Continuous Morphine Infusions

for Cancer Pain in Resource-Scarce Environments:

Comparison of the Subcutaneous
and Intravenous Routes of Administration
Rachel C. Koshy
Renju Kuriakose
Paul Sebastian
Cherian Koshy

ABSTRACT. Acute onset of severe pain in cancer patients may be due to multiple causes. Irre-
spective of the etiology, adequate analgesia has to be provided as quickly as possible. The standard
practices of relieving pain by using syringe pumps (syringe drivers) or infusion pumps may not be
feasible in resource-scarce developing nations where many cancer patients first present at ad-
vanced stages of disease for management. This study compared the efficacy of the subcutaneous
and intravenous routes of morphine administration continuously using a simple and economic
technique for cancer pain management. Both routes were found to be equally effective in produc-
ing good analgesia without side effects. The drip method is a cost-effective way of providing sub-
cutaneous morphine infusion for cancer patients and is applicable for both inpatients and home
care. [Article copies available for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH.
E-mail address: <docdelivery@haworthpress.com> Website: <http://www.HaworthPress.com>  2005 by
The Haworth Press, Inc. All rights reserved.]

KEYWORDS. Cancer, severe pain, morphine, subcutaneous, intravenous, continuous infusion

Acute pain can be distressing, particularly in
patients with advanced illness such as cancer.
Parenteral administration of opioids, most com-
monly morphine, has been proven to be effec-
tive in managing severe pain in such patients.1
Intermittent intravenous (IV) administration of
morphine is the most common parenteral route
used for this purpose. Continuous administra-
tion of morphine using syringe pumps (drivers)
and infusion pumps are standard practice in
controlling severe cancer pain in developed na-
tions.2-4 However, in developing nations, the

