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Efficacy and safety of pregabalin in patients

with neuropathic cancer pain undergoing
morphine therapy

Article in Asia-Pacific Journal of Clinical Oncology · December 2014

DOI: 10.1111/ajco.12311 · Source: PubMed

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Asia-Pacific Journal of Clinical Oncology 2014 doi: 10.1111/ajco.12311

ORIGINAL ARTICLE

Efficacy and safety of pregabalin in patients with

neuropathic cancer pain undergoing morphine therapy
Zhi DOU,1 Zongbin JIANG1 and Jincai ZHONG2
1
Department of Pain Management and 2Hospice Center, First Affiliated Hospital of Guangxi Medical University, Nanning,
Guangxi Province, China

Abstract
Aim: To evaluate the efficacy and the safety of pregabalin (PGB)-morphine combination for the treatment
of neuropathic cancer pain (NCP).
Methods: In this double-blind, randomized, placebo (PL)-controlled crossover study, 40 cancer patients
with severe NCP were randomized into two groups (20 per group): PGB-PL and PL-PGB. Patients in the
PGB-PL group received PGB plus oral morphine in phase I, and PL plus oral morphine in phase II. The
treatment sequence for the PL-PGB group was PL plus oral morphine in phase I, and PGB plus oral morphine
in phase II. These 2-week treatment periods were separated by a 1-week washout period. The primary
outcome measure was the decrements in morphine dose; secondary outcomes included quantitative assess-
ments of sleep (rated according to the Medical Outcomes Study Sleep Scale), the Constipation Assessment
Scale and adverse effects.
Results: The mean minimal effective dose of morphine was 184.4 ± 69.9 mg/day in the period of PGB
treatments, which was significantly lower than that of PL-controls (228.7 ± 66.9 mg/day; P < 0.001) and
baseline (247.5 ± 80.0 mg/day; P < 0.001). Compared with PL, PGB resulted in a significant sleep improve-
ment as measured by sleep disturbance, sleep quantity, and sleep problems index (P < 0.001), as well as a
Constipation Assessment Scale reduction (P < 0.001). PGB resulted in a higher frequency of dry mouth and
somnolence than PL (P < 0.05).
Conclusion: PGB enhances the efficacy of oral morphine and reduces dose-related adverse reactions. The
PGB-morphine combination is an effective approach to controlling NCP.
Key words: cancer pain, efficacy, morphine, neuropathic pain, pregabalin.

INTRODUCTION cancer therapies.1 The prevalence of neuropathic cancer

Cancer pain is one of the most severe symptoms in
patients with advanced cancer. Approximately 92% of
patients with cancer pain have one or more pain symp-
toms caused directly by cancer, and about 21% of
patients have one or more pain symptoms caused by
Correspondence: Dr Zongbin Jiang MD, Department of Pain
Management, First Affiliated Hospital of Guangxi Medical
University, 166 DaXue East Road, XiXiangTang District,
Nanning 530003, Guangxi Province, China.
Email: jiangzongbin@gmail.com
Conflict of interest: There are no conflicts of interest
Accepted for publication 28 September 2014.
pain (NCP) is estimated to be more than 30% in patients
with cancer pain.2 Oral opioids are advocated in several
international guidelines as first-line treatment for
moderate-to-severe cancer pain.3–5 Although opioids can
also be used to treat NCP, the response is often low,
requiring higher doses.6,7 Furthermore, the quality of life
(QOL) of patients with NCP refractory to opioid can be
substantially reduced by its side effects, even when the
dose is carefully titrated.8
For patients with incomplete response to opioids, it is
usually recommended combining adjuvant analgesics
(anticonvulsants, antidepressants, etc.).6,9 The use of
adjuvant analgesics in cancer patients, however, is
largely empirical and based on data derived from studies

