 (Rhodes, 1997), showing that the scale
appears to be fairly valid (Morrow, 1984, Tonato et al., 1993).

Reliability refers to the extent to which an instrument agrees with itself (Courrier,
1984). The MANE has been reported as being a reliable instrument to assess patient
reported nausea and vomiting. Test-retest reliabilities have been shown to be
commonly acceptable (Morrow, 1984, Carnike et al., 1988). The values obtained for
the MANE reliability coefficients (Test-retest) have ranged from 0.61 to 0.78
(Rhodes, 1997). Several studies of both pharmacological and behavioural
interventions aimed at the reduction of nausea and emesis, have also demonstrated
the MANEs sensitivity to clinical change, were a change in chemotherapy schedule
has been reflected in change of scale values (Morrow, 1984, Morrow and Dobkin,
1988).

269

5.4 The Development of a Portuguese Version of the MANE

In recent years, the use of cross-culturally assessment instruments has increased
allowing effective comparison amongst various clinical interventions occurring in
different contexts.

Assessment instruments that may be used cross-nationally in research stem in part by

the need to pool data from multinational studies in a single analytical structure in
clinical trials, and to compare and summarize results across independently conducted
studies as well as to facilitate the extrapolation of those results (EuroQol Group,
1990; Anderson et al., 1995; Herdman et al., 1997).

Although the method of representation and measurement of any construct should be

developed from the perspective of the cultures under investigation (Marsella, 1978),
human and material resources seem impractical most of the times, being preferable
to use translated instruments which have been developed in another country
(Herdman et al., 1997; Chang et al., 1999).

The methodology that has been used to evaluate the cross-national assessment,
namely instruments allocated to the measurement of health-related quality of life
(HRQOL) can be interpreted in terms of four basic vectors of measurement
equivalence. These vectors comprise: item-translation/semantic equivalence; scalar
equivalence; and metric equivalence (Anderson et al., 1995; Herdman et al., 1997).

270

These vectors form the hard core which influences validity and reliability across
cultural settings or language adapted versions of an instrument. The first step usually
considered when adapting an assessment instrument to a different language is the
item-translation equivalence (Anderson et al., 1993; Chang et al., 1999).

5.5 Aim
The purpose of this pilot study was to develop a Portuguese version of the MANE
questionnaire to assess cancer patients receiving antitumor chemotherapy, providing
to the Portuguese clinicians a valid and reliable outcome measure instrument to
assess nausea and vomiting in oncology patients.

5.6 Methodology
5.6.1 Translation and Validation Process
In translating an assessment instrument to a different language, the misrepresentation
from the original culture needs to be reduced, thus a multistep translation and
validation process is essential for the successful translation of assessment
instruments from their source language to a different one. These steps include a
forward translation, blind back translation and pilot testing (Bracken and Barona,
1991; Cull et al., 1998).

As recommended by the European Organization for Research and Treatment of

Cancer (EORTC) in their manual EORTC quality of life study group: translation

271

procedure (Cull et al., 1998), for all translations the translator(s) should be a native
of the language into which the questionnaire is being translated, with a high fluency
in the other relevant language. The translation back to the original language should
be undertaken independent of the forward translation, i.e. by a different translator,
independent of the first (Bracken and Barona, 1991; Cull et al., 1998). Therefore, a
number of procedures were used to determine the equivalence of the original and
Portuguese versions of the MANE. In the current study, translation procedures were
carried out by the Department of Translators, Faculty of Social and Human Sciences,
Lusfona University (Lisbon). Two lecturers of the translators and translation degree
course carried out, blindly, the forward and back translation of the MANE
questionnaire. In addition, bilingual nurses and medical doctors at the oncology
department and the pain unit carried out a discussion on the content equivalence,
relevance and sensitivity of the resulting translation of the MANE questionnaire for
the Portuguese population.

Permission to use and translate the original version of the MANE questionnaire was
granted by the author, Professor Garry Morrow.

5.6 2 Inclusion criteria

Following approval by the Garcias de Orta Hospitals Ethical Committee, a random
sample of 20 subjects (10M:10F; age 39-76yrs; mean age 62.15yrs) were selected
from the oncology patient population receiving chemotherapy, as suggested by the

272

EORTC in their manual EORTC quality of life study group: translation procedure
under the heading Pilot-testing (Cull et al., 1998).
To be recruited, patients had to be:
1. Aged 18 or over.
2. Receiving chemotherapy for the first time.
3. Receiving chemotherapy once a week, and on a chemotherapeutic protocol
considered by the American Society of Clinical Oncology (ASCO) as highly
or moderately emetogenic as in their document Recommendations for the
use of antiemetics: Evidence-based, practical guidelines (ASCO, 1999).
4. Not receiving opioid therapy.
5. Able to read and write.

5.6.3 Procedures
Following an explanation of the nature, purpose and procedures of the investigation,
the patients agreeing to participate were asked to sign an informed consent form
(Appendix XXIX). Patients were also told that they were free to decline to
participate in the study at any time. Immediately after, patients received the
chemotherapy treatment and were sent home. Seven days after the initial
chemotherapy cycle, patients had to return to the oncology department to complete
the Portuguese version of the MANE questionnaire (Appendix XXX). At this stage
(7th day), patients were also interviewed to determine whether the wording used
made any of the translated items:

273

1. Difficult to answer.
2. Confusing.
3. Difficult to understand.
All the patients completed the study.

5.7 Results
5.7.1 Validity
The equivalence between the English and Portuguese versions of the MANE
questionnaire namely concerning content validity was established by the forward and
back blind translation as well as by informal discussions on the appropriateness of
the content using a focus group which included medical personnel (three medical
doctors and four nurses). After interviewing the respondents on the conceptual
meaning used for nausea and vomiting as well as the semantic value of the
descriptors used, the results demonstrated that none of the patients expressed doubts
on the concept of vomiting (the most tangible and objective), or nausea. Although
the concept of nausea was less tangible, as it is a non-observable phenomena and
clearly subjective, respondents agreed with the semantics used to describe the
phenomena. Vomiting was described as: a forceful expulsion of the contents of the
stomach, and nausea as: unpleasant sensation experienced in the back of the
throat; feeling sick in the stomach; sea sickness.

274

Another form used to assess content validity was through the use of correlations.
Table 6.1 shows the Pearsons coefficient correlation (2-tailed) that was used to
evaluate the interrelationships between MANE traits (e.g. occurrence, severity,
duration) pre and post-treatment of nausea and of vomiting. Raw data for occurrence,
severity and duration of nausea and vomiting are presented in detail in Appendixes
XXXI, XXXII, XXXIII, XXXIV, XXXV and XXXVI respectively.

Results showed non-significant correlations between anticipatory nausea and posttreatment nausea as well as between anticipatory vomiting and post-treatment
vomiting, demonstrating therefore that anticipatory and post-treatment side effects
are fairly distinct phenomena.

Post-treatment Nausea
Occurrence
Anticipatory Nausea
Occurrence
Severity

Severity Duration

Post-treatment Vomiting
Occurrence

Severity Duration

0.28
0.32

Duration

-0.39

Anticipatory Vomiting
Occurrence

-0.11

Severity

-0.11

Duration

-0.05

Table 5.1: Correlation coefficients between anticipatory and post-treatment MANE

traits.

275

5.7.2 Reliability
To assess reliability, the standardized item alpha was used. The results obtained
showed a standardized item alpha coefficient of 0.83, pointing therefore to a high
degree of reliability.

5.8 Discussion
The overall equivalence of this Portuguese version of the MANE questionnaire was
high, as indicated by the level of validity achieved as well as reliability; moreover,
the results obtained in this Portuguese version, are in agreement with previous
studies carried out during and subsequent to the development of the original version
of the MANE questionnaire. In a study conducted by Morrow (1984) which included
500 cancer patients receiving highly and moderately emetogenic chemotherapeutic
agents, the author found a weak correlation among frequency, severity and duration
of anticipatory and post-treatment side effects suggesting that nausea and vomiting
are reasonably distinct phenomena and supporting content validity (Morrow, 1984;
Rhodes, 1997). Also in the Portuguese version of the MANE questionnaire, content
validity of the scale was supported by the discovery of non-significant relationships
between patient-reported anticipatory side effects and post-treatment side effects.

The MANE sensitivity to clinical change has also been shown in studies of both
pharmacologic and behavioural interventions whose final objective was the decrease
of nausea and vomiting (Morrow and Dobkin, 1988).

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The Portuguese version of the MANE questionnaire also appears to reliably assess
patient reported nausea and vomiting. Standardized item Alpha showed a coefficient
of 0.83, lending support to the view that this version is a reliable tool to be used as a
self-report of nausea and vomiting. These findings are in accordance with previous
studies carried out in the MANEs original language, where test-retest reliability
coefficients varied between 0.50 and 0.78 (Morrow, 1984, Carnike et al., 1988;
Rhodes, 1997).

5.9. Conclusion
There is little agreement on the efficacy of a variety of methods used to help control
chemotherapy-induced nausea and emesis as well as on the adequate assessment
techniques for their measurement. (Morrow, 1984). A rigorous appraisal of the
individuals experience of symptoms is the starting point for individually planned
symptom management; given the subjective nature of the phenomena involved, the
self-report format of nausea and vomiting seems to be of crucial importance
(Morrow, 1984; Rhodes, 1997). This initial evaluation of the Portuguese version of
the MANE showed that this version has adequate validity and reliability in assessing
both anticipatory and post-treatment nausea and vomiting. The lack of a validated
assessment tool for measuring nausea and vomiting in the Portuguese language turns
this preliminary study into an instrument that may be useful for the Portuguese
speaking clinicians of Portugal.

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The next chapter will assess the hypoalgesic and antiemetic effects of the TENS and
IFT in the management of cancer patients undergoing a chemoterapy regimen and
this Portuguese version of the MANE questionnaire will be used to collect data on
nausea and vomiting.

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Chapter 6
A Clinical Trial on the Hypoalgesic and Antiemetic Effectiveness of
Transcutaneous Electrical Nerve Stimulation and Interferential
Therapy in the Management of Cancer Patients Receiving a
High/Moderate Cytotoxic Chemotherapeutic Regimen

279

Abstract
Pain, nausea and vomiting are consistently recorded among the most frequent and
troublesome side effects related with the administration of chemotherapy. Despite
the advances in the development of antiemetic medication, nausea and vomiting
remain a prevalent side effect of chemotherapy posing therefore a substantial
challenge. Few studies have so far investigated the effectiveness of electrical
stimulation in the control of this symptomatology. The aim of the present study is
to investigate the effectiveness of Transcutaneous Electrical Nerve Stimulation
(TENS) and Interferential Therapy (IFT) upon pain, nausea and vomiting in the
management

of

cancer

patients

receiving

high/moderate

cytotoxic

chemotherapeutic protocol.

One hundred and thirty three patients diagnosed with oncological conditions and
receiving chemotherapy once a week were invited to participate in the study.
Following approval from the Hospital Garcia de Orta's Research Ethical
Committee (Lisbon, Portugal), patients were randomly assigned under strict
double-blind conditions to one of five groups: Control (n=31), Placebo TENS
(n=21), Placebo IFT (n=28), Active TENS (Frequency 10 Hz; Pulse duration 200
s, n=25), Active IFT (Frequency 10 Hz, Pulse duration 125 s, n=28). Outcome
measures included the daily incidence of nausea, vomiting and pain using a visual
analogue scale (VAS) as well as the Morrow Assessment of Nausea and Emesis
Questionnaire (MANE). Assessment procedures were carried out prior to

280

chemotherapy treatment, immediately after, and every 12 and 24 hours for five
days. Patients existential well-being was assessed on day one and on day seven
by using the Quality of Life Questionnaire C-30 developed by the European
Organization for Research and Treatment of Cancer. The administration of the
electrical stimulation (over the P6 antiemetic acupoint) took place 1 hour prior to
chemotherapy treatment, immediately after, and repeated at two-hourly intervals
(during waking hours) for 30 minutes over a 5 day period. Parametric and nonparametric tests were used to analyse the data as appropriate. Repeated measures
ANOVA of the VAS data showed a significant difference for patients over time
(p<0.001) but no significant difference between groups (p=0.87), nor a significant
interactive effect (p=0.42). The Kruskall-Wallis test showed no significant
differences between groups concerning duration of vomiting (p0.078)/nausea
(p0.29), and severity of vomiting (p0.26)/nausea (p0.23) at any of the time
points. Repeated measures ANOVA also showed no significant difference
between groups concerning the global health status (p=0.6), over time (p=0.15),
nor a significant interactive effect (p=0.99). These results suggest that IFT and
TENS at the parameters used do not have a hypoalgesic or antiemetic effect on
sickness associated with cancer chemotherapy. The findings, however, require
further investigation.

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6.1 Introduction
As previously stated in Chapter 2, electrical stimulation has been extensively used as
a clinical tool for the treatment of a variety of painful conditions (Leo et al., 1986;
Jette, 1986; Johnson, 1998) as well as used as an adjunct therapy to routine
medication in nausea and vomiting (McMillan et al., 1991; Shen et al., 2000; Tan et
al., 2001). Several authors have shown that 50-70% of cancer patients suffer
needlessly (Daut and Cleeland, 1990; Lubenow and Ivankovich, 1990; MacMillan,
1996). A survey of 47 published reports revealed that 71% of patients with advanced
cancer had pain as a major symptom and noted a 50% incidence of pain in patients
with intermediate stage disease (Arter and Rackz, 1990). Patients with cytostatic
treatment often also need concurrent analgesic therapy (Saller et al., 1986).
Analgesia can be achieved through the activation of the endogenous pain suppression
system by opioids (Chen-Yu and Liang-Fang, 1973; McMillan, 1991).

Surgery, radiotherapy and chemotherapy are the main interventions for the treatment
of cancer (Feyer et al., 1998). Patients have reported nausea and vomiting following
the administration of chemotherapy ever since drugs were first used to treat cancers
(Saller et al., 1986; Morrow et al., 1998; Kris et al., 1998). Although the
pharmacological control of chemotherapy-induced nausea and emesis has improved
with the widespread use of the new 5-HT3 antiemetic agents such as ondasetron
(Zofran), approximately 40% of patients still develop emesis following
chemotherapy, and over 75% report nausea (Morrow et al., 1998). If not adequately

282

controlled, these side effects can lead to further complications, and also contribute to
a general deterioration of the cancer patients psychological and physical condition
(Hesketh, 1994; Goldspiel and Curt, 1996; Bilgrani and Fallon, 1993; Strang, 1998).
Therefore, prevention and control of pain, nausea and vomiting are paramount in the
treatment of cancer patients.

Nausea and vomiting can result in serious metabolic derangements, nutritional

depletion and anorexia, deterioration of patients' physical and mental status,
oesophageal tears, fractures, wound dehiscence, withdrawal from potentially useful
and curative anti-neoplastic treatment, and degeneration of self-care and functional
ability. However, and despite advances in pharmacologic and non-pharmacologic
management, nausea and vomiting remain two of the most distressing side effects to
cancer patients and their families (Hesketh, 1994; Goldspiel and Curt, 1996; Tonato
and Roila, 1999).

The development of nausea and vomiting as a result of chemotherapy can be

considered as a response from the body to a stimulus corresponding that caused by
contaminated food in a biological context (Andrews and Sanger, 1993; Tonato and
Roila, 1999). The triggering of the reflex mechanism of vomiting by different stimuli
can be realized through various pathways that explain the different emetic potentials
of different antineoplastic agents and the different antiemetic activity of various
therapeutic regimens (Veyrat-Follet et al., 1997; Tonato and Roila, 1999).

283

The mechanisms of emetic action of antineoplastic agents have not been well defined
(Veyrat-Follet et al., 1997; Hogan and Grant, 1997; Tonato and Roila, 1999).
However, it is generally agreed that the act of vomiting is controlled by the vomiting
center, located in the lateral reticular formation in the floor of the fourth ventricle.
Stimulated by afferent impulses, it coordinates the emetic response (Borison and
McCarthy, 1983; Veyrat-Follet et al., 1997; Tonato and Roila, 1999). The
neurotransmitters involved in nausea and vomiting caused by antineoplastic agents
have not yet been clearly identified (Borison and McCarthy, 1983; Veyrat-Follet et
al., 1997; Tonato and Roila, 1999). Various neuroreceptors, however, have been
recognized in or around the area postrema and in the gastrointestinal tract, including
dopaminergic, cholinergic, H 1 and H 2 histaminergic, and opioid, and receptors for
serotonin (5-hydroxytriptamine, 5-HT). Among the 5-HT receptors, 5-HT 3 seems to
play a determinant role in chemotherapy-induced nausea and vomiting (Borison and
McCarthy, 1983; Cubeddu, 1996; Veyrat-Follet et al., 1997; Tonato and Roila,
1999).

Irrespective of the physiologic mechanisms that underpin nausea and vomiting,

several pharmacological and non-pharmacologic approaches have been used to try to
minimize the side effects associated with the administration of chemotherapy.

Convincing evidence demonstrates that electrical stimulation at trigger points or

acupunture points provides an effective method for relief of some forms of severe

284

pathological pain (Fox and Melzack, 1976; Knardahl et al., 1998) and has been
suggested that acupuncture can provide antiemesis during cancer chemotherapy
(Dundee et al., 1990; McMillan et al., 1991; Price et al., 1991; Vickers, 1996). Many
patients receiving cytostatic treatment often need analgesic therapy. Analgesia can be
achieved through activation of the endogenous pain suppressing system by opioids
(Jessel, 1982), which can also act as antiemetics (Borison and McCarthy, 1983), or
by electrical stimulation (Jacox et al., 1994; Ahmed et al., 1998). The opioid
antagonist naloxone can block the antiemetic effect of morphine, and may, by itself,
induce emesis. These data imply the involvement of opioid receptors in the control
of emesis. Because TENS has been shown to enhance the production of these
neurohormones that induce analgesia and reduce required doses of opioid for pain
control (Wolf, 1978; Yuan et al., 2002), TENS may influence the control of emesis
(Saller et al., 1986).

Several non-pharmacological techniques have been used to investigate the antiemetic

effect at PC6 acupoint. These include acupressure, acupuncture, electroacupuncture
and TENS (see Chapter 2). However, few studies to date have investigated the
effectiveness of TENS on nausea and vomiting. According to a meta-analysis carried
out by Vickers in 1996 that reviewed antiemesis trials on acupuncture over the last
30 years (Medline searches from 1966 to 1995, and EMBASE searches from 1985 to
1995 and re-searched with the same terms in the CISCOM), there were forty two
papers published world-wide, and only four of these concerned the use of TENS. So

285

it would appear that further research is needed in order to clarify the role of electrical
stimulation in the management of nausea and vomiting.

A new paradigm for medical practice is emerging. Evidence-based medicine deemphasizes intuition, unsystematic clinical experience, and pathophysiologic
rationale as sufficient grounds for clinical decision-making, and stresses the
examination of evidence from clinical research (Sackett et al., 1998).
Physiotherapists should base their intervention on clinical evidence from the findings
of randomized clinical trials. Moreover, using the results of TENS studies to infer a
relationship between physiological effects and frequencies of the amplitude
modulated wave of IFT is dangerous as the electrical caractheristics TENS and IFT
differ markedly (Johnson, 1999).

The current study was therefore designed to investigate the hypoalgesic and
antiemetic effectiveness of transcutaneous electrical nerve stimulation and
interferential therapy in the management of cancer patients receiving a
high/moderate cytotoxic chemotherapeutic regimen.

286

6.2 Methodology
Following approval from the Hospital Garcia de Ortas Research Ethical Committee
(Almada, Portugal), one hundred and thirty three patients diagnosed with various
oncological conditions and undergoing a chemotherapy programme at the Medical
Oncology Department, were invited to participate in the study.

For eligibility into the trial, a detailed list of inclusion/exclusion criteria was adhered
to. Inclusion criteria were as follows:

Patients undergoing a 5 day chemotherapy session;

Patients in a highly or intermediate emetic chemotherapy regimen as defined

by the Guidelines of the American Society of Clinical Oncology (ASCO)
concerning the emetic risk of the cytotoxic drugs as detailed in Tables 6.1
and 6.2.

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Table 6.1 High Emetic Risk: Chemotherapeutic Agents

Acute Emetic

Chemotherapy Agent

Category
High: Cisplatin

Cisplatin

High: Non Cisplatin

Dacarbazine
Actinomycin-D
Mechlorethamine
Streptozotocin
Hexamethymelamine
Carboplatin
Cyclophosphamide
Lamustine
Carmustine
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Cytarabine
Isofosfamide

288

Table 6.2 Intermediate Emetic Risk: Chemotherapeutic Agents

Acute Emetic

Chemotherapy Agent

Category
Intermediate

Irinotecan
Mitoxantrone
Paclitaxcel
Docetaxel
Mitomycin
Topotecan
Gemcitabine
Etoposide
Teniposide

Exclusion criteria were defined as follows:

Patients under 18 years of age;

Patients presenting with a clinical history of alcoholism (100g

alcohol/day);

Patients

presenting

with

clinical

(Creatine1.5mg/dl);

Patients undergoing an opioid treatment;

289

history

of

kidney

failure

Patients presenting with a clinical history of diabetes mellitus, and

receiving medication for this condition;

Patients presenting with a clinical history of major psychiatric disease;

Pacemaker;

Patients with decreased skin sensation on the forearm;

Pregnancy;

Patients unable to read or write or with cognitive problems.

6.2.1 Experimental Procedure:

The experimental procedure and purpose of the study were explained to the patients
(n=133; 83F:50M; age 20-76yrs; mean age 55.89yrs), who were then asked to sign a
consent form (Appendix XXXVII) and were randomly assigned under strict doubleblind conditions to one of five experimental groups: Control Group (n=31); Placebo
TENS Group (n=21); Placebo IFT Group (n=28); Active TENS Group (n=25);
Active IFT Group (n=28). To ensure double blinding, two separate investigators
carried out assessment and treatments.

An Acupad TPT2200/CT TENS unit (Nidd Valley Medical Ltd., North Yorkshire,
UK) (Fig. 6.1) as well as a portable interferential unit OMEGA Inter 4150
(TensCare, Kingston, UK) (Fig. 6.2) were used to deliver treatment. Prior to the
beginning of the investigation, the accuracy of the TENS and IFT units was verified
using an oscilloscope (Gould Electronics, Essex, UK) (see Chapter 3, Fig. 3.7).

290

Previous studies suggested that the best antiemetic results achieved by the
stimulation of the PC6 acupoint were at low frequency (10-15 Hz) (Dundee and
Yang, 1990; McMillan and Dundee, 1991; Roscoe et al., 2002). Therefore, the
stimulation parameters used were as follows: TENS with a fixed frequency of 10 Hz
and pulse duration of 200 s; Interferential with a beat frequency of 10 Hz, pulse
duration of 125 s, and a carrier frequency of 4000 Hz. The treatment parameters
were previously fixed on the units so the patients or the investigator could not
modify it.

Self adhesive PALS (Nidd Valley Medical Ltd., North Yorkshire, UK) electrodes
with a 3.8 cm diameter were placed (cathode) over the Neiguan, PC-6 antiemetic
acupoint (2 cun which equals 5 cm, proximal to the wrist crease between the tendons
of palmaris longus and flexor carpis radialis on the non-dominant forearm), and the
dorsal aspect of the forearm (anode) (Fig. 6.3).

For the Placebo groups (TENS and IFT), the procedure was identical to that in the
active groups, however the electrodes were connected to an inactivated unit which
did not deliver any electrical current. Patients in the Control group did not receive
any form of electrical stimulation.

Patients were screened for contraindications. In addition, peripheral sensation was

verified using a sharp/blunt test over the area to be treated. Patients were given a

291

demonstration of the treatment they would receive (by the Pain Unit nurses, who
were responsible for the administration of treatment) and they were taught to selfadminister the electrical stimulation.

The patients in the active groups (TENS and IFT) were instructed to increase the
current intensity to a level that was perceived as strong but comfortable. To
prevent accommodation induced by electrical stimulation delivered at a constant rate,
patients were also taught to increase the intensity to the original level if there was
any decrease in the sensation. Patients in the Placebo groups (TENS and IFT) were
told to increase the intensity to the mid point on the dial for the first 15 minutes of
treatment, and then to increase to the maximum intensity until the end of the
treatment session. Patients were given a telephone number (the Pain Unit number) in
case they needed assistance.

The electrical stimulation was applied as follows: immediately after the

administration of the antiemetic medication (one hour prior to the administration of
the chemotherapy) and immediately after chemotherapy treatment. At this stage,
patients went home and they self-applied electrical stimulation repeated at two-hour
intervals (during waking hours) for 30 minutes, over a five day period. Patients were
also provided with a log book (Appendix XXXVIII), which included all the relevant
information concerning the treatment protocol, as well as instructions on how to use
the TENS/IFT units and the assessment procedures.

292

On day 7 patients returned to the Oncology Department were they were asked to
complete the MANE questionnaire as well as the EORTC QLQ-C30, and returned
the logbook. Fig. 6.4 shows a flowchart of the procedures used from day one through
day seven.

293

Fig 6.4 Flowchart of the procedures on day 1

Inclusion/Exclusion
Criteria (patient is admitted
or rejected)

Oncology
Appointment

Pain Unit

Random Allocation,
Coding, Consent form

Measurement of Variables
(VAS, EORTC QLQ-C30 Baseline)
Electrical Stimulation
(Demo session)
Electrical stimulation
(1st session)

Chemotherapy

Electrical stimulation
(2nd session)

Measurement of Variables
(VAS, MANE Baseline)

Patients went home

294

Fig 6.4 (Continued) Flowchart of the procedures on days 2 to 5

(Morning)
Measurement
of Variables
(VAS)

Treatment
(TENS/IFT)

(Night)
Measurement of Variables
(VAS, MANE Daily)

Fig 6.4 (Continued) Flowchart of the procedures on day 7

Measurement of Variables
(MANE, EORTC QLQ-C30
Follow up)

In order to standardise the antiemetic medication, all patients were injected with 8
mg of dexamethasone and 10 mg of 5-HT 3 , one hour before the administration of
the chemotherapy treatment. An antiemetic regime was maintained for the five days
of the study, therefore patients were prescribed 10 mg of metoclopramide orally
three times a day to be taken 30 minutes before main meals (breakfast, lunch and
dinner).

295

6.2.2 Outcome Measures:

Self-administered Visual Analogue Scales (VAS) (Appendix XXXIX) were used to
assess patients pain intensity level. Validity, reliability, sensitivity and robustness of
this assessment instrument have previously been established (Huskisson, 1982).
Measurement was taken prior to the chemotherapy treatment and immediately after
the second session of electrical stimulation. Subsequent measurements were carried
out by the patients at home approximately every 12 hours (first thing in the morning
and before go to bed) over the five days of the investigation. The VAS was a printed
straight-line 10cm long marked at each end with labels that indicated the range being
considered. The markers used were: no pain or pain as bad as it can be. Patients
were asked to place a mark on the line at a point representing the severity of pain.

The European Organization for Research and Treatment of Cancer Quality of Life
Core Questionnaire (EORTC QLQ-C30) is a self-administered questionnaire
(Appendix XL) and was used to assess patients existential well-being. The EORTC
QLQ-C30 has been carefully developed in a multi-cultural setting, and translations
are available in more than 30 languages, including Portuguese from Portugal. The
instrument has shown to be valid, reliable and responsive to change (EORTC Quality
of Life Study Group, 1990). The EORTC QLQ-C30 is a multidimensional
instrument covering physical, psychological and social domains. It was administered
in two occasions: at the oncology day hospital prior to the chemotherapy treatment;
and seven days after. Patients were instructed to complete the questionnaire by

296

drawing a circle around the choice that best corresponded to his/her situation at the
time. Permission was granted from the EORTC Quality of Life Group to use this
questionnaire for this study together with a key-scoring algorithm for analysis.

The Morrow Assessment of Nausea and Emesis (MANE) (Appendix XLI) was used
to assess nausea and vomiting. The MANE questionnaire was originally developed at
the University of Rochester (Cancer Centre), USA. It is a 17-item self-administered
questionnaire, which assesses: anticipatory nausea; anticipatory vomiting; posttreatment nausea and post-treatment vomiting. The rationale behind the development
of this instrument is firmly rooted in the fact that nausea and vomiting are made of
intricate series of neurological, physiological and psychological events (Borison,
1983) and whilst a subjective phenomena, patient self-reporting of side effects may
be more accurate and clinically more relevant than other approaches (Del Favero,
1992).

The MANE has been reported as being a reliable instrument to assess patient
reported nausea and vomiting (Morrow, 1984; Carnike, 1988), therefore, a
Portuguese version of this instrument was developed which was also show to be
valid and reliable (see Chapter 5).

The baseline measurement took place at the oncology day hospital and was taken
immediately after the chemotherapy treatment. Subsequent measurements were

297

carried out by the patients at home every 24 hours over the five days of the
investigation using a modified version of the MANE questionnaire (daily version,
see Appendix XLII). Patients were instructed to complete the questionnaire by
drawing a circle around the choice that best corresponded to his/her situation.

In order to determine the appropriate sample size for the study, a priori power
analysis was carried out using a power of 0.80 which yielded a total number of 175
patients (35 per group). Due to time and staff restraints, as well as difficulties in
recruiting patients that could fulfil the inclusion criteria of the study, only 134
patients were recruited.

With the purpose of monitoring compliance, patients were given a telephone number
of the pain unit at the hospital, and nurses checked daily (by telephone) for any
possible problems. Out of these 133 patients, only 4 did not complete the study (one
died and three others were so sick that they couldnt fill in the questionnaires).
Statistical analysis was therefore carried out on the data obtained from 133 patients.

