Br. J. Anaesth. (1983), 55, 21
COMPARISON BETWEEN BUPRENORPHINE AND PENTAZOCINE GIVEN
I.V. ON DEMAND IN THE CONTROL OF POSTOPERATIVE PAIN
M. HARMER, P. J. SLATTERY, M. ROSEN AND M. D. VICKERS
A double-blind comparison between buprcnorphine and pentazocine was performed in 20 patients using an
on demand analgesic system to provide analgesia after operation. The quality of analgesia, nswyyd
subjectively, was good with both drugs and drug consumptions were compatible with previous potency
estimates. The mean doses demanded in 24h of buprenorphine (1.68 mg) and of pentazocine (382 mg) are
consistent with those found in other trials although the between-patient variation was five- or six-fold. There
was no significant difference in side-effects between the two groups. Buprenorphine and pentazocine may be
used successfully in an on demand system to provide relief of severe pain after operation.
Several potent analgesic drugs were compared in a
double-blind trial utilizing an on demand i.v. infusion system to provide analgesia for patients after
cholecystectomy. We report here a comparison of
buprenorphine and pentazocine.
Buprenorphine (N-cyclopropylmethyl-7a(l-(S)1 - hydroxy - 1 , 2 , 2 - trimethylpropyl) - 6, 14 - endoethano-6, 7, 8, 14-tetrahydro-nororipavine hydrochloride) is one of the partial agonist group of
drugs. In animals it seems to have a low physical
dependence liability (Cowan, Lewis and MacFarlane, 1977) and minimal effects on the cardiovascular system (Cowan, Doxey and Harry, 1977). In
clinical use it has been shown to be an effective
analgesic, with a dose of buprenorphine 0.3 mg
being approximately equianalgesic to morphine
10 mg. Its duration of action appeared longer than
morphine but cardiovascular and respiratory sideeffects were similar (Hovell and Ward, 1977).
Pentazocine, (1, 2, 3, 4, 5, 6-hexahydro-6, 11dimethyl-3- (3-methylbut-2-enyl) -2, 6-methano-3benzazocin-8-ol) a benzomorphan derivative has
been widely used in clinical practice. A review of the
literature by Potter and Payne (1970) confirmed
that, while the drug has good analgesic activity,
there is no universal agreement as to the dose of
pentazocine which is equianalgesic to morphine
10 mg; the suggested dose varies from 20 to 60 mg. It
has been suggested that pentazocine has less reM. HARMER, M.B., B.S., F.FAR.C.S.: P. J. SLATTERY, M.B., B.S.,
P.F_A R.A.C.S.; M. ROSEN, M.B., CH.B., F.F.A.R.C.S.; M. D. VICK-
ERS, M.B., B.S., F.F.A.R.C.S.; Department of Anaesthetics, Welsh
National School of Medicine, Heath Park, Cardiff CF44XN.
0007-O912/83/010O21-O5 $01.00
spiratory depressant effects than morphine (Jennett, Barker and Forrest, 1968), but it is difficult to
assess claims in this respect as the true equianalgesic
dose is not yet known. Pentazocine has been found
to have very limited dependence liability, but in
large doses it has been associated with unpleasant
dreams and hallucinations (Hamilton et al., 1967).
This trial was performed to determine the suitability of drugs of the partial agonist group for use in a
patient demand system, and to derive estimates of
the relative analgesic efficacy of pentazocine and
buprenorphine.
METHODS
The patients were those presenting for cholecystectomy with no complications, aged between 16 and
75 yr and not pregnant. The trial was conducted
double-blind, patients being randomly allocated
into matched groups of 10, to receive one of the
analgesics for 24 h after operation. The analgesic
was administered i.v. by a patient-controlled
syringe pump (Evans et al., 1976), available as the
Cardiff PaUiator.
Each patient was visited on the day before surgery
to obtain informed consent and instructed in the use
of the apparatus. They were also introduced to the
concept of the linear analogue (Revill et al., 1976)
which was to be used to record pain and other
subjective sensations.
