LORAZEPAM AND MORPHINE FOR I.V. SURGICAL PREMEDICATION

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1 Br. J. Anaesth. (1980), 52, 1259 LORAZEPAM AND MORPHINE FOR I.V. SURGICAL PREMEDICATION J. L'ARMAND, L. A. VREDEVOE, J. T. CONNER, G. P. HERR AND D. SCHEHL SUMMARY The effects of i.v. lorazepam alone, in doses of 2 mg and 4 mg, and combined with, were studied. Sedation, relief of anxiety, lack of recall, patient acceptance, physician acceptance and side-effects were evaluated. The addition of morphine to lorazepam significantly improved sedation and relief of anxiety. Physician acceptance and patient acceptance showed no significant difference between any of the combinations. Lack of recall was enhanced by increasing the dose of lorazepam from 2 mg to 4 mg, independent of the addition of morphine. The only significant side-effect was restlessness which occurred in 15% of patients receiving lorazepam 4 mg and of patients receiving lorazepam 2 mg, again independent of the addition of morphine. The introduction of lorazepam has created interest in its use for premedication. The effects of lorazepam alone (Conner et al., 1976, 1978) and its combination with atropine and hyoscine (Conner et al., 1978) have been reported. The present investigation concerns the use of i.v. lorazepam alone (2 mg or 4 mg), and in combination with i.v.. Relief of anxiety, sedation, lack of recall, acceptance by both the patient and physician and side-effects are evaluated. METHODS One hundred and twenty patients in the age range yr undergoing a variety of surgical operations were assigned randomly to four groups, each group receiving different preoperatdve medication: i.v. lorazepam 2 mg, lorazepam 4 mg, lorazepam 2 mg combined with, and lorazepam 4 mg combined with morphine 5mg. The drugs were administered over a period of 1 min approximately 1 h before surgery, using a double-blind technique. All observations were made by a trained nurse observer. Before premedication, each patient was asked to evaluate his level of anxiety as negligible, mild, moderate or severe. Four minutes after medication, his sedation relative to his unmedicated state was rated by the nurse observer as 0 (unchanged), 1, 2, 3, 4 (improved), or 1 -, 2, 3, 4, (worse). The patient was asked to rate his level of anxiety using a similar scale, and was asked if the overall sensation of the drug was pleasant, unpleasant, or neutral. The evaluations were repeated at 8, 16 and. Recall was tested by showing the patient a randomized series of pictures of familiar objects or scenes 1,2,4,8,16 and after injection of the drug. After 24 h the patient was asked to pick out the pictures previously shown to him from an array of eight pictures. Recall of pre-medication, the operating room and the recovery room were also sought. At 24 h the patient was asked to rate the premedication as poor (0), fair (1 ), good (2 ), or excellent (3 ). Each patient was asked if he would like to receive the drug again for future surgery. Just before induction of anaesthesia, the anaesthetists were asked to rate the premedicant as poor (0), fair (1 ), good (2 ), or excellent (3 ). They were also asked if they would use the drug again. Statistical analysis was performed by transforming the raw scores to ridits and using the analysis of variance procedure (Selvin, 1977). The raw scores were transformed into ridits using the combined lorazepam 4-min scores from this and previous studies (Conner et al., 1976, 1978; Pagano et al., 1978) as the reference population. We tested for an overall drug and dose response using repeated measures of analysis of variance with an appropriate test for time trends. Significance was taken at P^0.05. J. L'ARMAND, M.D.; L. A. VREDEVOE, M.D.; J. T. CONNER, M.D.; G. P. HERR, M.D.; D. SCHMHL, R.N.; Department of Anesthesiology, UCLA, School of Medicine, Los Angeles, California 90024, U.S.A. Correspondence to L. V /80/ RESULTS Anxiety The changes in anxiety as scored by the patient are shown in table I. The addition of morphine Macmillan Publishers Ltd 1980

