CLINICAL EVALUATION OF DIAZEPAM FOR RELIEF OF POSTOPERATIVE PAIN

Transcription

1 Br. J. Anaesth. (1981), 5, 81 CLINICAL EVALUATION OF DIAZEPAM FOR RELIEF OF POSTOPERATIVE PAIN P. N. SINGH, P. SHARMA, P. K. GUPTA AND K. PANDEY SUMMARY Morphine 10 mg or diazepam 10 mg or a mixture of morphine 5 mg and diazepam 5 mg were given i.m. to three groups of 5 patients for relief of pain in the period immediately after operation. The patients had undergone upper abdominal operation for which a uniform regime of premedication and anaesthesia had been used. Pain was assessed by an observer before and after treatment and by the subjects, using a fivepoint scoring scheme. The pain scores before treatment and at 0-, 60-, 90- and 10-min intervals after treatment were compared by Ridit analysis. All three treatments produced significant relief, but the relief after diazepam alone was not as long-lasting as after the other two treatments. No clinically significant cardiovascular or respiratory complications occurred. Diazepam alone was associated with significantly more restlessness and morphine alone was associated with significantly more sickness. The combination of morphine and diazepam was considered to be the treatment of choice. In an uncontrolled study Bruce (1968) compared the pain-relieving actions of diazepam and morphine in patients who had undergone surgical operations of varying severity and formed the opinion that the analgesic action of the two drugs was comparable. Hollis (1968), Kyles (1968) and Moore (1968) also observed that the use of diazepam reduced the requirement of narcotic analgesics in the period after operation, but the claim of an analgesic action of diazepam has not been supported by others (McClish, 1966; Haslettt, 1968; Dundee and Wyant, 1974). No clinical study evaluating the pain-relieving properties of diazepam has been reported. This double-blind study was undertaken to compare diazepam and morphine. METHODS Subjects One hundred and five patients complaining of pain following upper abdominal operations were studied. All patients weighed kg, were aged between 0 and 60 yr, and were of physical status grades 1 and of the American Society of Anesthesiologists' classification. None had re- P. N. SINGH, M. D. (ANAESTH.); P. SHARMA, MJ).(ANAESTH.); K. PANDEY, MJ.(ANAESTH.); Department of Anaesthesiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-1005, India. P. K. GUPTA, MJ.(ANAESTH.), PH.D.(BELFAST), Department of Anaesthesiology, H. P. Medical College, Simla, India. Correspondence to K. P., A-5, New Medical Enclave, Banaras Hindu University, Varanasi-1005, India /81/ J0100 ceived an analgesic drug before operation and all were considered to be capable of co-operating in the assessment of pain. Anaesthetic technique Atropine 0.6 mg and promethazine 5 mg were given i.m min before operation. Anaesthesia was induced with thiopentone -5 mgkg"' and tracheal intubation facilitated by suxamethonium mg. Anaesthesia was maintained with nitrous oxide and oxygen :1.5 litre min ~' in a circle system with spill-over and a nondepolarizing neuromuscular blocking drug was given to permit controlled ventilation of the lungs. At the end of operation, its action was antagonized by neostigmine 1- mg preceded by atropine sulphate mg. The duration of anaesthesia varied between 75 and 150 min. Assessment and relief of postoperative pain When patients had become fully conscious in the recovery ward, the severity of pain was estimated by both the patient and the observer (P. N. S.) according to the method described by Loan, Morrison and Dundee (1968). This rates pain on afive-pointscale (table I) and uses both the patient's and trained observer's estimate of severity. Only those subjects whose initial pain score was or 4 were included in the study. Patients were allocated at random to receive one of three treatments which was given i.m. by another investigator (so that its nature would not Macmillan Publishers Ltd 1981

