Anaesthesia, 1985, Volume 40, pages 529-532

Self-administered nalbuphine, morphine and pethidine

Comparison, by intravenous route, following cholecystectomy

M. BAHAR, M. ROSEN AND M . D. V I C K E R S

Summary
In a double-blind clinical trial of 48 patients, nalbuphine. morphine, and pethidine were compared by
on-demand intravenous analgesia during the first 24 hours after cholecystectomy. Overall pain relief
(visual analogue score) was recorded by the patients as 50 (SEM 4) for nalbuphine. 44 (SEM 4 ) for
morphine and 53 (SEM 5 ) .for pethidine. These scores were not significantly dfferent. The mean
demand for each drug over the 24-hour period was 70 (SEM 12) mg for nalbuphine, 46 (SEM 6 ) mg
for morphine and 614 (SEM 49) mg for pethidine. Pain on movement, either during deep breathing
or turning. was found to be less well controlled after nalbuphine (70, SEM 2). and pethidine (67
SEM 7) than after morphine (52, SEM 5; p < 0.01). The incidence of side effects was similar with each
drug. Nalbuphine is a useful postoperative analgesic, as effective as pethidine. Nalbuphine 15 mg is
apparently equipotent with morphine 10 mg or pethidine 120 mg by this mode of administration.

Key words
Pain; postoperative.
Analgesics. narcotic; morphine, nalbuphine, pethidine.

Nalbuphine is an agonist-antagonist opioid anal-
gesic with claimed low dependence potential and,
in contrast to morphine and pethidine, reputedly
has limited potential for respiratory depression.'
Such a drug should provide safety in the event
of accidental overdose or individual sensitivity
in postoperative patients. However, some other
drugs for which this is claimed also exhibit a
ceiling for analgesia which can result in in-
adequate pain relief. The efficacy and potency
of a new analgesic can be more economically
and sensitively evaluated by a self-administered
system than by extensive clinical trial^.^.^ Peth-
idine and morphine are suitable standards with
which to compare a new drug such as nal-
buphine and both drugs have already been used
successfully by self-administration for severe post-
operative pain.4
Method
Patients scheduled for elective cholecystectomy
were studied. Each subject was visited on the
evening before the operation to obtain informed
consent, instructed in the use of the apparatus
and told that other drugs for pain relief would
be available, if requested.
Oral diazepam 1&15 rng was administered

M. Bahar, FFARCS, Research Fellow, M. Rosen, FFARCS, Consultant, M.D. Vickers, FFARCS, Professor,
Department of Anaesthetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XW.
Correspondence should be addressed to: Dr M. Rosen.

ooO3-2409/85/060529 + 04 %03.00/0 @ 1985 The Association of Anaesthetists of Gt Britain and Ireland 529
530 M . Bahar, M . Rosen and M.D. Vickers
9&120 minutes before operation. Anaesthesia
was induced with thiopentone, followed by suxa-
methonium or a non-depolarising muscle re-
laxant and maintained with nitrous oxide, oxygen
and halothane. Up to 0.2 mg of fentanyl was
permitted for additional intra-operative anal-
gesia. Neuromuscular blockade was reversed at
the end of the operation with atropine and neo-
stigmine.
On arrival in the recovery ward, the Cardiff
PalliatorSwas connected to the patient’s infusion
using a valved Y-connector6 and set to deliver
an incremental dose of 0.4 ml of drug solution.
This increment contained either nalbuphine
3 mg, morphine 2 mg or pethidine 30 mg.
The drugs, prepared by the hospital pharmacy,
were administered in a double-blind manner and
when the patient had been allocated to one of
the groups the same solution was available for
self-administration intravenously for the first 24
hours postoperatively. The minimum interval
between each demand was set at 5 minutes. The
patient was handed the demand button, and
reminded how to use it if in pain. Each successful
demand was recorded automatically. Each patient
was kept in the recovery room until using the
apparatus successfully and then returned to a
surgical ward. Arterial blood pressure, heart rate
and respiratory rate were recorded according
to the usual routine of the ward staff. Meto-
clopramide 10 mg intramuscularly was prescribed
as necessary if any patient complained of nausea
or vomiting. An alternative intramuscular anal-
gesia. Neuromuscular blockade was reversed at
the end of the operation with atropine and neo-
stigmine.
In the third hour after the operation each
patient was visited by MB who questioned the
patient about pain, drowsiness, dizziness or sick-
ness (three grades: none, moderate and severe)
and noted the presence or absence of sweating
or pallor. At 24 hours after the operation the
patient’s overall assessment of pain was recorded
on a 100-mm linear analogue.'^^ In addition
to the overall pain, the patient was also asked
to score separately, pain at rest and pain during
sharp movement such as taking a deep breath,
coughing or turning onto the side.
Linear analogue scores were subject to arcsin
transformation. Probabilities of differences were
calculated by Kruskal-Wallis or Mann-Whitney
U-tests.
Results
The patients in each group were not significantly
different apart from a chance preponderance of
females in the nalbuphine group (Table I). As
a result, the male: female ratios are significantly
different between the drugs. The results for the
two sexes were compared for each observation.
There were no significant differences between
sexes in any comparison with the sole exception
of drowsiness (p < 0.05).
Table 1. Patients’ characteristics (mean, SEM)
Nalbuphine Morphine Pethidine
Total number
of patients 16 16 16
Females 15 9 12
Weight (kg) 69 (5) 67 (3) 68 (4)
Height (cm) 158 (2) 162 (2) 159 (2)
Age (years) 46 (3) 43 (3) 43 (3)
Two patients in the nalbuphine group, two
in the morphine group and one in the pethidine
group were withdrawn by the investigator (MB)
after less than 3 hours of self-administration.
One other patient in the morphine group de-
veloped a respiratory rate of 6 per minute and
was also withdrawn from the trial. This patient
was not attached by a Y-connector but had
a separate infusion. Examination of the site sug-
gested that he had received accidentally a sub-
cutaneous injection and because of inadequate
immediate effect, had taken a relative overdose
which was subsequently absorbed.
The cumulative mean drug consumptions are
shown in Table 2. The assessments at 3 hours
after operation (Table 3) show no important
differences between drugs. The mean linear
analogue scores evaluated at 24 hours are shown
in Table 4. Amongst the ten comparisons only
three were statistically significant, pain felt at
rest (p < 0.05), pain during coughing or moving
(p < 0.01), and pain at the infusion site (p < 0.05):
all were less after morphine, but similar with
pethidine and nalbuphine.
Discussion
Self-administration by any suitable apparatus,
such as the Cardiff Palliator, enables the patient
to demand a preset dose of analgesic and, pro-
vided that a suitable interval has elapsed since
 Self-administered nalbuphine 53 1