The patients were premedicated with diazepam
(approximately 0.15mgkg"') administered orally
1-2 h before operation. Anaesthesia was induced
with i.v. thiopentone, endotracheal intubation
facilitated using suxamethonium or a non© The Macmillan Press Ltd 1983
22
BRITISH JOURNAL OF ANAESTHESIA
depolarizing relaxant and the patients were ventilated with nitrous oxide, oxygen and halo thane supplemented with up to 0.2 mg of fentanyl. At the end
of the operation residual neuromuscular blockade
was antagonized using atropine and neostigmine.
On arrival in the recovery ward the Cardiff Pallia tor was connected to the patient's i.v. infusion
using a valved Y-connector (Rosen and Williams,
1979). The Palliator was set to deliver an incremental dose of 1 ml of analgesic solution at a minimum
interval of 10 min between demands. The analgesic
solutions used were buprenorphine 0.09 mg ml"1
and pentazocine 20 mg ml"1.
On awakening and requesting analgesia the patient was given the demand control and reminded
how to use it. Patients were kept in the recovery
ward until proficient in the use of the Palliator and
then returned to the surgical ward, to continue
taking analgesic as required. Arterial pressure, heart
rate and respiratory rate were recorded as usual by
ward staff. Metoclopramide 10mg i.m. was prescribed for any patient who complained of nausea or
vomited, and an alternative i.m. analgesic regime
was provided in case of rejection of the "on demand" system.
Between 2 and 4h after operation the patients
were visited on the ward by a research nurse, assessed with regard to their physical and conscious
states, and questioned as to the degree of pain,
dizziness, nausea and change of mood. At 24 h after
operation, patients were again visited and asked to
mark linear analogues representing overall pain,
dizziness, drowsiness, and nausea. The placement
of a mark on the linear analogue was to represent the
patient's average degree of sensation over the whole
24 h. At this visit patients were also questioned
directly concerning pain and the occurrence of unpleasant dreams. The Palliator was then removed
and the patient prescribed a standard analgesic to be
given i.m. when required.
Mean score and SEM were calculated for each set
of linear analogues and results for the two drugs
compared using the Mann-Whitney f/test to estimate statistical significance. Qualitative and noncontinuous data were analysed with Fisher Exact
Probability and Mann-Whitney U tests as appropriate.
RESULTS
The patients included in this comparison consisted
of 14 females and six males. The full details of each
patient are shown in table I.
The number of demands made in the 24 h and the
quantity of drug used by each group of patients are
shown in table II.
The 2-4h observations consisted of assessing
conscious level on a 1-4 scale (1 representing fully
awake) and noting the presence of sweating, pallor,
retching or wincing. Patients were also questioned
regarding pain, dizziness, nausea and mood change,
using a 1-5 scale for degree (1 representing no
pain and 5 very severe pain). The 2-4 Ivassessment
scores were compared and showed no significant
differences between the patients receiving buprenorphine and those receiving pentazocine.
The linear analogue obtained at 24 h for each
TABLE I. Patient details (all patients underwent uncomplicated cholecystectomy). *Fentanyl 0.1 mg; **metoclopramide 10mg administend
after operation
PENTAZOCINE
BUPRENORPHINE
No.
Age
(yr)
1
2
3
4**
5
6
7
8
9**
10**
Mean
64
40
24
33
44
52
20
61
64
51
45
Sex
F
F
F
F
F
M
F
M
F
F
Wt
(kg)
63
60
69
59
59
65
82
68
58
59
65
Analgesia
during
operation*
Total
dose
(mg)
None
None
None
None
None
Fentanyl
None
Fentanyl
Fentanyl
Fentanyl
1.89
2.34
1.44
0.99
0.63
2.52
2.07
3.42
0.72
0.81
No.
