PREMEDICATION WITH SLOW RELEASE MORPHINE (MST) AND ADJUVANTS

Br. J. Anaesth. (1988), 60, 825-830 PREMEDICATION WITH SLOW RELEASE MORPHINE (MST) AND ADJUVANTS K. H. SIMPSON, M. J. DEARDEN, F. R. ELLIS AND T. M. JACK Opioids are used widely for premedication, as they produce sedation, contribute to balanced anaesthesia and provide postoperative analgesia. Slow release morphine (MST Continus) has been evaluated for preoperative use, as the convenience of the oral route is attractive and its duration of action is 7-12 h [1, 2]. Kay and Healy [3] found that MST 30 mg, given 2 h before operation, provided sedation and decreased postoperative pain, but they suggested that MST 60 mg might be a more suitable dose. Pinnock and colleagues [4] found that the response to premedication with MST 40 mg was similar to that of morphine 10 mg i.m., both given with atropine 0.6 mg i.m. The present study was designed to evaluate the premedicant properties of MST 60 mg in women having major gynaecological surgery. MST alone was compared with MST with hyoscine 0.6 mg by mouth, to investigate the contribution of an anticholinergic drug to premedication and reduction in adverse effects. MST with diazepam 10 mg by mouth was also studied, as it was shown previously that MST alone did not produce anxiolysis [3, 4]. SUMMARY Sixty-one women undergoing major gynaecological surgery received slow release morphine (MST) 60 mg, with placebo, hyoscine 0.6 mg or diazepam 10 mg. by mouth 2 h before surgery. Plasma morphine concentrations reached a steady level usually within 3 h after administration of MST, and did not increase after surgery unless supplementary opioid was given. Hyoscine delayed morphine absorption. Before operation no fewer than 50 % of patients were sedated after MST alone, but this increased to 85% after MST and diazepam. Similarly, only the combination MST and diazepam produced anxiolysis. Postoperative mood was unhappier after MST and hyoscine. Emesis occurred in 40-57% of patients, and was not reduced by hyoscine. Therefore premedication with MST alone did not produce reliable sedation or anxiolysis. A combination of hyoscine and MST premedication cannot be recommended, as it did not produce sedation, anxiolysis or antiemesis and hyoscine may have delayed morphine absorption. PATIENTS AND METHODS Patient selection and observation Ethics Committee approval was granted for the study which involved 61 women undergoing major gynaecological surgery. All patients were healthy (ASA I or II), aged 25-60 yr, and none was taking analgesic or psychotropic medication. Two hours before surgery, patients received oral premedication, comprising slow release morpine K. H. SIMPSON, M.B. CH.B., F.F.A.R.C.S.; M. J. DEARDEN, M.B. CH.B., F.F.A.R.C.S.; F. R. ELLIS, PH.D., M.B. CH.B., F.F.A.R.C.S.; University Deparment of Anaesthesia, St James's University Hospital, Beckett Street, Leeds. T. M. JACK, M.B. B.S., M.R.C.S., L.R.C.P., F.F.A.R.C.S.; General Infirmary, Great George Street, Leeds. Accepted for Publication: December 1, 1987. Correspondence to K. H. S. 60 mg with placebo (MST-P), hyoscine 0.6 mg (MST-H), or diazepam 10 mg (MST-D), in a double-blind randomized manner. Patients were assessed and questioned by the anaesthetist before premedication, 1 h after premedication and in the anaesthetic, before induction of anaesthesia, using the following rating scales. Sedation: 1 = alert and wide awake; 2 = awake but drowsy; 3 = asleep but easily roused; 4 = asleep not easily roused. Anxiety: 1 = completely calm; 2 = fairly calm; 3 = fairly nervous; 4 = very nervous. Mood: 1 = elated feeling; 2 = pleasant happy feeling; 3 = unhappy feeling; 4 = unpleasant, disturbed feeling. Emesis:

826 BRITISH JOURNAL OF ANAESTHESIA 1 = none; 2 = nausea; 3 = nausea and vomiting; 4 = repeated vomiting. A standard anaesthetic was used which involved induction of anaesthesia with thiopentone 3-5 mg kg" 1, paralysis with a competitive neuromuscular blocking drug, tracheal intubation and ventilation of the lungs using 33 % oxygen and 66 % nitrous oxide, with 0.5% halothane if required. All patients received fentanyl (<59kg 0.1 mg, 60-80 kg 0.15 mg, > 81 kg 0.2 mg). Neuromuscular blockade was antagonized with atropine and neostigmine. The type and duration of surgery were noted. The same anaesthetist recorded sedation, anxiety, mood and emesis scores immediately after the patient was admitted to the recovery, and at 1, 2 and 3 h after operation. Pain was assessed also at these times, using a 10-cm visual analogue score and a fourpoint rating. scale: 1 = none; 2 = mild; 3 = moderate; 4 = severe. Postoperative analgesia was given on demand as i.m. papaveretum (<59kg 10 mg, 60-80 kg 15 mg, > 81 kg 20 mg), and emesis was treated with prochlorperazine 12.5 mg i.m. The time of administration of the first dose of postoperative opioid was recorded. Plasma