Table 2. Drug consumption (cumulative) at various the previous dose, a dose is then delivered intra-
intervals during the first 24 hours after cholecystectomy venously. This approach avoids bias from a
(mg, SEMI clinician's or a nurse's decision about the need
Nalbuphine Morphine Pethidine for a further increment of analgesic. In a
(n = 14) (n = 13) (n = 15) number of studies after upper abdominal surgery
&3 hours 23 (4.6) 15 (2.8) 168 (16.2) there have been reasonably consistent 24-hour
hours 33 (6.8) 20 (3.5) 236 (20.2) demands for pethidine and m ~ r p h i n e .In~ this
&9 hours 38 (7.5) 25 (3.7) 294 (25.4) study the mean demand for pethidine is consis-
24-hour total 70 (12.2) 46 (6.0) 614 (49.2)
Range 24183 2&86 21&960 tent with the previous range although the mor-
phine demand is rather lower. One might
attribute this lower demand for morphine to
Table 3. Observations and symptoms 3 hours post- the rather higher proportion of females in the
operatively
study, although no difference could bedetermined
Grade Nalbuphine Morphine Pethidine when males and females were compared in a
(n = 14) (n = 13) (n = 15) number of aspects: nor could Dahlstrom and
Drowsiness colleaguesI0 find any difference in analgesic
Alert 3 11 I requirements related to sex.
Drowsy II 13
Very drowsy 0 1 I There were more exclusions in this trial than
Pain have previously been reported. They were dis-
" Slight or tributed equally between drugs and all were due
absent 5 3 4* to the investigating clinician's assessment that
Moderate 7 5 9 pain relief was inadequate, although he did not
Severe 2 5 I know which drug was being given.
'Dizziness
Nalbuphine was as satisfactory as morphine
Slight or
absent I1 I1 10* and pethidine with regard to overall pain relief,
Moderate 2 2 3 and there was no greater incidence of side effects.
Severe I 0 I However, o n questioning about acute pain on
Sickness movement, coughing, or deep breathing, mor-
Slight or phine was on average judged to be a better
absent I1 10 10.
Moderate 2 2 3 analgesic. It is interesting to note that in this
Severe I I I trial morphine can be distinguished from pethi-
Sweating dine by this criterion, so supporting widespread
Present 0 I 3 clinical opinion. It seems that pain during move-
Pallor ment may prove to be a useful discriminator
Present 5 5 8 between drugs. Despite this, it is worth noting
*One patient in the pethidine group was very drowsy that on direct questioning, all patients were satis-
and unable to define his pain, dizziness or nausea.

Table 4. 100-mm linear analogue scores (mean %, SEM of arcsin transform)

Probability
Linear analogue Nalbuphine Morphine Pethidine by Kruskal~
(n = 14) (n = 13) (n = 15)
Wallis test
Overall pain 50 (3) 44 (4) 53 ( 5 ) N.S.
Resting pain 29 (4) 16 (3) 30 ( 5 ) p < 0.05
Pain during
coughing or moving 70 (2) 52 ( 5 ) 67 (6) p < 0.01
Pain at infusion site 27 (8) 2 (2) 32 (9) p < 0.05
Nausea 30 (7) 31 (9) 35 (8) N.S.
Dizziness 24 (4) 19 (7) 28 (6) N.S.
Dysphoria 12 (4) 25 (9) 9 (3) N.S.
Amnesia for the
evening of the
operation 37 (9) 32 (9) 28 (10) N.S.
Drowsiness 60 ( 5 ) 53 (6) 68 (4) N.S.
Itching 1(1) 1 1 (6) 5 (2) N.S.
532 M . Bahar, M . Rosen and M.D. Vickers

Table 5. Ratios of cumulative doses Acknowledgments

Ratio Our thanks are due to Professor W.W. Mapleson
95% confidence
Time of limits of ratio* for his guidance and help with the statistical
(hours) mean analysis. We are also grateful to the Pharmacy
doses Lower Upper
Quality Control Laboratory and the clinicians
Nalbuphine: 6 3 1.5 0.8 2.8 and nurses in the recovery ward and surgical
Morphine 6 1.6 0.9 2.9
9 1.5 0.8 2.5 unit of the University Hospital of Wales for
24 1.5 0.9 2.4 their help and cooperation.
Pethidine: (r3 11.2 7.5 18.7
Morphine 6 11.8 8.2 18.9 References
9 11.8 8.4 17.5
24 13.3 9.9 18.9 1. ROMAGNOLI A, GATS AS. Ceiling effect for
respiratory depression by nalbuphine. Clinical
*Calculated from data in Table 2 according to Fieller’s Pharmacology and Therapeutics 1980; 27: 478-85.
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