A double blind comparison of parenteral analgin with pethidine.
Narcotic analgesics have become the most dominant agents for the acute relief of moderate to severe pain. Their use however is fraught with the well recognised hazard of drug dependence. Consequently, renewed efforts to find potent drugs, devoid of the disadvantages of the opium poppy are underway.
In our hospital and several others in India, analgin is routinely used parenterally for the quick relief of moderate to severe pain. We, therefore, undertook a study to compare analgin with pethidine in the therapeutically recommended doses, using a strict double blind study design. We purported to show that if analgin was as effective as pethidine, it could definitely replace the latter, especially in the indication of post-operative relief of pain.
Analgin (2.5 gms) was supplied as a 50% solution in 5 ml ampoules. Pethidine was available as 2 ml. ampoules of 100 mg. The subjects were adult hospitalised patients suffering from moderate to severe pain after abdominal operations, requiring about 12-15 cms. incisions. Subject selection, was limited to those (1) without known allergy to pyrazolone derivatives, (2) who had no major card' orespiratory pathology, (3) who had no history of any narcotic drug abuse, and (4) who had not received any sedative/ hypnotic therapy or CNS stimulant or analgesic treatment from 11 p.m. the previous night.
On the first post-operative morning, patients were interviewed by a research worker who simply asked: "How are you this morning?" A complaint of pain, in reply to the above question was considered necessary to enter patients in the study. The research worker quantitated the pain as mild, moderate or severe and admitted only patients with pain of the latter two intensities into the study. Patients entered the study in consecutive order, according to a protocol number, being randomly allocated to each treatment group.
Drug administration was done by a second research worker, who had no contact with the first. Treatments were coded, randomized and labelled, to maintain `blind' conditions. Each injection was removed from the packet bearing the respective patients' protocol number and was given as a slow intramuscular injection.
Efficacy evaluation was done by the research worker who had initially graded the pain severity. Pain relief was the parameter studied at intervals of one half, one, two, three, four, five and six hours after medication. Patients were asked to state relief in terms of paise in the rupee (100 Paise = 1 Indian rupee). This answer, recorded as 25 p., 50 p., 75 p. and 100 p. was respectively graded as slight relief (1), moderate relief (2), marked relief (3) and complete relief (4). Patients who needed supplemental analgesia in the first hour were dropped from the study, after the same was given. All side effects volunteered were recorded in detail. Unavoidable concurrent therapy like parenteral alimentation and antibiotics was noted in the case records.
To permit mathematical treatment of the data, all the qualitative data was quantified into a scoring system with numerical values.
Demographic data was subjected to the Student's `t' test analysis. Pain relief mean scores of the two treatment groups were analysed by the Wilcoxon's Sum of Rank test, at the various periods of evaluation. Further analysis of the data was done by stratifying the population according to initial pain intensity of moderate and severe grade. Subsequently, the pain relief was compared in these groups of patients.
At the conclusion of the study, the code was opened for statistical treatment of the data. Patient characteristics are given in [Table 1.] A wide variety of surgical procedures were performed. Patients generally received a N20 gas-O2 mixture or spinal anaesthesia. Pre-operatively, all patients received atropine. Seventythree patients had pain of moderate intensity and 27 patients reported initial intensity of pain as severe. In both treatment groups, maximum pain relief was seen two hours after drug administration, mean relief scores being 2.90 for pethidine and 2.69 for analgin, of no statistical significance. The time effect curve showing the mean pain relief scores at different periods of evaluation are shown in [Fig. 1.] As seen, the curves run so closely parallel, almost overlapping and peak analgesia is maintained to the end of the evaluation period after 6 hours. Taking the criterion of 50% pain relief as the efficacy criterion, ,  analgin appears to provide better analgesic effect than pethidine, but the results were not statistically significant.
When the data based on intensity of moderate and severe pain was further analysed, it revealed the patterns, shown in [Fig. 2] and [Fig. 3]. In moderately severe pain, 2.5 gms analgin appears to be equivalent to 160 mg of pethidine, and has sustained analgesic effect. In severe pain, while differences between the two drugs are again of no statistical significance, the analgesic effect of analgin was more prolonged.
One patient had hypotension after analgin injection. In the pethidine series, one patient complained of rigors and retention of urine was observed in another Both complaints were attributed to postoperative conditions, not related to drug.
The assessment of analgesic drugs is notoriously difficult. Generally, analgesics may be tested either against experimentally induced pain or pathological pain. In extensive reviews on the study of pain and analgesia, pathological pain has been discussed as a better basis than experimentally induced pain for the study of analgesics.,  Interviewing patients for six hours after therapy provides adequate information on drug effect. In order to maintain strict double-blind conditions, all drugs were personally administered to patients by a research worker who had no contact with the person, evaluating efficacy. Further, all conversations with the patient to assess his initial pain intensity and subsequent relief, avoided the word "pain", a factor of much psychological impact. Both these points of methodology have been described as essential in the assessment of analgesics.
Though we acknowledge the pitfalls in the subjective assessment of analgesic activity, we feel our rigorous methodology provided a true comparison of the efficacy of analgin and pethidine.
Both treatment groups were homogenous in demography and surgery in all patients was through 15 cms. long abdominal incision. Factors after surgery and anaesthesia, like the site and extent of the surgical wound, and the degree of manipulation of organs rich in sensory fibres are additional problems which were controlled as far as possible by allocating all surgery to the same surgeon through the abdominal approach.
Our study compares, 2.5 gms of analgin with 100 mg of pethidine. Good pain relief was seen with both drugs within 30 minutes. The results clearly indicate that the analgesic effect of analgin is similar to that of pethidine at therapeutic doses in terms of onset, degree and duration of analgesia. Statistical analysis suggests that analgin provides a longer duration of action in patients who have severe pain; this is consistent with their plasma half lives.
Problems of narcotic abuse have led to severe restriction of their medical use and rigid accounting and documentation procedures. Drug rules in our country forbid the repacking of pethidine in fresh ampoules, which explains why 2 ml. ampoules were used along with 'the 5 ml ampoules of analgin. If misused, narcotic drugs are all addicting and people become tolerant to their analgesic effect. However, this danger is minimal when they are used to treat acute pain such as post-operative pain. With no potential for physical dependence, parenteral analgin offers some advantage over narcotic analgesics available for quick relief of acute pain of moderate and severe intensity. However, the dose of analgin which compared favourably with pethidine in this study is fairly large. The drug is known to produce fatal agranulocytosis and other blood dyscrasias and hence, it should be employed with due caution.
We thank Dr. C. K. Deshpande, M.D., the Dean for his permission to publish this paper. The trial was conducted under the auspices of the Research Society of the hospital. The drug (Analgin) was supplied by Hoechst Pharmaceuticals Ltd., which also supported the entire trial financially.