Rachel C. Koshy, MD, is Associate Professor and Head of Anaesthesiology, Renju Kuriakose, MD, is Assistant
Professor in Anaesthesiology, Paul Sebastian, MS, is Additional Professor and Head of Surgical Oncology, and
Cherian Koshy, MS, is Associate Professor and Head of Palliative Care, Regional Cancer Centre, Trivandrum,
Kerala, India.
Address correspondence to: Renju Kuriakose, MD, Department of Anaesthesiology, Regional Cancer Centre,
Medical College Campus, Post Box: 2417, Thiruvananthapuram, 695 011, Kerala, India (E-mail: renjurcc@
yahoo.co.in).
The authors acknowledge the valuable help provided in the statistical analysis and the preparation of the manu-
script by Dr. Manoj Pandey, MS, Associate Professor in Surgical Oncology, Regional Cancer Centre, Trivandrum
and also thank Pradeep Kumar for secretarial assistance.
Journal of Pain & Palliative Care Pharmacotherapy, Vol. 19(1) 2005
http://www.haworthpress.com/web/JPPCP
 2005 by The Haworth Press, Inc. All rights reserved.
Digital Object Identifier: 10.1300/J354v19n01_06 27
28 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY
capital costs of pumps and recurring cost of
disposables needed for the pumps are major
barriers to their use. Hence cost-effective meth-
ods of continuous delivery of parenteral opioids
for palliative care purposes were explored.
This study was undertaken to determine the
most cost-effective method of parenteral mor-
phine administration for cancer pain manage-
ment in a resource-constrained health care
system. The study compared the alternate subcu-
taneous (SC) route to the IV route for continuous
administration of morphine. Morphine was
studied because it is inexpensive and readily
available for use in rural and resource-scarce
settings. This strong opioid is well studied and it
can be used safely in a wide variety of settings.
PATIENTS AND METHODS
This study was conducted on the Pain and
Palliative Care ward of a regional cancer center
situated in southern India. Thirty terminally ill
cancer patients who presented consecutively to
the Pain Clinic at the Regional Cancer Centre in
Trivandrum, Kerala, India, with severe pain
(numerical pain intensity rating on a numeri-
cally-anchored visual analogue score [VAS]
greater than eight out of 10, with zero being no
pain and 10 being pain as bad as the patient
could imagine) were included. Informed con-
sent was obtained and the patients were allo-
cated randomized into two groups using a ran-
dom number table. Patients in Group I received
IV continuous morphine infusion. Patients in
Group II received SC continuous morphine in-
fusion. Patients with generalized edema, coag-
ulation disorders and erythema were excluded
from the study. Further stratification in each
group was as follows: (i) opioid-naïve group I
patients were given 20 mg morphine IV; group
II patients received 30 mg morphine SC over 24
hrs, (ii) patients who were previously taking
oral morphine but were presently experiencing
pain due to inability to take the medication
orally were given morphine equivalent to their
previous 24 hours oral intake in both groups I
and II, (iii) patients who had pain in spite of
regularly-scheduled oral morphine doses were
given morphine in a dose equivalent to 1.5
times the dose received in previous 24 hours
through the respective route.
The calculations for morphine dosage in
strata (ii) and (iii) were as follows:
Step (a): Totaloraldose of morphine required
to control pain was calculated as
described above,
Step (b): Equivalent dosages for IV(group I)
and SC (group II) routes were cal-
culated (oral: SC: IV–the dosage
conversion ratio for morphine was
3:2:1). Thus group I patients re-
ceived 33% and group II patients
received 50% of the calculated oral
dose of morphine over 24 hours
through the IV and SC routes, re-
spectively.
The dose of morphine was diluted in 0.9%
normal saline to a total volume of 60 mL in a
measured volume chamber with micro drip fa-
cility. This was hung from an IV pole at a height
of 1 meter from the patient’s bed and connected
to an 18 gauge small vein (butterfly) needle
placed subcutaneously with bevel facing down-
wards, in the right infraclavicular region in
group II patients, and to an indwelling venous
cannula in group I patients. The solution was al-
lowed to drip from the measured volume cham-
ber and the rate of was flow adjusted manually
(Figure 1). In both groups, flow was adjusted to
a rate of 20 micro drops per minute in the first
hour, 10 micro drops per minute in the second
hour, and thereafter 5 micro drops per minute.
At any time that pain was not controlled, infu-
sion rates were further increased by 5 micro
drops per minute.
The baseline parameters–pain intensity mea-
sured on the visual analogue scale (VAS), pulse
rate (PR), blood pressure (BP), and respiratory
rate (RR) were noted prior to drug administra-
tion. After initiating each infusion, these param-
eters as well as sedation score, pruritus, nausea,
and vomiting were noted at fixed intervals, i.e.,
1, 2, 3, 4, 8, 12, 16, 20 and 24 hours. Break-
through pain was managed with a rescue analge-
sic dose of intramuscular tramadol 50 mg.
STATISTICAL ANALYSIS
The between-group comparison of quantita-
tive data: respiratory rate, pulse rate, and blood
pressure was analyzed using the students ‘t’
 Koshy et al.
FIGURE 1. The Gravity Drip Administration Method
test. Qualitative data comparison between groups
was done by chi-square test for sex. VAS was
tested by paired ‘t’ test and paired correlation
and sedation tested with ANOVA.
DISCUSSION
Cancer is a major problem worldwide. Pres-
ent estimates indicate that every year, ten mil-
lion new cancer patients are diagnosed, of
whom six million die.5 The incidence of cancer
is estimated to be increasing each year. Two-
thirds of cancer patients are from developing
countries where eighty percent of cancers are
too far advanced to be curable at the time of di-
agnosis. Yet, developing countries have access
to only five percent of the world’s resources for
cancer control.6 The Indian scenario typically
depicts this picture with one million new can-
cer cases detected yearly of whom eighty per-
cent have disease beyond the scope of cure.7,8
This situation necessitates pain relief and pal-
liative care for the vast majority of Indian can-
cer patients at the time they are diagnosed.
Cancer patients presenting for relief of acute,
severe pain are common in oncology practice.
29
Uncontrolled pain in these patients may be due
to advancing malignancies or inadequate anal-
gesia.9 Pain; upper obstructive gastrointestinal
lesions; and nausea and vomiting induced by
radiation, chemotherapy, and disease may also
limit oral intake of analgesics.10,11 Parenteral
analgesia with strong opioids often is needed
for these patients.
Among the various parenteral routes for
morphine administration, we were interested in
the IV and SC routes, practiced commonly in
our center. The IV route was useful in those pa-
tients with an intravenous cannula, while the
SC route proved to be useful even in terminally
ill patients with poor venous access. In compar-
ison to intermittent boluses, continuous infu-
sions could provide constant blood levels of the
drug. Although the drug could be diluted in
larger volumes of infusion solution, we used
low volumes for both routes to ensure effective
comparison. We planned to use tramadol for
breakthrough pain because it was easily avail-
able in our center and is recommended as an
adjuvant for managing severe cancer pain.
We used the gravity-dependant drip method
to provide morphine infusions in our study. The
cost incurred in the use of various infusion tech-
niques is high and the problems associated are
many (Table 1). The use of measured volume
drip set and small (scalp) vein needle set was
considered because in outlying health centers in
developing countries this equipment is available
and personnel trained to manage infusion pumps
often are absent. Another advantage of simple
gravity drip administration was that the rate of
drug flow could be adjusted according to pa-
tient’s response. The technique is simple, easy to
administer, does not need trained personnel and
is cost effective. This can be safely provided
even for patients receiving homecare. However,
the titration of drug has to be judiciously fol-
lowed at the end of first and second hours. Oth-
erwise drug overdose resulting in respiratory de-
pression and sedation may occur.
Our study demonstrated that morphine ad-
ministered by the IV and SC routes produced
similar favorable effects on vital parameters.
The stability noticed among the groups in
pulse rate and respiratory rate along with a
steady, slight reduction in blood pressure over
time reflects the reduction in endogenous
catcholamine response resulting from relief of
pain and hence good analgesia (Tables 2 through
5). The pain relief achieved with morphine in-
30 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 1. Comparison of costs incurred with various techniques adopted for continuous morphine infu-
sions and associated problems (1 US dollar = 44 Indian rupees [Rs])

