Buprenorphine and pethidine in the treatment of post-operative pain.
Relief of post-operative pain is a problem that every anaesthetist and/or surgeon faces all the time. The severity of pain following different surgical procedures varies as does the capacity of the patient to bear the pain. A double-blind Phase III clinical trial of buprenorphine versus pethidine in the treatment of post-operative pain following the major cardiovascular and thoracic operations was carried out in the Department of Anaesthesiology and the Dr. P. K. Sen Department of Cardiovascular and Thoracic Surgery, K.E.M. Hospital, Bombay. This study was designed to assess the efficacy of buprenorphine as a post-operative analgesic and its cardiorespiratory side effects.
Fifty patients undergoing major cardiovascular and thoracic surgery were included in this study. Informed consent was obtained from each patient before his or her inclusion in the trial. The clinical trial was conducted in a double blind fashion. Twenty-five patients received buprenophrine for post-operative pain and the other 25 patients received pethidine. Distribution of patients to two different therapies was done by pre-decided randomisation. Ampoules of identical appearance were made available for the clinical trial. One box of ampoules containing one ampoule of 2 ml and 17 ampoules of 1 ml was prepared for each patient. Each of the ampoules was labelled with patient number. A sealed envelope containing the code for drugs for different patients was given to us before starting the trial. The code was opened only after completing the trial. In the pethidine group, there were 12 male and 13 female patients. The age range in this group was 9 to 52 years with a mean age of 40 years. In buprenorphine group (Group II) there were 9 male and 16 female patients. The age range was 8 to 45 years with a mean age of 30 years. In each case, age of the patient, diagnosis, type of surgical procedure, date and time of surgery, time of administration of the first and subsequent doses, and duration of therapy were noted. During the postoperative period, the first dose was administered when the patient complained of pain. In a few patients in the age group of 8 to 13 years (3 patients in buprenorphine group and 4 patients in pethidine group), the first dose was 1 ml i.m., while in the rest of the patients the first dose was 2 ml i.m. Subsequent injections of 1 ml were repeated when patients complained of pain. Severity of pain was assessed and recorded on the scale of 0 to 3 (0-nil, 3- severe) before therapy and 1, 2, 3, 4, 6, 3, 10, 12 hours following the injection. Other parameters noted were pulse rate, respiratory rate and blood pressure at 1, 2, 4, 8 and 12 hours following drug administration. Global evaluation of the efficacy was done as poor, fair, good or very good. Laboratory investigations included RBC count, WBC total and differential, serum bilirubin, alkaline phosphatase, SGOT and SGPT, before and after therapy. Side effects of therapy, if any, were noted.
Surgical procedures that these patients had undergone in the two groups are shown in [Table 1].
I. Number of doses required post-operatively:
[Table 2] shows the number of patients requiring 1, 2 or 3 doses post-operatively for relief of pain and 2nd and 3rd doses in the pethidine therapy group were 11.37 and 12.54 hours respectively as compared to 4.70 and 14.00 hours respectively in the buprenorphine group, indicating a more prolonged analgesic effect of buprenorphine, although the difference was not statistically significant.
Seventeen patients in buprenorphine therapy group (including 3 patients of paediatric age group who were given 1 ml as the first dose) required only one dose post operatively as compared to 9 patient in the group receiving pethidine therapy (including 3 patients who were given initial dose of 1 ml). The number of patients requiring only one dose was significantly higher (p<0.05) in buprenorphine therapy group as compared to pethidine therapy group. Less number of patients required second and third doses of buprenorphine (2nd dose-7 patients, 3rd dose -1 patient) as compared to pethidine (2nd dose-11 patients, 3rd dose-5 patients)
II. Mean intervals between two successive doses:
The mean intervals between 1st and 2nd, and 2nd and 3rd doses in the pethidine therapy group were 11.37 and 12.54 hours as compared to 4.70 and 14.00 hours respectively in the buprenorphine group, indicating a more prolonged analgesic effect of buprenorphine, although the difference was not statistically significant.