2 BRITISH JOURNAL OF ANAESTHESIA 8 TABLE I. Scoring scheme for pain severity Pain relief Table III illustrates the average initial pain scores in the three groups with the mean scores at Observer's estimate Score 0-, 60-, 90- and 10-min intervals after the treatments. 4 Very severe Patient writhing, sweating, distressed A within-group comparison of the mean ridits at Strained facial expression only Severe various times after treatment with the mean ridits Moderate Patient lying still, eyes open or closed, and avoiding movements before treatmeiil (ilie identified distribution) is 1 Patient drowsy or sleeping with no Mild illustrated in figure 1. All three treatments were tendency to avoid movements associated with a significant reduction in mean 0 No pain No discomfort, completely at ease pain score as revealed by the lack of overlap moving and coughing comfortably between the 95% confidence limits of the postand pre-treatment mean ridit. be known to the observer): group I = morphine A between-group comparison of the pain scores ; group II = diazepam ; group was also made. The mean ridits in the morphineiii = morphine 5mg + diazepam 5mg. treated groups at each time of assessment served as The severity of pain was estimated before and at 0-, 60-, 90- and 10-min intervals after treatment. Arterial pressure, heart rate and respiratory rate were also recorded at the same time as the pain scores. Other observations included the occurrence of restlessness, sleep, vomiting and pain at the site of injection of the trial drugs. Patient's estimate The significance of changes in the mean values of the mean arterial pressure (Jennings, 1964), heart rate and respiratory rate was assessed using the paired t test. The mean pain severity scores before and after treatment were compared using Ridit analysis (Bross, 1958; Dundee, Moore and Nicholl, 196; Pandey, Ratra and Badola, 1967). The numbers of subjects with and without a particular characteristic (table V) were charted as x contingency tables (Bailey, 1959). RESULTS Three groups of 5 fit patients were broadly comparable with respect to mean age, body weight, sex distribution and frequency of ASA risk grades (table II). TABLE II. Mean age ( ± SEAT), mean body weight ( ± SEM), sex and physical status in the three treatment groups Treatment group Morphine Diazepam Morphine 5mg + diazepam 5mg Mean age (yr) 9±1.5 Mean body weight 51 ±0.7 (kg) Males ASA grade ± ±0.8 8± ± Ridits FIG. 1. Mean pain score ridits (with 95% confidence limits) based on the patients' (thin bars) and observers' (thick bars) estimates at 0 (1), 60 (), 90 () and 10 (4) min after treatment. Mean pain score ridits and their 95% limits observed before giving the treatments form the identified distribution and these, being identical in each group, are represented by the single pair of thin and thick bars marked "Before treatment". (M), (D) and (D + M) indicate treatments with morphine, diazepam, and diazepam + morphine, respectively. Methods of statistical analysis

3 DIAZEPAM FOR POSTOPERATIVE PAIN RELIEF 8 TABLE III. Mean pain scores before and at various time intervals after the trial drugs. Scores: P = patient estimates; O ««observer estimates Treatment group Time of Morphine Diazepam Morphine 5mg + diazepam 5mg scores P O P O P O I 8 I s Before treatment 0min 60min 90 min 10 min OE oe i '4 '" O QK^KBBE On PE O E PEE OE PE O«P r I D VjWMwrn^^^^^ j 0 Before treatment o' Ridits FIG.. Comparison of mean pain score ridits in the three treatment groups, before and at 0-, 60-, 90- and 10-min after the treatments. P = ridits based on patients' estimate. O ridits based on observers' estimate. The mean ridits (with 95% confidence limits) in the dlazepam-treated group are shown by scored bars (marked ); stippled bars (marked ) represent the diazepam + morphine treated group. Mean ridits (with 95% confidence limits) in the morphine-treated group at each time form the identified distribution. The identified distributions, being identical, are represented by the thickly stippled bar at the bottom. Overlap between the 95% confidence limits of the mean ridits in the morphine + diazepam and morphine-treated groups indicates lack of any significant diflference in the efficacy of the two treatments. Diazepam alone is associated with significantly less pain relief at 60-, 90- and 10-min intervals (as indicated by a lack of overlap between the 95% confidence limits of the mean ridits in this group and those in the identified group)

4 84 BRITISH JOURNAL OF ANAESTHESIA the identified distributions and were compared with the corresponding mean ridits in the other two groups (fig. ). Using the method of comparison, the efficacy of the three treatments was indistinguishable 0min after drug administration. Thereafter, diazepam alone proved to be significantly less effective in relieving pain when compared with morphine alone or the combination of morphine and diazepam. These conclusions applied irrespective of the ridit analysis being based on the patient's or the observer's estimate of pain severity. Cardiovascular and respiratory effects A significant reduction in the mean of mean arterial pressure and mean respiratory rate was associated with each of the three treatments (table IV). However, the decrease in the mean of the of pain at the injection site. Treatment with diazepam alone was associated with a significantly greater frequency of restlessness and failure to sleep. Morphine alone was followed by a significantly greater frequency of sickness, but was not associated with persistent pain at the injection site. DISCUSSION Using subjective and observer pain scores as a means of assessing analgesia we found that significant pain relief occurred in the patients who had received diazepam, but it was not as sustained as after morphine or after a combination of morphine and diazepam in smaller doses. The precise mechanism of the "pain relieving" action of diazepam is difficult to explain and, as suggested by Brown (1968), its sedative and tranquillizing properties may, to a large extent, be TABLE IV. Mean changes in mean arterial pressure and respiratory rate after the three treatments. * Changes significant (P<0.05). I = morphine Wmg; II = diazepam ; III = morphine Smg + diazepam 5mg Change in mean arterial pressure Change in respiratory rate Treatment - group I II III I II III 0-7±* -5±1.* -7±1.8* -6±0.6* -±0.5* -5±0.6* mean arterial pressure observed after diazepam was of less duration than those after the other two treatments. Other observations Table V indicates the number of patients who remained awake or restless, felt sick or complained TABLE V. Other observations in patients in each group. * Significantly greater than in groups I and III (P<0.05); t Significantly greater than ingroups II and III (P < 0.05). Exact probabilities of obtaining the x contingency tables were calculated and then shown as more or less than 0.05, the critical level Awake and restless Awake but not restless Sick Pain at injection site Morphine 9t Ot Treatment group Diazepam 11* 7 5 Morphine 5mg + diazepam 5mg Time after administration (min) 60-10±1.6* -4+1.* -10±1.7* -8±0.6* -±0.5* -6 ±0.6* 90-9±1.6* -±1.* -8±1.7* -7±0.6* -±0.5* -6±0.6* ±1.8* -0. ± ±1.6* -6.0±0.6* -1.0 ±0.4* -5.0±0.6* responsible for our findings. The sedative action of morphine is thought to contribute to analgesia. The relative brevity of the "analgesic" action of diazepam, as compared with that of morphine, is reminiscent of the placebo response, where psychological factors play a major part. Another contributory factor may be the central muscle relaxant action of diazepam since muscle spasm is an invariable component of the pain following abdominal incisions. We do not know the nature of the "true analgesia" component of narcotic analgesics, and the "totality of behavioural change" still remains the only yardstick for measurement of analgesic action. This study has provided evidence of a strong interaction between morphine and diazepam. Our results show that, in the doses used, morphine alone was superior to the morphine diazepam combination as far as intensity of analgesia is concerned, but the use of the combination was associated with significantly less