6.3 Data Analysis

For the purpose of statistical analysis, difference scores (i.e. variation from the
baseline values) were calculated using pre-chemotherapy measurements as baseline
for pain and quality of life, while for nausea and vomiting differences scores were
calculated using post-chemotherapy values as baseline. Raw scores were used for

298

analysis of pain nausea and vomiting. The Quality of Life Questionnaire-C30 (QLQC30) is a quality of life instrument designed for use in clinical trials and is composed
of both multi-item scales and single item measures. These include five functional
scales, three symptom scales, a global health status/QOL scale, and six single items.
Each of the multi-item scales includes a different set of items no item occurs in
more than one scale. All the scales and single-item measures range in a score from 0
to 100. A high scale score represents a higher level of response. Thus a high score
for a functional scale represents a high/healthy level of functioning. A high score for
the global health status/QOL represents a high quality of life, but a high score for a
symptom scale/item represents a high level of symptomatology/problems.
Scoring procedures for the quality of life were transformed according to the EORTC
EORTC QLQ-C30 scoring manual.

In order to select the appropriate statistical analysis (i.e. parametric or nonparametric), a Levenes test of equality of error variances test was performed. This
test indicates whether the distribution of scores was normal or not (baseline only). If
data were normally distributed, parametric tests were performed (ANOVA Repeated
Measures). If not, non-parametric tests (Kruskal-Wallis, Mann-Whitney U) were
computed. All data were analysed using the SPSS software version 9.

299

6.4 Results
6.4.1 Morrow Assessment of Nausea and Emesis Duration of Vomiting
Raw data for the Morrow Assessment of Nausea and Emesis duration of vomiting are presented in Appendix XLIII and summarised in Table 6.3 and Figure 6.5.
Duration of vomiting is expressed in minutes and describes the amount of time that
this symptom lasted. Duration of vomiting scores showed two distinct patterns. The
values for the Control group showed a sharp increase on day 2 (56.146.7min,
means.e.m) that peaked on day 4 (6149.9min, means.e.m). The rest of the
experimental groups showed only a slight increase in values, namely the active
TENS group that showed an increase on day 2 (16.310.9min, means.e.m), then
decreased towards baseline on day 3 (00min, means.e.m). The values for the
placebo TENS peaked on day 3 (12.611.4min, means.e.m), then decreased
towards the baseline values (1.61.4min, means.e.m). The values for the active IFT
and placebo IFT group did not show major variations across the experimental period
but remained close to the baseline values. Levenes test of equality of error variances
showed that the variation of scores around the mean within groups were not similar,
therefore non-parametric analysis was performed. The Kruskal-Wallis test showed
no significant differences between groups at any of the time points (p0.07; see
Table 6.4).

300

6.4.2 Morrow Assessment of Nausea and Emesis Duration of Nausea

Raw data for the Morrow Assessment of Nausea and Emesis duration of nausea are presented in Appendix XLIV and summarised in Table 6.5 and Figure 6.6.
Duration of nausea is expressed in minutes and describes the amount of time patients
experienced a noxious sensation. The results showed a similar pattern for all groups.
The scores recorded for all groups peaked on day 3 with the exception of the IFT
placebo group that peaked on day 4 (14582min, means.e.m). After day 4 all the
groups showed a decrease in the values recorded. Levenes test of equality of error
variances showed that the variation of scores around the mean within groups were
not similar, therefore non-parametric analysis was performed. The Kruskal-Wallis
test showed no significant differences between groups at any of the time points
(p0.29; see Table 6.6).

6.4.3 Morrow Assessment of Nausea and Emesis Severity of Vomiting

Raw data for the Morrow Assessment of Nausea and Emesis severity of vomiting are presented in Appendix XLV and summarised in Table 6.7 and Figure 6.7.
Severity ratings of vomiting range from very mild to intolerable on a 6-point
Likert scale The results demonstrated that all groups except the Control group
showed an oscillating pattern where values peaked on day 2 and day 4. The values
for the Control group peaked on day 3 (0.68.26, means.e.m) and remained fairly
constant until the end of the experimental period. Levenes test of equality of error
variances showed that the variation of scores around the mean within groups were

301

not similar, therefore non-parametric analysis was performed. The Kruskal-Wallis

test showed no significant differences between groups at any of the time points
(p0.26; see Table 6.8).

6.4.4 Morrow Assessment of Nausea and Emesis Severity of Nausea

Raw data for the Morrow Assessment of Nausea and Emesis severity of nausea are presented in Appendix XLVI and summarised in Table 6.9 and Figure 6.8.
Severity ratings of nausea range from very mild to intolerable on a 6-point
Likert scale. The values obtained for all the groups showed a similar pattern reaching
a peak on day 3. The highest score was obtained in the TENS placebo group
(1.480.43, means.e.m). The results demonstrated that after day 3 the scores for all
the groups decreased until the experimental period ended. Levenes test of equality
of error variances showed that the variation of scores around the mean within groups
were not similar, therefore non-parametric analysis was performed. The KruskalWallis test showed no significant differences between groups at any of the time
points (p0.23; see Table 6.10).

6.4.5 Pain: VAS

Raw data for pain scores are presented in Appendix XLVII and summarised in Table
6.11. Measurements were taken pre and post chemotherapy and every day first thing
in the morning and at night before patients went to bed (approximately every 12
hours). Difference scores were calculated using pre-chemotherapy scores as baseline.

302

Figure 6.9 summarises mean VAS scores. The scores obtained showed an increase in
scores post-chemotherapy for the placebo TENS group that peaked on day 4
followed by a decrease on day 5. The Control and placebo IFT group showed an
increase in scores more noticeable when compared to the active TENS and active
IFT group.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed a significant effect over time (p<0.0001). There was no significant difference
between groups (p=0.87) nor an interactive effect (p=0.42; see Table 6.12).

6.5 Quality of Life Questionnaire C30 (QLQ-C30)

6.5.1 Global Health Status/QOL
Raw data for the global health status/QOL (QL2) are presented in Appendix XLVIII
and summarised in Table 6.13 and Figure 6.10. Global health status is expressed as
difference scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed a similar pattern for all groups
demonstrating a slight deterioration of the global QOL.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was

303

performed (ANOVA: repeated measures). The repeated measures ANOVA test

showed no significant effect over time (p=0.15). There was no significant difference
between groups (p=0.6) nor an interactive effect (p=0.99; see Table 6.14).

6.5.2 Physical Functioning (PF)

Raw data for physical functioning are presented in Appendix XLIX and summarised
in Table 6.15 and Figure 6.11. Physical functioning status is expressed as difference
scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed that only the TENS placebo group showed
a better level of physical functioning. The scores obtained for the rest of the
experimental groups showed a small decrease.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed no significant effect over time (p=0.29). There was no significant difference
between groups (p=0.81) nor an interactive effect (p=0.34; see Table 6.16).

6.5.3 Role Functioning (RF)

Raw data for role functioning are presented in Appendix L and summarised in Table
6.17 and Figure 6.12. Role functioning status is expressed as difference scores
between baseline and follow-up plotted against group scores for all experimental

304

groups. The results showed that the scores obtained for the TENS placebo group and
the IFT active groups indicate a deterioration on the level of role functioning. In
contrast, the scores obtained for the rest of the experimental groups showed a slightly
improvement on the role functioning.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed no significant effect over time (p=0.11). There was no significant difference
between groups (p=0.22) nor an interactive effect (p=0.08; see Table 6.18).

6.5.4 Emotional Functioning (EF)

Raw data for emotional functioning are presented in Appendix LI and summarised in
Table 6.19 and Figure 6.13. Emotional functioning status is expressed as difference
scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed a similar pattern for all the groups, i.e. an
improvement in emotional functioning.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test

305

showed no significant effect over time (p=0.96). There was no significant difference
between groups (p=0.23) nor an interactive effect (p=0.25; see Table 6.20).

6.5.5 Cognitive Functioning (CF)

Raw data for cognitive functioning are presented in Appendix LII and summarised in
Table 6.21 and Figure 6.14. Cognitive functioning status is expressed as difference
scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed that the TENS active and the TENS
placebo group followed the same pattern (the scores decreased) and that the scores
for the IFT active and the IFT placebo increased. The results for the control group
showed no variation.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was not normal, therefore non-parametric analysis
was performed (Kruskal-Wallis). The Kruskal-Wallis test demonstrated no
significant differences between groups (p=0.17; see Table 6.22).

6.5.6 Social Functioning (SF)

Raw data for social functioning are presented in Appendix LIII and summarised in
Table 6.23 and Figure 6.15. Social functioning status is expressed as difference
scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed that the general trend observed was a

306

decrease in the scores obtained for all the groups with the exception of the IFT
placebo group that showed an increase in the social functioning.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA repeated measures). The repeated measures ANOVA test
showed no significant effect over time (p=0.36). There was no significant difference
between groups (p=0.6) nor an interactive effect (p=0.74; see Table 6.24).

6.5.7 Fatigue (FA)

Raw data for fatigue are presented in Appendix LIV and summarised in Table 6.25
and Figure 6.16. Fatigue is expressed as difference scores between baseline and
follow-up plotted against group scores for all experimental groups. An increase in
the scores represents an aggravation of the symptoms. The results showed that the
scores for the active TENS, placebo TENS and active IFT increased denoting a
worsening of the patients performance. The results for the placebo IFT showed an
improvement and the results for the control group did not change.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was not homogeneous, therefore non-parametric tests
was performed (Kruskal-Wallis). The Kruskal-Wallis test showed no significant
differences between groups (p=0.11; see Table 6.26).

307

6.5.8 Nausea and Vomiting (NV)

Raw data for nausea and vomiting are presented in Appendix LV and summarised in
Table 6.27 and Figure 6.17. Nausea and vomiting are expressed as difference scores
between baseline and follow-up plotted against group scores for all experimental
groups. The results showed that there was an increase in the scores for all groups.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was not normal, therefore non-parametric analysis
was performed (Kruskal-Wallis). The Kruskal-Wallis test showed no significant
difference between groups (p=0.25; see Table 6.28).

6.5.9 Pain (PA)

Raw data for pain are presented in Appendix LVI and summarised in Table 6.29 and
Figure 6.18. Pain is expressed as difference scores between baseline and follow-up
plotted against group scores for all experimental groups. The results showed that the
general trend observed was an increase for all the groups with the exception of the
placebo IFT group that showed a decrease on scores.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test

308

showed no significant effect over time (p=0.08). There was no significant difference
between groups (p=0.42) nor an interactive effect (p=0.66; see Table 6.30).

6.5.10 Dyspnoea (DY)

Raw data for dyspnoea are presented in Appendix LVII and summarised in Table
6.31 and Figure 6.19. Dyspnoea is expressed as difference scores between baseline
and follow-up plotted against group scores for all experimental groups. The results
showed that there was a decrease in the scores for the active TENS group and
placebo TENS group and that the scores for all the other groups increased.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was not normal, therefore non-parametric tests was
performed. The Kruskal-Wallis test demonstrated that there was no significant
difference between groups (p=0.35; see Table 6.32).

6.5.11 Insomnia (SL)

Raw data for insomnia are presented in Appendix LVIII and summarised in Table
6.33 and Figure 6.20. Insomnia is expressed as difference scores between baseline
and follow-up plotted against group scores for all experimental groups. The results
showed a decrease in scores for the placebo TENS and active IFT, and an increase
for all the other groups.

309

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed no significant effect over time (p=0.43). There was no significant difference
between groups (p=0.62) nor an interactive effect (p=0.41; see Table 6.34).

6.5.12 Appetite Loss (AP)

Raw data for appetite loss are presented in Appendix LIX and summarised in Table
6.35 and Figure 6.21. Appetite loss is expressed as difference scores between
baseline and follow-up plotted against group scores for all experimental groups. The
results showed a general increase in scores for all the groups.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was not normal, therefore non-parametric analysis
was performed (Kruskal-Wallis). The Kruskal-Wallis test demonstrated that there
was no significant difference between the groups (p=0.45; see Table 6.36).

6.5.13 Constipation (CO)

Raw data for constipation are presented in Appendix LX and summarised in Table
6.37 and Figure 6.22. Constipation is expressed as difference scores between
baseline and follow-up plotted against group scores for all experimental groups. The

310

results showed a decrease on scores for the active TENS and control group, and an
increase for all the other groups.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed a no significant difference effect over time (p=0.16). There was no
significant difference between groups (p=0.95) nor an interactive effect (p=0.33; see
Table 6.38).

6.5.14 Diarrhoea (DI)

Raw data for diarrhoea are presented in Appendix LXI and summarised in Table
6.39 and Figure 6.23. Diarrhoea is expressed as difference scores between baseline
and follow-up plotted against group scores for all experimental groups. The results
showed a decrease in scores for the control group, and an increase for all the other
groups.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed no significant effect over time (p=0.65). There was no significant difference
between groups (p=0.85) nor an interactive effect (p=0.67; see Table 6.40).

311

6.5.15 Financial Difficulties (FI)

Raw data for financial difficulties are presented in Appendix LXII and summarised
in Table 6.41 Figure 6.24 summarises financial difficulties expressed as difference
scores between baseline and follow-up plotted against group scores for all
experimental groups. The results showed a decrease on scores for all the groups with
the exception of the IFT active group.

The Levenes test of equality of error variances showed that the distribution of scores
around the mean within groups was normal, therefore parametric analysis was
performed (ANOVA: repeated measures). The repeated measures ANOVA test
showed a significant effect over time (p<0.01). There was no significant difference
between groups (p=0.71) nor an interactive effect (p=0.11; see Table 6.42).

6.6 Discussion
The purpose of the present study was to compare the effectiveness of TENS and IFT
upon pain, nausea and vomiting in cancer patients receiving chemotherapy, and its
impact on the quality of life of these patients.

During the last decade, considerable progress has been made in the pharmacological
treatment of chemotherapy-induced emesis. The latest advance in antiemetic therapy
has been the introduction of widespread use of 5-HT 3 receptor antagonists. Not
withstanding these advances, emesis remains a critical problem in cancer patients

312

and several approaches have been used in the management of the clinical care of
patients receiving chemotherapy. Attention has been given to the ability of
acupuncture to reduce emesis evoked by different stimuli (Vickers, 1996).

Professor Dundee and his co-workers were some of the earliest medical practitioners
to investigate the beneficial effects of electrical stimulation of the PC-6 antiemetic
point as an adjuvant to standards antiemetics. Dundee et al. (1987) studied the effects
of electroacupuncture (10 Hz, 250 s) applied to the PC-6 point in 10 inpatients
receiving an infusion containing cisplatin (30 mg) as part of a regimen for testicular
cancer. Electroacupuncture to either the PC-6 point or to a dummy point was
applied immediately before or soon after the starting of the infusion. Every patient
had five or six electroacupuncture treatments over three days. At least eight hours
elapsed between successive treatments. The effects over eight hours were graded as
very poor, some benefit, no change or worse. The results showed that there
was significantly less sickness when PC-6 point was done than when the dummy
point was used (p<0.001).

Extending this previous work, Dundee et al. (1989), investigated the efficacy of PC6 electroacupuncture (10 Hz applied for 5 min) in 130 patients (15 in an open pilot
study, 10 in a randomised placebo controlled crossover study - the authors included
the results of the study carried out in 1989 and described above - and 105 in a

313

definitive study) who had a history of distressing sickness. The authors concluded
that sickness was completely reduced or absent in 97% of the patients.

Dundee and Yang (1990) following the methodology from previous work, carried
out a study that investigated if acupressure would prolong the antiemetic effect of
PC-6 acupoint. Forty subjects (20 inpatients and 20 outpatients) had PC-6
electroacupuncture (10 Hz applied for 5 min). The Sea Band was applied
immediately after acupuncture and patients were instructed to press the stud for 5
min. Both procedures were carried out before the administration of chemotherapy.
Inpatients were assessed during the first 6-8 hours after electroacupuncture and
thereafter until 24 hours. The outpatients were only seen at their next visit to the
clinic, which could be 1-3 weeks after. The results showed that 97% of the patients
benefited and in 95% of the patients the antiemetic action was maintained for 24
hours.

The results of the present investigation are in contrast with those from Dundee et al.
(1987, 1989) and Dundee and Yang (1990). This fact may be explained by the
different methodologies used by both studies. The Dundee studies did not include a
control group, they were not double-blinded and the assessment procedures were not
comparable to the ones used in this study. Moreover, the electroacupuncture
stimulation parameters used in the present study did not match the parameters used
in the previously cited studies thus rendering any sort of comparison inappropriate.

314

In addition, the combination of antiemetic drugs used in the studies carried out by
Dundee (metoclopramide, thiethyperazine, prochlorperazine and cyclizine with
lorazepam and a steroid) were different than the ones used in the present
investigation (metoclopramide and a 5-HT 3 antagonist).

Aglietti et al. (1990) conducted a study on 26 women who received cisplatin

chemotherapy

and

received

as

antiemetic

treatment

combination

of

metoclopramide, dexamethasone and diphenhydramine. Acupuncture according to

traditional Chinese medicine was also carried out. A needle was placed in the 6MC
point (pericardium meridian) during the infusion of cisplatin (20 min) and then
replaced by a needle for permanent use, which was removed 24 hours after the
cisplatin administration. The assessment of efficacy of antiemetic treatment was
based on the overall count of the number of vomiting episodes, the duration of
vomiting episodes, the intensity of nausea and its duration. The results showed that
there was no difference between the two groups in complete prevention from both
nausea and vomiting and from vomiting alone. However, complete prevention from
nausea, the mean number of vomiting episodes, the mean maximal score of nausea
and the duration of nausea and vomiting were reduced by the addition of
acupuncture. These results are in accordance with the results obtained in this study,
when the scores for the control group are compared to the other groups. However,
the Aglietti study (1990) did not include a placebo group that would validate the
results obtained and the sample size was very small. In addition, the acupoint used in

315

the Agliett study (6MC) was different than the one used in the present investigation
(PC-6).

The introduction of 5-HT 3 antagonists has revolutionised the treatment of nausea

and vomiting that frequently follows chemotherapy treatments. However, there
remain some patients for whom this 5-HT 3 antagonist gives only a partial
improvement of symptomatology, particularly on the 3rd and 4th days of treatment
(Kris et al., 1998).
MacMillan et al. (1991) conducted a randomised crossover study in 16 hospitalised
patients which investigated the degree of sickness over a five day period when the
chemotherapy was accompanied by ondansetron or by ondansetron and
transcutaneous electrical stimulation (TCES) of PC-6. The results showed that there
was a beneficial effect from TCES. Of the 16 patients, four showed no difference
between degrees of nausea and vomiting with ondansetron alone and when
combined with TCES. All of the remaining 12 showed a preference in favour of the
latter. It is interesting that the results of the present study, namely concerning the
duration and severity of vomiting the results in the active IFT group, are in
accordance with the ones quoted in the McMillan and Dundee study (1991).
However, these authors did not included a placebo group, was not double-blinded,
the sample size was very small and therefore the results may be questionable.

316

The development of 5-HT 3 receptor antagonist has considerably improved

antiemetic therapy. However, delayed nausea and vomiting has proven more difficult
to control. Prospective trials suggest that 50% to 93% of patients still suffer from
delayed nausea and vomiting (Kris et al., 1989; Marty et al., 1990). It is clear that
additional methods are needed to improve the quality of life of patients receiving
high cytotoxic chemotherapy.

Shen et al. (2000) compared the effect of electroacupuncture with manual needling
and sham electrical stimulation and antiemetic medication alone on 104 women
diagnosed with high-risk breast cancer and receiving a high-dose, multiple-day,
multiple-drug myeloablative chemotherapy (cisplatin, cyclophosphamide and
carmustine). The primary outcome was the total number of emetic episodes that
occurred during the 5-day study. The results demonstrated that adjunct
electroacupuncture was more effective in controlling emesis than minimal needling
or antiemetic pharmacotherapy alone. These results are difficult to contrast with the
results of the present study as the primary outcomes of the present investigation are
duration and severity of nausea and vomiting as opposed to number of episodes. In
addition, the electrical stimulation parameters, as well as the acupoints used in the
present investigation, were different than the ones used in the Shen et als study.
Moreover, the antiemetic protocol was different. The patients in the Shens study
received more antiemetic medication (10 mg of proclorperazine prechemotherapy,
followed by continuous intravenous infusion at 1 mg/m body surface area per hour;

317

lorazepam, 1 mg/m body-surface area, intravenously, every 4 hours; and

diphenhydramine hydrochloride, 25 mg/m body-surface area, intravenously, every 6
hours) than the patients who took part in the present investigation (a single dose of
10 mg of a 5HT3 antagonist - ondanseteron - as well as 8 mg of dexamethasone
injected 1 hour prior to the chemotherapy session). The differences between the
research protocols may render comparisons of the results questionable.

Recently, Tan et al. (2001) investigated whether the combination of TENS and
ondansetron had an increased antiemetic effect on patients receiving
chemotherapy regimens that included cisplatin. Fourteen testis and eleven bladder
cancer patients were invited to participate in the study. Patients were randomly
allocated to one of the following regimens: TENS alone vs. ondansetron alone vs.
a combination of both. Before cisplatin infusion, 4 mg of ondansetron was given
intravenously and repeated at the middle of the infusion and at the end. Thus the total
dose was 12 mg/day. TENS (4 Hz) was applied 1 hour before the infusion of
cisplatin and continued throughout the infusion. Patients were asked to report any
nausea and the number of emetic episodes experienced during the administration of
cisplatin. The results demonstrated that a statistically significant difference was
present between the number of emetic episodes observed with TENS +
ondansetron combination and TENS alone (p=0.000) or ondansetron alone
(p=0.001). Ondansetron was again better than TENS in preventing emetic attacks
(p=0.001). It is interesting that in this study the assessment of nausea and emesis

318

took place during the administration of the chemotherapy (8-hour period) when it has
been described by several authors (Tonato and Roila, 1995; Patter et al., 1997; Kris
et al., 1998) that acute emesis occurs in the first 24 hours after the administration of
the chemotherapy and that it is well controlled by the administration of 5-HT 3
antagonists. A limitation of this study is the non-existence of a control and a placebo
group in order to validate the results, as well as the small sample size. The results of
this study are in conflict with the results of the present investigation. The reason
might be explained by the different methodologies used as well as the use of
different antiemetic protocols.

Pain is one of the most common and feared symptoms associated with cancer.
According to Grossman (1999) approximately 20-50% of patients with cancer
present with pain, 33% have pain during the treatment of their disease, and 75 - 90%
in the advanced stages of their disease experience moderate to severe pain requiring
treatment with opioids. Unrelieved pain has a substantial effect on patients
activities, affect, motivation, social and personal interactions, and overall quality of
life.

In the present investigation, subjective pain assessment was carried out using a VAS.
Analysis of the results showed that there was a significant difference between groups
over time (p<0.0001). However, there was not an interactive effect (p=0.42).
Moreover, the average scores obtained for the active TENS and active IFT groups

319

(1.10.37; 1.180.35) were lower then the scores obtained for the Control and
placebo TENS groups (1.180.26; 1.360.43). An aspect that is worthwhile taking
into account is the severity of baseline pain. The results showed that the baseline
scores for the active TENS and IFT groups were substantially higher (1.260.36,
means.e.m. and 1.40.33, means.e.m) when compared to the placebo TENS group
(0.950.28, means.e.m.), placebo IFT group (0.940.22, means.e.m.) and the
Control group (0.770.18, s.e.m.). This fact might have implications on the analysis
and interpretation of the results. The results also showed a substantial decrease in the
scores post-chemotherapy, which is open to speculation in terms of a possible
placebo effect. Cognitive factors like expectation of pain relief are supposed to
trigger the release of endogenous opioids (Amanzio and Benedetti, 1999) and in
addition the so called anxiety theory (Evans, 1985) postulates that placebo
analgesia is caused by a reduction of anxiety. This may well explain the results
obtained.

Chemotherapy-induced emesis has been a major apprehension to patients receiving

chemotherapy, as illustrated in a multiplicity of studies (Laszlo, 1983; Levine et al.,
1987; Richardson et al., 1988; Roscoe et al., 2002). The extent to which such
symptoms disrupt various domains of health-related quality of life has become a
subject for systematic study (Lindley et al., 1992; OBrien et al., 1993; Lebeau et al.,
1997; Harousseau et al., 2000). In the present study, quality of life was measured by
the EORTC QLQ-C30 questionnaire. Findings of this study indicated that overall

320

quality of life (global health status), pain, and nausea and vomiting did not improve.
These findings are in accordance with a pilot study conducted by Gadsby et al.
(1997) who also reported that the use of acupuncture-like transcutaneous electrical
nerve stimulation to alleviate pain nausea and vomiting were not demonstrated.

Compliance can be defined as the extent to which a patient's behaviour coincides

with clinical advice (Haynes, 1979). Poor compliance may produce adverse effects
on the quality of medical care (Giuffrida and Torgerson, 1997). Many strategies have
been suggested to improve compliance. These include providing written and verbal
information (Sandler et al., 1989). In the present investigation compliance was
achieved and promoted by providing the patients with a manual of instruction
concerning the use of the electrical stimulators as well as with information regarding
the filling of the questionnaires. Compliance was monitored on a daily basis by a
telephone call to the patients. A high degree of compliance was achieved. This is
reflected by the small number of non-compliant patients (four).

6.7 Conclusion
The effects of acupuncture on health care are generally difficult to assess (Vickers,
1996; NHI, 1997). Randomised controlled trials designed to test the efficacy of
acupuncture seem to produce contradictory outcomes (Kaptchuk, 2002; Roscoe et
al., 2002). Different methodologies, inappropriate sample sizes and other factors

321

such as the lack of appropriate controls and inadequate follow-up have rendered
comparisons between studies difficult (NIH, 1977; Kaptchuk, 2002).

According to the parameters used in this investigation, the application of TENS and
IFT for the control of chemotherapy-induced pain, nausea and vomiting did not show
statistically significant differences between groups. However, the results showed a
trend towards the effectiveness of the TENS and IFT when compared to the control
group namely concerning the duration and severity of vomiting and nausea.
Therefore, the findings of the present investigation provide enough justification for
further studies on the use of the electrical stimulation as an adjuvant therapy in the
control of nausea and vomiting induced by chemotherapy.

322

Figure 6.1
Acupad TPT2200/CT TENS unit (Nidd Valley Medical Ltd.,
North Yorkshire, UK)

323

Figure 6.2
Interferential unit OMEGA Inter 4150 (Tens Care, Kingston, UK)

324

Figure 6.3
Electrode placement over the PC6 Neiguan acupoint

325

326

IFT Active

80

60

40

Duration of Vomiting (min)

Control

TENS Placebo

IFT Placebo

100

TENS Active

20

Figure 6.5

3
Days
2
1

326

Summary of duration of vomiting scores plotted against time (min) (means.e.m.)

120

250

200

150

100
Duration of Nausea (min)

TENS Placebo
TENS Active

IFT Active

50

3
2
1

Days

Figure 6.6

327

Summary of duration of nausea scores plotted against time (min) (means.e.m.)

IFT Placebo

300

Control

350

0,8

0,6
Severity of Vomiting

TENS Placebo
IFT Placebo
IFT Active

0,4

0,2

Figure 6.7

3
2
1

Days

328

Summary of severity of vomiting scores plotted against time (days) (means.e.m.)

TENS Active

Control

1,2

1,5

1
Severity of Nausea

Control

TENS Placebo
IFT Placebo

TENS Active
IFT Active

0,5

Figure 6.8

329

5
4
3
2
1

Days

Summary of severity of nausea scores plotted against time (days) (means.e.m.)

2,5

IFT Placebo

TENS Active
IFT Active

1,5

0,5

Figure 6.9

3
2
1

Days
330

Summary of VAS pain scores (%) plotted against time (days) (means.e.m.)

Pain Score

Control

2,5

TENS Placebo

s
100

80
70

Scores

60
50
40
30
20
QOL Baseline
QOL Follow-up

10
0
Placebo TENS

Active IFT

Groups
331

Placebo IFT

Control

Figure 6.10

Active TENS

Summary of global health scores plotted against group scores (means.e.m.)

90

100

80
70

Scores

60
50
40
30
20
PF Baseline

10

PT Follow-up

0
Active TENS

Placebo TENS

Active IFT

332

Control

Figure 6.11

Groups

Placebo IFT

Summary of physical functioning scores plotted against group scores (means.e.m.)

90

100

80
70

Scores

60
50
40
30
20
RF Baseline
RF Follow-up

10

Active TENS

Placebo TENS

IFT Active

Groups

333

Placebo IFT

Control

Figure 6.12

Summary of role functioning plotted against group scores (means.e.m.)

90

90
80
70

Scores

60
50
40
30
20
EF Baseline
EF Follow-up

10
0
Placebo TENS

Active IFT

Groups

334

Placebo IFT

Control

Figure 6.13

Active TENS

Summary of emotional functioning scores plotted against group scores (means.e.m.)

100

90
80
70

Scores

60
50
40
30
20
CF Baseline
CF Follow-up

10

Active TENS

Placebo TENS

Active IFT

Groups

335

Placebo IFT

Control

Figure 6.14

Summary of cognitive functioning plotted against group scores (means.e.m.)

100

100
90

70

Scores

60
50
40
30
20
10

SF Baseline
SF Follow-up

0
Placebo TENS

Active IFT
Groups

336

PlaceboIFT

Control

Figure 6.15

Active TENS

Summary of social functioning plotted against group scores (means.e.m.)

80

100

90
80

Scores

60

50

40

30

20
FA Baseline

10

FA Follow-up

0
Placebo TENS

Active IFT

Groups

337

Placebo IFT

Control

Figure 6.16

Active TENS

Summary of fatigue plotted against group scores (means.e.m.)