1
2
3
4
5
6
7**
8
9
10
Mean
Age
(yr)
52
43
43
32
42
62
46
70
44
72
51
Sex
F
M
M
F
F
F
F
M
M
F
Wt
(kg)
68
74
50
67
60
79
48
59
69
60
63
Analgesia
during
operation*
None
None
None
None
Fentanyl
Fentanyl
Fentanyl
None
None
Fentanyl
Total
dose
(mg)
400
120
360
620
420
280
260
680
500
180
BUPRENORPHINE AND PENTAZOCINE FOR ON DEMAND ANALGESIA
TABLE III. Linear analogue scon (mean ± SEM) (% of whole line)
Significance assessed using Mann-Whitney U test
TABLE II. Analgesic dose details
No. of
demands
in24h
Buprenorphine
(n=10)
Mean
Range
Pentazocine
(«-10)
Mean
Range
Dose(mg)
Dose
(mgkg"1
per 24 h)
1.68
0.63-3.42
0.026
0.011-0.051
19
382
6-34
120-680
6.16
1.62-11.56
19
7-38
23
sensation ranged from none at one end to the greatest imaginable degree at the other. The subject of
each analogue and the results, expressed as a percentage of the whole line, are shown in table III.
Analysis of linear analogue scores by nonparametric testing showed that the degree of
analgesia and frequency of side-effects were not
different for the two drugs. Both groups showed a
reasonably high degree of drowsiness.
In addition to the linear analogue, patients were
questioned directly as to the overall degree of pain
felt, using a five-point scale ranging from no pain to
very severe pain. A similar scale was used to assess
unpleasant dreams. The dream and pain ratings
were compared and there was no significant difference between the two groups ( P < 0 . 0 5 ) .
From the collected data it was possible to calculate the mean analgesic consumption for selected
intervals within the 24-h period. This information is
presented in table IV.
DISCUSSION
The two groups of patients in this double-blind trial
were similar with respect to age, weight, sex and
operation. The degree of analgesia which each group
attained, as assessed by the linear analogue, was
again similar and comparable to previous studies
using an on demand analgesic system (Chakravarty
et al., 1979). The mean analgesic linear analogue
score
for
buprenorphine
was
33.5 ±9.5
(mean ± SEM) compared with 36.6 ±6.5 for pentazocine. These linear analogue scores represent
good levels of analgesia, and are lower than those
reported by similar patients receiving staffadministered i.m. analgesics (Slattery at el., 1982).
Analysis of the frequency of side-effects showed no
significant difference between the two groups, both
drugs appeared to cause a similar moderate degree of
Pain
Drowsiness
Dizziness
Nausea
Buprenorphine
(n-10)
Pentazocine
(n=10)
33.5 + 9.5
59.0±9.3
18.8±9.9
19.5 + 8.3
36.6±6.5
63.2 ±8.4
26.8 ±10.8
26.8±13.0
drowsiness but we were unable to confirm the occurrence of dysphoric phenomena associated with
large doses of pentazocine (Hamilton et al., 1967).
The frequency of nausea and vomiting was low in
both groups and would have had little influence on
analgesic consumption.
Any trial comparing different analgesic drugs has
the problem of setting parameters so that groups
may be assessed in a uniform manner. The choice,
basically, is between using a set dose regime and
then accurately measuring the response (a difficult
procedure as pain, nausea, dizziness and dysphoria
are subjective sensations), or producing a comparable response in all patients and using the amount of
each drug required and the frequency of side-effects
to compare the effectiveness of the drugs.
If an on demand analgesic system is used, then
within the limits of efficacy of the drugs used, all
patients are able to achieve optimal pain relief,
where the concept of optimal pain relief relates to a
compromise between the desirable (analgesic) effects of a drug and the undesirable (emetic and
dysphoric) effects.