Cost of Availability of
Equipment Capital cost Ease of handling by nursing staff
disposables disposables
Graseby syringe driver Rs 35,000 Rs 130 Freely available High
Braun Perfusor Rs 35,000 Rs 20 Freely available Technical expertise required
IVAC PcA Machine Rs 150,000 Rs 85 Freely available Technical expertise required
Spring fusor Rs 2,000 Rs 150 Not freely available Difficult to handle
Nippin Rs 1,500 Rs 10 Device not freely Difficult to fit
available
Measured volume drip set Rs 35 Rs 10 Widely available Easy to handle

TABLE 2. Demographic data: Comparison of baseline parameters, Group I: received morphine intrave-
nously, Group II: received morphine subcutaneously (n = 15 in each group)

Variable Mean standard deviation F value/t Chi square value P value

Group I Group II
Age 56.8 ± 14.74 58.87 ± 11.46 0.43 0.671
Sex (M:F) 10:5 8:7 0.556 0.456
Pulse rate 85.4 ± 14.5 86.4 ± 8.02 0.055 0.817
Respiratory rate 22.27 ± 4.4 21.07 ± 4.65 0.527 0.474
Systolic blood pressure 116.67 ± 9.76 118.8 ± 36.39 0.048 0.828
Visual analogue score 8.4 ± 1.12 8.4 ± 1.12 0.0001 1.000
P value significant (P < 0.05). This table shows both Group I and Group II were comparable in the various parameters noted.

TABLE 3. Pulse rate (PR) measured at fixed intervals in Group I (received intravenous morphine) and
Group II (received subcutaneous morphine). In each group n = 15

Pulse rate Group I Group II

measured
Mean Standard Mean Standard Inter group t value P value
during infusion
(per minute) deviation deviation

Baseline 85.4 14.50 86.4 8.02 0.055 0.817

1 hour 84.93 16.64 83.93 9.99 0.04 0.843
2 hours 86.07 15.07 82.87 7.38 0.545 0.466
3 hours 85.20 13.15 81.20 8.87 0.954 0.337
4 hours 86.07 15.43 81.73 9.74 0.846 0.365
8 hours 85.87 12.39 83.67 8.55 0.321 0.576
12 hours 81.73 10.08 81.73 9.95 0.000 1.000
16 hours 83.07 9.07 80.53 10.23 0.515 0.479
20 hours 82.67 10.65 82.20 10.42 0.015 0.904
24 hours 82.13 11.02 80.00 10.79 0.001 0.974
* P < 0.05 Significant. No statistically or clinically significant difference was noted in pulse rate in either group.This indicates that both Groups
were comparable and had effective pain relief maintaining this vital sign in normal limits.
 Koshy et al. 31