70

90
80
70

Scores

60
50
40
30
20
N & V Baseline
N & V Follow-up

10
0
Active TENS

Place bo TENS

Active IFT

338

Control

Figure 6.17

Groups

Place bo IFT

Summary of nausea and vomiting scores plotted against group scores (means.e.m.)

100

100
90

70

Scores

60
50
40
30
20
PA Baseline

10

PA Follow-up

Active TENS

Placebo TENS

Active IFT

Groups

339

Placebo IFT

Control

Figure 6.18

Summary of pain scores plotted against group scores (means.e.m.)

80

100

90

70

Scores

60

50

40

30

20

DY Baseline
DY Follow-up

10

Active TENS

Placebo TENS

Active IFT

Groups
340

Placebo IFT

Control

Figure 6.19

Summary of dyspnoea plotted against group scores (means.e.m.)

80

100
90

70

Scores

60
50
40
30
20
SL Baseline
SL Follow-up

10
0
Placebo TENS

Active IFT

Groups
341

Placebo IFT

Control

Figure 6.20

Active TENS

Summary of insomnia plotted against group scores (means.e.m.)

80

100
90

70

Scores

60
50
40
30
20
AP Baseline

10

AP Follow-up

Active TENS

Placebo TENS

Active IFT

Groups

342

Placebo IFT

Control

Figure 6.21

Summary of appetite loss plotted against group scores (means.e.m.)

80

100
90
80

Scores

60
50
40
30
20
CO Baseline

10

CO Follow-up

0
Active TENS

Placebo TENS

Active IFT

343

Control

Figure 6.22

Groups

Placebo IFT

Summary of constipation plotted against group scores (means.e.m.)

70

100
90
80

Scores

60
50
40
30
20
DI Baseline

10

DI Follow-up

0
Placebo TENS

Active IFT

Groups

344

Placebo IFT

Control

Figure 6.23

Active TENS

Summary of diarrhoea plotted against group scores (means.e.m.)

70

90
80
70

Scores

60
50
40
30
20
FI Baseline
FI Follow-up

10

Active TENS

Placebo TENS

Active IFT

Groups

345

Placebo IFT

Control

Figure 6.24

Summary of financial difficulties plotted against group scores (means.e.m.)

100

346

345

Table 6.3
Summary of raw data for duration of vomiting (min) (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

PostChemo

00

00

00

00

00

Day 2

56.1246.78

1.660.99

2.42.4

16.3310.97

3.463.46

Day 3

60.9746.69

12.6211.4

2.42.4

0.090.09

1.21.2

Day 4

61.0349.97

2.861.71

2.42.4

0.870.68

0.080.08

Day 5

41.4527.42

1.661.43

2.42.4

0.650.47

0.20.2

346

Table 6.4
Summary of statistical analysis for duration of vomiting

(a) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Post
Chemo

Day 2

Day 3

Day 4

Day 5

KW p value

0.17

0.07

0.35

0.44

347

Table 6.5
Summary of raw data for duration of nausea (min) (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

PostChemo

1.91.9

0.30.19

00

0.10.1

3.52.3

Day 2

171.659.4

139.570.7

22.510.1

130.568.7

122.351.1

Day 3

21078.7

173.572.2

8457.9

139.1874.2

222.787.6

Day 4

165.5166.8

102.247.4

14582

130.8668.3

72.726.7

Day 5

11052.8

48.834.7

89.459.7

9366.5

65.235.8

348

Table 6.6
Summary of statistical analysis for duration of nausea

(a) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Post
Chemo

Day 2

Day 3

Day 4

Day 5

KW p value

0.29

0.4

0.51

0.96

0.98

349

Table 6.7
Summary of raw data for severity of vomiting (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

PostChemo

00

00

00

00

00

Day 2

0.420.21

0.620.36

00

0.580.28

0.260.2

Day 3

0.680.26

0.480.26

0.350.25

0.220.15

0.190.14

Day 4

0.650.26

0.670.38

0.080.08

0.540.31

0.120.08

Day 5

0.580.25

0.330.25

0.160.16

0.260.18

0.20.16

350

Table 6.8
Summary of statistical analysis for severity of vomiting

(a) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Post
Chemo

Day 2

Day 3

Day 4

Day 5

KW p value

0.26

0.38

0.4

0.63

351

Table 6.9
Summary of raw data for severity of nausea (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

PostChemo

0.190.13

0.430.3

00

0.080.08

0.330.23

Day 2

1.230.28

1.10.36

0.360.14

1.210.34

0.890.21

Day 3

1.320.29

1.480.43

0.770.26

0.960.3

1.310.27

Day 4

1.260.29

1.150.34

0.80.25

0.920.28

1.040.24

Day 5

0.870.27

0.810.34

0.560.25

0.610.25

0.680.23

352

Table 6.10
Summary of statistical analysis for severity of nausea

(a) Kruskal-Wallis/Mann-Whitney U tests

Time (Days)

Post
Chemo

Day 2

Day 3

Day 4

Day 5

KW p value

0.29

0.23

0.58

0.86

0.96

353

Table 6.11
Summary of mean VAS for pain (%) (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Day 1

0.770.18

0.950.28

0.940.22

1.260.36

1.40.33

Day 2

1.060.22

1.160.37

0.670.19

0.990.39

1.070.32

Day 3

1.450.31

1.460.43

1.080.34

1.050.37

1.360.41

Day 4

1.220.27

1.750.55

1.240.42

1.060.33

1.110.43

Day 5

1.410.32

1.520.52

1.440.43

1.160.41

0.860.29

354

Table 6.12
Summary of statistical analysis for pain VAS data (%)

(a) Levenes test of equality of error variances.

Group

p value

VAS pre chemo

0.12

VAS post chemo

0.47

Day 2

0.05

Day 3

0.07

Day 4

0.38

Day 5

0.6

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

2.688

0.307

0.873

Repeated Measures (B)

2.698

18.763

6.93

<0.0001

Interaction AB

10.792

2.783

1.028

0.421

355

Table 6.13
Summary of raw data for quality of life - global health status raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

51.83.7

57.55.26

56.83.9

53.65.16

60.45.2

Follow-up

48.94

56.36

55.43.5

515.16

55.54.7

356

Table 6.14
Summary of statistical analysis for global health status

(a) Levenes test of equality of error variances

Time

p value

Global health
status baseline

0.46

Global health
status follow-up

0.15

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

526.275

2.016

0.15

Repeated Measures (B)

603.72

0.69

0.6

Interaction AB

14.933

0.057

0.99

357

Table 6.15
Summary of raw data for quality of life physical functioning raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

75.43.5

76.14.6

75.92.9

76.54.2

81.93.5

Follow-up

75.23.6

79.33.5

74.33.2

72.24.1

78.24

358

Table 6.16
Summary of statistical analysis for physical functioning

(a) Levenes test of equality of error variances.

Time

p value

Physical functioning
0.69

baseline
Physical functioning

0.74

follow-up

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

94.136

1.118

0.29

Repeated Measures (B)

254.712

0.387

0.81

Interaction AB

94.734

1.125

0.34

359

Table 6.17
Summary of raw data for quality of life role functioning raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

656.2

79.35.8

85.13.9

69.36.2

85.14.8

Follow-up

68.26.3

63.48.1

89.13.5

70.65.8

5320.9

360

Table 6.18
Summary of statistical analysis for role functioning

(a) Levenes test of equality of error variances.

Time

p value

Role functioning
0.15

baseline
Role functioning

0.04

follow-up

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

3882.368

2.505

0.11

Repeated Measures (B)

3599.988

1.452

0.22

Interaction AB

3232.45

2.086

0.08

361

Table 6.19
Summary of raw data for quality of life emotional functioning raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

63.14.9

65.86.6

76.74.3

665.3

754.5

Follow-up

75.53.6

71.26.1

78.24.8

66.36.4

833.9

362

Table 6.20
Summary of statistical analysis for emotional functioning

(a) Levenes test of equality of error variances.

Time

p value

Emotional functioning
0.41

baseline
Emotional functioning

0.04

follow-up

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

2.934

0.002

0.96

Repeated Measures (B)

3100.53

1.415

0.23

Interaction AB

2320.347

1.352

0.25

363

Table 6.21
Summary of raw data for quality of life cognitive functioning raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

74.75.6

84.15.3

84.53.1

864.5

86.33.6

Follow-up

74.75.2

80.14.5

88.43

814.4

87.64.5

364

Table 6.22
Summary of statistical analysis for cognitive functioning

(a) Levenes test of equality of error variances.

Time

p value

Cognitive functioning
0.01

baseline
Cognitive functioning

0.09

follow-up

(b) Kruskal-Wallis test.

Difference scores
cognitive functioning
KW
p value

0.17

365

Table 6.23
Summary of raw data for quality of life social functioning raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

80.15.2

88.84.1

86.34.5

83.34.3

85.74.6

Follow-up

77.45.6

82.55.4

89.73.7

806.2

825.4

366

Table 6.24
Summary of statistical analysis for social functioning

(a) Levenes test of equality of error variances.

Time

p value

Social functioning
0.25

baseline
Social functioning

0.28

follow-up

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

343.605

0.834

0.36

Repeated Measures (B)

648.518

0.685

0.6

Interaction AB

203.088

0.493

0.74

367

Table 6.25
Summary of raw data for quality of life fatigue raw data (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

37.94.9

25.36.1

28.13.3

37.35.4

20.23.6

Follow-up

37.94.7

37.56.7

24.73.5

44.85.3

31.64.3

368

Table 6.26
Summary of statistical analysis for fatigue

(a) Levenes test of equality of error variances

Time

p value

Fatigue baseline

0.03

Fatigue follow-up

0.09

(b) Kruskal-Wallis test

Difference scores fatigue

KW
p value

0.11

369

Table 6.27
Summary of raw data for quality of life nausea and vomiting raw data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

8.64.1

6.33.1

6.53.1

1.30.9

2.32.3

Follow-up

21.55.1

194.9

10.22.9

205

17.23.6

370

Table 6.28
Summary of statistical analysis for nausea and vomiting

(a) Levenes test of equality of error variances.

Time

p value

Nausea and vomiting

0.04

baseline
Nausea and vomiting

0.14

follow-up

(b) Kruskal-Wallis test.

Difference scores nausea and vomiting

KW
p value

0.25

371

Table 6.29
Summary of raw data for quality of life pain data (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

23.63.9

17.45.6

16.64.1

17.34.7

18.45

Follow-up

26.85.1

27.76.3

13.44

225.4

22.25.8

372

Table 6.30
Summary of statistical analysis for pain

(a) Levenes test of equality of error variances.

Time

p value

Pain baseline

0.55

Pain follow-up

0.24

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

1025.133

3.047

0.08

Repeated Measures (B)

940.426

0.971

0.42

Interaction AB

200.675

0.597

0.66

373

Table 6.31
Summary of raw data for quality of life dyspnoea (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

6.43.9

7.93.9

4.72.8

9.33.6

1.11.1

Follow-up

7.54

4.72.6

6.43.2

5.33.1

3.72.7

374

Table 6.32
Summary of statistical analysis for dyspnoea

(a) Levenes test of equality of error variances.

Time

p value

Dyspnoea baseline

0.01

Dyspnoea follow-up

0.45

(b) Kruskal-Wallis test.

Difference scores dyspnoea

KW
p value

0.35

375

Table 6.33
Summary of raw data for quality of life insomnia (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

30.16.2

33.38.2

23.86.8

21.36.9

21.45.9

Follow-up

32.26.4

28.56.6

26.96.9

33.37.6

18.55.4

376

Table 6.34
Summary of statistical analysis for insomnia

(a) Levenes test of equality of error variances.

Time

p value

Insomnia baseline

0.9

Insomnia follow-up

0.44

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

374.39

0.624

0.43

Repeated Measures (B)

1162.761

0.656

0.62

Interaction AB

600.451

1.001

0.41

377

Table 6.35
Summary of raw data for quality of life appetite loss (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

20.45.7

14.25.4

8.32.7

165.4

9.54.1

Follow-up

295.9

22.26.6

10.23

327

19.75.6

378

Table 6.36
Summary of statistical analysis for appetite loss

(a) Levenes test of equality of error variances.

Time

p value

Appetite loss baseline

0.01

Appetite loss follow-up

0.06

(b) Kruskal-Wallis test.

Difference scores Appetite loss

KW
p value

0.45

379

Table 6.37
Summary of raw data for quality of life constipation (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

17.25

9.55.2

10.24.2

165.1

135.5

Follow-up

13.94.3

14.25.8

19.25.6

14.64.7

20.95.6

380

Table 6.38
Summary of statistical analysis for constipation

(a) Levenes test of equality of error variances.

Time

p value

Constipation baseline

0.58

Constipation-up

0.51

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

599.271

1.93

0.16

Repeated Measures (B)

175.477

0.16

0.95

Interaction AB

353.621

1.14

0.33

381

Table 6.39
Summary of raw data for quality of life diarrhoea (means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

8.63

4.72.6

2.92.9

6.64.3

3.51.9

Follow-up

5.32.2

6.33.7

6.43.7

10.64.7

4.92.3

382

Table 6.40
Summary of statistical analysis for diarrhoea

(a) Levenes test of equality of error variances.

Time

p value

Diarrhoea baseline

0.23

Diarrhoea follow-up

0.12

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

33.094

0.2

0.65

Repeated Measures (B)

135.437

0.339

0.85

Interaction AB

97.807

0.591

0.67

383

Table 6.41
Summary of raw data for quality of life financial difficulties data
(means.e.m.)

Time

Control

Placebo
TENS

Placebo
IFT

Active
TENS

Active IFT

Baseline

21.56.2

23.87.6

14.25.5

21.36.6

15.45.5

Follow-up

19.36.1

20.68.1

10.24.4

5.33.1

162.3

384

Table 6.42
Summary of statistical analysis for financial difficulties

(a) Levenes test of equality of error variances.

Time

p value

Financial difficulties
0.59

baseline
Financial difficulties

0.001

follow-up

(b) Repeated measures analysis of variance (ANOVA)

Source

df

Mean Square

F-test

p value

Condition (A)

1790.856

6.794

0.01

Repeated Measures (B)

875.675

0.533

0.71

Interaction AB

502.496

1.906

0.11

385

Chapter 7
General Discussion and Conclusion

386

7.1 Introduction
Torpedo fish, amber, and magnetic rings were used by Ancients Egyptians for
electrical treatment of painful states. However, most of the electrical devices used in
medicine were invented in the last three centuries (Cartwright, 1977).

By the late 1700s, Luigi Galvani (1791-1972) described a new phenomenon: a frogs
leg in a nerve-muscle preparation contracted every time the muscle and the nerve
were connected by a metal arc, which usually consisted of two different metals
(Kipnis, 1987; Bick, 1972; Geddes, 1994). Aldini, Galvanis nephew, championed
the use of direct-current stimulation. In a demonstration in England, he twitched the
muscles in the decapitated head of an executed criminal. This event linked electricity
and life and it was believed that electricity could restore life, a process called
reanimation (Geddes, 1994). Soon, all kinds of excitable tissues became the focus of
attention and the need for controllable electrical stimuli to induce activity emerged
(Geddes, 1994). The first stimulator was the capacitor, then the electrochemical cell
connected to a switch appeared, which could initiate and arrest current flow. Several
switches were developed to control repetition and duration of current flow. However,
it was the discovery of magnetic induction by Faraday in 1832 that paved the way for
creation of the most controllable stimulator, the inductorium (Geddes, 1994).

Following the development of the Leyden jar (around 1745) and the early theoretical
underpinnings of the electrical phenomenon disseminated by Benjamin Franklin

387

(1706-1790), the application of electricity to physiology was approached in a more

experimentally rigorous manner (Wu, 1984; Clower, 1998).

The analgesic properties of electricity have been known and used for thousands of
years (Kane and Taube, 1995). During the Renaissance period, the medical and
technological developments were determinant to the progressive sophistication of
methods of applying electricity to the human body, namely with the introduction of
the electric battery. Researchers continued to investigate electroanalgesia, but it was
only with the publication of the Melzack and Walls gate theory that electrical
stimulation induced analgesia was accepted by medical practitioners.

TENS is a non-pharmacological method of pain relief that involves the application of

controlled low voltage electrical pulses to the nervous system via electrodes placed
on the skin. TENS is applied at varying frequencies, intensities, and pulse durations
of stimulation. Frequency of stimulation is broadly classified as high frequency (>50
Hz), low frequency (<10 Hz), or burst (bursts of high frequency stimulation applied
at much lower frequency) TENS. Intensity is determined by the response of the
patient as either sensory level TENS or motor level TENS (Sluka and Walsh, 2003).

IFT is a form of current that utilize two sinusoidal output circuits that differ
somewhat from one another in frequency (e.g. 4000 and 4100 Hz respectively).
When these two outputs intersect, the difference in frequency causes the sine waves

388

amplitudes to summate, resulting in the so-called beat or envelope shaped pulse

(Alon, 1989).

As previously stated, the use of electrotherapeutic modalities by physiotherapists for

patient management represents a popular form of non-pharmacological clinical
intervention (Lindsay et al., 1995; Pope et al., 1995; Robertson and Spurritt, 1998).
Despite its widespread use from the beginning of the physiotherapy profession, there
is a lack of substantive scientific investigation of the effectiveness of this form of
clinical intervention. It is often poorly understood, sometimes inappropriately used
and the topic of substantial debate (Johnson, 1999, 2000; Watson, 2000). Thus,
continued research in this area is essential in order to optimise this form of clinical
intervention.

This thesis aimed to:

i). To determine the effectiveness of electrical stimulation (IFT and TENS) using
a validated pain model (delayed onset muscle soreness).
ii). To investigate any neurophysiological changes induced by electrical
stimulation (IFT, TENS and APS).
iii). To investigate the clinical effectiveness of electrical stimulation in the
management of pain, nausea and vomiting in cancer patients receiving antitumor chemotherapy.

389

iv). To investigate a possible relation between parameter manipulation and

observed outcomes.
v). To compare the effects of these three forms of electrical stimulation (IFT,
TENS, APS).

The first part of this thesis (Chapter 2) reviewed the studies carried out over the last
twenty-three years (1980-2003) on the use of electrical stimulation (TENS and IFT)
concerning its hypoalgesic, neurophysiological and anti-emetic effects. Two human
laboratory controlled studies (Chapters 3 and 4) were conducted in order to examine
the effects of TENS, IFT and a novel form of electrical stimulation named Action
Potential Stimulation (APS) upon pain and nerve conduction velocity. An RCT
(Chapter 6) was designed in order to investigate the role of electrical stimulation
(TENS and IFT) in the management of nausea and vomiting in cancer patients
receiving a high/moderate cytotoxic chemotherapeutic regimen.

Despite the widespread use of electrical stimulation (TENS and IFT) in the
management of pain, the literature review in Chapter 2 questions its effectiveness,
namely the mechanisms by which TENS and IFT produce pain relief (i.e. gating or
descending inhibitory pathways). Methodological problems related to TENS and IFT
trial design are also reported: randomization; blinding procedures; sample size;
adequate placebos; outcome measures and different stimulation parameters used
have rendered comparison between studies very difficult.

390

Electrical stimulation, namely TENS, has also been used as adjuvant therapy in the
management of nausea and vomiting (e.g. chemotherapy induced nausea and
vomiting, post-operative nausea and vomiting, motion induced-nausea and
vomiting). The literature review also points out methodological problems related to
the number and selection of acupoints used, treatment parameters, number and
frequency of sessions, blinding and sham procedures and adequate controls.

The following discussion will underline the most relevant findings of the chapters
presented in this thesis and stress their implication to the clinical environment as well
as recommendations of areas that require further investigation.

7.2 Hyopalgesic effects of electrical stimulation (TENS and IFT)

In order to investigate the hypoalgesic effects of electrical stimulation and the
possible importance of parameter selection, a double-blind placebo-controlled
laboratory study was developed to compare the effects of IFT using two different
stimulation protocols (10-20 Hz; 80-100 Hz with a fixed pulse duration of 125 s)
upon an experimental pain model (DOMS) over an extended duration (i.e. 5 days)
(Chapter 3). Several authors have suggested that DOMS may be used as a model to
study the effectiveness of various forms of treatment for controlling acute
inflammation and pain (Smith, 1990; Craig et al., 1996; OGrady et al., 1999). This
model has also been extensively used at this research centre to investigate the
hypoalgesic effects of various forms of therapeutic modalities. Findings from

391

analysis of daily treatment effect for pain VAS upon extension on day 2
demonstrated a significant difference favouring IFT1 (10-20 Hz) when compared
with the control (p =0.02) and IFT2 (80-100 Hz) (p=0.01) groups respectively but
not compared with the placebo (see Fig 3.13). The results also demonstrated a
statistically significant difference on day 3 (VAS at point 2) in favour of control
when compared with IFT2 (p=0.001) and placebo (p=0.002) (see Fig 3.15). Trends
were found in favour of IFT for MPT and VAS scores. However, the analysis of
results did not provide substantial evidence of any significant hypoalgesic effect of
IFT treatment upon DOMS-associated pain, at least at the parameters used in this
study. These results are in contrast to the work of Schmitz et al. (1997) on the effect
of interferential current on perceived pain and serum cortisol levels associated with
DOMS. The authors claimed a significant decrease in perceived pain scores across
time but no significant difference in serum cortisol. However, the authors did not
include placebo and control groups, and the sample size included only five subject in
each group. Moreover, the stimulation parameters used were different than the ones
used in this investigation, namely the carrier frequency. Denegar and Huff (1988)
and Denegar et al. (1989) reported statistically significant reductions in perceived
pain levels when applying TENS to DOMS. In the Denegar et al. (1989) study, the
authors also recorded the effects of TENS on the serum cortisol concentration and
concluded that the levels of cortisol did not increase. It is interesting that in the
Denegar et al. (1989) and Schmitz et al. (1997) studies the perceived pain levels
decreased, whereas the levels of serum cortisol did not rise. This is open to

392

speculation on how the mechanisms acted via electrical stimulation, either by spinal
gating mechanisms or by the release of endogenous opioids (it is believed that TENS
can increase the release of -endorphin with consequent increase in the synthesis and
liberation of serum cortisol) (Schmitz et al.,1997).

The results of the present study (see Chapter 3) are novel as no previous published
study of IFT on DOMS has included control and placebo groups, therefore
contradictory findings reported here might have occurred as a result of the
differences in experimental protocols, possibly as a consequence of the lack of
blinded controls as well as in the randomisation procedures in the previous studies.

Experimentally induced mechanical pain threshold (MPT) has been used extensively
to evaluate the perception of pain, and the efficacy of therapeutic interventions for
the treatment of painful conditions (Kosek and Ordeberg, 2000; Chesterton et al.,
2003). Treatment induced changes in MPT observed in laboratory research are
proposed to correlate well with changes in clinical status of pain, and as such MPT is
considered a useful and reliable experimental model (Fisher, 1987a,b; Nussbaum and
Dowes, 1998; Chesterton et al., 2003). Zoppi et al. (1981) and Marchand et al.
(1991) both reported changes in a range of sensory thresholds after the application of
TENS (50-100 Hz). Furthermore, Ward and Robertson (1998) showed that
manipulating the frequency of alternating currents over a wide range of 1-35 kHz
(amplitude modulated at 50 Hz) produced clear separation of sensory and motor and

393

pain thresholds. They found that the three thresholds decreased as frequency
increased up to 10 kHz; above 10 kHz, the thresholds increased again.

To extend the previous work described in Chapter 3 on the hypoalgesic effects of

electrical stimulation, a double-blind placebo-controlled laboratory study was carried
out to compare the effects of three different types of electrical stimulation (see
Chapter 4), i.e. IFT (150 Hz, 125 s), TENS (150 Hz, 125 s) and a novel form of
electrical stimulation named Action Potential Therapy (APS) (153 Hz, 6.4 ms). In
order to measure MPT, two recording points were marked on the palmar surface of
the right hand as this represented an area innervated by the median nerve. The results
showed no statistically significant differences between groups (p0.32). However,
findings showed a marginal hypoalgesic effect in the IFT group (see Fig 4.15). These
findings are in accordance with previous work conducted by Johnson and Wilson
(1997) and Tabasam and Johnson (1999) who reported increases in ice pain
thresholds after the application of IFT, but it contradicts previous work conducted by
this research group (Walsh et al., 1995; 1998). However, the stimulation parameters
used in the NCV study (see Chapter 4) were different than the parameters used in
previous studies (different frequencies and different pulse duration), which
emphasize the idea of parameter specific effects as stated by Walsh et al. (1995).

Although laboratory studies indicate that electrical stimulation can have

physiological effects (see Chapter 4), clinical studies in the area are frequently

394

inconclusive. Randomised controlled clinical trials are the gold standard to test for
the specific effectiveness of a therapy (Koes and Hoving, 1998; Sackett et al., 1998).
Therefore, a double-blind randomised placebo controlled clinical trial was carried
out to compare the hypoalgesic effects of TENS and IFT on cancer patients receiving
antineoplastic chemotherapy. The results for pain VAS showed significant
differences for patients across time (p<0.0001). There was no significant difference
between groups (p=0.87) or significant interaction (p=0.42). However, it is
interesting that the pain variations from baseline showed a decrease in pain scores for
the active TENS and active IFT groups when compared to placebo TENS, placebo
IFT and control groups respectively, which scores raised consistently throughout the
experimental period (see Chapter 6, Fig 6.9). The hypoalgesic trends observed in
favour of active IFT and active TENS are in accordance with the work of Avellanosa
and West (1982). The authors investigated the use of TENS in 60 cancer patients
with intractable pain for two weeks. Evaluation of the results showed seventeen
patients with an excellent response (28.3%), twenty-two patients reported a fair
response (36.2%) and twenty-one patients reported no relief (35.0%). Recently,
Ahmed et al. (1998) use a nonpharmacological analgesic therapy known as
percutaneous electrical nerve stimulation (PENS) in the management of opioidresistant cancer pain. In this study PENS was administered to three patients. Results
showed that two of the three patients achieved good to excellent pain relief that
lasted 24-72 hours after each treatment session. However, the design and quality of
both studies is open to debate once they were not double blinded, did not have

395

control and placebo groups and the sample size was too small. Nevertheless the
results described in the RCT, presented in Chapter 6, seem to be promising and
should be reason for further research.

7.3 Neurophysiological effects of electrical stimulation (TENS and IFT)

The effectiveness and explanation of the putative mechanisms underpinning
electrical stimulation-induced analgesia have been assessed using several
neurophysiological techniques that record from nociceptive afferents and allow
correlations between the discharge of afferents and the reported sensations of the
subject (Torebjrk and Hallin, 1974; Oosterwijk et al., 1994; Daube, 1999; Srinivasa
et al., 1999). However, the comprehensive antinociceptive mechanisms of action of
electrical stimulation are still largely unknown. In an attempt to identify the possible
mechanism(s) of action responsible for the neurophysiological and hypoalgesic
effects of electrical stimulation, a double blind controlled laboratory study was
carried out in order to compare the effects of three electrotherapeutic modalities
TENS, IFT and APS upon nerve conduction velocity (NCV) in the human median
nerve. The results demonstrated that the IFT group (150 Hz, 125 s) alone showed a
statistically significant difference in peak to peak amplitude of the compound action
potential measurements of the human median nerve. Previous work carried out at this
research centre showed a significant increase in negative peak latency (NPL) in the
superficial radial nerve after the application of TENS (110 Hz, 200 s) for 15 min
(Walsh et al., 1998). These findings contradict the results of the study presented in

396

Chapter 4. However, as several authors have previously stated, different stimulation

parameters produce different effects (Walsh and Baxter, 1996; Chakour et al., 2000).

The skin temperature affects nerve conduction velocity (Stalberg and Erdem, 2000).
There is a progressive increase in latency and a decrease in conduction velocity with
decreasing skin temperature (Sethi and Thompson, 1989; DeLisa et al., 1994). The
results of the nerve conduction study in this thesis showed no statistically significant
differences between groups for the ambient temperature or for skin temperature.
Therefore, the changes observed in peripheral nerve conduction may indicate an
ability to induce neurophysiological changes due to IFT.

7.4 Antiemetic effects of electrical stimulation (electroacupuncture) of the

acupoint PC-6 by TENS and IFT in the management of chemotherapy-induced
emesis.
As part of the holistic health movement, an increasing interest in unconventional
therapies as a supplement to conventional health care is an international phenomenon
(Thomas et al., 1991; Fisher and Ward, 1994; Richardson et al., 2000; Vickers and
Cassileth, 2001). The development of a scientific neuroelectrical acupuncture has
made it possible to consider a variety of clinical applications (Ulett, 1998).

In Chapter 6, the antiemetic effects of TENS and IFT were evaluated within a 5-day
study period and a 7-day follow-up. Statistical analysis showed no significant

397

differences between groups for duration of vomiting (p0.078)/nausea (p0.29), and

severity of vomiting (p0.26)/nausea (p0.23) at any of the time points. Further
statistical analysis (ANOVA repeated measures) also showed a non-significant
difference between groups for the global health status (p=0.6), no significant
difference for patients over time (p=0.15), nor a significant interactive effect
(p=0.99). The main conclusion was that the efficacy of TENS and IFT for the control
of chemotherapy-induced nausea and vomiting at the parameters used in this
investigation did not show statistically significant differences between groups.
However, the results showed a trend in favour of the effectiveness of the TENS and
IFT when compared to the control group namely the duration and severity of
vomiting and nausea.