If patients using different drugs are generally
similar with respect to operation type (and hence
degree of pain) then the amount of analgesic consumed per unit time will provide an index of relative
"potency", where potency is defined in terms of the
amount of analgesic needed to produce a desired
TABLE IV. Analgetic consumption Qigkg-' h~') (mean ± SEM) in
separate intervals within 24 h
Time after
operation
00
Buprenorphine
(«-10)
0-3
3-6
6-12
12-24
0-24
2.2±0.6
1.5±0.14
0.8±0.09
0.810.09
1.110.18
Relative
consumption
Pentazocine (Pentazodne/
(n-10)
Buprenorphine)
5181125
328146
217133
185110
256139
235 x
219 x
271 x
231 x
233 x
BRITISH JOURNAL OF ANAESTHESIA
24
TABLE V. Equianalgesic doses ofstudied drugs given i.v. on demand
Drug
Dose
Buprenorphine
Pentazocine
Pethidine
Meptazinol
0.27 mg
60 mg
100 mg
240 mg
effect. This concept is the principle behind the
clinician's interpretation of drug potency. In this
study the mean relative potency ratio between buprenorphine and pentazocine is 233:1. From previous work using pethidine and meptazinol in comparable conditions (Slattery et al., 1981) and using
pethidine 100 mg as a standard, a table of relative
analgesic potency can be constructed (table V).
The relative doses derived in this manner for
buprenorphine, pentazocine and pethidine are consistent with previously published estimates established from extensive clinical trials (Jaffe and Martin, 1980).
This agreement between analgesic potencies of
established drugs found in our studies and those
derived by extensive clinical usage suggests that an
on demand system may provide a relatively rapid
method of screening analgesic potencies of newer
agents.
ACKNOWLEDGEMENTS
The authors wish to express their gratitude to Mrs M. Davies,
Miss P. James and Mrs J. Webster for their nursing assistance
and Miss D. Forbes for her secretarial help.
REFERENCES
Chakravarty, K., Tucker, W., Rosen, M., and Vickers, M. D.
(1979). Comparison of buprenorphine and pethidine given
intravenously on demand to relieve postoperative pain. Br.
Med.J.,2,S95.
Cowan, A., Doxey, J. C , and Harry, E. J. (1977). The animal
pharmacology of buprenorphine, an oripavine analgesic agent.
Br. J. Pharmacol, 60, 547.
Lewis, J. M., and MacFarlane, I. R. (1977). Agonist and
antagonist properties of buprenorphine, a new antinociceptive
agent. Br. J. Pharmacol, 60, 537.
Evans, J. M., Rosen, M., MacCarthy, J., and Hogg, M. I. J.
(1976). Apparatus for patient controlled administration of
intravenous narcotics during labour. Lancet, 1,17.
Hamilton, R. C , Dundee, J. W., Clarke, R. S. J., Loan, W. B.,
and Morrison, J. D. (1967). Studies of drugs given before
anaesthesia XIII: Pentazocine and other opiate antagonists. Br.
edn (eds L. S. Goodman and A. Gilman), p. 494. New York:
Macmillan.
Jennert, S., Barker, J. G., and Forrest, J. B. (1968). A doubleblind controlled study of the effects on respiration of pentazocine, phenoperidine and morphine in normal man. Br. J.
Anaesth., 40, 864.
Poner, D. R., and Payne, J. P. (1970). Newer analgesics: with
special reference to pentazocine. Br. J. Anaesth., 42,186.
Revill, S. I., Robinson, J. O., Rosen, M., and Hogg, M. I. J.
(1976). The reliability of a linear analogue for evaluating pain.
Anaesthesia, 31,1191.
Rosen, M., and Williams, B. (1979). The Valved-Y-Cardiff
connector (V. Y. C. Con). Anaesthesia, 34, 882.
Slattery, P. J., Harmer, M., Rosen, M., and Vickers M. D.
(1981). Intravenous meptazinol for postoperative analgesia.
Br. J. Anaesth., 53,927.
(1982). An open comparison between
routine and self administered postoperative pain relief. Ann.
Coll. Surg., (in press).