III. Pain intensity:
Scores of pain intensity before administration of different doses in the two groups and 4 hours after administration are given in [Table 3]. The two groups were found to be comparable in respect of the scores of pain intensity before administration of different doses. Majority of the patients had severe pain (Score 3) when they were given first dose of either buprenorphine or pethidine. At the end of 4 hours, more number of patients had 'O' score (no pain) after the first dose of buprenorphine as compared to pethidine. After the 2nd and 3rd doses of buprenorphine all patients had 'O' pain score (no pain) at the end of 4 hours. In the pethidine group at the end of 4 hours, 7 of 16 patients after the second dose and 1 of 4 patients after third dose still had some pain. This indicates that at the end of 4 hours buprenorphine had better analgesic effect as compared to pethidine and therefore recurrence of pain was delayed.
IV. Pain relief:
The number of patients who had complete pain relief and the mean time required to achieve it after different doses of buprenorphine and pethidine are shown in [Table 4].
Higher percentage of patients achieved complete pain relief with buprenorphine as compared to pethidine. Mean time required to achieve complete pain relief in the two groups was comparable (differences statistically non-significant). Mean duration of complete pain relief after different doses of buprenorphine (1st dose-4.22 hours, 2nd dose 4.86 hours and 3rd dose-10 hours) was comparable to the mean duration of complete pain relief following different doses of pethidine (1st dose-4.86 hours, 2nd dose-4.57 hours and 3rd dose-6.80 hours). The differences were not statistically significant.
V. Side Effects:
Two patients who received buprenorphine had nausea. With pethidine, one patient had nausea and another had mild hypotension. There were no drug related changes in the laboratory parameters.
VI. Global evaluation of efficacy:
In patients receiving buprenorphine therapy, efficacy considering relief of pain duration of pain relief, need for subsequent doses and side effects, was graded as good to very good in 92% of the patients and fair in 8%. In those receiving pethidine therapy, efficacy was graded good to very good in 84% of the patients and fair in 16%.
Buprenorphine is a new potent analgesic. It is a derivative of the alkaloid thebaine and is a strong analgesic with partial agonist activity (mixed against antagonist properties). It is available abroad both for parenteral as well as sublingual (tablet) administration. It is several times more potent analgesic as compared to morphine and pethidine, 0.3 mg buprenorphine being approximately equivalent to 10 mg morphine. It is reported to be rapidly acting analgesic (acts within 15 minutes after i.v. injection and sublingual administration). Its duration of action is longer as compared to pethidine and morphine.1 Its addiction liability is claimed to be very low. Several research workers have published clinical trial reports on buprenorphine in the treatment of post-operative pain.,,, Buprenorphine was found to be a potent and relatively safe analgesic in the treatment of post-operative pain in patients under- going major cardiovascular and thoracic surgery. It did not produce hypotension in any of these patients. Rosenfeldt et al also did not observe an undesirable effect on cardiovascular system in their study of hemodynamic effects of buprenorphine after heart surgery. Morphine may lower blood pressure by causing peripheral vasodilatation and this effect may be exaggerated after open heart surgery. Other conventional analgesics are well known to cause hemodynamic changes. In this study, significantly higher number of patients were managed post-operatively for relief of pain with a single dose of buprenorphine as compared to pethidine. The former had more prolonged analgesic effect. Similar observations were made by Hovell and Ward. They observed similar cardiovascular and respiratory effects with buprenorphine and morphine. Eighty percentage of patients achieved 'O' pain scor (no pain) four hours after administration of the first dose of buprenorphine as compared to 72% in the pethidine group. In this study, two patients had nausea following buprenorphine injections. With pethidine therapy, one patient had nausea and another had mild hypotension. Kamel and Geddes had a lower incidence of nausea, drowsiness, and dizziness following buprenorphine 50 µg/kg compared with pethidine 1 mg/kg. However, Kay reported an increased frequency of drowsiness with the use of former in comparison with morphine although no difference in the incidence of nausea and vomiting in either group was detected. Sear et al found buprenorphine to be a superior analgesic to morphine though when given alone as a premedicant, had a higher and unacceptable frequency of adverse side effects.