The results obtained from Chapter 6 are novel, as to date there is no existing data
comparing the effectiveness of IFT and TENS upon pain, nausea and vomiting in
cancer patients receiving antitumoral chemotherapy. However, these results are in
accordance with a recent clinical trial on the use of electroacupuncture for the control
of high-dose, multiple-day, multiple-drug myeloablative chemotherapy-induced
emesis on 104 women. The authors reported a non-significant difference between
groups. The electroacupuncture group had fewer episodes of emesis than the
minimal needling group (p<0.001), whereas the minimal needling group had fewer
episodes of emesis than the antiemetic pharmacotherapy group (p=0.1). The

398

differences among groups were not significant during the 9-day follow-up period
(p=0.18) (Shen et al., 2000).

More recently, Roscoe et al. (2002) examined the effectiveness of an acustimulation

wristband for the relief of chemotherapy-induced nausea. The results showed no
statistically significant differences in average severity between groups. Therefore,
the authors stated that the findings were positive but not conclusive (Roscoe et al.,
2002).

Previous studies have suggested the effectiveness of electroacupuncture in

controlling nausea and emesis after cancer chemotherapy (Dundee and Yang, 1990;
McMillan and Dundee, 1991; Dundee et al., 1991; Tan et al., 2001). However,
methodological disparities between them such as research design, blinding
procedures, insufficient sample size, methods used for statistical analysis, acupoints
used and stimulation protocols have rendered comparisons between studies difficult
(Vickers, 1996; White et al., 2001; Kaptchuk, 2002).

In summary, the results of the clinical trial presented in this thesis on the efficacy of
TENS and IFT on the management of nausea and vomiting (severity and duration)
for the control of chemotherapy-induced nausea showed a trend towards their
effectiveness. Further studies will be needed regarding the effectiveness of TENS
and IFT in reducing nausea and vomiting.

399

Although trends were identified concerning the hypoalgesic and antiemetic effects of
TENS and IFT, conclusions should be taken cautiously while statistical significant
differences between groups were not found.

7.5 Clinical Implications

Electrical stimulation is one of the main therapeutic resources within
physiotherapeutic practice. Despite its widespread use from the early professional
times, it is often poorly understood. Advocates of evidencebased clinical practice
believe that clinical decision making should be based on the best available external
clinical evidence often derived from the basic medical sciences, as well as from
patient-centered clinical research (Sackett et al., 1998; Johnson, 2000). The primary
aim of this thesis was to evaluate the hypoalgesic, neurophysiological and antiemetic
effects of TENS and IFT. The following clinical implications can be derived from
the findings of these studies:

(i)

IFT applied at low (10-20 Hz) and high frequency (80-100 Hz) with 1:1
swing pattern did not show a hypoalgesic effect upon an acute pain model
(DOMS).

(ii)

The hypoalgesic effect of IFT did not significantly differ from TENS in
the management of cancer pain as demonstrated in Chapter 6.

400

(iii)

Despite the fact that the hypoalgesic effects of IFT were not statistically
significant different from TENS, some trends were observed in favour of
a hypoalgesic effect induced by IFT. This could be observed in Chapter 4,
where the results obtained demonstrated that the peak to peak duration
amplitude of a compound action potential recoded from the human
median nerve was significantly altered by IFT when compared to TENS
and APS.

(iv)

Findings from Chapter 6 suggest that IFT and TENS at the parameters
used did not have an antiemetic effect associated with cancer
chemotherapy. However, the clinical trial showed some trends for the
effectiveness of the IFT active group.

(v)

Results from chapter 6 namely concerning the duration of vomiting

indicates that it may be more appropriate to assess the effectiveness of
IFT and TENS on patients receiving only Cisplatin (highly emetogenic
compound).

(vi)

The utilization of TENS and IFT devices that could record the number of
treatments applied as well as the intensity applied would be desirable.
This would better control both variables and would allow inquiring about
their possible influence on the outcomes.

401

(vii)

A cross-cultural adaptation of the MANE questionnaire to the Portuguese

language of Portugal was carried out. Results from Chapter 5 showed that
the Portuguese version of MANE has content validity as well as a high
degree of reliability. These findings are particularly important taking into
account that the literature review did not identify a specific instrument to
assess nausea and vomiting in Portuguese. Therefore this Portuguese
version of the MANE questionnaire has provided an assessment tool for
Portuguese speaking clinicians.

7.6 Future Research

As previously stated, electrical stimulation namely, TENS and IFT, are very popular
modalities used within the physiotherapy profession. However, there is not enough
quality evidence available concerning the putative mechanisms of action, stimulation
parameters, and clinical efficacy regarding the clinical use of these modalities
(Chakour et al., 2000; Noble et al., 2000; Johnson, 2001).

The findings from this thesis provide some promising evidence for the potential
hypoalgesic and antiemetic effects of IFT. However, more research is necessary in
order to validate the results found in this thesis.

402

Although the gate control theory provides a putative neurophysiological

explanation for the use of electrical stimulation, the exact hypolagesic mechanisms
by which electrical stimulation interfere with nociceptive stimuli are still a matter of
debate, namely the role of the amplitude modulated carrier frequency used by IFT
units. Palmer et al. (1999) reported no differences in the threshold stimulation of
sensory and pain pathways when 4000 Hz carrier frequency was used in the presence
or absence of an amplitude-modulated wave. Taking into account the controversy
surrounding this issue, it is advisable to design further neurophysiological studies to
address this aspect.

Much of the debate around electrical stimulation appears to stem directly from
poorly defined stimulation protocols (Chakour et al., 2000). It has also been reported
that the effectiveness of electrical stimulation is parameter dependent, that is, each
mode of stimulation is thought to operate via a different underlying mechanism (Cox
et al., 1993; Walsh et al., 1995; Ma and Sluka, 2001). Clinicians use several
parameter combinations that usually involve a set of combinations between
frequency, intensity and pulse duration, and habitually, electrical stimulation is
applied at low frequency (<10 Hz) and high intensities (motor contraction) or high
frequency (>50 Hz) and low intensities (sensory perception) (Robinson and SnyderMackler, 1995). As Ma and Sluka (2001) state, one cannot be sure if the effects are a
result of frequency or intensity differences. Wang et al. (1997) assessed the effect of
intensity of TENS applied over an acupoint on postoperative patient-controlled

403

analgesia requirement for hydromorphone. The authors concluded that the higher the
intensity (9-12 Miliamp) the lower the consumption of hydromorphone. Thus, it
seems that further research is needed in order to clarify the role of intensity on
hypoalgesia induced by electrical stimulation.

The antiemetic mechanisms underpinning acupoint stimulation are not yet fully
understood (Al-Sadi, 1997; Dibble et al., 2000; Shen et al., 2000). However, it is
believed that electroacupuncture modulates serotonin, substance P, and endogenous
opiates, namely the release of -endorphin inducing an antiemetic action via the
receptors (Debreceni, 1993; Al-Sadi, 1997; Ulett, 1998; Shen et al., 2000). Thus,
further neurophysiological and neurochemical research is needed in order to have a
better understanding of the complexity of emesis mechanisms.

Clinical research using distinct parameters combined with different acupuncture

point stimulation may provide information about the effectiveness of electrical
stimulation over acupuncture points or non-acupuncture sites. According to
Kaptchuk (2002) randomised controlled trials designed to test the efficacy of
acupuncture seem to produce contradictory outcomes that resemble random events.
Therefore, discerning clinical research is needed to examine the effectiveness for
each clinical condition that has been claimed to be treatable by acupuncture.

404

7.7 Summary/Conclusion
The origins of magnetism and electricity are lost in time. In 46 A.D., the Roman
physician Scribonius Largus lead into the era of electrical stimulation using the
torpedo fish (Kellaway, 1946). Headache, even if it is chronic and unbearable, is
taken away and remedied forever by a live black torpedo placed on the spot which is
on pain, until the pain decreases.

Since the discovery of electricity and before, current has been applied to the human
body by a variety of methods to cure a multitude of afflictions. Although
electrotherapy has a well-established role within physiotherapy practice, it is often
poorly understood, sometimes inappropriately used and topic of substantial debate
(Watson, 2000). The research within thesis has provided relevant information with
respect to the hypoalgesic, neurophysiological and antiemetic effects of electrical
stimulation, namely TENS and IFT. Irrespective of the mechanisms that underpin
electrical analgesia, Chapter 4 clearly demonstrated significant neurophysiological
alterations (peak to peak amplitude) of a compound action potential recorded from
the human median nerve followed IFT stimulation (153 Hz). In Chapter 3 IFT using
low and high frequencies (10-20 Hz and 80-100 Hz respectively) failed to
demonstrate a hypoalgesic effect upon an acute model of pain (DOMS). However, in
Chapter 6 a clinical trial that investigated the hypoalgesic effects in cancer patients,
showed a trend towards hypoalgesia mediated by IFT at 10 Hz. With regard to the
use of electrical stimulation as an adjunctive therapy in the management of nausea

405

and vomiting in cancer patients, the results also showed a trend favouring the IFT
(10 Hz) group concerning the severity of vomiting.

The studies that compared different forms of electrical stimulation (TENS, IFT and
APS) suggest that even though there were no statistically significant differences
between these modalities, the trend indicate that IFT produced marginally greater
effects. Finally, the work provided in this thesis points towards the need for further
laboratory and clinical research to unequivocally establish the analgesic and
antiemetic potential of TENS and IFT and inform clinicians on the appropriate
protocols to be used.

We find ourselves compelled to admit that there

is in existence a certain power, which by the very
emissions there from is enabled to affect the
members of the human body. What then are we not
to hope from the remedial influences which Nature
has centred in this and all animated creatures
Pliny the Elder, circa A.D. 70

406

407

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466

APPENDICES
APPENDIX I
DOMS study consent form

Title: Investigation of the effects of interferential therapy upon delayed onset muscle
soreness.
Outline Explanation: You have been asked to participate in a study carried out by
an undergraduate student. This experiment has been approved by the Universitys
Research Ethical Committee.
In this study you may or may not be administered interferential therapy for five days.
On the first day of the experiment you will be asked to exercise your non-dominant
arm to assess your maxim strength. Once obtained, this weight will be used to
exercise that arm, particularly by using eccentric exercises until fatigue sets in. Prior
to and following the eccentric exercise measurements will be made of peak torque,
range of movement and discomfort. Interferential therapy may or may not be
administered and these same measurements will then be re-recorded.
You will then be required to return on the next four days at the same time for
treatment and assessment. Finally, on the first, third and fifth day, as well as the
previous measures, you will be asked to complete a McGill pain questionnaire.
Note: (i) You are reminded of your right to withdraw from the study at any time
without explanation; (ii) all data collected will be treated in the strictest confidence.
Records stored on our computer will be protected under the provisions of the Data
Protection Act (1984).

I name).
Of (address).
I hereby consent to participate in the above investigation, the nature and purpose of
which have been explained to me. Any questions I whished to ask have been
answered to my satisfaction. I understand that I may withdraw from the investigation
at any stage without necessarily giving a reason for doing so.

Signed:
(volunteer)Date....
(Investigator)Date

467

APPENDIX II
DOMS study MPQ sensory rating raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
1
6
0
10
1
9
18
2
6
2
6
11
17
10
6
6
14
5
18
11
14
23
1
2
7
17
0
7
24
12
11
0
1
3
10
3
1
10
6
9

Day 3
7
3
5
16
10
10
22
6
5
1
5
15
10
13
1
14
15
9
9
14
20
27
3
7
18
14
12
13
28
13
24
0
17
9
14
5
10
7
19
11
468

Day 5
3
2
3
7
2
1
19
6
2
1
5
15
10
8
2
7
14
2
14
11
15
26
0
11
15
12
10
5
12
13
25
0
13
4
3
2
6
3
3
16

APPENDIX III
DOMS study MPQ affective pain index raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
0
1
0
0
0
1
2
0
0
1
1
1
0
1
0
2
2
0
0
0
1
2
5
0
0
0
0
0
0
7
1
1
0
0
0
2
0
1
2
1

Day 3
1
1
0
2
0
0
0
2
0
0
1
0
0
0
0
5
2
1
1
1
1
2
6
0
0
0
0
0
2
11
0
4
0
0
0
2
0
0
5
1
469

Day 5
0
1
0
0
0
0
0
0
1
0
1
1
0
0
0
3
1
0
0
2
0
2
5
0
0
1
0
0
1
1
0
4
0
0
0
0
0
0
1
0

APPENDIX IV
DOMS study MPQ evaluative pain index raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
0
1
0
1
0
0
1
0
0
0
0
0
1
0
0
1
0
0
1
2
1
1
0
0
0
1
0
0
2
0
1
0
0
1
2
0
0
0
1
1

Day 3
1
1
0
0
0
2
1
1
0
0
0
1
1
1
0
2
2
4
0
1
1
1
0
0
0
1
1
1
3
1
2
0
1
1
1
0
0
2
3
1
470

Day 5
1
1
0
1
0
0
1
1
3
0
0
1
1
1
0
1
0
0
1
1
1
1
0
1
0
1
1
1
1
1
3
0
1
1
1
0
0
0
1
1

APPENDIX V
DOMS study MPQ miscellaneous pain index raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
0
1
0
2
0
0
2
1
1
2
1
1
4
0
1
3
6
0
7
2
5
8
0
1
3
5
0
0
9
3
8
0
1
2
5
0
2
1
6
4

Day 3
6
1
1
6
0
1
2
6
1
4
0
5
2
3
2
2
8
2
2
2
3
4
0
1
2
4
0
0
12
3
6
0
4
0
2
1
2
0
6
2
471

Day 5
1
0
1
1
0
0
2
6
1
0
0
1
2
3
0
3
5
1
2
4
3
5
0
1
2
4
0
1
3
3
12
0
4
0
0
1
2
0
0
4

APPENDIX VI
DOMS study MPQ pain rating index raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
0
1
0
2
0
0
2
1
1
2
1
1
4
0
1
3
6
0
7
2
5
8
0
1
3
5
0
0
9
3
8
0
1
2
5
0
2
1
6
4

Day 3
6
1
1
6
0
1
2
6
1
4
0
5
2
3
2
2
8
2
2
2
3
4
0
1
2
4
0
0
12
3
6
0
4
0
2
1
2
0
6
2
472

Day 5
1
0
1
1
0
0
2
6
1
0
0
1
2
3
0
3
5
1
2
4
3
5
0
1
2
4
0
1
3
3
12
0
4
0
0
1
2
0
0
4

APPENDIX VII
DOMS study MPQ present pain index raw data
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz)
IFT 1 (10-20 Hz
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
IFT 2 (80-100 Hz)
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Day 1
0
1
0
2
0
2
2
0
2
1
0
0
2
2
0
2
1
1
1
0
2
1
0
0
1
1
0
0
1
1
2
0
0
1
1
0
1
0
2
1

Day 3
0
1
1
2
1
2
2
2
2
2
0
2
1
2
2
3
2
2
1
2
2
2
1
0
2
1
2
0
3
2
1
0
2
1
3
1
1
1
3
2
473

Day 5
1
0
1
1
1
1
1
1
1
1
1
1
1
1
2
3
2
1
1
2
2
1
1
1
2
1
2
2
1
2
2
0
1
0
1
1
1
1
0
2

APPENDIX VIII
DOMS study MPT points 1 to 8 raw data (N)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

Preind
40
40
40
36.125
39
32.75
22.5
39.75
40
40
27.125
40
35.375
39.125
35
40
39.125
39.5
40
39.5
34.5
34.625
36.5
40
38.5
40
39.5
40
39.5
28.875
38.125
37.875
40
40
40
34.625
40
40
36.75
38.25

Postind
40
40
40
38
39.5
31.375
19
38.625
40
40
23.125
40
29.25
39.125
35.75
38.75
36.625
39.625
40
40
30.875
40
34.75
40
39.5
40
34.625
40
40
34.875
36.5
34
40
40
40
30
40
39.75
34.125
38.25

Post rx

D2 pre

40
39.375
39.75
29.625
40
26.75
19.875
38.75
40
37.625
20.5
40
28.75
39.125
35.625
34.375
36.625
40
40
36.5
23
36.625
31.125
40
39.75
38.125
35.75
40
40
32.625
34.125
34.625
40
40
40
27.5
40
40
34.625
38.5

37.5
39.5
34.375
24.125
38.75
18.5
16.125
19.875
38.25
31.688
23.5
40
26.875
36.5
28.875
23.875
22.25
38.875
40
32.875
22.375
36.5
31
38.125
39.25
30.5
33.25
40
31.875
27.75
29.625
31.125
40
39.375
39.5
20
40
38.625
21.75
33.25

474

D2
post
36.25
38.25
29.75
24.375
37.875
17.375
17.125
21.75
38.5
34.875
19
40
31.5
35.375
32.5
21.875
22.125
36.375
40
25
22.875
35.375
22.875
39.375
38.875
26.25
36.375
40
35.625
27.875
33.25
31.875
40
40
40
18.5
40
39.625
18.125
36.75

D3 pre
33
39.625
36
20.875
35.5
17.625
9.75
27.625
38.25
23.875
13.625
35.875
30.375
36.75
19.75
15.75
27.125
40
37.625
23.125
27.125
40
22.125
37.5
38.875
26.375
36.5
34.25
28.75
29.375
31.625
30.25
39.875
39.25
40
20.5
40
38.875
15.5
34.5

D3
post
32.625
40
32.25
16.875
32
18
14
27.625
40
25.125
18.375
33.875
32.5
28.75
33.125
19.875
27.625
39.75
35.625
14.125
24.625
38.75
20.625
39.875
39.125
29
36.125
40
28.75
38.75
27.375
30.125
40
37.875
40
15.875
40
40
16.25
36.625

APPENDIX VIII
DOMS study MPT points 1 to 8 raw data (N) (Continued)
Group

D4 pre

D4 post

D5 pre

D5 post

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

30.875
40
33.125
20.75
40
20.875
12.25
30.5
40
34.625
13.25
35.125
30.25
33.375
27.75
25
29
40
40
15
32.125
38.75
21.875
38.875
40
29.5
39.25
35
31.375
36.375
31.75
22.75
38.875
39.25
40
20.25
40
38.5
20.375
38.125

31
40
36.625
23.625
40
20.375
12.75
32.75
40
35.5
14.625
35.125
32.25
28.5
31.75
29.125
27.75
40
40
14.75
34.875
39.625
20.25
40
40
27.5
39.375
39.5
33.125
34.125
32.125
24.625
38.5
39.75
40
20.375
40
38.5
21.125
37.75

35.875
40
36.375
27.125
40
29.25
18.125
38
40
35.75
18.125
34.25
34.75
36.875
32.125
34.875
34.5
40
40
17.875
35.625
40
26.375
40
38.625
31.625
39.5
40
35.25
35.375
31.25
33.125
40
38
40
24.875
40
38.875
26
39.125

37
40
37.625
30.875
40
25.375
20.25
38.625
40
39
13.375
31.25
36.25
37
37.75
37.25
31.375
40
40
16.875
38.375
40
23.375
40
38.75
23.5
39.75
40
35.625
35.375
31
30.625
40
36.625
40
19.75
40
39.5
24.625
38.375

475

APPENDIX IX
DOMS study MPT points 3 to 6 raw data (N)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
40
40
40
38.5
39.75
31
21.5
40
40
40
25.75
40
36
38.25
31.75
40
40
39
40
40
33
33.5
37.75
40
38.75
40
39
40
39.5
30.75
38.25
39
40
40
40
33
40
40
36.75
39.25

Postind
40
40
40
38.75
40
28
17.75
40
40
40
23.75
40
29.25
39.75
32.25
38.25
37
39.25
40
40
30.25
40
38
40
40
40
33
40
40
35.5
37.25
33.5
40
40
40
29.5
40
39.5
32.5
38.5

Post rx

D2 pre

40
39.5
40
29
40
25.5
17.5
39.5
40
36.5
20.75
40
26.75
39
33.5
35.75
36.5
40
40
36.5
22.5
36
26
40
39.5
36.25
34.25
40
40
27.75
34.25
34.75
40
40
40
25.75
40
40
33.25
39.75

35.75
39
34
24.5
40
15.5
13
13.25
37
26.875
23.5
40
26.875
36.5
28.875
23.875
22.25
38.875
40
32.875
25
34.75
28.5
36.5
38.5
29.75
30.5
40
32
23.25
27.25
28.75
40
38.75
39
20
40
37.5
21.5
34.75

476

D2
post
36.75
36.5
27.25
25
39
14
14.75
16.75
37
34
18
40
29.75
37
29.75
17.75
18
32.75
40
24.25
26.25
33
24
40
37.75
22.25
33.75
40
33.75
23
32.75
32.75
40
40
40
18.75
40
39.5
17.75
39.5

D3 pre
31.5
39.25
39.75
24
36
17.25
8
26
37.5
22
13.75
31.75
30.25
39.25
16
11
29.75
40
35.25
24.75
26.25
40
14.25
35
37.75
18.25
33
28.5
23
30
32.25
30
39.75
38.5
40
20
40
37.75
11.75
34.25

D3
post
33
40
32.75
17.75
29
16.25
12.25
26.5
40
21.5
18.75
32.75
31.75
24.25
31.5
14
30.75
39.5
33.75
12
24.75
37.5
16.25
39.75
38.25
26
32.25
40
27.75
38
25.5
29.5
40
40
40
14.25
40
40
14.5
39.25

APPENDIX IX
DOMS study MPT points 3 to 6 raw data (N) (Continued)
Group

D4 pre

D4 post

D5 pre

D5 pre

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

29.75
40
32
20.25
40
19.25
12.5
26.25
40
31.25
11.75
33.75
29
31.75
23
21.75
30.5
40
40
16
34.75
37.5
13.75
37.75
40
25.5
38.5
35.25
29.5
38
31.25
21.75
39
40
40
20.75
40
37
20
39

30
40
38.5
25
40
19.5
12.25
28
40
34.25
14.75
33.75
31.5
24.75
32
25.5
26.75
40
40
16
36
39.25
13
40
40
24.5
38.75
40
33.5
30.5
32
25.5
37
40
40
20
40
37
18.75
38.5

32.75
40
38.25
23
40
27.25
19.5
40
40
31.75
17.5
30.25
36
35
30
34
36.25
40
40
18
37.5
40
18.75
40
37.25
32
39
40
33.25
32.25
30.75
32.5
40
37.25
40
24
40
37.75
29.25
38.75

36.25
40
39
28.25
40
24
21
40
40
38
13.5
31.5
37.5
34
37.25
37.75
33.5
40
40
16.5
39.75
40
21.75
40
37.5
21.75
39.5
40
31.5
37.5
33
30.25
40
33.5
40
19.5
40
39
24.5
40

477

APPENDIX X
DOMS study VAS at rest raw data (%)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
21.5
8
0
12.5
1
7
42.5
0.5
18
8
0
0.5
27
6.5
7.5
7.5
7.5
0
2.5
15
14
16
13
0
0.5
0
12
0
13.5
14.5
6
15
0
12.5
2.5
3
7
0
13
0.5

Postind
0
0
0
7
20
9.5
52
0.5
14
5
0
0
30.5
2.5
22
22
21.5
10.5
8.5
11.5
11
9.5
24
0
0.5
27.5
8
0
9
11.5
24.5
15
0
3.5
10
4.5
2
4.5
13.5
0

Post rx

D2 pre

14
6.5
0
32.5
9
28
56
5
22
21.5
0
0.5
42
21
5.5
40
25
2
4.5
36
25.5
16
33
0
0
36
16
0
7.5
19.5
37
84
0
5.5
10
12
2.5
3.5
37
0

17
14
1
27
11
19
50
4
28
9.5
0
0
47.5
14.5
9.5
33.5
18.5
17.5
4.5
30
28.5
15.5
34
0
1
41
15
0
9.5
33
56
7
0
10
10
17
8
1
39
0

478

D2
post
23.5
4.5
1
49.5
22.5
16
73
10.5
26
10.5
0
0
49
0
13.5
55
8.5
0
2.5
30.5
31
28.5
34.5
0
8
40
12.5
6.5
2
17
47.5
89
0
7.5
2.5
7.5
6.5
5
33.5
0

D3 pre
25
7
3
28.5
15
23.5
50
5.5
14
5.5
0
0
34
1
9
37.5
19
3
5
37
34
9.5
39
0
1
48
7.5
0
6.5
24.5
69.5
47
0
2.5
0
8
3
5
33.5
0

D3
post
29.5
0.5
1.5
11.5
4
11.5
78.5
2.5
18.5
2.5
4.5
0
46.5
0
24
39
8
0
2.5
35.5
22.5
22
43
0
6.5
47.5
9.5
8
6
20.5
60
12.5
0
2.5
4.5
4
3
2
28.5
0

APPENDIX X
DOMS study VAS at rest raw data (%) (Continued)
Group

D4 pre

D4 post

D5 pre

D5 post

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

24
2.5
0.5
16.5
4.5
9.5
67.5
1
10
1
3
0
35.5
0
7.5
35
14.5
5.5
5
43
19
12.5
44.5
0
1.5
60
10.5
5
2.5
22
74
12
0
4.5
3
3.5
0
0.5
24.5
0

29
0
0
8.5
9.5
8.5
53
2
4.5
5.5
0
0
18
0
7.5
32
22
0
2.5
40
11.5
7
35.5
0
6
44
2.5
4.5
2
16.5
67
7.5
0
9
2
0
9.5
0.5
7
0

21
2.5
0
7.5
9.5
6
54
1.5
2.5
4.5
0
5.5
17.5
0
0
24
10.5
0
3
36
15.5
3.5
39.5
0
1
60
1
5
6
22
64
7.5
0
3
2
0.5
0
0
11.5
0

21.5
8
0
12.5
1
7
42.5
0.5
18
8
0
0.5
27
6.5
7.5
7.5
7.5
0
2.5
15
14
16
13
0
0.5
0
12
0
13.5
14.5
6
15
0
12.5
2.5
3
7
0
13
0.5

479

APPENDIX XI
DOMS study VAS at extension raw data (%)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
10.5
10
0
5.5
1
8.5
59
4
19
11
0
0
47
20
17
21.5
6
0
1.5
43
27.5
15.5
19
0
0.5
15.5
7
0
8.5
17
21.5
29
0
10.5
4
11
4.5
0
20.5
0

Postind
0
7.5
0
2
18.5
13
7.5
1
8.5
20.5
0
0
33.5
3
3.5
26
31.5
0
3
14.5
20.5
15
28
0
0
29
4
0
4
23.5
40.5
23.5
0
2.5
9.5
8.5
0.5
2
19.5
0

Post rx

D2 pre

12
9.5
8.5
26
19.5
29
67
16
35
16.5
14
0
63
49.5
8.5
44
23
4
2
35.5
32
8.5
32.5
2
7
26.5
13.5
0
5.5
30.5
58.5
47.5
0
6
13
11.5
35.5
6.5
35.5
0

15
18
9.5
32
21.5
27.5
65
17.5
36
16.5
15
0
58
42
12
40
16
1.5
2
34.5
46.5
19
33
0
3
48.5
17.5
0.5
9.5
33
63
11
0
7
7.5
17
27
2
40
0

480

D2
post
35.5
15.5
9.5
49
26
22
91.5
20.5
46.5
20.5
25.5
14
63
18
18.5
66
38.5
6
2
42
45
40.5
37.5
2
6.5
38.5
12.5
0
5.5
22
63
82
0
10.5
1
9
8
6
36.5
3.5

D3 pre
35.5
9
7.5
40.5
24
29
59.5
17
31
17
28
18
44.5
18
7.5
35.5
32
4.5
2.5
36
43
32.5
40
1
0
44
12
0
7.5
28
74.5
41.5
0
12
2
8
18.5
4.5
32.5
7

D3
post
25
4.5
14
9
6
21
82
10
23.5
10
39
27
31.5
49
24
45.5
72
4.5
2
47
30
49
40.5
2
10
53
11
1.5
6
19.5
76
29
0
3.5
4
6.5
14.5
3
25
0

APPENDIX XI
DOMS study VAS at extension raw data (%) (Continued)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

D4 pre
23
3.5
15.5
24.5
10
12.5
82.5
7
25
7
48
34
47
44
16
41.5
39
4
2.5
47.5
21.5
25
42.5
1
0.5
46
5
5.5
4.5
22.5
76
20
0
3
3.5
6.5
11
1.5
21
1

D4 post
24
5
14
3.5
8
15
58
6
8.5
12
53.5
25.5
23.5
33
6.5
37.5
23
0
1.5
45
21.5
15
33
1
5.5
48.5
3.5
3
13
17.5
74.5
32.5
0
5.5
4
2.5
32
3
9.5
0
481

D5 pre
15.5
2
6.5
4
5.5
10.5
59.5
4
12
15.5
45
29
11.5
13.5
1
30.5
20.5
0
2
45.5
26
13.5
35
1
5
58.5
2.5
4.5
5
28
79
30.5
0
3
5
0
18.5
1
10.5
0

D5 post
10.5
10
0
5.5
1
8.5
59
4
19
11
0
0
47
20
17
21.5
6
0
1.5
43
27.5
15.5
19
0
0.5
15.5
7
0
8.5
17
21.5
29
0
10.5
4
11
4.5
0
20.5
0

APPENDIX XII
DOMS study VAS point 2 raw data (%)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
5.5
0
0
6
10
6.5
35
1
22.5
19
4
0
2.5
8.5
21
9.5
8.5
0
1
5
20.5
4
22
0
0
14.5
3
1.5
2
14
33
0
0
2.5
1.5
9
3
0.5
1.5
2

Postind
3.5
7.5
0
1.5
14
13
7
1.5
2
33
10.5
0
3
2.5
6
28
5
0
4.5
11.5
22
1
28.5
2
0
19.5
3.5
0.5
4.5
15
39.5
11
0
2.5
1.5
11.5
2
2
27.5
1