morphine, catecholamine and cortisol measurement Venous blood was sampled before induction of anaesthesia, in the recovery and 2 h after surgery for measurement of morphine, catecholamine and cortisol concentrations. Blood samples were collected into heparinized glass tubes on ice, siliconized for morphine assay or containing EDTA and glutathione for catecholamine assay. Plasma was stored at 20 C until required for assay. Morphine was measured using a radioimmunoassay, with a prior liquid-solid extraction to reduce cross-reactivity with glucuronides. All results were expressed as morphine base, and the lowest limit of detection was 2-3ngml"'. The mean deviation of measured values from standard values was 8.1 %. Plasma adrenaline and noradrenaline concentrations were measured using high performance liquid chromatography and electrochemical detection. Catecholamines were separated on a column using a mobile buffer, and extraction was performed using the method of Hjemdahl, Daleskog and Kahan [5]. A mixture of adrenaline, noradrenaline and dihydroxybenzylamine was used as an extracted standard, and dihydroxybenzylamine was used as an internal standard. The lowest limit of detection was 0.05 nmol litre" 1 for adrenaline and 0.10 nmol litre" 1 for noradrenaline. The intra-assay coefficient of variation was 11.0% for adrenaline and 6.7 % for noradrenaline. Plasma cortisol concentrations were measured using a radioimmunoassay kit (RIA U.K. Ltd), which used on antibody covalently bound to the inner surface of a polypropylene tube and 125 I- cortisol. The lowest limit of detection was 1.1 nmol litre" 1. The interassay coefficient of variation was 5.0% and the intra-assay coefficient of variation was 5.7%. Statistics Parametric data were analysed using the Pearson product moment correlation coefficient, t test, one-way analysis of variance for independent groups and two-way analysis of variance with repeated measures on one factor, followed by the Tukey test where appropriate. Non-parametric data, including pain scores, were analysed using Chi-square and Kruskal- Wallis analysis of variance. Differences in sedation, anxiety and mood scores in each group, at each time, were analysed using the Mann- Whitney U test. Differences in scores before and after premedication were analysed using the Wilcoxon matched pairs signed ranks test. RESULTS The ages and weights of patients in the three groups were not significantly different. Fourteen patients received premedication more than 15 min early, and three patients received premedication more than 15 min late. The doses of thiopentone, fentanyl and the use of halothane were comparable in each group. The type and duration of surgery were similar in the three groups (table I). Morphine absorption Before induction of anaesthesia mean (SD) plasma morphine concentrations were not significantly different in patients who had received morphine on time (19.6 (6.3) ngml" 1 ) compared with those who had not (19.9 (6.6) ngml" 1 ). Plasma morphine concentrations in the anaesthetic and recovery s were not significantly different; however, plasma concentrations were lower after MST-H compared with MST-D

SLOW RELEASE MORPHINE (MST) PREMEDICATION 827 TABLE I. Mean (SD) age and weight, details of surgery and mean (SD) time of first dose of postoperative opioid in each group MST-P = MST+placebo; MST-H = MST+hyoscine; MST-D = MST+ diazepatn. No significant difference between groups in age (f = 1.45) or weight (f = 1.63). No significant difference between groups in type (Chi square = 1.43) or duration (f = 1.04) of operation. No significant difference between groups in time of opioid administration after surgery (f = 0.04) or after premedication MST-P («= 21) MST-H (n = 20) MST-D (n = 20) Age (yr) Weight (kg) Abdominal surgery Vaginal surgery Duration of surgery (min) Time of first analgesia After surgery (h) After premed. (h) 44.1 (8.7) 62.9 (16.9) 14 7 81.6 (30.3) 4.4 (23.0) 8.2 (23.8) 42.5 (6.7) 68.4 (12.0) 10 10 75.3 (22.7) 3.4 (14.8) 6.4(11.6) 39.9 (8.5) 64.0 (6.3) 13 7 87.0 (30.0) 3.4 (7.3) 6.9 (7.3) 30 r I 20-10 - o MST- P» MST-H MST- D Anaesthetic! Awake Asleep 18.6 (6.3) 20.6 (9.8) 2 h 24.5(18.1) 33.0(17.1)* (P < 0.01) (fig. 1). Thirty-two patients required papaveretum during the first 2 h after surgery, before the third blood sample was obtained for morphine assay. Mean (SD) plasma morphine concentrations were significantly higher when i.m. opioid had been given (41.6 (15.8) ngml" 1 ) compared with when it had not (16.9 (7.0) ng ml" 1 ) (t = 7.8, P < 0.01). Only one patient, who had received MST-H, showed an increase in plasma morphine without receiving i.m. opioid, from 7.8 ngml" 1 in the recovery, to 19 ngml" 1 2 h later. Sedation 100 200 300 400 No patient was sedated before receiving MST Time (min) and adjuvants, and all groups showed significant FIG. 1. Plasma