© 2014 Wiley Publishing Asia Pty Ltd

2 Z Dou et al.
of nonmalignant neuropathic pain.8 Although NCP may
resemble nonmalignant neuropathic pain, the underly-
ing mechanisms clearly are not the same.10 For instance,
in murine models, both NCP and nonmalignant neuro-
pathic pain can cause the up-regulation of glial fibrillary
acidic protein (GFAP), but the increase in GFAP in non-
malignant neuropathic models is mostly observed in the
ventral horn of the spinal cord with a small increase in
the dorsal horn, whereas the increase in GFAP in cancer
pain models is equally intense in both the dorsal and
ventral horns.11 Thus far, the true efficacy of these adju-
vant analgesics in opioid-based treatment for NCP has
not been established.8,12
Anticonvulsants are commonly used as adjuvant anal-
gesic drugs for the management of neuropathic pain.
Among new generation anticonvulsants, the effective-
ness of pregabalin (PGB) has been shown in several
experimental and clinical models of nonmalignant neu-
ropathic pain.13–15 PGB is a ligand of the alpha-2-delta
receptor, an auxiliary protein associated with voltage-
gated calcium channels.16 Its potent binding at this site
reduces calcium influx at nerve terminals and, thereby,
the release of several neurotransmitters, such as gluta-
mate, noradrenaline and substance P,17 resulting in anal-
gesic, anxiolytic and anticonvulsant activities. Although
its predecessor, gabapentin, has been shown to have
analgesic efficacy and mild adverse effects when com-
bined with opioids,18–20 the efficacy and safety of PGB as
an adjuvant analgesic in opioid-based therapy for NCP
are largely unknown.21 The aim of this study is to dem-
onstrate the efficacy and safety of PGB in opioid-based
combination therapy for the management of NCP com-
pared with the opioid monotherapy.
METHODS
Study design and patients
The study was a double-blind, randomized, placebo
(PL)-controlled crossover trial with two treatment
sequences. The study protocol and human subjects use
were reviewed and approved by the Ethics Committee of
the First Affiliated Hospital of Guangxi Medical Univer-
sity (Guangxi, China). Patients ≥ 18 years old with his-
tologically proved cancer, having cancer-related or
cancer-treatment-related neuropathic pain, and having
been treated with morphine for over 3 months were
enrolled in this study. Each of the patients gave their
written informed consent prior to participating in the
study. Other inclusion criteria were as follows: pain
intensity ≥ 4 on a 0–10 numerical rating scale (NRS)
before analgesia treatment, in which the higher number
© 2014 Wiley Publishing Asia Pty Ltd
indicates a higher pain intensity; pain that could be
controlled with morphine monotherapy at an intensity
range of 0–3 with breakthrough pain < 3 times per day;
dosage of morphine ≥ 180 mg/day; and neuropathic
pain diagnosis, according to the Douleur Neuropathique
4 Questions score ≥ 4 on a 0–10 scale, in which the
higher number indicates a higher probability of neuro-
pathic pain.22 Participants were randomly allocated
to receive either morphine-PGB combination or
morphine-PL combination in period I, and vice versa in
period II.
In order to make sure that each of the patients was at
a stable stage of cancer during the study, we evaluated
his/her Karnofsky performance status (KPS) (consider-
ing a score ≥ 40 to remain in the study on a 0–100 scale,
in which higher numbers indicate a greater ability of
living independence) and QOL (considering a score > 30
to remain in the study on a 0–60 scale, in which higher
numbers indicate a better health-related QOL).23 The
variation of both KPS and QOL scores should not be
over 10% throughout the study. Patients who were
unable to take medications orally, currently receiving
oncologic treatment, unable to cooperate, with
plasma creatinine > 1.5 mg/mL or creatinine clear-
ance < 60 mL/min, and/or taking non-opioid analgesics
or other adjuvant drugs were excluded from the study.
Patients were removed from the study when they devel-
oped a new pain due to disease progression, intolerable
side effects occurred, or their KPS and QOL scores
changed > 10% from baseline.
Treatments and dose adjustments
Sustained-release morphine (SR morphine) (MS Contin
tablets, Mundipharma Pharmaceutical Co., Ltd.,
Beijing, China) and immediate-release morphine (IR
morphine) (morphine hydrochloride tablets, Qinghai
Pharmaceutical Factory Co., Ltd., Qinghaii, China)
were the chosen opioids for this study. All patients had
their morphine dose optimized for 1 week prior to enter-
ing the study (pain intensity < 4 on the NRS and break-
through pain < 3 times per day), according to European
Association for Palliative Care recommendations.4 The
dose achieved was used as the opioid starting dose
(OSD).24
After the screening, eligible patients were randomized
by computer-generated random numbers to one of the
two treatment groups: morphine-PGB combination fol-
lowed by morphine-PL combination (PGB-PL group),
or morphine-PL combination followed by morphine-
PGB combination (PL-PGB group). These 2-week treat-