Post rx

D2 pre

9.5
7.5
9.5
21
15.5
35
58.5
13.5
33
24.5
16
0.5
7
21.5
7
44
28.5
0
4.5
22.5
27
0
30
0
0.5
39
13
0
5
12
56
9.5
0
6.5
9
20.5
27
5
40.5
1

11
0.5
8.5
30
18
37.5
62.5
7
10.5
14.5
16
0
11
21
8
41
30.5
0
3
31
25
2.5
33
0
1
29
14
0
5.5
24
69
5.5
0
4.5
5.5
26.5
23
3.5
44
1

482

D2
post
32
0
9
52
19.5
30
83.5
16
42
16
28.5
0
5
10
21.5
54
43
7
2.5
30
30
2.5
33.5
0
1
40.5
9.5
1
3.5
17.5
67
9.5
0
16.5
0
18
14.5
6.5
42
6

D3 pre
27
0.5
8
32.5
8.5
28
74
7.5
14.5
7.5
16.5
0
3.5
21
6.5
42
21
0
1.5
38
29
2.5
37.5
0
0
43.5
9
0
2
30
79.5
50
0
15
1
28.5
13.5
2
41
4.5

D3
post
22.5
0
13
14
4.5
19
77
6
8
6
42.5
0
12.5
3
24
45
73.5
0
2.5
39.5
20.5
8.5
45
0
8.5
51
18
3
6.5
21.5
69.5
15.5
0
3.5
0
9.5
7.5
1.5
32
0

APPENDIX XII
DOMS study VAS point 2 (%) raw data (Continued)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

D4 pre
24.5
1.5
9.5
9
5.5
18.5
74
4.5
16
4.5
39
0
4
41.5
14.5
40
27.5
0.5
1.5
37.5
20.5
2.5
41.5
0.5
10.5
60.5
9.5
11
1.5
27.5
82
15.5
0
0
4
8
8.5
1.5
33.5
0

D4 post
17
20
0
0
82
4.5
18.5
4.5
0.5
41
0
0
2
0
0
8.5
2.5
56.5
0
11.5
10
14.5
18.5
2
9
3.5
4
4.5
34
13
0
3.5
12.5
40.5
52
0
19.5
1
4
10
483

D5 pre
14.5
20.5
0
5
87.5
4
21.5
22
1
34.5
0
0
2
0
0
1.5
6
59.5
0
8.5
3
16
14.5
2.5
2.5
3
5.5
6
29.5
13.5
0
3.5
8
44.5
59.5
0
23.5
0
11
16

D5 post
5.5
0
0
6
10
6.5
35
1
22.5
19
4
0
2.5
8.5
21
9.5
8.5
0
1
5
20.5
4
22
0
0
14.5
3
1.5
2
14
33
0
0
2.5
1.5
9
3
0.5
1.5
2

APPENDIX XIII
DOMS study VAS point 5 raw data (%)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
19
7.5
0
11
22
16.5
47
1
25.5
6
13.5
0
45.5
8.5
9
10
4
1
6.5
19
26,5
3,5
24
1
0
4
13,5
0,5
4
25,5
36
2,5
0
3
5,5
13
9
0
7,5
0

Postind
2.5
18
0
3
15
28
56.5
2
8
13
16
0
44.5
2
3
33
9
4.5
30
2.5
24,5
1,5
25
1
1
22
6
0
4
20
42,5
44
0
2
2,5
15
1,5
1,5
20,5
0

Post rx

D2 pre

26
7.5
8
19.5
24
52.5
64.5
18.5
38.5
12
23
0
44
37.5
7
46.5
27
6
26.5
26
37
3,5
38,5
0
11
32,5
20,5
2
5
16,5
61
16
0
7,5
5,5
25,5
13
6
41,5
0

14.5
4
15
33
22
53
69.5
10
37.5
10.5
16
0
24.5
21
4
44.5
41
1.5
34
14.5
39,5
19
33
0
14
39,5
20
0
20,5
28,5
81
21,5
0
10,5
2,5
20
23
5
38,5
4,5

484

D2
post
30.5
0
10.5
29
13
44
68.5
5
33
5
24
13
43.5
17
22
57
21.5
2
31.5
30.5
35,5
0
37,5
0
3
50
12,5
10
4,5
18,5
72,5
74,5
0,5
20
1
7
11
6
39,5
4

D3 pre
34.5
8.5
9
29.5
22.5
37
59.5
11
19.5
11
21.5
23.5
53.4
26
7.5
52
24.5
9.5
38.5
34.5
31,5
4,5
40,5
0
0,5
49,5
11
2
7
31,5
87
40,5
0
14,5
2
15,5
13
2
35
2,5

D3
post
30
6
13
17.5
3
66
83.5
7
18
7
43
16
36.5
9
23.5
43
76.5
2
35.5
30
26,5
3,5
24
1
0
4
13,5
0,5
4
25,5
36
2,5
0
3
5,5
13
9
0
7,5
0

APPENDIX XIII
DOMS study VAS point 5 raw data (%) (Continued)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

D4 pre
24
9
2.5
21.5
10
27.5
78
7.5
16
7.5
26.5
32.5
50.5
9
6
41.5
13.5
9.5
38.5
24
21
6
48,5
0
17,5
56
8,5
9
13
18
83,5
33
0
9,5
2
10
7,5
4
28,5
0

D4 post
28
0
8
14
9
23
52.5
1
8.5
11.5
19
0
21.5
16.5
7
31
4
2
45.5
28
20,5
15
54,5
0
9
59,5
4,5
6
2
29
86,5
33,5
0
0
5
12,5
9,5
1,5
30
0
485

D5 pre
19
0
0
5
3.5
16.5
64
3.5
13.5
14
16
0
27
12.5
2
24
15
1.5
41
19
17,5
0,5
40,5
0
7
55
4,5
3
3
23,5
75,5
22,5
0
1,5
2,5
8,5
12,5
1,5
12
0

D5 post
19
7.5
0
11
22
16.5
47
1
25.5
6
13.5
0
45.5
8.5
9
10
4
1
6.5
19
16,5
0
40,5
0
12
63
2
5
8
20
86,5
14
0
2
2
2
11
2
8
0

APPENDIX XIV
DOMS study RANG raw data ()
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
26
28
23
32
31
30
30
32
31
33
27
26
31
36
24
32
35
24
31
26
39
26
30
36
31
20
33
28
29
32
36
25
25
22
32
40
33
36
30
26

Postind
32
36
37
40
40
32
35
46
42
42
45
35
45
58
34
45
45
28
40
41
50
36
39
35
36
31
46
31
34
43
59
42
31
29
32
46
48
37
34
41

Post rx

D2 pre

34
36
49
40
34
29
31
45
50
50
36
44
40
54
31
45
41
28
26
41
46
33
27
41
42
28
41
30
36
40
51
45
26
26
35
46
45
33
34
41

31
31
35
39
40
40
39
39
46
42
41
37
42
53
28
43
41
31
35
58
35
35
34
40
45
31
45
35
32
41
49
24
31
30
40
45
51
36
31
58
486

D2
post
29
31
36
42
37
33
43
45
46
42
32
37
42
45
29
41
41
31
31
60
35
36
30
37
45
30
45
31
34
40
50
30
27
29
42
55
51
33
30
60

D3 pre
30
32
36
40
44
32
50
46
45
38
34
40
49
50
46
45
42
33
44
55
58
35
40
46
50
42
50
35
35
40
45
32
33
30
43
54
50
31
37
55

D3
post
31
33
38
42
35
35
50
46
43
38
32
40
47
45
44
41
42
35
45
60
56
35
37
45
45
35
44
35
34
41
47
41
30
30
45
56
50
30
33
60

APPENDIX XIV
DOMS study RANG raw data () (Continued)
Group

D4 pre

D4 post

D5 pre

D5 post

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

26
22
32
41
30
30
50
40
36
34
52
40
37
41
65
35
38
30
49
55
52
55
33
38
49
52
31
43
34
36
51
55
26
34
22
36
50
45
31
32

27
23
34
41
31
29
52
38
38
36
55
39
35
41
60
32
40
31
51
60
53
51
35
35
42
51
29
45
30
35
49
55
29
35
22
40
49
45
33
32

30
26
33
40
31
28
44
35
30
33
41
41
34
33
42
35
37
28
37
56
45
50
33
32
40
70
20
44
32
30
49
46
30
30
23
36
47
43
32
33

28
25
31
32
30
30
35
33
32
33
55
36
34
34
43
35
41
29
38
61
49
48
34
31
41
65
20
45
40
30
52
50
30
30
22
36
45
42
29
33

487

APPENDIX XV
DOMS study IPT at 60 raw data (N)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
48
21.8
32.2
12.5
30.4
28.9
34.6
43.8
36.6
63.5
26.5
32.8
36.6
52.4
10.4
34.9
33.1
25
22
51.8
42
44.7
41.5
46.5
30.7
22.3
26.8
32.5
24.7
10.1
31
59
36.1
24.4
15.8
17.6
56.3
32.5
25
18.8

Postind
46.1
17.6
22.3
9.2
20.6
21.5
20.3
38.4
30.4
32.2
15.2
24.7
24.7
41.7
8.9
25.3
23.5
23.2
16.1
34.6
25.9
27.1
32.2
33.7
20.6
14.6
20
27.1
10.1
8
22.9
46.5
38.7
19.1
18.2
12.2
34.3
17.6
23.2
9.5

Post rx

D2 pre

47.9
25.9
20.9
14.3
21.8
21.5
19.7
36.6
36.6
39.6
13.7
17.9
28.9
39
10.4
23.2
23.8
15.5
15.5
30.1
22.6
21.2
40.8
22
17
11.9
17.9
23.2
11.3
7.4
21.8
40.2
40.2
17
9.5
12.5
31.3
18.8
15.5
11.9

62.2
23.2
28
13.1
16.7
16.4
18.8
35.2
28.3
45.3
13.4
15.8
27.4
31.6
8
27.4
26.2
19.7
15.2
27.4
22
21.2
48.9
19.4
19.1
9.2
14.9
28.6
11.3
9.5
16.4
38.4
38.7
15.5
11.9
7.7
31.3
8.9
19.7
8.3

488

D2
post
57.4
21.8
25.3
9.8
14.3
16.7
17
33.1
28.9
44.4
11.6
11
30.7
36.9
6.3
26.5
20.9
17.2
12.5
15.8
17.6
10.4
39.3
21.5
18.8
10.4
10.1
16.7
8.6
5.4
15.8
39.9
39.6
17.3
12.2
15.2
35.5
9.5
17.2
10.7

D3 pre
54.1
22.9
26.5
10.7
20.3
20.9
20.9
40.2
28.6
42.9
13.7
23.2
27.4
33.7
16.1
38.1
20.6
14.3
17
29.8
20
15.8
52.7
26.5
22.9
11
20.3
31.6
13.1
11
18.8
41.4
32.5
10.1
9.8
10.4
31.3
14.9
14.3
12.2

D3
post
51.9
22
25
9.5
20
13.1
19.1
36.1
28.9
43.8
11.9
17.9
25.3
26.8
9.2
36.1
22.6
14.9
16.7
18.5
20.9
14.9
38.1
24.7
19.4
8
11
33.4
11.6
7.2
9.2
40.5
37.5
11.6
10.4
9.5
31.3
25
14.9
11.9

APPENDIX XV
DOMS study IPT at 60 raw data (N) (Continued)
Group

D4 pre

D4 post

D5 pre

D5 post

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

47.6
31.9
23.8
10.4
19.4
16.7
18.2
47.7
28.9
42
14.6
24.1
34.9
31.3
9.8
31.3
30.1
18.8
24.1
16.1
22
12.8
59
29.2
19.1
11.6
14.9
33.1
12.8
7.7
25
38.1
39
18.5
13.7
14.6
28.6
23.5
18.8
9.8

45.2
31
24.1
11
22.6
20.6
15.5
48.3
27.4
42.3
12.2
20.6
28.9
32.2
10.4
32.8
24.1
18.8
20.6
25.3
27.1
14.6
58.1
28.6
17.9
9.2
16.7
26.2
10.4
8
32.2
41.1
36.6
31.6
13.4
14.9
32.8
25
18.8
9.5

53.7
28.6
23.8
15.2
22.6
25.3
22
42.6
24.1
49.3
15.2
24.7
43.8
32.5
10.4
56.6
36.1
21.5
23.2
21.2
25.3
14.6
40.5
36.6
20.6
9.5
27.1
30.1
11.3
9.8
17.6
46.2
37.2
24.7
15.8
15.5
19.7
14.3
21.5
11

55.7
29.5
25
11
16.4
26.2
24.1
40.2
31
49.8
15.2
26.5
41.4
27.1
14
58.1
36.1
18.2
24.1
29.5
27.4
15.5
31.9
27.1
17.6
9.5
24.4
21.2
9.5
12.5
15.5
34.9
38.4
24.1
15.5
16.1
22.6
17.6
18.2
14.6

489

APPENDIX XVI
DOMS study IPT at 90 raw data (N)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

Preind
27.1
45
34.9
38.1
26.5
38.4
58.7
53.9
52.9
74.2
35.2
24.4
68.2
32.5
65.8
39.3
42.3
40.5
53.9
33.1
26
39
26
30
36
31
20
33
28
29
32
36
25
25
22
32
40
33
36
30

Postind
17.9
22.3
28
22.9
20.9
19.7
34.3
38.4
48.1
36.4
17
15.8
33.4
17.6
40.2
27.4
34
26.8
35.8
11.3
41
50
36
39
35
36
31
46
31
34
43
59
42
31
29
32
46
48
37
34

Post rx

D2 pre

20
23.8
24.4
26.2
24.7
22
41.7
39.9
51.9
40.2
12.5
14.3
31.3
18.5
49.5
17.9
25
28.9
33.4
10.4
41
46
33
27
41
42
28
41
30
36
40
51
45
26
26
35
46
45
33
34

16.4
22.9
22.6
18.2
31
29.2
30.7
39.9
79.6
48.9
11.9
15.8
25.3
18.8
42.9
25.3
31.9
32.8
37.2
11.3
58
35
35
34
40
45
31
45
35
32
41
49
24
31
30
40
45
51
36
31

490

D2
post
13.4
18.5
19.7
14.3
35.5
22
26.5
31.9
68.9
33.7
9.8
15.5
20
17.3
37.5
14.6
33.1
25.6
31.3
9.8
60
35
36
30
37
45
30
45
31
34
40
50
30
27
29
42
55
51
33
30

D3 pre
9.2
20.6
27.1
26.5
27.7
36.9
33.1
44.4
64.7
54.2
14.3
26.8
30.4
18.5
39.6
30.1
36.9
28.3
37.5
12.8
55
58
35
40
46
50
42
50
35
35
40
45
32
33
30
43
54
50
31
37

D3
post
11.9
20
22.6
23.2
32.2
28.3
30.7
38.1
75.3
48.3
12.2
22
24.4
23.2
36.4
27.1
32.5
31.9
36.1
11.3
60
56
35
37
45
45
35
44
35
34
41
47
41
30
30
45
56
50
30
33

APPENDIX XVI
DOMS study IPT at 90 raw data (N) (Continued)
Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 1
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT 2
IFT2
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo

D4 pre
14
18.5
24.7
25.9
33.7
32.2
35.2
64.1
51.5
52.1
15.5
22.9
26.5
28
37.2
34
34.3
42.9
45.9
11.6
52
55
33
38
49
52
31
43
34
36
51
55
26
34
22
36
50
45
31
32

D4 post
13.7
18.2
25.6
21.5
36.1
32.8
27.1
51.5
53.2
41.7
14.9
19.4
28
26.5
30.4
25.6
34.6
38.7
40.8
9.8
53
51
35
35
42
51
29
45
30
35
49
55
29
35
22
40
49
45
33
32
491

D5 pre
21.5
24.1
24.7
28
28.7
29.9
36.6
55.7
61.3
63.2
17.3
22
23.8
25.9
36.6
42.9
47.1
49.5
60.2
13.4
45
50
33
32
40
70
20
44
32
30
49
46
30
30
23
36
47
43
32
33

D5 post
13.7
25
25.6
24.7
36.9
31.6
31.9
51
52.2
44.4
16.4
21.5
32.2
25
32.5
37.2
42.9
42.3
56.9
10.4
49
48
34
31
41
65
20
45
40
30
52
50
30
30
22
36
45
42
29
33

APPENDIX XVII
NCV study contra-indications form

CONTRA-INDICATIONS

Please carefully read through the following conditions and inform the investigator if
any are applicable to you.

(1) Current ill health.

(2) Injuries or pain of any kind.
(3) Current use of medication.
(4) Pregnancy.
(5) Diabetes.
(6) Cardiovascular problems (e.g. DVT or pacemaker; Hypotension/Hypertension)
(7) Rheumatoid arthritis.
(8) Epilepsy.
(9) Injuries or fractures to the right arm.
(10)

Decrease or loss of skin sensation.

(11)

Sensitivity/allergic reaction to gel/tape/electrodes.

Signed (subject)

492

APPENDIX XVIII
NCV study consent form form

CONSENT FORM FOR PARTICIPATION IN RESEARCH PROJECTS AND

CLINICAL TRIALS

Title of project: Investigation of the effects of three different electrotherapeutic

modalities on nerve conduction in the median nerve and mechanical pain threshold
Outline Explanation: You are invited to participate in a study conducted by
postgraduate research students on the mechanical pain threshold and
neurophysiological effects of three different electrical modalities. The Universitys
Research Ethical Committee has approved this experiment.
For the purpose of this experiment you will be asked to lie on a wooden treatment
plinth exposing your right forearm. Your forearm will be prepared with alcohol and a
colloidal abrasive; electrodes will then be attached to your forearm and second digit.
Once you have acclimatised for approximately fifteen minutes, low intensity
electrical stimulation will be applied to the upper pair of electrodes to allow
recording of nerve conduction at the lower point. This is a standard technique, which
is used, routinely in clinical practice.
Between the nerve conduction tests, electrical stimulation may or may not be applied
to a specified site on your forearm. This is neither painful nor harmful and widely
used in physiotherapeutic practice. You may experience some redness under the
electrodes after the period of electrical stimulation. Nerve conduction tests and
mechanical pain thresholds will be completed after the application of the electrical
stimulation
Note: You are reminded of your right to withdraw from the study at any time without
explanation.

493

APPENDIX XVIII
NCV study consent form (Continued)

All data collected will be treated in the strictest confidence. Records stored on
computer will be protected under the provisions of the data protection act
I (name)
Of (address)
I hereby consent to take part in the above investigation, the nature of and purpose of
which has been explained to me. Any questions I wished to ask have been answered
to my satisfaction. I understand that I may withdraw from the investigation at any
stage without necessarily explanation.
Signed (volunteer)

Date

(Investigator)

Date

Skin Test ___________ Contra-indications__________ Explanation_________

494

APPENDIX XIX
NCV study NPL raw data (ms)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

8.11
7.51
6.61
7.4
6.61
7.46
6.19
6.05
5.86
6.65
7.99
6.71
6.65
6.9
6.05
6.05
5.97
5.51
6.26
6.85
6.25
6.69
7.01
7.16
7.38
6.01
6.26
6.23
6.18
5.46
7.87
5.45
6.16
6.81
7.61
6.85
6.86
5.8
6.42
6.07

15
Minutes
8.16
7.45
6.69
7.35
6.63
7.35
6.21
6.01
5.81
6.55
7.96
6.74
6.56
6.87
5.84
6.02
5.88
5.45
6.22
6.87
6.41
6.76
6.98
7.23
7.38
6
6.3
6.17
6.18
5.56
8.05
5.48
6.27
6.69
7.35
6.89
6.75
5.77
6.4
6.01
495

25
Minutes
8.21
7.39
6.55
7.28
6.6
7.38
6.25
5.99
5.85
6.61
7.98
6.73
6.56
6.77
5.79
6.04
5.91
5.46
6.22
6.91
6.42
6.76
6.99
7.39
7.37
5.99
6.29
6.16
6.24
5.47
8.1
5.39
6.22
6.7
7.2
6.88
6.51
5.63
6.41
5.95

35
Minutes
8.1
7.36
6.57
7.25
6.6
7.47
6.05
5.96
5.87
6.49
8.07
6.63
6.57
6.76
5.74
6.07
5.89
5.48
6.09
6.85
6.31
6.82
6.84
7.49
7.32
6.01
6.31
6.13
6.17
5.41
8.09
5.4
6.23
6.7
7.21
6.85
6.42
5.62
6.27
6.07

45
Minutes
7.98
7.44
6.58
7.28
6.64
7.49
6.17
5.93
5.89
6.5
7.96
6.64
6.5
6.83
5.74
6.1
5.91
5.44
6.13
6.68
6.35
6.78
6.79
7.53
7.44
6.01
6.3
6.11
6.19
5.42
8.05
5.35
6.29
6.66
7.23
6.82
6.41
5.6
6.24
5.99

APPENDIX XX
NCV study PPL raw data (ms)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

9.26
8.57
7.54
8.45
7.64
8.5
7.15
6.76
6.55
8.4
9.13
7.88
7.56
7.94
6.75
7.18
6.95
6.31
6.99
7.96
7.02
7.62
8.03
8.28
8.38
6.96
7
6.86
6.82
6.31
9.23
6.14
7.21
8.11
8.96
7.79
8.02
6.7
7.33
7.11

15
Minutes
9.29
8.22
7.52
8.64
7.67
8.4
7.19
6.72
6.66
8.41
9.01
7.84
7.44
7.9
6.76
7.35
6.82
6.28
7.08
8.03
7.46
7.67
7.91
8.32
8.43
6.91
7.04
6.84
6.83
6.32
10
6.11
7.45
7.63
8.76
7.79
7.94
6.58
7.27
6.9
496

25
Minutes
9.3
8.38
7.57
8.43
7.62
8.47
7.14
6.67
6.68
7.94
9.17
7.77
7.5
7.76
6.38
7.28
6.94
6.21
7.02
7.99
7.53
7.67
7.82
8.58
8.23
7.33
6.99
6.82
6.83
6.23
10.1
6.07
7.4
7.56
8.86
7.83
7.59
6.38
7.09
6.88

35
Minutes
9.32
8.32
7.47
9.1
7.67
8.51
6.83
6.66
6.69
7.52
9.1
7.75
7.23
7.75
6.49
7.25
6.77
6.2
6.94
7.89
7.48
7.67
7.88
8.75
8.33
8.82
7.04
6.75
6.8
6.12
9.46
6.14
7.36
7.67
8.16
7.8
7.44
6.36
7.19
7

45
Minutes
9.29
8.19
7.64
8.16
7.68
8.63
6.92
6.64
6.69
8.03
9.09
7.72
7.43
7.74
6.63
7.2
6.77
6.25
6.95
7.72
7.5
7.75
7.78
8.76
8.38
6.93
7.06
6.75
6.78
6.19
9.58
6.06
7.24
7.5
8.76
7.72
7.34
6.3
7.09
6.99

APPENDIX XXI
NCV study PPD raw data (ms)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

1.15
1.06
0.93
1.05
1.03
1.04
0.96
0.71
0.69
1.75
1.14
1.17
0.91
1.04
0.7
1.13
0.98
0.8
0.73
1.11
0.77
0.93
1.02
1.12
1
0.95
0.74
0.63
0.64
0.85
1.36
0.69
1.05
1.3
1.35
0.94
1.16
0.9
0.91
1.04

15
Minutes
1.13
0.77
0.83
1.29
1.04
1.05
0.98
0.71
0.85
1.86
1.05
1.1
0.88
1.03
0.92
1.33
0.94
0.83
0.86
1.16
1.05
0.91
1.01
1.09
1.05
0.91
0.74
0.67
0.65
0.76
1.95
0.63
1.18
0.94
1.41
0.9
1.19
0.81
0.87
0.89
497

25
Minutes
1.09
0.99
1.02
1.15
1.02
1.09
0.89
0.68
0.83
1.33
1.19
1.04
0.94
0.99
0.59
1.24
1.03
0.75
0.8
1.08
1.11
0.91
0.83
1.19
0.86
1.34
0.7
0.66
0.59
0.76
2.04
0.68
1.18
0.86
1.66
0.95
1.08
0.75
0.68
0.93

35
Minutes
1.22
0.96
0.9
1.85
1.07
1.04
0.78
0.7
0.82
1.03
1.03
1.12
0.66
0.99
0.75
1.18
0.88
0.72
0.85
1.04
1.17
0.85
1.04
1.26
1.01
2.81
0.73
0.62
0.63
0.71
1.37
0.74
1.13
0.97
0.95
0.95
1.07
0.74
0.92
0.93

45
Minutes
1.51
0.75
1.06
0.88
1.03
1.14
0.75
0.71
0.8
1.53
1.13
1.08
0.93
0.91
0.89
1.1
0.86
0.81
0.82
1.04
1.15
0.97
0.99
1.23
0.94
0.92
0.76
0.64
0.59
0.77
1.45
0.71
0.95
0.84
1.53
0.9
0.93
0.7
0.85
1

APPENDIX XXII
NCV study PPA raw data (V)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

13.1
13.2
13.1
16.3
30
10.1
15
21.6
12.8
31.6
22.4
26.2
10
8.86
12.5
7.36
13.8
11.4
9.74
26.2
16
21.8
9.18
17.8
9.36
8.06
12.8
12.7
7.5
9.5
32.6
19.2
9.56
11.3
10.7
16.7
11.1
25.2
12.8
11.2

15
Minutes
14.5
9.24
9.68
16.3
31.2
11
20.2
23.2
15
28
17.6
25
2.24
10.1
2.92
11.9
5.18
12.2
16.6
25.2
22.6
21.2
11
24.8
12.6
8.86
15.8
14.7
8
9.92
75
15.2
13.2
9.18
13.1
17.1
11.4
29
11.8
13.7
498

25
Minutes
10.4
13.3
9.18
17.7
29
13.7
13.5
20.8
14.6
21.2
19.6
26
2.3
9.18
2.18
8.06
13.5
11
14.2
26.8
24.6
29
7.8
23
11.4
14.7
17.1
14.7
9.36
9.92
34
20.8
7.74
10.6
20
16
8.5
26
10.7
12.6

35
Minutes
13.1
12.1
10.8
24.6
23.2
113.8
12.8
23.2
15.1
12.1
19.7
23.4
4.5
9.68
2
10.8
9.8
10.7
13
23.2
20.8
26.2
10.1
25.6
13.2
25.6
16.7
14.5
7.86
9.74
32.8
20.8
17.1
11.6
7.56
15.8
8.62
27.6
14
13

45
Minutes
17.1
8.12
12.2
13.1
27
14.5
15.7
22.6
8.86
38.4
21.2
26.4
5.06
9.92
2.3
9.74
7.5
13.1
13.1
19.2
21
28.2
8.8
24
13.1
9.86
16.3
17
7.92
12.2
29.8
21
9.42
10.1
12.7
19.6
8.56
23.6
12.8
12.5

APPENDIX XXIII
NCV study Proximal MPT raw data (N)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

33.15
24.4
42.35
44.5
56.1
58.15
47.4
74.5
47.6
33.1
36.6
41.75
34.35
59.05
37.55
24.15
27.45
27.35
43.05
40.6
20.85
39.85
54.9
46.3
56.85
44.5
39.3
39.9
38.2
37.95
29.05
29.25
34.6
53.2
74.75
36.75
38.75
46.45
41.85
36.05

15
Minutes
25.85
25.7
39.7
36.25
51.15
56.45
40.4
67.6
26.55
28.9
28.9
37.75
46.15
57.05
35.25
23.35
25.1
32.9
35.7
34.9
17.85
42.7
62
34.25
45.75
44.65
29.75
44.2
34.55
31.15
27.25
29.6
35.15
46.95
66.9
41.6
34.8
40.05
44.85
31.4
499

25
Minutes
30.8
22.65
33.2
17.95
44.5
42.3
43.75
69.05
32.6
22.7
28.85
38.45
43.1
52.05
26.85
23.65
24.85
23.95
27.6
36.5
21.65
28.45
57
39.7
48.9
36.8
27.7
37.9
34.95
27.6
26.2
23.45
38
45.35
63.5
44.2
29.05
36.35
50.05
23.4

35
Minutes
23.45
20.3
28.1
33.6
48.65
44.85
48.85
56.2
31.25
24.05
27
33.75
43.85
46.35
21.7
23.65
25.4
25.75
30.9
35.95
14.35
26.75
51.1
39.75
46.4
35.65
22.8
41.2
35.8
26.35
25.25
28.85
31.75
46.8
63.65
45.95
30.05
36.55
48.2
19.5

45
Minutes
32.35
21.35
32.85
22.9
43.65
48.5
41.05
67.53
30.2
21.75
30.65
35.05
43.2
39.65
22.85
22.15
26.15
27.45
26.45
40.25
15.55
35.3
55.4
41.25
51.9
37.45
29.45
44.25
33.5
29.35
19.3
27.15
31.35
45.2
65.1
43.65
28.55
37.05
42.75
18.25

APPENDIX XXIV
NCV study Distal MPT raw data (N)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

46.65
23.65
40.45
30.65
46.75
58.65
42.6
56.25
29.35
23.4
27.2
38.3
42.95
64.95
27.85
18.95
28.6
23.05
29.15
35.75
20.5
32.35
48.1
37.35
51.2
34.25
25.1
31
33.1
32
21
25.9
31.6
45.75
68.6
42.05
34.8
37.95
29.3
20.7

15
Minutes
32
23.65
43.65
27.1
53.8
54.65
47.3
59.1
34.9
20.6
25.25
38.75
53.85
49.75
23.55
23.85
25.1
25.7
31.1
34.95
23.85
34.8
57.35
33.6
57.6
36.75
26.7
45.45
40.45
28.15
25
29.3
29.55
45.45
62.6
42.25
34.35
36.15
35.1
21.8
500