5 DIAZEPAM FOR POSTOPERATIVE PAIN RELIEF 85 sickness. The cardiovascular and respiratory effects of the combination and morphine alone were identical. The frequency of pain at the injection site was low when the combination was used and should not detract from its value (Marks, 1967; Eisenberg, Taub and Burana, 1974). Lawrence (1966) has suggested that the use of drugs to relieve pain should not be guided solely by their efficacy, but also by their propensity to produce wanted side actions. The value of tranquillizers as adjuvants in the relief of chronic pain is well known and they have an established place in treatment. This is the first report of their use in the treatment of pain following surgery. Undoubtedly this subject is worthy of further investigation. It must be emphasized that our encouraging results apply to mg doses of diazepam; if these are increased then the prolonged soporific effect of the benzodiazepine might be a disadvantage. Furthermore, the preoperative use of diazepam with "normal" doses of analgesic has resulted in undue cardiovascular depression (Dundee et al., 1970). REFERENCES Bailey, N. T. J. (1959). Statistical Methods in Biology, 1st edn. Oxford: English Universities Press. Bross, I. D. J. (1958). How to use ridit analysis. Biometrics, 14, 18. Brown, S. S. (1968). Studies of diazepam: an intravenous anaesthetic; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 5. Bristol: John Wright & Sons Ltd. Bruce, I. S.( 1968). Postoperative use of diazepam; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 89. Bristol: John Wright & Sons Ltd. Dundee, J. W., Haslett, W. H. K., Keilty, S. R., and Pandit, S. K. (1970). Studies of drugs given before anaesthesia. XX: Diazepam-containing mixtures. Br. J. Anaesth., 4, 14. Moore, J., and Nicholl, R. M. (196). Studies of drugs given before anaesthesia. I: A method of preoperative assessment. Br. J. Anaesth., 4, 458. Wyant, G. M. (1974). Intravenous Anaesthesia, nd edn, p. 8. Edinburgh: Churchill-Livingstone. Eisenberg, L., Taub, H. A., and Burana, A. (1974). Memory under diazepam-morphine neuroleptanaesthesia in male surgical patients. Anesth. Analg. (Cleve.), 5, 488. Haslett, W. H. K. (1968). A controlled study of diazepam and chlordiazepoxide as premedicant for a standard operation; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 19. Bristol: John Wright & Sons Ltd. Hollis, D. A. (1968). Diazepam as an induction agent, II; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 60. Bristol: John Wright & Sons Ltd. Jennings, A. M. C. (1964). Some observations of critical closing pressures in the peripheral circulation of anaesthetised patients. Br. J. Anaesth., 6, 68. Kyles, J. R. (1968). Observations on the use of diazepam in anaesthesia; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 66. Bristol: John Wright & Sons Ltd. Lawrence, D. R. (1966). In Clinical Pharmacology, 4th edn (ELBS). Edinburgh: Churchill-Livingstone. Loan, W. B., Morrison, J. D., and Dundee, J. W. (1968). Evaluation of a method for assessing potent analgesics. Clin. Pharmacol. Ther., 9, 765. McClish, A. (1966). Diazepam as an intravenous induction agent for general anaesthesia. Can. Anaesth. Soc. J., 1, 56. Marks, M. M. (1967). Talwin (Pentazocine), a new nonnarcotic analgesic in rectal surgery: a three year evaluation. Internal. Surg., 48, 519. Moore, P. H. (1968). Diazepam as induction agent, I; in Diazepam in Anaesthesia (eds P. F. Knight and C. G. Burgess), p. 56. Bristol: John Wright & Sons Ltd. Pandey, K., Ratra, C. K., and Badola, R. P. (1967). Clinical trial of antiemetic drugs for postoperative vomiting: methodology. Ind. J. Anaesth., IS,. EVALUATION CLINIQUE DU DIAZEPAM POUR LE SOULAGEMENT DES DOULEURS POST- OPERATOIRES RESUME On a administre par voic intramusculaire a trois groupes de 5 patients: 10 mg de morphine, ou 10 mg de diazepam, ou un melange de 5 mg dc morphine et de 5 mg de diazepam pour soulager la douleur au cours de la periode qui a immediatement suivi l'intervention chirurgicale. Les patients avaient subi une operation a la partie haute de l'abdomen, pour laquelle on avait utilise un regime uniforme de medication preoperatoire et d'anesthesie. La douleur a etc evaluee par un observateur, avant et apres le traitement, et par les sujets, a l'aide d'un systeme de notation a cinq points. Les points relanfs a la douleur avant le traitement et a des intervalles de 0min, 60min, 90min ct 10 min apres le traitement ont etc compares par analyse Ridit. Ces trois traitements ont chacun produit un soulagement signincatif, mais le soulagement apres le diazepam seul n'a pas etc d'aussi longe duree qu'apres les deux autres traitements. II ne s'est produit aucune complication respiratoire ou cardiovasculaire ayant une importance clinique. Le diazepam seul a etc associe a une nervosite plus marquee et la morphine seule a davantage de nausees. La combinaison de morphine et dc diazepam a etc consideree comme etant un traitement de choix. KLINISCHE BEURTEILUNG VON DIAZEPAM ALS POSTOPERATIVES SCHMERZLINDERUNGSMITTEL ZUSAMMENFASSUNG Zehn mg Morphium oder Diazepam, bezw. eine Mischung aus je 5mg beider Drogen wurde intramuskular als Schmerzlinderungsmittel unmittelbar nach Operational an drei Gruppen von 5 Patienten verabreicht. Die Patienten hatten Eingriffe im oberen Unterleib hinter sich, mit einheitlicher Vorbehandlung und Narkose. Die Schmerzen wurden vor und nach der Behandlung von einem Beobachter und von den Patienten selbst eingeschatzt, mit Hilfe einer Funf-Punkte-Skala. Die Schmerz-Werte vor der Behandlung