ment periods were separated by a 1-week washout
Asia-Pac J Clin Oncol 2014
PGB-morphine combined therapy for NCP
period. The purpose of our study was to compare the
differences in efficacy and safety profiles between these
two treatments.
The PGB treatment included 150 mg/day of PGB
(Lyrica, Pfizer GmbH Arneimittelwerk, Freiburg,
Germany) in two equally divided doses on days 1–3, and
300 mg/day in two equally divided doses on days 4–14.
Similar looking corn starch capsules were used as the PL
treatment, which was administered in the same schedule
as the PGB treatment. The PGB or PL treatment was
withdrawn during the 1-week washout period, in which
patients underwent a 3-day dose tapering (the dose
decrease was 75 mg/day) and a 4-day complete
washout.
Morphine was used throughout the entire trial with
alterable doses according to each patient’s pain intensity.
SR morphine was used as a maintenance treatment for
background pain while IR morphine was used for res-
cuing breakthrough pain. Patients took morphine at
their OSD on days 1–3 of each phase. Then the mor-
phine dose was decreased by 30% and the NRS and
breakthrough pain were rated. If the pain could be con-
trolled by the fewer doses of morphine for additional 1
or 2 days, the dose reduction continued. Judgment cri-
teria of tolerance were NRS at 0–3 and breakthrough
pain < 3 times per day. If the pain was intolerable, IR
morphine was given once and the SR morphine dose was
increased to the upper level. A decrease in morphine
dose was attempted one more time when the pain was
controlled again. If this next decrease resulted in
moderate-to-severe pain again, the morphine dose was
increased to the previous level, which was defined as the
minimal effective dose (MED).24 The morphine dose was
returned to OSD for each patient during the washout
week.
Outcome measures
The primary endpoint was the decrements in morphine
dose, including daily and rescue doses. The OSD of
screen week was recorded as the baseline. The MED of
morphine of each treatment period was also observed.
Secondary endpoints were quantitative assessments of
sleep, according to the Medical Outcomes Study Sleep
Scale (MOS-SS) (a 12-item measure aiming to evaluate
key constructs of sleep, with derived subscales for
domains of sleep disturbance, quantity of sleep, snoring,
awakening due to shortness of breath or with headache,
sleep adequacy, and somnolence), the Constipation
Assessment Scale (CAS) (on a 0–30 scale, in which
higher numbers indicate a severe constipation), and
other adverse effects. Assessments were made at the end
Asia-Pac J Clin Oncol 2014
3
of screen week as the baseline and at the end of each
treatment period. The NRS was recorded daily by
patients themselves as their daily pain scores.
Statistical analysis
We adopted the intention-to-treat principle (ITT) to
analyze all outcomes, meaning that data from partici-
pants were analyzed according to the group to which
they were randomized, irrespective of whether they
actually received the intervention. The power analysis
indicated that 34 patients would be required to provide
the study with 80% power to detect (with a two-sided
alpha of 0.05) a mean difference in morphine MED
between the two treatments.
Baseline comparability of treatment sequence groups
for demographic, KPS and QOL scores, duration of
pain, and intensity of pain variables was assessed by
analysis of variance (ANOVA) or chi-square tests. A
linear mixed model was employed with subject treated
as a random factor nested in the sequence of treatment
periods and drug regimen, sequence and treatment
period as fixed factors. Differences in morphine MED
during each treatment period, scores on MOS-SS and
CAS were compared using ANOVA in the Proc Mixed
procedure as implemented in SAS.25 Differences in the
incidence of adverse events between treatments were
assessed with matching chi-square test. Repeated mea-
sures ANOVA was used to compare changes from base-
line in pain intensity scores.
For all estimates, 95% confidence intervals were also
calculated. All reported P-values were two sided. All
statistical analyses were conducted by using the SAS
software v9.2 (SAS Institute Inc., Cary, NC, USA).
RESULTS
A total of 58 patients underwent the screening assess-
ment in our study. Among them, 18 were excluded and
40 underwent randomization (20 per group). Two
patients from PGB-PL group withdrew during treatment
periods because of adverse effects. Thirty-eight patients
completed the trial and 40 were analyzed following the
ITT principle. Demographic characteristics and baseline
parameters of patients who underwent randomization
are shown in Table 1. These characteristics were bal-
anced among the two treatment sequences and there
were no significant differences between them. No
patients were excluded from the analysis because of
missing data. Daily averages of pain scores for each
treatment sequence are shown in Figure 1. After each
patient adjusted his/her morphine dose to MED, there
© 2014 Wiley Publishing Asia Pty Ltd
4 Z Dou et al.