2 1260 BRITISH JOURNAL OR ANAESTHESIA TABLE I. Patient anxiety relief scored by patient (ft ±4 scale) 4 mg Mean scores Ridit scores mg produced a significant decrease in patient anxiety, with lorazepam 4 mg scoring significantly better than lorazepam 2 mg. When the individual time periods were analysed separately, significant differences were detected at 4, 8, and only. The most significant improvement was seen with lorazepam 4 mg plus compared with lorazepam 2 mg. Sedation (table II) Sedation as evaluated by the nurse observer also showed significant improvement by the addition of to either lorazepam 2 mg or 4 mg. However, the most significant improvement (/ 3 <0.01) occurred with the increased dose of lorazepam (2 mg to 4 mg). Again, the significant differences were limited to the periods 4, 8, and. four drug combinations in patient acceptance or physician acceptance. Recall (table V) Failure of recall was significantly greater during the period before operation with lorazepam 4 mg than with lorezapam 2 mg, with or without morphine. In the recovery room, the differences between the four combinations were slight, although the greater dose of lorazepam produced somewhat less recall. Side-effects Side-effects were not frequent and were not bothersome to the patient. The one possible exception to this was restlessness which appeared to be related to the dose of lorazepam. Restlessness occurred approximately min after injection and was seen in 15% of patients receiving loraze- 4 mg alone or with morphine, and in 3 % of Patient acceptance and physician acceptance (tablespam HI, IV) patients receiving lorazepam 2 mg alone or with There was no significant difference between the morphine. The addition of morphine did not TABLE II. Patient sedation scored by nurse observer (ft ±4 scale) 2 mg 4 mg Mean scores Ridit scores

3 LORAZEPAM AND MORPHINE FOR I.V. PREMEDICATION 1261 TABLE III. Patient acceptance {0-3) at 24 h and patient's subjective rating at 2 mg 4 mg Acceptance (percentage of patients) Poor Fair Good Excellent Mean score Ridit score Subjective rating (percentage of patients) Pleasant Unpleasant No opinion Percentage of patients who would take drugs again 44% 56% % 42% % % 3 61% % 15% 79% % 41% TABLE IV. Physician's acceptance {0-3) at time of surgery 2 mg 4 mg Percentage of patients Poor Fair Good Excellent Physician's acceptance Mean score Ridit score Percentage of physicians who will use the drug again 15% 3 55% % 2 27% % 35% 45% % 22% 12% 5 16% % TABLE V. Failure to recall {values in percent) 2 mg 4 mg Memory card 1 min 2 min Operating room Recovery room

4 1262 BRITISH JOURNAL OR ANAESTHESIA appear to change the frequency of this side-effect. Restlessness was not marked in most patients. DISCUSSION A number of studies have been published describing lorazepam as an effective premedicant (Blitt, 1976; Conner et al., 1976, 1978; Pandit, Heisterkamp and Cohen, 1976; Dundee et al., 1977). is not known to have analgesic properties. This study was designed to assess its effects when combined with morphine. In an earlier study, it was reported that lorazepam combined with hyoscine produced agitation and restlessness which prohibited their use together (Pagano et al., 1978). There was concern about possible drug interaction seen with lorazepam. In this study the frequency of restlessness seen with lorazepam alone was dose related ( with lorazepam 2 mg and 15% with lorazepam 4 mg). The addition of morphine did not change the frequency of this side-effect. This frequency of restlessness, or agitation, seen with lorazepam alone is greater than has been previously reported (Connor et al., 1978; Pagano et al., 1978). In these earlier studies, patients were not closely observed after 30 min. However, it was suspected that restlessness might occur later and this was specifically sought in this study. Indeed it was found that many patients did display restlessness at these later times. The combination of morphine with lorazepam did not produce any troublesome side-effects specifically related to drug interactions. In fact, lorazepam appeared to diminish unpleasant sideeffects seen with i.v. morphine in previous studies (such as tingling, heaviness, flushing and nausea). The addition of morphine to lorazepam enhanced sedation and relief of anxiety, although patient acceptance, physician acceptance and lack of recall were not significantly altered. It is important to note that patient acceptance scores of lorazepam alone are very high, thus making improvement difficult. Likewise, physician acceptance scores for the study drugs are high in comparison to our other studies. This is despite a tendency by physicians to rate the effects of premedicants lower than do patients. It is again difficult to demonstrate significant difference in physician acceptance. Although high, sedation and anxiety relief scores of lorazepam are equalled by other drugs studied, and can be improved. Morphine has never been known to produce lack of recall and, as such, no change in recall was expected. The addition of morphine to lorazepam proved to be a compatible combination of drugs for surgical premedication. There were no adverse effects from the combination and, in general, the drugs complemented each other. REFERENCES Blitt, C. (1976). Clinical evaluation of injectable lorazepam as a premedicant: the effect on recall. Anesth. Analg. (Clevc), 55, 532. Conner, J., Katz, R., Bellville, J., Graham, C, Pagano, R., and Dorey, F. (1978). Diazepam and lorazepam for intravenous surgical premedication. J. Clin. Pharmacol., 18, 285. Parson, N., Katz, R., Wapner, S., and Bellville, J. (1976).., Evaluation of lorazepam and pentobarbital as surgical prcmedicants. Clin. Pharmacol. Ther., 19, 24. Dundee, J., Lilbum, J., Nan, S., and George, K. (1977). Studies of drugs given before anaesthesia. XXVI:,.. Br. J. Anaesth., 49, Pagano, R., Conner, J., Bellville, J., Graham, C, Schehl, D., and Katz, R. (1978)., hyoscine, and atropine as i.v. surgical premedicants. Br. J. Anaesth., 50, 471. j. Pandit, S., Hcisterkamp, D., and Cohen, P. (1976). Further studies of the anti-recall effect of lorazepam: a dose-time-effect relationship. Anesthesiology, 45, 495. Selvin, S. (1977). A further note in the interpretation of ridit analysis. Am.J. Epidermiol., 105, 16. LORAZEPAM ET MORPHINE DANS LA PREMEDICATION I.V. EN CHIRURGIE RESUME On proceda a l'etude des effets du lorazepam seul en doses de 2 mg et 4 mg, ainsi que combine avec 5 mg de morphine. Des evaluations de la sedation, du soulagement de l'angoisse, de la perte de memoire, de l'acceptation par le patient, dc l'acceptation du medecin et des effets secondaires ont ete realisees. L'addition de morphine au lorazepam ameliora grandement la sedation et le soulagement de l'angoisse. L'acceptation tant du medecin que du patient ne fit etat d'aucune difference significative entre l'une quelconque des combinaisons. La perte de memoire fut plus forte lorsqu'on augmentait la dose de lorazepam de 2 a 4 mg, independamment de l'addition de morphine. Le seul effet secondaire significatif fut 1'agitation dont firent preuve 15% des patients auxquels on avait administre 4 mg de lorazepam et de ceuz auquels on avait administre 2 mg de lorazepam, une fois encore independamment de l'addition de morphine. LORAZEPAM UND MORPHIN BEI DER INTRAVENOSEN CHIRURGISCHEN VORBEHANDLUNG ZUSAMMENFASSUNG Die Wirkung von intravenos verabreichtem alldn, in Dosen von 2 mg und 4 mg, und mit Morphin 5 mg kombiniert wurden untersucht. Beruhigungseffekt, Erleichterung ' ' i