6 86 BRITISH JOURNAL OF ANAESTHESIA und in Abstanden von 0, 60, 90 und 10min nach der Behandlung wurden durch Ridit-Analyse vcrglichen. Alle drei Behandlungsweisen erzielten signifikante Schmerzlinderung, doch war die Wirkung mit Diazepam allein nicht so lang andauemd als mit den beiden anderen Behandlungsweisen. Klinisch signifikante kardiovaskulare oder respiratorische Komplikationen traten nicht auf. Diazepam alltin bewirkte wesentlich erhohte Ruhelosigkeit, Morphium allein wcsentlich mehr uoeikeii. Die rcurribiii^non von i\icrph:um und Diazepam wird als beste Behandlungsweise betrachtet. EVALUACION CLINICA DEL DIAZEPAM PARA EL ALIVIO DEL DOLOR POSOPERATIVO SUMARIO Se administro por via intramuscular 10 mg de morfina, 6 10 mg de diazepam, o una mezcla de 5mg de morfina y 5mg de diazepam, a tres grupos de 5 pacientes, para aliviar el dolor inmediatamente despues de la operacion. A los pacientes se les sometio a operacion quinirjica de la parte superior del abdomen, para lo que se uso un regimen uniforme de premedicacion y de anestesia. El dolor se evaluo mediante un observador antes y despues del tratamiento, asi como por pane de los sujetos, utilizando para esto un plan de puntuacion de 5 puntos. La puntuacion de dolor antes del tratamiento y a intervalos de 0, 60,90 y 10 mm dsspu" de dicho tratamiento se comparo con el analisis de Ridit. Los tres tratamientos produjeron un alivio significativo, pero el producido por la administracion exclusiva de diazepam no fue de tanta duration como el alivio conseguido despues de los otros dos tratamientos. No tuvieron lugar complicaciones cardiovasculares ni respiratorias de signification clinica. Solo el diazepam vino asociado con un significativo aumento de la inquietud y solo la morfina vino asociada con un grado significativo de aumento de la enfermedad. Se considero que la combination de diazepam y morfina es el tratamiento opcional.