Table 1 Demographic characteristics and baseline of patients†

PGB-PL group (N = 20) PL-PGB group (N = 20)
Age (years)
Mean ± SD 57.7 ± 10.6 55.3 ± 12.1
Range 33–77 38–80
Sex (N, %)
Male 13 (65) 11 (60)
Female 7 (35) 9 (40)
Weight (kg) 54.3 ± 12.5 55.4 ± 13.2
KPS scores 42.8 ± 4.7 43.5 ± 5.3
QOL scores 37.1 ± 6.3 39.6 ± 4.6
Primary tumor site (N, %)
Breast 7 (35) 4 (20)
Lung 4 (20) 6 (30)
Colorectal 3 (15) 3 (15)
Sarcoma 2 (10) 2 (10)
Liver 2 (10) 1 (5)
Others 2 (10) 4 (20)
Cancer stage (current) (N, %)
Stage I 4 (20) 2 (10)
Stage II 3 (15) 3 (15)
Stage III 3 (15) 6 (30)
Stage IV 10 (50) 9 (45)
Duration of pain (month) 15.5 ± 14.7 18.6 ± 12.5
Intensity of pain before morphine treatment‡ 7.3 ± 0.7 7.1 ± 1.0
Intensity of pain at the end of screen week‡ 1.7 ± 0.6 1.4 ± 1.1
†
Plus-minus values are means ± SD. ‡Pain was measured on a 0–10 scale, in which 0 indicates “no pain” and 10 “the worst pain imaginable.”
There are no significant differences in characteristics between two groups. KPS, Karnofsky performance status ; PGB, pregabalin; PL, placebo; QOL,
quality of life.

was no significant difference of pain scores between
treatment period and the washout period (we used the
pain score at the last day of each treatment period as the
final pain intensity of the treatment period).
Results showed that the sequence or treatment period
assignment between two groups had no significant effect
on outcome assessment. As shown in Figure 2, the mean
morphine MED was 184.4 ± 69.9 mg/day in the period
of PGB treatments, which was significantly lower than
that of PL-controls (228.7 ± 66.9 mg/day; P < 0.001)
and baseline (247.5 ± 80.0 mg/day; P < 0.001). There
was also a significant difference in MED between
PL-controls and baseline (P < 0.05).
According to responses to the MOS-SS, PGB treat-
ments resulted in significantly lower scores for sleep
disturbance (P < 0.001) and sleep problems index
(P < 0.001), and longer hours for sleep (7.7 ± 1.2 h)
than those of PL-controls (6.5 ± 1.4 h; P < 0.001;
Fig. 3).
Table 2 lists adverse effects reported by patients
during the treatments. The PGB treatment was associ-
ated with a higher frequency of dry mouth (P = 0.029)
and somnolence (P = 0.004), and lower scores of CAS
(P = 0.017), compared with those results of PL-controls.
DISCUSSION
An ideal adjuvant analgesic added to morphine mono-
therapy should either provide better analgesia than that
of monotherapy or reduce the opioid-associated adverse
effects, without producing additional toxicity. In this
respect, most studies have demonstrated an increased
analgesia when either PGB or gabapentin is added to
morphine.19,20,26 However, when added to different doses
of morphine, the effect of PGB has not been further
assessed in a clinical setting. Effects of this combination
therapy may be morphine dose dependent and/or time
dependent under various states of opioid tolerance, or
be dependent upon individual characteristics or the type
of pain. Moreover, in most reported studies, doses of
administered opioids and methods used for symptom
assessment were rarely reported.27 It is unclear whether