morphine concentrations (mean + SEM) at sedation after premedication and after operation each time after premedication. Closed symbols show data from all patients (MST-P n = 21, MST-H n = 20, MST-D (P < 0.001). One hour after premedication, more n = 20), open symbols show data from patients who had not patients were sedated after MST-D (95%) received supplementary opioid at the time of the final blood compared with MST-P (62 %) or MST-H (55 %) sample (MST-P n= 11, MST-H n = 8, MST-D n= 10). (P < 0.05). There was no significant difference in Plasma morphine concentrations not significantly different at each time (/= 0.11). Plasma morphine concentrations significantly lower after MST-H compared with MST-D, in the : MST-P 62%, MST-H 60% and MST-D sedation between the groups in the anaesthetic anaesthetic and recovery s (f' 5.78, P < 0.01). 85%. The number of patients sedated at both preoperative assessments was significantly greater after MST-D (85%) than MST-P (48%) and TABLE II. Mean (SD) plasma morphine base concentrationsmst-h (35 %) (P < 0.05). After operation there (ng tng' 1 ) in n 61 patients classified as awake or asleep\ *Significantly greater than awake (t: 2.04, P< 0.05)) were no significant differences between the groups: MST-P 86 %, MST-H 90 % and MST-D 100%. Inadequate sedation occurred more often after MST-P and MST-H than after MST-D (P<0.01), and oversedation occurred in four patients, two MST-P, one MST-H and one

828 MST-D. Sedation in the recovery was not related to plasma morphine concentration; however, 2 h after operation morphine concentrations were greater in patients who were asleep compared with those who were awake (P < 0.05) (table II). Anxiety Before premedication, there were no significant differences in anxiety between the groups. Only MST-D patients showed significant anxiolysis in the anaesthetic (P < 0.001); MST-D patients were less anxious than MST-P or MST-H (P < 0.05). Anxiety was reduced in all groups after surgery (P < 0.05). BRITISH JOURNAL OF ANAESTHESIA 100 80 \ 1 Abdominal surgery (n.38) I Vaginal surgery (n. 23) 60 40 20 1h 3h FIG. 2. Percent of patients at each time, after abdominal or vaginal surgery, with no pain or mild pain. The type of surgery had no effect on postoperative pain: pain scores were not significantly different during the first 3 h after abdominal or vaginal operations (fig. 2). Severe pain occurred in only 17 % patients after vaginal surgery, and 18 % patients after abdominal surgery. The mean (SD) time to administration of the first supplementary opioid was not significantly different after vaginal surgery (4.6 (2.9) h), compared with abdominal surgery (3.1 (4.7) h). Surprisingly, the present study showed that pain was not significantly different after abdominal or vaginal surgery. Nearly 30% of the patients did not require supplementary analgesia within the first 4 h after surgery, which was approximately 7 h after premedication. Patients who had received MST Emesis and diazepam seemed to complain of less pain The incidence of emesis was not significantly than the other two groups; this was not related to different in the three groups: 57 % MST-P, 45 % increased sedation. MST-H and 40 % MST-D patients suffered from 1.4 nausea, vomiting, or both. There was no sig MST-P (n-21) nificant relationship between emesis and plasma MST-H (n.20) MST-D(n.20) -. 1.2 morphine concentrations. Mood A simple rating of happiness was used in the present study, but unhappy mood because of pain was specifically excluded. Mood scores before surgery were similar in the three groups but, after operation, patients were unhappier after hyoscine than after diazepam. Premedication did not significantly alter preoperative mood scores in any group. However, MST-H patients were unhappier than MST-D patients at 1 and 2 h after operation (P < 0.05). Unhappy mood was recorded significantly more often after MST-H compared with MST-D (P < 0.01) and MST-P (P < 0.05). Pain The ranked 10-cm visual analogue pain scores correlated well with the four-point ranking system (r = 0.69, t = 14.4, P < 0.01), and there was disparity between the two scoring systems on only 7.8% occasions. Analysis of pain scores showed that, at 1 and 2 h after operation, pain was reduced after MST-D compared with MST-H and, at 3 h, pain was reduced after MST-D compared with MST-H and MST-P (P < 0.05). Twenty-five percent of patients needed supplementary analgesia within 90 min, 52 % within 2 h and 69 % within 4 h. The time of first postoperative analgesia was not significantly different in the three groups (table I). I to c 1-8 C 1 0.6 Q> S 0.4 II (A I 0.2 Anaesthetic FIG. 3. Plasma adrenaline concentrations (mean + SEM) increased in the recovery compared with in the anaesthetic, in all three groups (/= 3.5, P < 0.05). No significant differences between the three premedication regimens.