COMPARAISON ENTRE BUPRENORPHINE ET
PENTAZOCINE ADMINISTREE PAR VOIE
INTRAVEINEUSE SUR LA DEMANDE
DANS LE CONTROLE
DE LA DOULEUR POST-OPERATOIRE
RESUME
Une comparaison en double aveugle entre buprinorphine et
pentazocine a ite erfectuee chez 20 patients en utilUant un
systeme d'analgesie a la demande pour fournir use analgesic
post-operatoire.
La qualite
de
l'analgesie, estirnee
subjectivement, etait bonne avec les deux produits et les
consommations medicamenteuses etaient compatibles avec les
estimations anterieures de puissance. Les doses moyennes
demandees en 24 h de buprenorphine (1,68 mg) et de pentazocine
(382 mg) etaient compatibles avec celles retrouvees dans d'autres
£tudes bien que les differences individuelles aient un ordre de
grandeur de cinq ou six fois. II n'y a pas eu de differences
signifies tives dans les effets secondaires entre les deux groupes.
La buprinorphine et la pentazocine peuvent etre utilisees avec
succes dans un systeme d'administration a la demande pour
toulager des douleurs post-operatoires severe*.
VERGLEICH ZWISCHEN BUPRENORPHIN
UND PENTAZOZIN, DAS BEI BEDARF I.V.
VERABREICHT WURDE, BEI DER BEHANDLUNG
VON POSTOPERATIVEN SCHMERZEN
ZUSAMMHNFASSUNG
Ein doppelblinder Vergleich zwischen Buprenorphin und
Pentazozin wurde mit 20 Patienten durchgefuhrt, wobei zur
postoperativen Schmerzbekampfung ein "on-demand"System
Verwendung fand. Die Qualita't der Analgesic, die subjektiv
bewertet wurde, war mit beiden Praparaten gut und der
Verbrauch an Analgetika entsprach den Erwartungen. Die
durchschnittlich in 24 h benotigten Mengen an Buprenorphin
l,68mg und Pentazozin 382mg stimmen mit den in anderen
Untersuchungen gefundener Mengen iiherein, obwohl die
J.Anaath., 39, 647.
Hovell, B. S., and Ward, A. E. (1977). Pain relief in the Variation zwischen den Patienten 5-bis 6-fach war. Es gab keine
postoperative period: a comparative trial of morphine and a signifikanten Unterschiede in den Nebenwirkungen zwischen
beiden Gruppen. Buprenorphin und Pentazozin konnen
new analgesic buprenorphine. / . Int. Mtd. Res., 5,417.
Jaffe, J. H., and Martin, W. R. (1980). Narcotic analgesics and erfolgreich in einem "on-demand" System zur Bekfimpfung von
antagonists; in The Pharmacological Basis of Therapeutics, 6th starken postoperativen Schmerzen verwendet werden.
BUPRENORPHINE AND PENTAZOCINE FOR ON DEMAND ANALGESIA
COMPARACI6N ENTRE LA BUPRENORFINA Y LA
PENTAZOCINA ADMINISTRADAS I.V. SOBRE
PEDIDO EN EL CONTROL DE LOS DOLORES
POSTOPERATORIOS
SUMARIO
Se Ilev6 a cabo una comparacion doble-ciega entre la buprenorfina y la pentazocina en 20 pacientes al usar un sistema analgesico
sobre pedido para proveer analgesia despues de una operacion. La
25
calidad de la annlgi-^iiij evaluada subjetivamente, fue buena con
ambas substancias y los consumer de las mismas fueron cor&patibles con las cifras estimadas previas de potencia. Las dosis medias
' ^as durante 24 h de buprenorfina (1,68 mg) y de pentazocina (382 mg) son compatibles con las recogidas durante otros
ensayos aunque la variaci6n entre pacientes e n de cinco a seis
veces mayores. No hubo diferencia significativa en los efectos
secundarios en ambos gnipos. La buprenorfina y la pentazocina
pueden usarse con exito en un sistema sobre pedido para proveer
un alivio de los dolores agudos despues de una operacidn.