© 2014 Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014
PGB-morphine combined therapy for NCP 5

Figure 1 Mean daily pain scores. The figure shows mean daily scores for pain intensity throughout the trial for each of the two
groups, including 38 patients who completed the trial and 2 who completed one treatment period. Scores for pain intensity were
rated on a 0–10 scale, in which higher numbers indicate a more severe pain. Days 1–14 and 21–35 denote the two treatment
periods. At each treatment period, there was a variation of pain scores in the first 7 days because of dose titration. After morphine
dose was adjusted to MED, the pain scores tended to be stable. The gray area denotes the washout week, in which patients
underwent a 3-day dose tapering (T) and a 4-day complete washout (W). , PGB-PL; , PL-PGB.

In the present study, patients had been treated with

Figure 2 Morphine MED in all ITT patients. The figure
shows the mean (±SD) morphine MED when it is used as single
agent (baseline) or as PGB-PL combination. *P < 0.001 versus
baseline and PL-morphine combination. △P < 0.05 versus
baseline.
either the morphine-sparing effect is sufficiently large to
have clinical significance or the trend to better pain relief
could be achieved through increasing the morphine
dose, without adding a second agent. Because of limita-
tions of these previous studies,28 a definitive conclusion
cannot be drawn.
morphine or adjuvant analgesics-morphine combination
for over 3 months before they were enrolled. Although
they could get pain relief in their previous therapy, the
categories of administered drugs were complicated. In
order to wash off the effects of previous adjuvant anal-
gesics and standardize the administration of morphine,
1-week morphine monotherapy was employed prior to
the study, so that we could access the changes in mor-
phine dose accurately. According to the study, we found
that after adding PGB the same pain relief was achieved
at lower doses of morphine. When PGB was used as an
adjuvant for NCP treatment, 26% of morphine dose
was reduced compared with baseline, and the opioid-
sparing effect was achieved, regardless of the adminis-
tered morphine doses. Although PL also revealed a
morphine-sparing effect compared with baseline (<7%),
it might not be of clinical significance compared with
PGB. Nausea and vomiting are dose-limiting adverse
effects during morphine therapy. Constipation also is an
intolerable adverse effect, which is sometimes hard to
treat without a dose reduction or switching opioids.5
These adverse effects associated with opioids directly
affect the QOL of patients. A reasonable opioid and
adjuvant-based combination should produce antinocice-
ptive synergy with less adverse effects than those of

Asia-Pac J Clin Oncol 2014 © 2014 Wiley Publishing Asia Pty Ltd
6 Z Dou et al.

Figure 3 Scores of MOS-SS. The figure shows the mean (±SD) scores in six different domains and in sleep problems index of
MOS-SS at the end of each period. *P < 0.001 for the comparison between PGB treatments and PL-controls. , PGB-morphine;
, PL-morphine.

Table 2 Adverse effects

PGB-morphine PL-morphine
Adverse effect N % N % P-value
Dizziness 6/40 15.0 2/40 5.0 0.263
Nausea/vomiting 5/40 12.5 3/40 7.5 0.712
Dry mouth 8/40 20.0 1/40 2.5 0.029†
Somnolence 16/40 40.0 4/40 10.0 0.004†
Peripheral edema 3/40 7.5 0/40 0.0 0.241
CAS (mean ± SD) 6.4 ± 4.4 8.6 ± 3.7 0.017†
†
Data are reported only for moderate-to-severe adverse effects with an incidence greater than 5% for any treatment. CAS, Constipation Assessment
Scale; PGB, pregabalin; PL, placebo.