25
Minutes
39.5
24.75
29.55
26.85
44.25
47
46.6
59.45
33.6
19
22.5
36.95
43.8
42.25
23.15
26.3
29.75
33.55
25.35
38
19.75
31.4
61.6
30.75
47.45
33.75
19.7
40.75
43.5
30.5
26.55
17.4
30.5
45.7
64.9
41.6
30.6
37.45
43.1
18.75

35
Minutes
35.5
22.95
25.7
26.45
44.7
41.6
43.75
51.5
29
19.35
24.3
35.45
42.45
45.6
18.95
20.2
29.85
25.1
35.35
38.75
14.1
30.35
53.8
33.4
52.25
34.65
18.75
46.1
36.6
22.5
20.8
18.45
31.25
42.15
49.75
43.2
28.05
37.4
37.3
16.8

45
Minutes
39.95
19.15
25.95
23.85
43.5
45.05
46.45
50.3
31.85
19.65
25
30.2
51.6
42.05
21.85
16.85
32.1
23
25.6
44.95
15.6
35.15
58.8
26.2
44.9
34.4
21.05
43.15
31.25
22.3
20.45
15.9
27.8
47.4
57.05
40.15
26.3
34.8
38.15
13.4

APPENDIX XXV
NCV study Overall MPT raw data (N)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

39.9
24.025
41.4
37.575
51.425
58.4
45
65.375
38.475
28.25
31.9
40.025
38.65
62
32.7
21.55
28.025
25.2
36.1
38.175
20.675
36.1
51.5
41.825
54.025
39.375
32.2
35.45
35.65
34.975
25.025
27.575
33.1
49.475
71.675
39.4
36.775
42.2
35.575
28.375

15
Minutes
28.925
24.675
41.675
31.675
52.475
55.55
43.85
63.35
30.725
24.75
27.075
38.25
50
53.4
29.4
23.6
25.1
29.3
33.4
34.925
20.85
38.75
59.675
33.925
51.675
40.7
28.225
44.825
37.5
29.65
26.125
29.45
32.35
46.2
64.75
41.925
34.575
38.1
39.975
26.6
501

25
Minutes
35.15
23.7
31.375
22.4
44.375
44.65
45.175
64.25
33.1
20.85
25.675
37.7
43.45
47.15
25
24.975
27.3
28.75
26.475
37.25
20.7
29.925
59.3
35.225
48.175
35.275
23.7
39.325
39.225
29.05
26.375
20.425
34.25
45.7
64.2
42.9
29.825
36.9
46.575
21.075

35
Minutes
29.375
21.625
26.9
30.025
46.675
43.225
46.3
53.85
30.125
21.7
25.65
34.6
43.15
45.975
20.325
21.925
27.525
25.425
33.125
37.35
14.225
28.55
52.45
36.575
49.325
35.15
20.775
43.65
36.2
24.425
23.025
23.65
31.5
42.15
56.7
44.575
29.05
36.875
42.75
18.15

45
Minutes
36.15
20.25
29.4
23.375
43.575
46.775
43.75
58.915
31.025
20.7
27.825
32.625
47.4
40.85
22.35
19.5
29.175
25.225
26.025
42.6
15.325
35.225
57.1
33.725
48.4
35.15
25.25
43.7
32.375
25.825
19.875
21.525
29.575
47.4
61.075
41.9
27.425
35.925
40.45
15.825

APPENDIX XXVI
NCV study Ambient temperature raw data (C)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

23.1
23.4
25.45
25.75
24.45
24.25
24.15
23.55
26.55
25.15
25.2
25.5
25.9
25.25
27.15
25.45
27.75
28
28.05
27.1
23.7
25.4
25.55
22.95
25.05
27.4
28.15
27.05
27.4
27.35
25.25
27.45
25.8
27.45
25.85
26.6
27.25
25.45
26
26.25

15
Minutes
23.25
23.55
25.4
25.85
24.6
24.4
24.45
23.6
26.6
25.45
25.35
25.55
25.9
25.2
27.45
25.4
27.75
28
28.2
27.05
23.8
25.45
25.65
23.25
25.15
27.6
28.05
27.2
27.45
27.45
25.3
27.55
25.8
27.55
25.7
26.8
27.25
25.65
26.15
26.4
502

25
Minutes
23.35
23.65
25.45
25.8
24.7
24.45
24.25
23.85
26.65
25.25
25.35
25.65
25.9
25.25
27.35
25.45
27.65
28
28
27.1
23.85
25.55
25.55
23.25
25.15
27.65
28.05
27.25
27.55
27.45
25.3
27.5
25.9
27.5
25.95
26.7
27.3
25.55
26.1
26.35

35
Minutes
23.25
23.65
25.5
25.85
24.7
24.45
24.25
23.9
26.5
25.2
25.3
25.75
26
25.4
27.15
25.55
27.75
28.05
28.15
27.15
23.85
25.5
25.55
23.4
25.15
27.6
28.05
27.05
27.6
27.2
25.3
27.5
26.1
27.45
25.85
26.6
27.35
25.55
26.2
26.4

45
Minutes
23.4
23.55
25.55
25.8
24.8
24.5
24.5
23.95
26.6
25.15
25.3
25.6
25.95
25.3
27.35
25.5
27.8
28.05
28.05
27
23.8
25.55
25.55
23.3
25.3
27.45
28.1
27.1
27.4
27.3
25.3
27.55
25.9
27.6
25.9
26.6
27.2
25.7
26.15
26.35

APPENDIX XXVII
NCV study Skin temperature raw data (C)
Group

0 Minutes

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
APS
APS
APS
APS
APS
APS
APS
APS
APS
APS
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
IFT
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS
TENS

33.3
32.2
33.45
31.75
31.95
31.55
30.8
30.65
32.45
31.4
31.4
33.25
32.3
32.15
32.95
32.25
34.85
33.4
33.4
32.5
30.25
32.95
32.75
31.25
32.75
33.7
33.85
32.9
32.8
32.25
31.65
33.65
32.35
33.85
32
32.85
31.2
31.8
32.1
31.35

15
Minutes
33.1
32.4
33.45
32
32.2
31.55
30.9
30.25
32.3
31.5
31.05
33.55
32.5
32.5
33.65
32.15
34.95
33.65
34.15
33
30.15
32.9
33.35
31.3
32.95
33.95
34
33.1
32.8
32.2
32
33.55
32.3
34
32.35
33.15
31.3
32.05
32.55
31.5
503

25
Minutes
33.1
32.45
33.75
32
32.25
31.55
31.15
31.3
32.45
31.55
30.95
33.85
32.65
32.5
33.6
32.1
34.95
33.85
34.05
33
30.55
32.8
33.6
30.95
33.1
34
33.9
33.1
32.8
32.3
31.65
33.7
32.6
34
32.6
32.95
31.45
32.45
32.85
31.75

35
Minutes
33
32.55
33.7
32
32.05
31.6
31.05
30.8
32.2
31.55
31.05
33.85
33.1
32.65
33.85
32.3
35
33.95
34.2
33.2
30.35
33.15
33.65
30.75
32.9
34
34.05
33.15
32.9
32.3
31.3
33.85
32.55
34
32.55
33.15
31.6
32.65
33
31.8

45
Minutes
33.2
32.2
33.85
32.05
32.35
31.4
31.25
32.2
32.35
31.5
30.95
33.9
33.25
32.65
34
32.3
35
34.05
34.25
33
30.05
33.05
33.8
30.5
32.8
33.95
33.6
33.15
32.65
32.3
30.9
33.9
32.45
34.15
32.55
33
31.75
32.7
33.05
31.8

APPENDIX XXVIII
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The MANE questionnaire

Morrow Assessment of Nausea and Emesis Questionnaire

Question 1. Did you experience nausea DURING or AFTER your last chemotherapy
treatment?

Yes
No (if no go to question no.2)

How long did the nausea last?______hours

How would you describe the nausea at its worst?
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable

When was the nausea the worst?

1 During treatment
2 0-4 hours after treatment
3 4-8 hours after treatment
4 8-12 hours after treatment
5 12-24 hours after treatment
6 24 or more hours after treatment
7 No time more severe than any other

504

APPENDIX XXVIII
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The MANE questionnaire (Continued)

Question 2. Did you experience vomiting DURING or AFTER your last

chemotherapy treatment?

Yes
No (If no go to question 3)

How long did the vomiting last?______hours

How would you describe the vomiting at its worst?

1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
When was the vomiting the worst?
1 During treatment
2 0-4 hours after treatment
3 4-8 hours after treatment
4 8-12 hours after treatment
5 12-24 hours after treatment
6 24 or more hours after treatment
7 No time more severe than any other

505

APPENDIX XXVIII
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The MANE questionnaire (Continued)

Question 3. Did you experience nausea BEFORE your last chemotherapy treatment?

Yes
No (if no go to question no.4)

How would you describe the nausea at its worst before treatment
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
How many hours before treatment did it first occur?______hours

506

APPENDIX XXVIII
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The MANE questionnaire (Continued)

Question 4. Did you experience vomiting BEFORE your last chemotherapy

treatment?

Yes
No (if no go to question no.5)
How would you describe the vomiting at its worst before treatment?
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
How many hours before treatment did it first occur?______hours

Question 5. Did you take medication for nausea/or vomiting for your last treatment?
1 Yes
2 No
If yes, was it useful?
1 Very
2 Somewhat
3 Works a little
4 Doesnt seem to help

507

APPENDIX XXIX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: Consent form

AN INVESTIGATION OF THE EFFECTIVENESS OF TRANSCUTANEOUS

ELECTRICAL NERVE STIMULATION (TENS) vs. INTERFERENTIAL
THERAPY (IFT) AFTER CHEMOTHERAPY

You are invited to participate in a study by a group of researchers from the Hospital
Garcia de Orta Portugal and the University of Ulster (Northern Ireland) on the effect
of Transcutaneous Electrical Nerve Stimulation (TENS) and Interferential Therapy
following chemotherapeutic treatments. This study is being undertaken to examine
the effects of TENS and IFT on any symptoms or discomfort which may occur postchemotherapy. This study has been approved by The Hospital Ethical Committee.
For the purposes of this study, low intensities of electrical stimulation may be
applied to a specific point on your forearm by self-adhesive surface electrodes before
and after the chemotherapy session. This will be demonstrated to you by a health
professional. Data will be collected on your well-being after the chemotherapy
session by one of the researchers.
You are assured that your participation in the trial will not affect your standard of
care in any way.

508

APPENDIX XXIX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: Consent form (Continued)

You are reminded of your right to withdraw from the study at any time without
explanation; if you withdraw this will have no effect on any aspect of your care. All
data collected will be treated in the strictest confidence. Any publications arising out
of this study will not identify any individual who participates in this study.

I (name)

Of (address)
I hereby consent to take part in the above study, the nature and purpose of which
have been explained to me. Any questions I wished to ask have been answered to my
satisfaction. I understand that I may withdraw from the investigation at any stage
without necessary giving a reason for doing so.

Signed (volunteer)
Investigator
Date

509

APPENDIX XXX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The Portuguese version of the MANE
questionnaire

Avaliao da Nusea e Vmito: Questionrio de Morrow

As perguntas que se seguem dizem respeito nusea e ao vmito em separado.
NUSEA sentir-se indisposto do estmago; agoniado; sensao de enjoo. O
VMITO o acto de expulsar o contedo do estmago.
A informao contida neste questionrio estritamente confidencial.
Por favor faa um crculo ou preencha o nmero correspondente.
Pergunta n 1 Sentiu NUSEA durante ou depois do seu ltimo tratamento de
quimioterapia?
1. Sim
2. No (se no, passe pergunta n 2 por favor)
Quanto tempo durou a sensao de NUSEA? _____ horas

510

APPENDIX XXX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The Portuguese version of the MANE
questionnaire (Continued)

Como descreveria a NUSEA na sua fase mais forte?

1 Muito ligeira
2 Ligeira
3 Moderada
4 Forte
5 Muito forte
6 Insuportvel
Quando que a sensao de NUSEA foi mais forte?
0.1 Durante o tratamento
0.2 Entre 0 e 4 horas aps o tratamento
0.3 Entre 4 e 8 horas aps o tratamento
0.4 Entre 8 e 12 horas aps o tratamento
0.5 Entre 12 e 24 horas aps o tratamento
0.6 24 ou mais horas aps o tratamento
0.7 Foi sempre igual

Pergunta n 2 VOMITOU durante ou depois do seu tratamento de quimioterapia?

1
2

Sim
No (se no, passe pergunta n 3 por favor)

Durante quanto tempo durou o VMITO? _____ horas

511

APPENDIX XXX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The Portuguese version of the MANE
questionnaire (Continued)

Como descreveria o VMITO na sua fase mais forte?

1 Muito ligeiro
2 Ligeiro
3 Moderado
4 Forte
5 Muito forte
6 Insuportvel
Quando que o VMITO foi mais forte?
0.1 Durante o tratamento
0.2 Entre 0 e 4 horas aps o tratamento
0.3 Entre 4 e 8 horas aps o tratamento
0.4 Entre 8 e 12 horas aps o tratamento
0.5 Entre 12 e 24 horas aps o tratamento
0.6 24 ou mais horas aps o tratamento
0.7 Foi sempre igual
Pergunta n 3 Sentiu NUSEA antes do seu ltimo tratamento de quimioterapia?
1. Sim
2. No (se no, passe pergunta n 4 por favor)
Como descreveria a sensao de NUSEA antes do tratamento?
1 Muito ligeira
2 Ligeira
3 Moderada
4 Forte
5 Muito forte
6 Insuportvel
Quantas horas antes do tratamento ocorreu pela primeira vez a sensao
de NUSEA? _____ horas.

512

APPENDIX XXX
The development of the adaptation of the MANE questionnaire for the
Portuguese language of Portugal: The Portuguese version of the MANE
questionnaire (Continued)

Pergunta n 4 VOMITOU antes do seu ltimo tratamento?

1. Sim
2. No ( se no, passe pergunta n 5 por favor)
Como descreveria o VMITO na sua fase mais forte antes do tratamento?
1 Muito ligeiro
2 Ligeiro
3 Moderado
4 Forte
5 Muito forte
6 Insuportvel
Quantas horas antes do tratamento ocorreu o primeiro VMITO?_____ horas.
Pergunta n 5 Tomou medicao para a NUSEA ou para o VMITO durante o
seu ltimo tratamento?
1. Sim
2. No
Em caso afirmativo, foi a medicao eficaz?
1.
2.
3.
4.

Muito
Em parte
Um pouco
No pareceu ajudar

Obrigado pela sua colaborao

513

Appendix XXXI
MANE pilot data Occurrence of nausea raw data

* Missing data is coded as 99

Group

Anticipatory
nausea

Post chemo

Control

Control

Control

Control

Active IFT

Active IFT

Active IFT

Active IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

Active TENS

Active TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

514

Appendix XXXII
MANE pilot data Severity of nausea raw data

* Missing data is coded as 99

Group

Anticipatory
nausea

Post chemo

Control

Control

Control

Control

Active IFT

Active IFT

Active IFT

Active IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

Active TENS

Active TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

515

Appendix XXXIII
MANE pilot data Duration of nausea raw data (min)

* Missing data is coded as 99

Group

Anticipatory
nausea

Post chemo

Control

Control

Control

20160

240

Control

Active IFT

Active IFT

60

Active IFT

Active IFT

Placebo IFT

1440

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

180

Active TENS

Active TENS

Placebo TENS

Placebo TENS

Placebo TENS

240

Placebo TENS

10080

516

Appendix XXXIV
MANE pilot data Occurrence of vomiting raw data

* Missing data is coded as 99

Group

Anticipatory
vomiting

Post chemo

Control

Control

Control

Control

Active IFT

Active IFT

Active IFT

Active IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

Active TENS

Active TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

517

Appendix XXXV
MANE pilot data Severity of vomiting raw data

* Missing data is coded as 99

Group

Anticipatory
vomiting

Post chemo

Control

Control

Control

Control

Active IFT

Active IFT

Active IFT

Active IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

Active TENS

Active TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

518

Appendix XXXVI
MANE pilot data Duration of vomiting raw data (min)

* Missing data is coded as 99

Group

Anticipatory
vomiting

Post chemo

Control

Control

Control

20160

Control

Active IFT

Active IFT

720

Active IFT

Active IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Active TENS

Active TENS

10

Active TENS

Active TENS

1.5

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

519

APPENDIX XXXVII
Clinical trial Consent form

AN INVESTIGATION OF THE EFFECTIVENESS OF TRANSCUTANEOUS

ELECTRICAL NERVE STIMULATION (TENS) vs. INTERFERENTIAL
THERAPY (IFT) AFTER CHEMOTHERAPY
You are invited to participate in a study by a group of researchers from the Hospital
Garcia de Orta and the University of Ulster (Northern Ireland) on the effect of
Transcutaneous Electrical Nerve Stimulation (TENS) and Interferential Therapy
following chemotherapeutic treatments. This study is being undertaken to examine
the effects of TENS and IFT on any symptoms or discomfort which may occur postchemotherapy. This study has been approved by The Hospital Ethical Committee.
For the purpose of this study low intensity of electrical stimulation may be applied to
a specific point on your forearm by self-adhesive surface electrodes before and after
the chemotherapy session. This will be demonstrated to you by a health professional.
Data will be collected on your well-being after the chemotherapy session by one of
the researchers.
You are assured that your participation in the trial will not affect your standard of
care in any way.
You are reminded of your right to withdraw from the study at any time without
explanation; if you withdraw this will have no effect on any aspect of your care. All
data collected will be treated in the strictest confidence. Any publications arising out
of this study will not identify any individual who participates in this study.
I (name)
Of (address)
I hereby consent to take part in the above study, the nature and purpose of which
have been explained to me. Any questions I wished to ask have been answered to my
satisfaction. I understand that I may withdraw from the investigation at any stage
without necessary giving a reason for doing so.
Signed (volunteer)
Investigator
Date

520

APPENDIX XXXVIII
Clinical trial log book

CLINICAL TRIAL ON THE EFFECTIVENESS OF TRANSCUTANEOUS

ELECTRICAL NERVE STIMULATION (TENS) vs. INTERFERENTIAL
THERAPY (IFT) AFTER CHEMOTHERAPY

Log Book

Patient Initials
Date
Allocation Number
Code
521

APPENDIX XXXVIII (Continued)

Log book: electrical stimulator instruction manual

In order to operate properly the unit provided, you should read and follow the
instructions carefully:

1. Before use wash the area of skin over the electrodes are to be applied to
remove, medications, creams, oils, powders, etc which can contaminate the gel
and reduce adhesion.
2. Insert the lead wires while the electrodes are in the plastic sheet, this will
ease the electrodes application.

522

APPENDIX XXXVIII (Continued)

Log book electrical stimulator instruction manual

3. Apply the circular pads to the 2 points marked by an X on your arm (see Figure
below). The black electrode on the anterior aspect of your arm, and the red
electrode opposite to the red electrode.

4. Turn the ON/OFF switch to ON.

5. Turn the knob up SLOWLY until you feel a strong but comfortable
sensation. However if you do not feel any sensation when the knob is turned up
to medium level (if your device goes till 10, turn to 5; if your device goes to 5,
turn to 2.5) then leave it at this level for the treatment time.
6. Once you have done this, set the timer for 30 minutes.
7. After a short period of time you may feel the sensation wear off/fade away,
please turn the knob up, again until you feel a strong but comfortable
sensation. If you have not experienced any sensation, please turn the knob to
the maximum after 15 minutes of treatment.
523

APPENDIX XXXVIII (Continued)

Log book Instruction manual

8. Once the alarm goes off at the end of the treatment time, gently turn the knob
down to the OFF position and remove the pads from your skin and return them
to the plastic sheet provided. Do not pull on the lead wires when removing
electrodes from the skin or storage sheet, as this may cause damage.
9. In the event of skin rash, discontinue use and contact the nurses at the pain
unit (Phone 21 2727100).
10. Do not use electrical stimulation whilst driving.

524

APPENDIX XXXVIII (Continued)

Log book recordings of the number of treatment*. Days 1, 2, 3, 4, 5
Evening assessment (Before patient go to bed)

* The log book for patients in the control group did not include this sheet

Please circle the number of times you did the treatment

Number of Times you did the

treatment
+ + + + + + + + + +

Day

525

APPENDIX XXXVIII (Continued)

Log book. Days 2, 3, 4 and 5
VAS - morning and evening assessment (first thing in the morning and before
go to bed)

PAIN ASSESSMENT

The following scale will assess your pain in this precise moment. The far left end of
the scale represents no pain at all. The far right end of the scale represents pain as
bad as it can be.

Please place a mark across the line that represents best the pain that you feel in
this precise moment.

No Pain at all

Pain as bad as it can be

526

APPENDIX XXXVIII (Continued)

Log book. Days 2, 3, 4 and 5
MANE questionnaire - evening assessment (before patient go to bed)

These questions will ask about nausea and vomiting separately. NAUSEA is
feeling sick to your stomach; VOMITING is actually throwing up. Please circle
or fill in the corresponding number.
Question 1. Did you experience nausea over the last 24 hours?
Yes
No (if no, please go to question 2)
How long did the nausea last?______hours
How would you describe the nausea at its worst?
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable

Question 2. Did you experience vomiting over the last 24 hours?

Yes
No (if no, please go to question 3)
How long did the vomiting last?______hours
How would you describe the vomiting at its worst?
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable

527

APPENDIX XXXVIII (Continued)

Log book. Days 2, 3, 4 and 5
MANE questionnaire - evening assessment (before patient go to bed)

Question 3. Did you need to take medication for nausea and or vomiting over
the last 24 hours?
Yes
No
If yes state the name of the drug and time of ingestion

528

APPENDIX XXXIX
Clinical trial Visual Analogue Scale (VAS)

- PAIN ASSESSMENT -

The following scale will assess your pain in this precise moment. The far left end of
the scale represents no pain at all. The far right end of the scale represents pain as
bad as it can be.

Please place a mark across the line that represents best the pain that you feel in
this precise moment.

No Pain at all

Pain as bad as it can be

529

APPENDIX XL
Clinical trial EORTC Quality of Life Questionnaire C30

530

APPENDIX XL (Continued)
Clinical trial EORTC Quality of Life Questionnaire C30

531

APPENDIX XLI
Clinical trial MANE questionnaire Baseline and follow-up

Morrow Assessment of Nausea and Emesis

These questions will ask about nausea and vomiting separately. NAUSEA is
feeling sick to your stomach; VOMITING is actually throwing up. Please circle
or fill in the corresponding number.

Question 1. Did you experience nausea DURING or AFTER your last

chemotherapy treatment?
Yes
No (if no, please go to question 2)

How long did the nausea last?______hours

How would you describe the nausea at its worst?

1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
When was the nausea the worst?
1 During treatment
2 0-4 hours after treatment
3 4-8 hours after treatment
4 8-12 hours after treatment
5 12-24 hours after treatment
6 24 or more hours after treatment
7 No time more severe than any other

532

APPENDIX XLI (Continued)

Clinical trial MANE questionnaire Baseline and follow-up

Question 2. Did you experience vomiting DURING or AFTER your last

chemotherapy treatment?

Yes
No (if no, please go to question 3)

How long did the vomiting last?______hours

How would you describe the vomiting at its worst?

1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable

When was the vomiting the worst?

1 During treatment
2 0-4 hours after treatment
3 4-8 hours after treatment
4 8-12 hours after treatment
5 12-24 hours after treatment
6 24 or more hours after treatment
7 No time more severe than any other

533

APPENDIX XLI (Continued)

Clinical trial MANE questionnaire Baseline and follow-up

Question 3. Did you experience nausea BEFORE your last chemotherapy

treatment?

Yes
No (if no, please go to question 4)

How would you describe the nausea at its worst before treatment
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
How many hours before treatment did it first occur?______hours

Question 4. Did you experience vomiting BEFORE your last chemotherapy

treatment?

Yes
No (if no, please go to question 5)
How would you describe the vomiting at its worst before treatment?
1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable
How many hours before treatment did it first occur?______hours
534

APPENDIX XLI (Continued)

Clinical trial MANE questionnaire Baseline and follow-up

Question 5. Did you take medication for nausea/or vomiting for your last
treatment?

Yes
No

If yes, was it useful?

1 Very
2 Somewhat
3 Works a little
4 Doesnt seem to help

535

APPENDIX XLII
Clinical trial MANE (Modified) Daily questionnaire (once every 24 hours)

Morrow Assessment of Nausea and Emesis

These questions will ask about nausea and vomiting separately. NAUSEA is
feeling sick to your stomach; VOMITING is actually throwing up. Please circle
or fill in the corresponding number.

Question 1. Did you experience nausea over the last 24 hours?

Yes
No (if no, please go to question 2)

How long did the nausea last?______hours

How would you describe the nausea at its worst?

1 Very mild
2 Mild
3. Moderate
4 Severe
5 Very severe
6 Intolerable

536

APPENDIX XLII (Continued)

Clinical trial MANE (Modified) Daily questionnaire (once every 24 hours)

Question 2. Did you experience vomiting over the last 24 hours?

Yes
No (if no, please go to question 3)

How long did the vomiting last?______hours

How would you describe the vomiting at its worst?

1 Very mild
2 Mild
3 Moderate
4 Severe
5 Very severe
6 Intolerable

Question 3. Did you need to take medication for nausea and or vomiting over
the last 24 hours?