TABLE 4. Respiratory rate (RR) measured at fixed intervals in Group I (who received intravenous mor-
phine) and Group II (who received subcutaneous morphine). In each Group n = 15

Respiratory rate Group I Group II

noted during
Mean Standard Mean Standard Inter group t value P value
infusion
(per minute) deviation deviation

Baseline 22.27 4.40 21.07 4.65 0.527 0.474

1 hour 21.07 3.53 18.8 5.0 2.054 0.163
2 hours 21.73 3.20 19.13 4.91 2.953 0.097
3 hours 20.67 5.89 19.33 4.51 0.484 0.492
4 hours 21.47 3.42 19.53 5.69 1.271 0.269
8 hours 21.87 2.56 18.67 5.0 4.875 0.036*
12 hours 21.33 3.18 18.67 4.76 3.256 0.082
16 hours 21.6 2.41 19.07 4.46 3.738 0.063
20 hours 22.00 3.46 19.60 5.03 2.319 0.139
24 hours 21.73 2.71 18.87 4.32 4.732 0.038*
* P< 0.05 significant. No clinically significant difference was noted in the respiratory rates during infusion among both groups although statisti-
cally significant difference was noted at 8 and 24 hours. This shows that both Groups had similar and comparable effects on respiratory rate.

TABLE 5. Systolic blood pressure (SBP) measured at fixed intervals in Group I (who received intrave-
nous morphine) and Group II (who received subcutaneous morphine). In each group n = 15

Systolic blood Group I Group II

pressure
measured Mean Standard Mean Standard Inter group t value P value
during infusion deviation deviation
(in mms of Hg)
Baseline 116.67 9.76 118.80 36.39 0.048 0.828
1 hour 114.67 9.15 120.40 12.05 2.153 0.153
2 hours 114.00 8.28 122.00 17.40 2.585 0.119
3 hours 114.80 10.16 118.27 15.75 0.513 0.480
4 hours 113.27 13.52 115.33 11.25 0.207 0.653
8 hours 109.33 12.23 114.93 11.18 1.713 0.201
12 hours 106.00 11.83 115.87 10.51 5.828 0.023*
16 hours 107.20 9.59 117.00 9.60 7.828 0.009*
20 hours 108.67 12.89 115.87 8.23 3.326 0.079
24 hours 108 10.82 115.67 6.23 5.653 0.024*
* P< 0.05 significant. Systolic blood pressure showed a decreasing trend over time in both Groups although not clinically significant. Both
groups showed a statistically significant difference in SBP at 12, 16 and 24 hours. The mild fall in blood pressure could be the result of effective
analgesia and hence reduced catecholamine release in these patients.

fusions by both routes was similar and effec-
tive, irrespective of the initial pain score
throughout infusion (Table 6). The only side ef-
fect noticed in both groups was mild sedation
(Tables 7 and 8). This was acceptable, rather
clinically useful and there was not a need for
close supervision of the patient during medica-
tion. Vomiting, nausea, and pruritus were
absent in these patients. The absence of break-
through pain in both groups could be the result
of constant blood levels of morphine during
medication. Thus, the SC route of administra-
32 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 6. Paired sample t test showing comparison of VAS scale at different time intervals

Standard 95% confidence

Standard limits t P
Group Mean error
deviation value value
(mean) Upper Lower
Group I Pair 1 V0 & V1 2.33 1.59 0.41 3.21 1.45 5.688 0.0001 *
Group I Pair 2 V0 & V2 3.73 2.25 0.58 4.98 2.49 6.424 0.0001 *
Group I Pair 3 V0 & V3 4.87 1.73 0.45 5.82 3.91 10.917 0.0001 *
Group I Pair 4 V0 & V4 5.20 1.93 0.50 6.27 4.13 10.410 0.0001 *
Group I Pair 5 V0 & V5 5.80 1.86 0.48 6.83 4.77 12.081 0.0001 *
Group I Pair 6 V0 & V6 6.47 1.64 0.42 7.38 5.56 15.256 0.0001 *
Group I Pair 7 V0 & V7 6.73 1.53 0.40 7.58 5.88 17.003 0.0001 *
Group I Pair 8 V0 & V8 6.73 1.71 0.44 7.68 5.79 15.251 0.0001 *
Group I Pair 9 V0 & V9 7.13 1.41 0.36 7.91 6.35 19.629 0.0001 *