either drug alone. In the present study, PGB-morphine
combination showed lower scores of CAS than those of
PL-controls, and there was no evidence showing that
PGB has a laxative effect. So we conclude that the CAS
scores might be reduced by lower morphine doses.
However, this result may not have remarkable clinical
significance. In the present study, we gave all patients
laxative to prevent severe constipation, and the doses
used were adjusted in the screen week and fixed
throughout the entire study. Additionally, there was no
linear correlation between the severity of constipation
and the dose of morphine used.
Although rates of dry mouth and somnolence during
the PGB-morphine combination treatment were higher
than those of PL-controls, these adverse effects usually
exist at the titration period and are generally tolerable.
Safety data from the present study suggest that it
is safe when PGB and morphine were used in
combination.
NCP is more complicated than other chronic pain,
such as rheumatoid arthritis and osteoarthritis, and
usually is associated with a substantial socioeconomic
burden resulting from excess health resource utilization
and reductions in productivity and QOL. It also results
in other symptoms including sleep disturbance, a major
complaint of patients with NCP.29–31 Sleep disturbance is
more than a single symptom and an important indicator
for the pain intensity. Poor sleep was associated with
pain on average, pain at its worst and pain relief, con-
firming that sleep disturbances may indicate either a

© 2014 Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014
PGB-morphine combined therapy for NCP
poorly controlled pain situation or that poor sleep alone
may cause more pain.32
PGB has been shown to be effective in increasing the
duration of non-rapid eye movement sleep with decreas-
ing of rapid eye movement sleep in rats.33 Furthermore,
an increase in slow-wave sleep has been demonstrated
during the polysomnography study in healthy volun-
teers.13,34 For its part, the slow-wave sleep has been
correlated with restorative aspects of sleep.15 Patients
with painful diabetic polyneuropathy, postherpetic neu-
ralgia and fibromyalgia receiving PGB at a dose of
300 mg/day experienced a reduced fatigue and an
improved sleep quality when compared with PL.35 These
findings suggest that PGB may have a direct effect on
sleep. Our results indicated improvements in sleep dis-
turbance, sleep quantity and sleep problems index,
which occurred in the first few days. However, we did
not find significant changes in other domains of MOS-
SS, and we did not observe the impact of PGB on sleep
in the long term, according to the constraints of the trial
design. Therefore, its function in sleep continuity should
be further studied.
The study was conducted at Nanning Hospice Center
of China; the center’s primary mission was to offer free
psychological service and pain medication to hospice
patients with severe cancer pain, and had no desire for
any active cancer treatment. Most of the patients had
KPS less than 60. We have no evidence to determine
whether PGB can be effective in the population with
better activities of daily living and mild-to-moderate
cancer pain. Therefore, there was a limited representa-
tiveness of the patients to the pain treatment. In order to
make sure that each of the patients was at a stable stage,
relatively short treatment periods were considered.
Although the titration of morphine could be completed
in 2-week treatment period, we can hardly investigate
the long-term results of the combination of PGB and
morphine.
CONCLUSIONS
The use of PGB in patients with NCP either reduces the
need for morphine dose escalation or allows the use of
lower doses, resulting in less opioid-related adverse
effects, such as constipation. It also improves patients’
sleep quality. It is associated with more intense discom-
fort of dry mouth and somnolence, but these adverse
effects are generally tolerable. The efficacy and safety of
PGB-morphine combination should be further investi-
gated in future large-scale clinical studies.
Asia-Pac J Clin Oncol 2014
7
ACKNOWLEDGMENT
This study was supported by a postgraduate innovative
award from the Department of Health of Guangxi
Zhuang Autonomous Region, People’s Republic of
China.
AUTHOR CONTRIBUTIONS
Zhi Dou performed the statistical analysis and drafted
the manuscript. Jincai Zhong participated in the design
of the study and data collection. Zongbin Jiang con-
ceived the study and participated in its design and coor-
dination, as well as helped draft the manuscript. All
authors read and approved the final manuscript.
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