5 LORAZEPAM AND MORPHINE FOR I.V. PREMEDICATION 1263 des Angstzustandes, nachlassendes Erinnerungsvennogen, Vertraglichkeit beim Patienten, gunstige Aufhahme bein Arzt und Seiteneffekte wurden ausgewertet. Durch Beimischung von Morphin wurde der Beruhigungseffekt und die Erleichterung von Angstzustanden bedeutend verbessert. In Bezug auf Vertraglichkeit und Aufhahme bei dan Arzt waren zwischen den einzelnen Kombinationen keine bedeutende Unterschiede festzustellen. Das Nachlassen des Erinnerungsvenndgens wurde durch cine Vergrosserung des anteils von 2 mg auf 4 mg gesteigert, unabhangig von der Beimischung von Morphin. Der einzige bedeutende Seiteneffekt war eine Ruhelosigkeit, die sich bei 15% der Patienten einstellte, die 4 mg bekommen hatten und bei 3 % von denen, die 2 mg bekommen hatten, wiederum unabhangig von der Beimischung von Morphin. LORAZEPAM Y MORFINA EN LA PREMEDICACION QU1RUGICA INTRAVENOSA Se estudiaron los efectos de la administradon de 2 mg y de 4 mg de lorazepam sola por via intravenosa, y en combinacion con 5 mg de morfina. Se evaluaron la sedadon, eliminacion de la ansiedad, la falta de memoria, la aceptadon que present6 el paciente y la aceptadon del medico por parte de aquel, ademas de los efectos secundarios. La Lncorporacion de morfina al lorazepam mejoro signincan'vamente la sedadon y la eliminacion de la ansiedad. La aceptadon del paciente y del medico no mostraron diferencia significativa alguna entre las dos combinaciones. El fallo de la memoria se puso de manifiesto al incrementar la dosis de lorazepam desde 2 mg a 4 mg, independientemente de la presencia o ausencia de morfina. El unico efecto secundario signincativo fue la inquietud que tuvo lugar en un 15% de los pacientes que redbieron 4 mg de lorazepam y en un de los pacientes que redbieron 2 mg de lorazepam, independientemente de la presenda o ausencia de morfina.