Yes
No
If yes state the name of the drug and time of ingestion

537

Appendix XLIII
Clinical trial Duration of vomiting raw data (min)

* Missing data is coded as 99

Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

Post
chemo
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Day 2

Day 3

Day 4

Day 5

0
0
0
0
0
30
0
0
0
0
0
240
0
0
0
0
0
0
0
0
0
0
0
0
0
0
30
0
0
0
1440

0
0
0
0
0
0
0
0
5
60
0
180
0
0
0
0
0
0
0
0
10
0
1440
0
0
0
15
0
0
0
180

0
0
0
0
0
60
0
0
0
30
0
0
0
0
0
0
0
0
0
0
99
0
1440
0
0
0
60
0
0
0
240

0
0
120
0
15
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
780
0
0
0
10
0
0
0
360

538

Appendix XLIII (Continued)

Clinical trial Duration of vomiting raw data (min)
Group

Post
chemo

Day 2

Day 3

Day 4

Day 5

Placebo TENS

Placebo TENS

Placebo TENS

240

20

30

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

30

Placebo TENS

15

Placebo TENS

15

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

15

10

10

Placebo TENS

539

Appendix XLIII (Continued)

Clinical trial Duration of vomiting raw data (min)

Placebo IFT

Post
chemo
0

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

60

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

60

60

Placebo IFT

Group

Day 2

Day 3

Day 4

Day 5

540

Appendix XLIII (Continued)

Clinical trial Duration of vomiting raw data (min)

Active TENS

Post
chemo
0

Active TENS

120

.00

Active TENS

Active TENS

99

Active TENS

Active TENS

99

99

99

99

Active TENS

Active TENS

Active TENS

30

15

10

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

99

99

99

Active TENS

240

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Group

Day 2

Day 3

Day 4

Day 5

541

Appendix XLIII (Continued)

Clinical trial Duration of vomiting raw data (min)

Active IFT

Post
chemo
0

Active IFT

90

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

99

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

99

99

Active IFT

99

Active IFT

Group

Day 2

Day 3

Day 4

Day 5

542

Appendix XLIV
Clinical trial Duration of nausea raw data (min)

* Missing data is coded as 99

Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

Post
chemo
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
0
0
60
0
0
0
0
0
0
0
0
0
0
0
0

Day 2

Day 3

Day 4

Day 5

0
0
0
0
30
840
180
0
0
0
30
240
0
480
0
0
10
180
720
600
0
0
0
0
0
30
420
0
120
0
1440

0
0
0
0
30
1440
120
0
0
240
60
180
0
480
0
0
0
240
720
0
30
0
1440
0
0
30
60
0
0
0
1440

99
0
0
0
0
30
99
0
0
120
60
0
0
480
0
0
0
360
540
1200
30
0
1440
0
0
0
60
0
0
0
480

0
0
1440
0
240
0
180
0
0
0
0
0
0
360
0
0
0
120
0
0
0
0
780
0
0
35
15
0
0
0
240

543

Appendix XLIV (Continued)

Clinical trial Duration of nausea raw data (min)
Group

Post
chemo

Day 2

Day 3

Day 4

Day 5

Placebo TENS

Placebo TENS

Placebo TENS

240

30

30

Placebo TENS

30

30

30

30

Placebo TENS

15

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

180

480

300

180

Placebo TENS

720

720

300

Placebo TENS

99

Placebo TENS

60

Placebo TENS

1200

1200

600

60

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

10

Placebo TENS

240

60

Placebo TENS

720

720

720

720

Placebo TENS

544

Appendix XLIV (Continued)

Clinical trial Duration of nausea raw data (min)

Placebo IFT

Post
chemo
0

Placebo IFT

Placebo IFT

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

300

Placebo IFT

Placebo IFT

1440

480

Placebo IFT

30

60

120

Placebo IFT

60

Placebo IFT

99

99

99

Placebo IFT

60

120

Placebo IFT

Placebo IFT

30

30

30

30

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

60

Placebo IFT

Placebo IFT

Placebo IFT

30

99

99

99

Placebo IFT

120

150

Placebo IFT

Placebo IFT

120

30

30

15

Placebo IFT

120

1440

1440

1440

Placebo IFT

Group

Day 2

Day 3

Day 4

Day 5

240

120

180

120

545

Appendix XLIV (Continued)

Clinical trial Duration of nausea raw data (min)

Active TENS

Post
chemo
0

Active TENS

Active TENS

120

10

Active TENS

99

Active TENS

99

Active TENS

99

Active TENS

99

30

99

99

Active TENS

30

30

30

Active TENS

30

Active TENS

30

540

30

Active TENS

360

600

600

Active TENS

1440

Active TENS

1440

1440

Active TENS

300

Active TENS

180

99

240

1440

Active TENS

99

480

99

Active TENS

120

Active TENS

Active TENS

Active TENS

60

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

720

Group

Day 2

Day 3

Day 4

Day 5

546

Appendix XLIV (Continued)

Clinical trial Duration of nausea raw data (min)

Active IFT

Post
chemo
0

Active IFT

720

720

480

240

Active IFT

Active IFT

99

Active IFT

120

Active IFT

Active IFT

720

360

300

480

Active IFT

60

120

Active IFT

60

60

60

60

Active IFT

20

10

99

99

99

Active IFT

60

60

60

60

Active IFT

15

Active IFT

15

60

Active IFT

Active IFT

99

99

99

99

Active IFT

Active IFT

720

360

30

Active IFT

60

120

180

Active IFT

Active IFT

Active IFT

20

60

60

30

Active IFT

Active IFT

720

300

Active IFT

720

1440

720

Active IFT

Active IFT

99

99

99

99

99

Active IFT

15

1440

120

99

Active IFT

Group

Day 2

Day 3

Day 4

Day 5

547

Appendix XLV
Clinical trial Severity of vomiting raw data

* Missing data is coded as 99

Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

Post
chemo
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Day 2

Day 3

Day 4

Day 5

0
0
0
0
0
2
0
0
0
0
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
0
0
0
5

0
0
0
0
0
0
0
0
2
3
0
2
0
0
0
0
0
0
0
0
1
0
5
0
0
0
3
0
0
0
5

0
0
0
0
0
4
0
0
0
3
0
0
0
0
0
0
0
0
0
0
1
0
4
0
0
0
3
0
0
0
5

0
0
3
0
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4
0
0
0
2
0
0
0
5

548

Appendix XLV (Continued)

Clinical trial Severity of vomiting raw data
Group

Post
chemo

Day 2

Day 3

Day 4

Day 5

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

549

Appendix XLV (Continued)

Clinical trial Severity of vomiting raw data

Placebo IFT

Post
chemo
0

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Group

Day 2

Day 3

Day 4

Day 5

550

Appendix XLV
Clinical trial Severity of vomiting raw data (Continued)

Active TENS

Post
chemo
0

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

99

99

99

99

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

99

99

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Group

Day 2

Day 3

Day 4

Day 5

551

Appendix XLV (Continued)

Clinical trial Severity of vomiting raw data

Active IFT

Post
chemo
0

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

99

99

Active IFT

99

Active IFT

Group

Day 2

Day 3

Day 4

Day 5

552

Appendix XLVI
Clinical trial Severity of nausea raw data

* Missing data is coded as 99

Group
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

Post
chemo
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
0
0
0
3
0
0
0
0
0
0
0
0
0
0
0
0

Day 2

Day 3

Day 4

Day 5

0
0
0
0
2
2
3
0
0
0
2
3
0
4
0
0
2
2
4
1
0
0
0
0
0
1
4
0
3
0
5

0
0
0
0
2
3
2
0
0
4
1
2
0
4
0
0
0
3
4
0
3
0
4
0
0
2
3
0
0
0
4

3
0
0
0
0
4
3
0
0
3
2
0
0
3
0
0
0
4
3
1
2
0
4
0
0
0
3
0
0
0
4

0
0
4
0
4
0
3
0
0
0
0
0
0
2
0
0
0
2
0
0
0
0
3
0
0
2
2
0
0
0
5

553

Appendix XLVI (Continued)

Clinical trial Severity of nausea raw data
Group

Post
chemo

Day 2

Day 3

Day 4

Day 5

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

99

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

554

Appendix XLVI (Continued)

Clinical trial Severity of nausea raw data

Placebo IFT

Post
chemo
0

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Group

Day 2

Day 3

Day 4

Day 5

555

Appendix XLVI (Continued)

Clinical trial Severity of nausea raw data

Active TENS

Post
chemo
0

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

99

99

99

99

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

99

99

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Group

Day 2

Day 3

Day 4

Day 5

556

Appendix XLVI (Continued)

Clinical trial Severity of nausea raw data

Active IFT

Post
chemo
0

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

99

99

99

99

Active IFT

99

Active IFT

Group

Day 2

Day 3

Day 4

Day 5

557

Appendix XLVII
Clinical trial VAS raw data (%)
* Missing data is coded as 99

Group

Pre
che
mo

Post
che
mo

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
.1
0
0
.5
.0
1.7
.2
.4
4.6
.5
1
0
0
0
.9
0
.2
0
0
1.2
.5
1.9
.9
.2
1.5
1.9
2.5
0
2.5
.7

1
.1
0
0
.4
0
3.3
.2
.3
2
.5
.4
.4
.1
0
.7
0
.1
2.2
0
.5
.1
.2
.7
.5
2
.4
2
0
1
.3

Day
2
morn
ing
.1
0
.1
0
.1
.1
2.7
.4
.9
1.1
.4
.6
.2
0
.2
.5
0
.2
2.6
0
.3
3.2
1
.4
.5
2.3
1.2
2.3
10
1.1
1.3

Day
2
night
.1
0
.2
0
.1
.2
2.9
.3
.8
1
.8
.7
.2
.2
.2
.9
0
.2
1.1
0
.2
5.2
1.3
.3
.5
1.9
2
3.1
0
2.7
2.1

Day
3
morn
ing
.1
0
.1
.0
5.1
.2
3.8
.2
.3
3.9
.6
.5
.2
.2
2.9
.7
0
.1
1.2
0
.5
3.3
4.4
.2
0
2.7
.6
2.4
0
.7
1.8
558

Day
3
night
.2
0
0
0
5
.8
4
.2
.2
4.9
.4
.5
.2
.3
4.9
1
0
.1
3.0
0
1.6
5.2
7
.2
0
3.3
2
2.5
0
4.1
1.9

Day
4
morn
ing
1.8
0
0
0
.1
.5
4.5
.2
.2
2.9
.7
.5
.1
0
4.9
.5
0
.1
2.9
0
.6
4.3
2.5
.1
.4
2.7
.3
2.2
0
.7
2.5

Day
4
night
1.5
0
0
0
.1
.5
4.4
.3
.2
2.9
1.1
.6
.1
.1
3.3
.6
0
.2
3.3
0
.5
5.9
4.2
.2
.5
3.2
.5
2.2
0
1.5
1.9

Day
5
morn
ing
.1
0
4.2
0
.1
.4
4.8
.2
.3
1.2
1.2
.4
0
0
1.5
.6
0
.1
.9
0
.9
6.3
4.1
.1
.6
4.3
.2
2.5
0
.2
3.5

Day
5
night
2.5
0
5.5
0
4.7
.7
4.9
.3
.4
1
.6
.5
.2
0
2.3
.5
0
.1
.9
0
1.1
7
4.5
.2
.4
4.7
.3
2.9
0
.9
1.9

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

.3

.3

.2

.2

.2

.4

.4

.3

.3

.5

.2

.2

.2

.3

.2

.2

.2

.1

.2

.2

.4

.4

9.6

9.5

.5

9.5

9.3

9.2

9.3

.3

.1

5.7

5.7

6.5

6.5

8.3

5.4

4.3

2.9

3.3

2.9

3.2

3.3

3.3

3.9

4.3

1.9

1.2

.6

.7

.7

.7

.9

.8

.5

.4

.4

.4

.5

.5

.4

.6

.4

.5

.4

.5

.2

.2

.1

.4

.3

.2

.3

.5

.3

.6

.1

.4

.3

.5

1.4

7.9

2.5

5.3

.8

.8

2.3

2.9

4.7

4.7

2.0

3.2

.8

.5

.3

.1

.5

.7

.4

.3

.2

1.1

3.7

1.3

4.9

.9

3.3

.7

.3

.2

.2

.1

.1

2.4

.4

.9

.1

3.7

4.5

1.7

1.2

3.3

559

Appendix LVII (Continued)

Clinical trial VAS raw data (%)

Group
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS
Placebo
TENS

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

.3

.5

.3

.3

.5

.3

.2

.4

.1

.2

.2

.1

.1

.2

.2

.2

.5

.4

.3

.5

.5

.3

.4

1.5

1.3

3.5

.7

.6

1.1

.9

.5

.6

.7

.6

.3

.6

.7

.2

.2

.2

.2

.3

.2

.2

560

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

.4

.2

.3

.2

.3

.4

.3

.3

.3

.3

3.8

.6

.5

.3

.3

.2

.2

.2

.3

1.3

.7

.5

1.3

2.4

1.9

2.5

2.3

2.9

.2

.4

.1

.1

.1

.1

.6

.6

.5

.6

.2

.1

.1

.2

.2

.3

.2

.2

.1

.2

.5

.5

.3

.5

.3

.2

.2

.2

.2

.1

2.5

.9

.1

.2

.1

.2

.1

.2

2.1

1.1

1.2

1.1

1.2

1.3

1.3

1.3

1.1

.4

.3

.5

.9

1.3

1.7

1.3

1.4

3.9

3.7

1.9

.1

.2

1.6

.4

.5

.3

.6

.9

.5

99

99

99

99

99

99

.7

1.4

1.2

1.1

.8

1.2

.5

.5

.1

.5

.3

99

99

99

99

99

99

.7

.2

.4

.3

.4

.4

.2

.3

.3

.2

561

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT
Placebo
IFT

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

.3

.3

.3

.3

.9

.5

.9

.6

.5

.1

1.7

1.7

5.5

6.1

2.5

4.9

.1

.2

.5

.5

.3

.9

.4

.4

.6

.5

1.2

1.3

.5

.5

1.9

1.1

1.3

1.3

1.3

1.5

3.4

3.1

1.5

1.5

6.7

8.5

99

99

99

99

.1

.2

.3

.3

.2

1.1

4.2

4.7

4.1

4.8

.4

.4

.5

.5

.7

.6

1.5

2.4

2.7

2.7

2.2

2.2

2.5

2.2

2.7

.4

.4

.3

.3

.3

.5

.5

.4

10

10

10

10

562

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

5.2

4.5

4.2

2.5

2.1

1.8

1.8

1.1

.9

.9

7.3

1.3

1.3

99

1.4

1.6

1.3

1.3

1.0

1.3

2.3

.3

.6

.3

.3

.3

.3

.2

.3

.2

.4

.1

.4

.4

.5

.4

.4

.4

.4

.2

.2

99

99

99

99

99

99

99

1.1

.7

8.9

8.9

8.2

9.0

6.7

7.5

8.2

8.9

.3

.2

.2

.2

.1

.3

.4

.2

.2

.3

.3

.3

7.2

3.2

3.7

4.6

3.7

.7

.1

.2

.4

.9

.1

.7

.2

.1

.2

.1

.1

.1

.1

.1

.1

.2

.5

.5

.4

.5

.5

.3

.3

.5

.4

.3

.3

.3

.4

.3

.4

.5

.4

.4

.3

.7

.7

.9

.9

1.1

.9

2.6

.4

2.5

.5

.7

.3

1.2

6.7

.5

.7

.1

.1

.2

3.6

.4

1.7

.1

.3

2.2

1.5

1.1

1.4

1.7

1.8

1.7

1.8

1.7

1.7

1.4

.5

.4

.2

.2

1.8

1.8

.2

.1

9.5

563

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS
Active
TENS

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

1.2

.7

.7

.1

.2

.3

.2

.3

.8

.7

.7

.3

.4

.2

.2

.1

.2

.2

.2

.2

.2

.2

.2

.1

.2

.2

.2

.1

.4

.5

.4

.1

.2

.9

1.2

.7

.5

.3

.3

.3

.6

.5

.0

.4

564

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

.2

.2

.3

.2

.2

.2

.2

.3

.3

.3

.1

1.5

1.5

1.1

.8

.9

.6

.5

.3

.3

.5

2.1

1.3

1.5

1.9

.2

.5

.4

.3

.3

.3

.2

.3

.2

.2

.2

.3

.7

.2

.3

.2

.4

.3

.2

.3

.2

.2

3.1

.3

2.2

1.6

1.5

.4

.2

.1

.2

2.1

.9

3.3

4.1

3.3

4.0

5.3

5.5

4.9

4.9

1.5

.6

.9

.4

.6

.4

.3

.2

7.5

99

99

99

99

99

99

2.4

.2

.1

.2

.3

.4

.4

.3

.3

.2

.3

.3

.2

.7

.3

1.5

5.3

3.9

2.1

1.5

1.1

.2

.1

.1

.1

.1

.1

.1

.2

.2

.1

.1

.5

2.2

.4

5.2

9.3

9.4

9.5

9.7

9.7

9.7

.2

4.2

.3

.4

.5

1.4

2.0

1.7

1.7

2.2

2.8

2.4

.5

3.5

1.2

4.2

4.4

2.7

4.0

1.5

.4

565

Appendix XLVII (Continued)

Clinical trial VAS raw data (%)

Group
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT
Active
IFT

Pre
che
mo

Post
che
mo

Day
2
mor
ning

Day
2
night

Day
3
mor
ning

Day
3
night

Day
4
mor
ning

Day
4
night

Day
5
mor
ning

Day
5
night

1.5

.5

.5

.6

.4

.5

.4

.8

.9

.6

.9

7.5

1.9

1.2

.9

3.4

1.7

1.4

.7

.5

2.2

2.6

.4

.9

1.1

.4

.4

.2

.1

99

99

99

99

99

99

99

99

99

.2

.1

.2

.5

2.7

99

99

99

99

566

Appendix XLVIII
Clinical trial Quality of life global health status raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

33.33
50
0
50
25
58.33
58.33
50
58.33
91.67
33.33
50
50
66.67
33.33
41.67
75
50
58.33
83.33
50
50
50
58.33
83.33
0
50
75
50
75
50

58.33
41.67
83.33
41.67
33.33
50
41.67
33.33
41.67
50
66.67
41.67
41.67
58.33
100
0
50
75
66.67
75
25
58.33
41.67
83.33
41.67
33.33
50
41.67
33.33
41.67
50
567

Appendix XLVIII (Continued)

Clinical trial Quality of life global health status raw data

Group

Baseline

Follow-up

Placebo TENS

83.33

100

Placebo TENS

75

66.67

Placebo TENS

8.33

16.67

Placebo TENS

33.33

33.33

Placebo TENS

75

25

Placebo TENS

58.33

66.67

Placebo TENS

91.67

83.33

Placebo TENS

100

100

Placebo TENS

58.33

50

Placebo TENS

58.33

16.67

Placebo TENS

50

25

Placebo TENS

58.33

33.33

Placebo TENS

41.67

Placebo TENS

66.67

58.33

Placebo TENS

33.33

41.67

Placebo TENS

66.67

100

Placebo TENS

50

83.33

Placebo TENS

50

66.67

Placebo TENS

58.33

33.33

Placebo TENS

66.67

66.67

Placebo TENS

66.67

75

568

Appendix XLVIII (Continued)

Clinical trial Quality of life global health status raw data

Group

Baseline

Follow-up

Placebo IFT

66.67

50

Placebo IFT

25

83.33

Placebo IFT

41.67

58.33

Placebo IFT

33.33

41.67

Placebo IFT

83.33

91.67

Placebo IFT

58.33

50

Placebo IFT

16.67

Placebo IFT

50

50

Placebo IFT

66.67

50

Placebo IFT

66.67

58.33

Placebo IFT

58.33

58.33

Placebo IFT

66.67

50

Placebo IFT

75

41.67

Placebo IFT

50

83.33

Placebo IFT

75

50

Placebo IFT

50

99

Placebo IFT

50

83.33

569

Appendix XLVIII (Continued)

Clinical trial Quality of life global health status raw data

Group

Baseline

Follow-up

Placebo IFT

33.33

58.33

Placebo IFT

100

33.33

Placebo IFT

50

41.67

Placebo IFT

91.67

66.67

Placebo IFT

75

58.33

Placebo IFT

16.67

99

Placebo IFT

50

50

Placebo IFT

83.33

66.67

Placebo IFT

50

58.33

Placebo IFT

66.67

50

Placebo IFT

41.67

58.33

570

Appendix XLVIII (Continued)

Clinical trial Quality of life global health status raw data

Group

Baseline

Follow-up

Active TENS

66.67

50

Active TENS

16.67

33.33

Active TENS

66.67

50

Active TENS

33.33

41.67

Active TENS

75

66.67

Active TENS

66.67

33.33

Active TENS

50

25

Active TENS

66.67

50

Active TENS

58.33

50

Active TENS

33.33

16.67

Active TENS

83.33

91.67

Active TENS

75.00

100

Active TENS

100

91.67

Active TENS

50

50

Active TENS

8.33

33.33

Active TENS

58.33

50

Active TENS

50.00

50

Active TENS

41.67

41.67

Active TENS

50

75

Active TENS

Active TENS

50

50

Active TENS

66.67

83.33

Active TENS

8.33

8.33

Active TENS

83.33

83.33

Active TENS

83.33

50
571

Appendix XLVIII (Continued)

Clinical trial Quality of life global health status raw data

Group

Baseline

Follow-up

Active IFT

50

50

Active IFT

25

Active IFT

66.67

66.67

Active IFT

66.67

83.33

Active IFT

75

33.33

Active IFT

100

58.33

Active IFT

66.67

50

Active IFT

50

50

Active IFT

41.67

66.67

Active IFT

66.67

50

Active IFT

75

66.67

Active IFT

83.33

66.67

Active IFT

66.67

58.33

Active IFT

50

50

Active IFT

66.67

83.33

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

33.33

Active IFT

50

50

Active IFT

58.33

83.33

Active IFT

83.33

66.67

Active IFT

100

100

Active IFT

66.67

50

Active IFT

66.67

75

Active IFT

83.33

100

Active IFT

75

99

Active IFT

66.67

50

Active IFT

100

572

Appendix XLIX
Clinical trial Quality of life physical functioning raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

26.67
93.33
26.67
66.67
86.67
60
60
73.33
93.33
100
100
66.67
60
93.33
60
86.67
60
93.33
93.33
93.33
100
53.33
60
86.67
86.67
60
73.33
73.33
93.33
86.67
73.33

46.67
93.33
20
86.67
86.67
66.67
80
93.33
93.33
66.67
100
73.33
53.33
80
66.67
80
60
73.33
80
86.67
100
53.33
66.67
100
86.67
33.33
93.33
73.33
100
86.67
53.33
573

Appendix XLIX (Continued)

Clinical trial Quality of life physical functioning raw data

Group

Baseline

Follow-up

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

40

40

Placebo TENS

80

73.33

Placebo TENS

73.33

73.33

Placebo TENS

80

80

Placebo TENS

93.33

100

Placebo TENS

86.67

86.67

Placebo TENS

66.67

60

Placebo TENS

73.33

66.67

Placebo TENS

33.33

53.33

Placebo TENS

66.67

80

Placebo TENS

33.33

60

Placebo TENS

100

93.33

Placebo TENS

86.67

93.33

Placebo TENS

100

80

Placebo TENS

60

86.67

Placebo TENS

93.33

80

Placebo TENS

60

80

Placebo TENS

86.67

86.67

Placebo TENS

86.67

93.33

574

Appendix XLIX (Continued)

Clinical trial Quality of life physical functioning raw data

Group

Baseline

Follow-up

Placebo IFT

73.33

80

Placebo IFT

60

66.67

Placebo IFT

60

66.67

Placebo IFT

73.33

73.33

Placebo IFT

100

100

Placebo IFT

66.67

80

Placebo IFT

86.67

86.67

Placebo IFT

86.67

86.67

Placebo IFT

80

73.33

Placebo IFT

66.67

80

Placebo IFT

86.67

86.67

Placebo IFT

73.33

60

Placebo IFT

93.33

80

Placebo IFT

86.67

93.33

Placebo IFT

93.33

86.67

Placebo IFT

86.67

99

Placebo IFT

93.33

73.33

Placebo IFT

60

86.67

Placebo IFT

40

33.33

Placebo IFT

53.33

46.67

Placebo IFT

100

93.33

Placebo IFT

86.67

86.67

575

Appendix XLIX (Continued)

Clinical trial Quality of life physical functioning raw data

Group

Baseline

Follow-up

Placebo IFT

60

99

Placebo IFT

60

60

Placebo IFT

86.67

86.67

Placebo IFT

60

53.33

Placebo IFT

86.67

66.67

IFT Placebo

66.67

46.67

576

Appendix XLIX (Continued)

Clinical trial Quality of life physical functioning raw data

Group

Baseline

Follow-up

Active TENS

86.67

80

Active TENS

26.67

40

Active TENS

53.33

60

Active TENS

93.33

66.67

Active TENS

80

86.67

Active TENS

93.33

73.33

Active TENS

66.67

66.67

Active TENS

60

33.33

Active TENS

26.67

46.67

Active TENS

60

26.67

Active TENS

100

100

Active TENS

93.33

86.67

Active TENS

100

80

Active TENS

73.33

60

Active TENS

66.67

60

Active TENS

93.33

93.33

Active TENS

80

73.33

Active TENS

86.67

80

Active TENS

80

66.67

Active TENS

80

66.67

Active TENS

80

93.33

Active TENS

93.33

93.33

Active TENS

46.67

73.33

Active TENS

100

100

Active TENS

93.33

100
577

Appendix XLIX (Continued)

Clinical trial Quality of life physical functioning raw data

Group

Baseline

Follow-up

Active IFT

100

93.33

Active IFT

80

80

Active IFT

100

100

Active IFT

86.67

80

Active IFT

93.33

86.67

Active IFT

73.33

66.67

Active IFT

86.67

80

Active IFT

80

80.00

Active IFT

53.33

66.67

Active IFT

93.33

86.67

Active IFT

86.67

86.67

Active IFT

80

93.33

Active IFT

86.67

86.67

Active IFT

100

60

Active IFT

33.33

60

Active IFT

33.33

Active IFT

53.33

46.67

Active IFT

73.33

66.67

Active IFT

80

80

Active IFT

86.67

93.33

Active IFT

93.33

93.33

Active IFT

100

86.67

Active IFT

86.67

93.33

Active IFT

86.67

86.67

Active IFT

100

100

Active IFT

100

99

Active IFT

66.67

60

Active IFT

100

100

578

Appendix L
Clinical trial Quality of life role functioning raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
100
0
66.67
66.67
50.00
0
0
100
100
50.00
83.33
66.67
83.33
83.33
100
100
100
100
50.00
100
66.67
33.33
50.00
100
16.67
66.67
83.33
33.33
100
66.67

33.33
100
0
100
66.67
66.67
16.67
83.33
100
83.33
100
100
66.67
66.67
100
100
100
50.00
0
66.67
100
0
0
50.00
100
66.67
66.67
100
100
100
33.33
579

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

33.33

16.67

Placebo TENS

33.33

50

Placebo TENS

100

16.67

Placebo TENS

100

100

Placebo TENS

100

83.33

Placebo TENS

100

83.33

Placebo TENS

66.67

100

Placebo TENS

16.67

Placebo TENS

66.67

Placebo TENS

50

50

Placebo TENS

100

83.33

Placebo TENS

100

50

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

83.33

100

Placebo TENS

66.67

66.67

Placebo TENS

66.67

66.67

Placebo TENS

83.33

Placebo TENS

100

66.67
580

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Placebo IFT

100

100

Placebo IFT

66.67

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

66.67

100

Placebo IFT

83.33

100

Placebo IFT

100

100

Placebo IFT

83.33

83.33

Placebo IFT

100

100

Placebo IFT

83.33

83.33

Placebo IFT

50.00

66.67

Placebo IFT

100

83.33

Placebo IFT

100

100

Placebo IFT

83.33

66.67

Placebo IFT

100

99

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

33.33

100

Placebo IFT

33.33

50.00

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

66.67

99

581

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

66.67

83.33

Placebo IFT

100

66.67

Placebo IFT

66.67

33.33

582

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Active TENS

83.33

83.33

Active TENS

16.67

Active TENS

33.33

100

Active TENS

66.67

83.33

Active TENS

83.33

33.33

Active TENS

100

33.33

Active TENS

100

33.33

Active TENS

66.67

83.33

Active TENS

66.67

83.33

Active TENS

66.67

Active TENS

100

100

Active TENS

83.33

100

Active TENS

100

100

Active TENS

66.67

66.67

Active TENS

83.33

Active TENS

100

100

Active TENS

66.67

66.67

Active TENS

100

83.33

Active TENS

33.33

66.67

Active TENS

33.33

33.33

583

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Active TENS

100

100

Active TENS

83.33

100

Active TENS

33.33

66.67

Active TENS

100

83.33

Active TENS

66.67

66.67

584

Appendix L (Continued)
Clinical trial Quality of life role functioning raw data

Group

Baseline

Follow-up

Active IFT

100

100

Active IFT

100

33.33

Active IFT

100

100

Active IFT

83.33

100

Active IFT

100

100

Active IFT

66.67

100

Active IFT

100

83.33

Active IFT

100

83.33

Active IFT

33.33

66.67

Active IFT

100

66.67

Active IFT

100

83.33

Active IFT

100

100

Active IFT

100

66.67

Active IFT

100

66.67

Active IFT

66.67

100

Active IFT

Active IFT

50.00

16.67

Active IFT

66.67

66.67

Active IFT

100

100

Active IFT

50.00

100

Active IFT

100.00

66.67

Active IFT

66.67

.00

Active IFT

100

50.00

Active IFT

100

83.33

Active IFT

100

100

Active IFT

100

100

Active IFT

100

33.33

Active IFT

100

100

585

Appendix LI
Clinical trial Quality of life emotional functioning raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

16.67
91.67
41.67
83.33
25
25
58.33
75
83.33
75
58.33
50
83.33
91.67
66.67
83.33
41.67
83.33
50
83.33
100.00
75
41.67
100
16.67
8.33
58.33
100
66.67
91.67
33.33

58.33
91.67
75
91.67
66.67
50
66.67
83.33
83.33
91.67
75
66.67
100
75
66.67
100
66.67
75
75
100
83.33
75
66.67
75
66.67
0
75
100
100
91.67
50
586

Appendix LI (Continued)
Clinical trial Quality of life emotional functioning raw data

Group

Baseline

Follow-up

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

66.67

Placebo TENS

33.33

75

Placebo TENS

83.33

66.67

Placebo TENS

66.67

66.67

Placebo TENS

75.00

83.33

Placebo TENS

100

100

Placebo TENS

41.67

16.67

Placebo TENS

8.33

25

Placebo TENS

50

41.67

Placebo TENS

83.33

100

Placebo TENS

50

50

Placebo TENS

50

41.67

Placebo TENS

41.67

41.67

Placebo TENS

100

100

Placebo TENS

83.33

100

Placebo TENS

75

75

Placebo TENS

50

75

Placebo TENS

91.67

99

Placebo TENS

100

100
587

Appendix LI (Continued)
Clinical trial Quality of life emotional functioning raw data

Group

Baseline

Follow-up

Placebo IFT

66.67

91.67

Placebo IFT

41.67

83.33

Placebo IFT

91.67

91.67

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

83.33

91.67

Placebo IFT

50.00

58.33

Placebo IFT

83.33

100

Placebo IFT

25

16.67

Placebo IFT

25

Placebo IFT

75

75

Placebo IFT

66.67

91.67

Placebo IFT

83.33

91.67

Placebo IFT

91.67

91.67

Placebo IFT

66.67

50

Placebo IFT

100

99

Placebo IFT

100

83.33

Placebo IFT

83.33

83.33

Placebo IFT

91.67

91.67

Placebo IFT

33.33

58.33

Placebo IFT

100

100

Placebo IFT

91.67

91.67

Placebo IFT

75.00

99

Placebo IFT

66.67

66.67

Placebo IFT

83.33

83.33

Placebo IFT

91.67

83.33

Placebo IFT

100

83.33

Placebo IFT

83.33

75
588

Appendix LI (Continued)
Clinical trial Quality of life emotional functioning raw data

Group

Baseline

Follow-up

Active TENS

66.67

58.33

Active TENS

33.33

83.33

Active TENS

75

91.67

Active TENS

33.33

41.67

Active TENS

91.67

83.33

Active TENS

33.33

25.00

Active TENS

66.67

66.67

Active TENS

83.33

25

Active TENS

50

16.67

Active TENS

25

25

Active TENS

83.33

83.33

Active TENS

83.33

91.67

Active TENS

100

100

Active TENS

50

75

Active TENS

66.67

66.67

Active TENS

83.33

83.33

Active TENS

58.33

75

Active TENS

8.33

8.33

Active TENS

83.33

75

Active TENS

100

100

Active TENS

100

100

Active TENS

83.33

100.00

Active TENS

25.00

Active TENS

91.67

100

Active TENS

75

83.33
589

Appendix LI (Continued)
Clinical trial Quality of life emotional functioning raw data

Group

Baseline

Follow-up

Active IFT

66.67

75

Active IFT

16.67

16.67

Active IFT

41.67

91.67

Active IFT

91.67

91.67

Active IFT

75

100

Active IFT

58.33

91.67

Active IFT

66.67

66.67

Active IFT

100

100

Active IFT

91.67

100

Active IFT

83.33

91.67

Active IFT

100

91.67

Active IFT

83.33

75

Active IFT

75

100

Active IFT

41.67

58.33

Active IFT

100

75

Active IFT

83.33

100

Active IFT

16.67

75

Active IFT

83.33

75

Active IFT

83.33

91.67

Active IFT

83.33

100

Active IFT

75

66.67

Active IFT

91.67

100

Active IFT

41.67

58.33

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

99

Active IFT

66.67

50

Active IFT

100

100

590

Appendix LII
Clinical trial Quality of life cognitive functioning raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