Group II Pair 1 V0 & V1 2.40 2.06 0.53 3.54 1.26 4.505 0.0001 *
Group II Pair 2 V0 & V2 3.87 1.77 0.46 4.85 2.89 8.473 0.0001 *
Group II Pair 3 V0 & V3 4.60 2.23 0.58 5.83 3.37 7.990 0.0001 *
Group II Pair 4 V0 & V4 5.33 1.76 0.45 6.31 4.36 11.741 0.0001 *
Group II Pair 5 V0 & V5 5.73 1.79 0.46 6.73 4.74 12.395 0.0001 *
Group II Pair 6 V0 & V6 6.27 1.67 0.43 7.19 5.34 14.554 0.0001 *
Group II Pair 7 V0 & V7 6.60 1.96 0.51 7.68 5.52 13.064 0.0001 *
Group II Pair 8 V0 & V8 7.20 1.66 0.43 8.12 6.28 16.837 0.0001 *
Group II Pair 9 V0 & V9 7.60 1.30 0.34 8.32 6.88 22.671 0.0001 *
* P < 0.05 significant. Statistically significant pain relief was achieved in both groups throughout the period of infusion.

TABLE 7. Between-group comparison of sedation
score at fixed time intervals tested by ANOVA (n =
15 in each group). Group I received intravenous
morphine and Group II received morphine subcu-
taneously
TABLE 8. Paired sample t test showing comparison
of sedation score at different time intervals (S1 = 1
hour, S2 = 2 hours, S3 = 3 hours, S4 = 4 hours, S5 =
8 hours, S6 = 12 hours, S7 = 16 hours, S8 = 20
hours and S9 = 24 hours)

Pairs Group t value P value

Time
F value P value Group I Pair 1 S1 & S2 0.713 0.004 *
intervals Group I Group II
Group I Pair 2 S1 & S3 0.548 0.043 *
1 hour S1 S1 0.2732 0.6054 Group I Pair 3 S1 & S4 0.228 0.433
2 hours S2 S2 3.0624 0.0915 Group I Pair 4 S1 & S5 0.228 0.433
Group I Pair 5 S1 & S6 0.175 0.549
3 hours S3 S3 0.2342 0.6323
Group I Pair 6 S1 & S7 0.000 1.000
4 hours S4 S4 0.2996 0.5886 Group I Pair 7 S1 & S8 0.300 0.297
8 hours S5 S5 0.2024 0.6564 Group I Pair 8 S1 & S9 0.411 0.145

12 hours S6 S6 1.0065 0.3246 Group II Pair 1 S1 & S2 0.535 0.040 *

16 hours S7 S7 2.2400 0.1457 Group II Pair 2 S1 & S3 0.431 0.108
Group II Pair 3 S1 & S4 0.200 0.474
20 hours S8 S8 0.1489 0.7025
Group II Pair 4 S1 & S5 0.559 0.030 *
24 hours S9 S9 0.1273 0.7240 Group II Pair 5 S1 & S6 0.354 0.196
P < 0.05 significant. S1, 2, 3, 4, 5, 6, 7, 8, 9 stands for sedation at 1, 2, Group II Pair 6 S1 & S7 0.302 0.275
3, 4, 8, 12, 16, 20 and 24 hours, respectively. Group II Pair 7 S1 & S8 0.354 0.196
Group II Pair 8 S1 & S9 0.134 0.635
*P < 0.05 significant. Statistically significant sedation was noticed at 1
hour and 8 hours of onset of infusion in Group II and at 1st and 2nd
hours in Group.
 Koshy et al.
tion for morphine was as effective as the IV
route for continuous administration. Either of
these routes could be used to provide good an-
algesia in emergencies.
In conclusion, the SC route may be an excel-
lent alternative to IV administration for mor-
phine. Continuous infusions provided good pain
relief throughout the duration of the morphine
administration by both the SC and IV routes. The
gravity-dependant drip method of continuous
drug delivery is a cost-effective, simple tech-
nique effective in ensuring adequate analgesia.
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RECEIVED: 05/15/04
REVISED: 06/20/04
ACCEPTED: 07/07/04