33.33
100
66.67
83.33
50
100
66.67
100
100
83.33
100
83.33
66.67
83.33
83.33
100
83.33
100
16.67
100
100
0
83.33
100
50
16.67
66.67
100
100
100
0

33.33
100
66.67
66.67
50
100
50
100
100
83.33
83.33
100
66.67
83.33
50
100
100
66.67
33.33
100
100
0
66.67
83.33
66.67
66.67
100
100
100
100
0
591

Appendix LII (Continued)

Clinical trial Quality of life cognitive functioning raw data

Group

Baseline

Follow-up

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

16.67

66.67

Placebo TENS

100

83.33

Placebo TENS

100

66.67

Placebo TENS

83.33

83.33

Placebo TENS

100

100

Placebo TENS

83.33

83.33

Placebo TENS

50

50

Placebo TENS

66.67

50

Placebo TENS

66.67

33.33

Placebo TENS

100

100

Placebo TENS

33.33

50.00

Placebo TENS

83.33

66.67

Placebo TENS

100

83.33

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

100

83.33

Placebo TENS

83.33

83.33

Placebo TENS

100

100

Placebo TENS

100

100
592

Appendix LII (Continued)

Clinical trial Quality of life cognitive functioning raw data

Group

Baseline

Follow-up

Placebo IFT

100

100

Placebo IFT

66.67

66.67

Placebo IFT

100

100

Placebo IFT

100

66.67

Placebo IFT

83.33

83.33

Placebo IFT

83.33

83.33

Placebo IFT

66.67

100

Placebo IFT

83.33

100

Placebo IFT

100

100

Placebo IFT

83.33

66.67

Placebo IFT

66.67

50.00

Placebo IFT

66.67

100

Placebo IFT

100

100

Placebo IFT

66.67

83.33

Placebo IFT

83.33

100

Placebo IFT

100

99

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

66.67

66.67

Placebo IFT

100

100

Placebo IFT

83.33

83.33

Placebo IFT

33.33

99

593

Appendix LII (Continued)

Clinical trial Quality of life cognitive functioning raw data

Placebo IFT

83.33

83.33

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

83.33

100

Placebo IFT

66.67

66.67

594

Appendix LII (Continued)

Clinical trial Quality of life cognitive functioning raw data

Group

Baseline

Follow-up

Active TENS

100

66.67

Active TENS

100

83.33

Active TENS

83.33

100

Active TENS

100

100

Active TENS

100

83.33

Active TENS

100

100

Active TENS

83.33

66.67

Active TENS

100

100

Active TENS

50

100

Active TENS

16.67

16.67

Active TENS

100

83.33

Active TENS

100

100

Active TENS

100

100

Active TENS

33.33

50

Active TENS

83.33

66.67

Active TENS

100

100

Active TENS

100

100

Active TENS

100

50

Active TENS

66.67

66.67

Active TENS

66.67

83.33

Active TENS

100

100

Active TENS

83.33

83.33

Active TENS

83.33

50

Active TENS

100

100

Active TENS

100

83.33
595

Appendix LII (Continued)

Clinical trial Quality of life cognitive functioning raw data

Group

Baseline

Follow-up

Active IFT

66.67

83.33

Active IFT

33.33

33.33

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

83.33

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

100

Active IFT

100

100

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

100

Active IFT

83.33

100

Active IFT

66.67

66.67

Active IFT

100

100

Active IFT

100

66.67

Active IFT

33.33

16.67

Active IFT

66.67

100

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

100

Active IFT

83.33

100

Active IFT

66.67

100

Active IFT

100

83.33

Active IFT

100

100

Active IFT

100

83.33

Active IFT

83.33

33.33

Active IFT

100

100

596

Appendix LIII
Clinical trial Quality of life social functioning raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

50
100
0
100
66.67
100
50
100
100
100
50
100
100
100
100
100
100
83.33
50
100
100
83.33
0
66.67
66.67
100
66.67
100
100
100
50

100
100
0
50
66.67
83.33
50
83.33
100
100
66.67
100
100
100
66.67
100
100
66.67
0
100
100
50
100
66.67
66.67
100
83.33
100
100
100
0
597

Appendix LIII (Continued)

Clinical trial Quality of life social functioning raw data

Group

Baseline

Follow-up

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

33.33

66.67

Placebo TENS

83.33

66.67

Placebo TENS

100

33.33

Placebo TENS

100

100

Placebo TENS

66.67

100

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

50

16.67

Placebo TENS

100.00

83.33

Placebo TENS

83.33

66.67

Placebo TENS

100

100

Placebo TENS

66.67

50

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

100

100

Placebo TENS

83.33

83.33

Placebo TENS

100

100

Placebo TENS

100

66.67

Placebo TENS

100

100
598

Appendix LIII (Continued)

Clinical trial Quality of life social functioning raw data

Group

Baseline

Follow-up

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

83.33

100

Placebo IFT

100

100

Placebo IFT

16.67

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

33.33

50

Placebo IFT

100

100

Placebo IFT

66.67

66.67

Placebo IFT

66.67

66.67

Placebo IFT

83.33

100

Placebo IFT

100

100

Placebo IFT

66.67

66.67

Placebo IFT

100

99

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

66.67

100

Placebo IFT

33.33

33.33

Placebo IFT

100

83.33

Placebo IFT

100

100

Placebo IFT

100

99

599

Appendix LIII (Continued)

Clinical trial Quality of life social functioning raw data

Group

Baseline

Follow-up

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

100

100

Placebo IFT

100

66.67

Placebo IFT

100

100

600

Appendix LIII (Continued)

Clinical trial Quality of life social functioning raw data

Group

Baseline

Follow-up

Active TENS

100

66.67

Active TENS

83.33

100

Active TENS

100

83.33

Active TENS

50

100

Active TENS

100

66.67

Active TENS

100

100

Active TENS

100

33.33

Active TENS

100

Active TENS

83.33

100

Active TENS

66.67

33.33

Active TENS

100

100

Active TENS

83.33

100

Active TENS

100

100

Active TENS

66.67

83.33

Active TENS

50

100

Active TENS

83.33

100

Active TENS

83.33

83.33

Active TENS

100

66.67

Active TENS

33.33

100

Active TENS

100

100

Active TENS

100

100

Active TENS

83.33

83.33

Active TENS

33.33

Active TENS

100

100

Active TENS

83.33

100
601

Appendix LIII (Continued

Clinical trial Quality of life social functioning raw data)

Group

Baseline

Follow-up

Active IFT

100

100

Active IFT

50

Active IFT

66.67

83.33

Active IFT

100

100

Active IFT

100

100

Active IFT

100

66.67

Active IFT

100

66.67

Active IFT

83.33

100

Active IFT

50

100

Active IFT

100

83.33

Active IFT

100

83.33

Active IFT

100

100

Active IFT

83.33

100

Active IFT

100

100

Active IFT

100

100

Active IFT

100

Active IFT

33.33

83.33

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

100

Active IFT

83.33

66.67

Active IFT

83.33

Active IFT

500

66.67

Active IFT

100

100

Active IFT

100

100

Active IFT

83.33

99

Active IFT

100

66.67

IFT Active

100

100

602

Appendix LIV
Clinical trial Quality of life fatigue raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

88.89
11.11
100
22.22
22.22
33.33
22.22
33.33
0
11.11
22.22
22.22
22.22
77.78
33.33
66.67
33.33
0
33.33
22.22
11.11
55.56
55.56
55.56
33.33
77.78
33.33
11.11
88.89
11.11
66.67

66.67
22.22
55.56
33.33
33.33
22.22
22.22
0
11.11
33.33
11.11
44.44
22.22
11.11
66.67
44.44
33.33
55.56
33.33
33.33
22.22
100
100
11.11
33.33
77.78
33.33
22.22
11.11
22.22
88.89
603

Appendix LIV (Continued)

Clinical trial Quality of life fatigue raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

66.67

44.44

Placebo TENS

44.44

33.33

Placebo TENS

66.67

Placebo TENS

33.33

11.11

Placebo TENS

33.33

Placebo TENS

33.33

Placebo TENS

22.22

33.33

Placebo TENS

66.67

100

Placebo TENS

55.56

100

Placebo TENS

33.33

44.44

Placebo TENS

100.00

66.67

Placebo TENS

22.22

66.67

Placebo TENS

22.22

Placebo TENS

Placebo TENS

22.22

22.22

Placebo TENS

11.11

33.33

Placebo TENS

33.33

11.11

Placebo TENS

22.22

66.67

Placebo TENS

0
604

Appendix LIV (Continued)

Clinical trial Quality of life fatigue raw data
Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

55.56

Placebo IFT

44.44

33.33

Placebo IFT

33.33

33.33

Placebo IFT

11.11

Placebo IFT

11.11

33.33

Placebo IFT

11.11

44.44

Placebo IFT

22.22

Placebo IFT

33.33

22.22

Placebo IFT

33.33

33.33

Placebo IFT

22.22

22.22

Placebo IFT

33.33

33.33

Placebo IFT

33.33

22.22

Placebo IFT

33.33

Placebo IFT

33.33

55.56

Placebo IFT

11.11

99

Placebo IFT

22.22

Placebo IFT

22.22

Placebo IFT

11.11

11.11

Placebo IFT

66.67

33.33

Placebo IFT

11.11

22.22

Placebo IFT

33.33

22.22

Placebo IFT

66.67

99

Placebo IFT

33.33

33.33

Placebo IFT

22.22

33.33

Placebo IFT

22.22

22.22

Placebo IFT

22.22

44.44

Placebo IFT

55.56

66.67
605

Appendix LIV (Continued)

Clinical trial Quality of life fatigue raw data

Group

Baseline

Follow-up

Active TENS

33.33

33.33

Active TENS

77.78

55.56

Active TENS

66.67

22.22

Active TENS

33.33

55.56

Active TENS

11.11

55.56

Active TENS

33.33

Active TENS

44.44

77.78

Active TENS

33.33

88.89

Active TENS

55.56

55.56

Active TENS

44.44

77.78

Active TENS

Active TENS

33.33

22.22

Active TENS

11.11

Active TENS

55.56

44.44

Active TENS

100

88.89

Active TENS

22.22

33.33

Active TENS

33.33

33.33

Active TENS

11.11

77.78

Active TENS

22.22

44.44

Active TENS

77.78

77.78

Active TENS

33.33

11.11

Active TENS

11.11

Active TENS

77.78

55.56

Active TENS

22.22

22.22

Active TENS

33.33

44.44
606

Appendix LIV (Continued)

Clinical trial Quality of life fatigue raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

22.22

44.44

Active IFT

11.11

Active IFT

22.22

33.33

Active IFT

11.11

Active IFT

33.33

33.33

Active IFT

22.22

33.33

Active IFT

22.22

33.33

Active IFT

55.56

Active IFT

22.22

33.33

Active IFT

22.22

33.33

Active IFT

22.22

33.33

Active IFT

22.22

Active IFT

33.33

Active IFT

33.33

44.44

Active IFT

66.67

88.89

Active IFT

55.56

66.67

Active IFT

44.44

55.56

Active IFT

22.22

33.33

Active IFT

33.33

11.11

Active IFT

33.33

Active IFT

11.11

22.22

Active IFT

33.33

Active IFT

33.33

33.33

Active IFT

Active IFT

99

Active IFT

22.22

77.78

Active IFT

607

Appendix LV
Clinical trial Quality of life nausea and vomiting raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
0
66.67
0
0
0
0
0
0
0
0
0
0
16.67
0
0
0
0
0
0
0
0
0
0
0
0
33.33
0
100
0
50

0
0
0
0
33.33
100
16.67
0
16.67
33.33
16.67
83.33
0
33.33
0
0
16.67
16.67
33.33
16.67
16.67
0
100
0
0
16.67
50
0
16.67
0
50
608

Appendix LV (Continued)
Clinical trial Quality of life nausea and vomiting raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

50

66.67

Placebo TENS

33.33

16.67

Placebo TENS

16.67

Placebo TENS

Placebo TENS

16.67

Placebo TENS

Placebo TENS

Placebo TENS

33.33

Placebo TENS

50

Placebo TENS

33.33

Placebo TENS

16.67

Placebo TENS

16.67

50

Placebo TENS

Placebo TENS

33.33

Placebo TENS

Placebo TENS

16.67

Placebo TENS

16.67

Placebo TENS

66.67

Placebo TENS

0
609

Appendix LV (Continued)
Clinical trial Quality of life nausea and vomiting raw data

Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

16.67

Placebo IFT

Placebo IFT

16.67

Placebo IFT

Placebo IFT

Placebo IFT

16.67

Placebo IFT

Placebo IFT

33.33

16.67

Placebo IFT

16.67

Placebo IFT

16.67

Placebo IFT

Placebo IFT

50

Placebo IFT

Placebo IFT

16.67

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

66.67

Placebo IFT

50

16.67

Placebo IFT

Placebo IFT

Placebo IFT

16.67

99

610

Appendix LV (Continued)
Clinical trial Quality of life nausea and vomiting raw data

Group

Baseline

Follow-up

Placebo IFT

33.33

Placebo IFT

Placebo IFT

16.67

Placebo IFT

50

Placebo IFT

611

Appendix LV (Continued)
Clinical trial Quality of life nausea and vomiting raw data

Group

Baseline

Follow-up

Active TENS

16.67

Active TENS

33.33

Active TENS

Active TENS

33.33

Active TENS

16.67

Active TENS

83.33

Active TENS

16.67

Active TENS

33.33

Active TENS

33.33

Active TENS

100

Active TENS

Active TENS

16.67

Active TENS

Active TENS

16.67

Active TENS

16.67

16.67

Active TENS

33.33

Active TENS

Active TENS

Active TENS

16.67

Active TENS

Active TENS

16.67

Active TENS

Active TENS

Active TENS

16.67

Active TENS

16.67
612

Appendix LV (Continued)
Clinical trial Quality of life nausea and vomiting raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

83.33

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

Active IFT

16.67

Active IFT

Active IFT

33.33

Active IFT

33.33

Active IFT

16.67

Active IFT

66.67

50

Active IFT

16.67

Active IFT

Active IFT

16.67

Active IFT

Active IFT

16.67

Active IFT

16.67

Active IFT

Active IFT

99

Active IFT

33.33

Active IFT

613

Appendix LVI
Clinical trial Quality of life pain raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

66.67
0
0
0
33.33
50
33.33
50
16.67
0
33.33
16.67
33.33
16.67
33.33
0
0
0
16.67
0
0
50
66.67
16.67
16.67
16.67
66.67
33.33
0
33.33
33.33

66.67
0
0
0
50
66.67
66.67
33.33
16.67
0
16.67
0
0
16.67
50
0
0
16.67
83.33
16.67
16.67
66.67
100
16.67
0
33.33
16.67
16.67
0
16.67
50
614

Appendix LVI (Continued)

Clinical trial Quality of life pain raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

66.67

50

Placebo TENS

66.67

33.33

Placebo TENS

33.33

50

Placebo TENS

16.67

Placebo TENS

Placebo TENS

16.67

Placebo TENS

16.67

.00

Placebo TENS

33.33

83.33

Placebo TENS

83.33

Placebo TENS

16.67

33.33

Placebo TENS

83.33

66.67

Placebo TENS

16.67

Placebo TENS

66.67

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

16.67

33.33

Placebo TENS

0
615

Appendix LVI (Continued)

Clinical trial Quality of life pain raw data
Group

Baseline

Follow-up

Placebo IFT

16.67

16.67

Placebo IFT

66.67

Placebo IFT

16.67

16.67

Placebo IFT

16.67

Placebo IFT

Placebo IFT

Placebo IFT

16.67

Placebo IFT

16.67

Placebo IFT

Placebo IFT

33.33

16.67

Placebo IFT

16.67

33.33

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

Placebo IFT

16.67

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

50

33.33

Placebo IFT

16.67

Placebo IFT

Placebo IFT

83.33

99

Placebo IFT

16.67

50

Placebo IFT

16.67

Placebo IFT

Placebo IFT

16.67

33.33

Placebo IFT

50

83.33
616

Appendix LVI (Continued)

Clinical trial Quality of life pain raw data

Group

Baseline

Follow-up

Active TENS

50

16.67

Active TENS

83.33

66.67

Active TENS

33.33

Active TENS

33.33

Active TENS

16.67

Active TENS

16.67

Active TENS

16.67

50

Active TENS

66.67

Active TENS

16.67

Active TENS

66.67

Active TENS

Active TENS

16.67

Active TENS

Active TENS

33.33

16.67

Active TENS

16.67

Active TENS

16.67

Active TENS

33.33

33.33

Active TENS

100

Active TENS

Active TENS

16.67

Active TENS

Active TENS

33.33

Active TENS

33.33

50

Active TENS

Active TENS

50
617

Appendix LVI (Continued)

Clinical trial Quality of life pain raw data

Group

Baseline

Follow-up

Active IFT

16.67

16.67

Active IFT

66.67

Active IFT

Active IFT

16.67

16.67

Active IFT

Active IFT

Active IFT

16.67

Active IFT

16.67

33.33

Active IFT

66.67

Active IFT

16.67

33.33

Active IFT

Active IFT

16.67

Active IFT

16.67

33.33

Active IFT

16.67

Active IFT

Active IFT

83.33

100

Active IFT

100

100

Active IFT

66.67

50

Active IFT

16.67

16.67

Active IFT

16.67

Active IFT

Active IFT

16.67

Active IFT

16.67

33.33

Active IFT

16.67

16.67

Active IFT

Active IFT

99

Active IFT

66.67

Active IFT

618

Appendix LVII
Clinical trial Quality of life dyspnoea raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
33.33
0
0
66.67
0
0
100
0
0
0
0
0

0
0
0
0
33.33
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
66.67
0
0
100
33.33
0
0
0
0
619

Appendix LVII (Continued)

Clinical trial Quality of life dyspnoea raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

66.67

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

Placebo TENS

Placebo TENS

0
620

Appendix LVII (Continued)

Clinical trial Quality of life dyspnoea raw data
Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

Placebo IFT

33.33

Placebo IFT

99

Placebo IFT

66.67

66.67

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

0
621

Appendix LVII (Continued)

Clinical trial Quality of life dyspnoea raw data

Group

Baseline

Follow-up

Active TENS

Active TENS

Active TENS

33.33

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

33.33

Active TENS

33.33

33.33

Active TENS

Active TENS

33.33

Active TENS

Active TENS

Active TENS

33.33

33.33

Active TENS

Active TENS

66.67

66.67

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

0
622

Appendix LVII (Continued)

Clinical trial Quality of life dyspnoea raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

66.67

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

99

Active IFT

33.33

Active IFT

623

Appendix LVIII
Clinical trial Quality of life insomnia raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
0
33.33
33.33
33.33
100
33.33
0
0
0
33.33
0
66.67
33.33
0
100.00
66.67
0
33.33
0
0
0
100
33.33
0
100
33.33
0
0
33.33
66.67

33.33
0
0
0
0
100
33.33
66.67
0
0
0
0
33.33
66.67
0
0
66.67
0
100
33.33
33.33
66.67
100
33.33
33.33
33.33
66.67
0
0
0
100
624

Appendix LVIII (Continued)

Clinical trial Quality of life insomnia raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

100

66.67

Placebo TENS

66.67

Placebo TENS

33.33

66.67

Placebo TENS

66.67

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

66.67

Placebo TENS

100

100

Placebo TENS

33.33

Placebo TENS

66.67

66.67

Placebo TENS

100

33.33

Placebo TENS

33.33

33.33

Placebo TENS

66.67

Placebo TENS

Placebo TENS

33.33

Placebo TENS

33.33

Placebo TENS

33.33

Placebo TENS

Placebo TENS

33.33
625

Appendix LVIII (Continued)

Clinical trial Quality of life insomnia raw data
Group

Baseline

Follow-up

Placebo IFT

33.33

Placebo IFT

66.67

Placebo IFT

100

33.33

Placebo IFT

Placebo IFT

33.33

Placebo IFT

Placebo IFT

33.33

100

Placebo IFT

Placebo IFT

66.67

100

Placebo IFT

33.33

66.67

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

33.33

Placebo IFT

Placebo IFT

Placebo IFT

66.67

99

Placebo IFT

Placebo IFT

100

100

Placebo IFT

Placebo IFT

100

66.67

Placebo IFT

Placebo IFT

Placebo IFT

66.67

99

Placebo IFT

33.33

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

66.67
626

Appendix LVIII (Continued)

Clinical trial Quality of life insomnia raw data

Group

Baseline

Follow-up

Active TENS

33.33

66.67

Active TENS

100

66.67

Active TENS

Active TENS

Active TENS

Active TENS

33.33

33.33

Active TENS

100

Active TENS

100

Active TENS

66.67

Active TENS

100

66.67

Active TENS

Active TENS

Active TENS

Active TENS

33.33

Active TENS

Active TENS

33.33

Active TENS

66.67

Active TENS

33.33

Active TENS

Active TENS

33.33

100

Active TENS

Active TENS

33.33

33.33

Active TENS

100

100

Active TENS

Active TENS

33.33
627

Appendix LVIII (Continued)

Clinical trial Quality of life insomnia raw data

Group

Baseline

Follow-up

Active IFT

33.33

33.33

Active IFT

66.67

66.67

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

33.33

Active IFT

33.33

Active IFT

Active IFT

33.33

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

66.67

Active IFT

Active IFT

100

33.33

Active IFT

100

100

Active IFT

33.33

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

66.67

66.67

Active IFT

Active IFT

Active IFT

99

Active IFT

33.33

66.67

Active IFT

628

Appendix LIX
Clinical trial Quality of life appetite loss raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
0
0
0
33.33
0
0
33.33
0
0
33.33
0
0
33.33
33.33
100
33.33
33.33
0
0
0
0
0
0
0
33.33
66.67
0
100.00
0
100

0
0
0
66.67
33.33
0
0
0
33.33
0
33.33
66.67
0
66.67
33.33
100
33.33
66.67
33.33
0
0
33.33
100
33.33
0
33.33
33.33
0
0
0
100
629

Appendix LIX (Continued)

Clinical trial Quality of life appetite loss raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

66.67

66.67

Placebo TENS

66.67

33.33

Placebo TENS

66.67

Placebo TENS

Placebo TENS

33.33

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

33.33

33.33

Placebo TENS

66.67

Placebo TENS

Placebo TENS

66.67

33.33

Placebo TENS

33.33

100

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

0
630

Appendix LIX (Continued)

Clinical trial Quality of life appetite loss raw data
Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

33.33

Placebo IFT

Placebo IFT

33.33

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

33.33
631

Appendix LIX (Continued)

Clinical trial Quality of life appetite loss raw data

Group

Baseline

Follow-up

Active TENS

33.33

Active TENS

33.33

33.33

Active TENS

Active TENS

33.33

Active TENS

33.33

Active TENS

Active TENS

33.33

100

Active TENS

Active TENS

100

66.67

Active TENS

66.67

100

Active TENS

33.33

Active TENS

Active TENS

Active TENS

33.33

Active TENS

Active TENS

33.33

Active TENS

33.33

33.33

Active TENS

100

Active TENS

.00

Active TENS

100

Active TENS

Active TENS

66.67

Active TENS

33.33

Active TENS

33.33

Active TENS

33.33

33.33
632

Appendix LIX (Continued)

Clinical trial Quality of life appetite loss raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

100

66.67

Active IFT

33.33

100

Active IFT

33.33

66.67

Active IFT

66.67

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

66.67

Active IFT

Active IFT

Active IFT

99

Active IFT

33.33

33.33

Active IFT

633

Appendix LX
Clinical trial Quality of life constipation raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

33.33
33.33
0
33.33
0
100
0
33.33
0
0
0
0
0
0
0
0
33.33
0
66.67
0
33.33
0
0
0
0
0
33.33
0
33.33
0
100

0
0
0
33.33
66.67
100
33.33
33.33
0
0
0
0
0
0
0
33.33
33.33
0
0
0
33.33
0
0
0
33.33
.00
0
0
0
0
33.33
634

Appendix LX (Continued)
Clinical trial Quality of life constipation data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

66.67

Placebo TENS

Placebo TENS

Placebo TENS

33.33

100

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

Placebo TENS

100

33.33

Placebo TENS

Placebo TENS

33.33

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

0
635

Appendix LX (Continued)
Clinical trial Quality of life constipation raw data
Group

Baseline

Follow-up

Placebo IFT

33.33

Placebo IFT

33.33

Placebo IFT

33.33

66.67

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

100

100

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

66.67

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

66.67

Placebo IFT

Placebo IFT

33.33

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

33.33
636

Appendix LX (Continued)
Clinical trial Quality of life constipation data

Group

Baseline

Follow-up

Active TENS

33.33

33.33

Active TENS

Active TENS

33.33

33.33

Active TENS

Active TENS

33.33

Active TENS

Active TENS

33.33

Active TENS

Active TENS

Active TENS

Active TENS

33.33

66.67

Active TENS

Active TENS

Active TENS

33.33

Active TENS

.00

66.67

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

66.67

66.67

Active TENS

33.33

.00

Active TENS

100

33.33

Active TENS

33.33

33.33

Active TENS

Active TENS

0
637

Appendix LX (Continued)
Clinical trial Quality of life constipation data

Group

Baseline

Follow-up

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

Active IFT

66.67

33.33

Active IFT

Active IFT

Active IFT

33.33

Active IFT

33.33

66.67

Active IFT

33.33

Active IFT

33.33

Active IFT

100

100

Active IFT

Active IFT

Active IFT

Active IFT

33.33

66.67

Active IFT

100

66.67

Active IFT

Active IFT

33.33

Active IFT

Active IFT

99

Active IFT

66.67

Active IFT

638

Appendix LXI
Clinical trial Quality of life diarrhoea raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

33.33
0
66.67
0
0
0
0
0
0
0
0
0
0
0
0
33.33
0
0
0
33.33
0
0
0
0
33.33
0
33.33
0
33.33
0
0

0
0
33.33
0
0
33.33
0
0
0
0
0
0
0
33.33
0
33.33
0
0
0
33.33
0
0
0
0
0
0
0
0
0
0
0
639

Appendix LXI (Continued)

Clinical trial Quality of life diarrhoea data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

66.67

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

33.33

Placebo TENS

Placebo TENS

0
640

Appendix LXI (Continued)

Clinical trial Quality of life diarrhoea raw data
Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

Placebo IFT

.00

Placebo IFT

33.33

66.67

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

66.67

66.67
641

Appendix LXI (Continued)

Clinical trial Quality of life diarrhoea raw data

Group

Baseline

Follow-up

Active TENS

Active TENS

Active TENS

Active TENS

33.33

Active TENS

Active TENS

Active TENS

33.33

Active TENS

Active TENS

33.33

66.67

Active TENS

33.33

33.33

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

100

Active TENS

Active TENS

Active TENS

100

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

0
642

Appendix LXI (Continued)

Clinical trial Quality of life diarrhoea raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

33.33

Active IFT

Active IFT

33.33

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

Active IFT

99

Active IFT

Active IFT

643

Appendix LXII
Clinical trial Quality of life financial difficulties raw data

* Missing data is coded as 99

Group

Baseline

Follow-up

Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control
Control

0
0
0
0
0
100
33.33
0
0
0
100
0
0
0
0
0
33.33
0
66.67
33.33
0
100
0
0
0
33.33
33.33
0
33.33
0
100

0
33.33
0
0
0
66.67
66.67
0
0
0
66.67
0
0
0
0
0
33.33
0
100
33.33
0
100
0
0
0
0
0
0
0
0
100
644

Appendix LXII (Continued)

Clinical trial Quality of life financial difficulties raw data

Group

Baseline

Follow-up

Placebo TENS

Placebo TENS

Placebo TENS

100

100

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

66.67

66.67

Placebo TENS

Placebo TENS

Placebo TENS

Placebo TENS

66.67

Placebo TENS

100

100

Placebo TENS

66.67

Placebo TENS

33.33

100

Placebo TENS

Placebo TENS

33.33

33.33

Placebo TENS

33.33

33.33

Placebo TENS

Placebo TENS

645

Appendix LXII (Continued)

Clinical trial Quality of life financial difficulties raw data

Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

100

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

33.33

Placebo IFT

33.33

33.33

Placebo IFT

Placebo IFT

66.67

33.33

Placebo IFT

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

33.33

Placebo IFT

Placebo IFT

33.33

33.33

Placebo IFT

99

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

100

100

Placebo IFT

Placebo IFT

Placebo IFT

99

646

Appendix LXII (Continued)

Clinical trial Quality of life financial difficulties raw data

Group

Baseline

Follow-up

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

Placebo IFT

647

Appendix LXII (Continued)

Clinical trial Quality of life financial difficulties raw data

Group

Baseline

Follow-up

Active TENS

66.67

33.33

Active TENS

33.33

66.67

Active TENS

Active TENS

100

Active TENS

Active TENS

33.33

Active TENS

Active TENS

100

Active TENS

.00

Active TENS

66.67

Active TENS

33.33

Active TENS

33.33

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

33.33

Active TENS

66.67

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

Active TENS

648

Appendix LXII (Continued)

Clinical trial Quality of life financial difficulties raw data

Group

Baseline

Follow-up

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

66.67

100

Active IFT

100

66.67

Active IFT

Active IFT

Active IFT

Active IFT

33.33

33.33

Active IFT

100

100

Active IFT

33.33

33.33

Active IFT

Active IFT

Active IFT

99

Active IFT

Active IFT

649