SLOW RELEASE MORPHINE (MST) PREMEDICATION 829 "V» 5 MST-P(n.2D MST-H (n.20) MST-D (n.20) Catecholamine concentrations Plasma adrenaline concentrations were riot significantly different after the three premedication regimens (fig. 3). Overall plasma adrenaline concentrations increased in the recovery compared with in the anaesthetic (P<0.05); however, there was no significant difference between adrenaline concentrations in the recovery and at 2 h after surgery. In the three groups plasma noradrenaline concentrations increased in the recovery, at 2 h after operation (P < 0.01). Plasma noradrenaline concentrations were lower after MST-D compared with MST-H (P < 0.05) (fig. 4). Postoperative adrenaline and noradrenaline concentrations were greater in patients who were asleep compared with those who were awake (P < 0.05). Plasma catecholamine concentrations were not related to anxiety, mood, pain or plasma morphine concentrations. Anaesthetic FIG. 4. Plasma noradrenaline concentrations (mean + SEM) increased in the recovery and after operation in all three groups (J = 5.08, P<0.01). Noradrenaline concentrations were reduced after MST-D compared with MST-H (/=3.19, P<0.05). '(D o 1000 800 j 600 c u I 400 8 CO (0 _C0 " 200 0 1 - Anaesthetic MST-P (n-21) MST-H (n.20).mst-d (n.20) II FIG. 5. Plasma cortisol concentrations (mean + SEM) increased, in all three groups, in the recovery and after operation (f = 158.6, P < 0.01). Cortisol concentrations Plasma cortisol concentrations increased in the recovery and after operation, compared with values in the anaesthetic (P < 0.01), but there was no significant difference in cortisol concentrations between the three groups (fig. 5). Plasma cortisol concentrations were not related to plasma morphine concentrations, pain, sedation or anxiety. DISCUSSION The perioperative use of MST is not now recommended, because of concern regarding delayed absorption of morphine in the presence of decreased gastric emptying, produced by pharmacological or pathological causes [6]. The present study, commenced early in 1984, has shown that one preoperative dose of MST, given to healthy patients, was absorbed well and that the timing of its administration was not critical. If supplementary opioid was not needed, plasma morphine concentrations remained fairly stable throughout the study period. Peak plasma morphine concentrations were reached in the anaesthetic or recovery in all but one patient, who had received MST and hyoscine and in whom plasma morphine concentration increased at 2 h after operation. Perhaps the anticholinergic drug had slowed gastric emptying sufficiently to delay morphine absorption from the small intestine. In support of this hypothesis, patients who received MST and hyoscine had lower preoperative plasma morphine concentrations than those who received MST and diazepam. Preoperative anxiety decreases gastric emptying [7], therefore anxiolysis following diazepam may have promoted morphine absorption, whilst gastric stasis following hyoscine may have had the opposite effect. Forty-eight percent of patients did not receive further analgesia before blood was sampled 2 h after operation. Plasma morphine concentrations were not increased in these patients, approximately 5 h after MST administration, remaining

830 BRITISH JOURNAL OF ANAESTHESIA stable after surgery, therefore the use of supplementary i.m. opioid appeared to be safe in this group of patients. However, a marked increase in plasma morphine concentration occurred after i.m. papaveretum. The present study confirmed previous observations of significant sedation when MST premedication was administered [3, 4]. However, although sedation occurred in all three groups, the addition of diazepam to MST produced more predictable results, with 85 % of patients sedated at both assessments. As fewer than 50% of the patients were drowsy or asleep at 1 and 2 h after MST alone or with hyoscine, these regimens cannot be recommended. Postoperative sedation was shown to be associated with higher plasma morphine and catecholamine concentrations. Increased catecholamine concentrations may have been associated with pain, which resulted in the administration of supplementary opioid and consequent sedation. Anxiety is difficult to measure, and several scoring systems have been used before operation. In the present study, a four-point rating scale was chosen for simplicity and brevity. A predictable postoperative reduction in anxiety [8] was detected, suggesting that the rating system was sensitive to acute changes. Reduction of apprehension is an important feature of good premedication, and the lack of anxiolysis after MST alone, shown previously [3, 4], was confirmed in the present study. It was also demonstrated that the addition of hyoscine to MST did not improve anxiolysis, whereas diazepam was effective. Overall, unhappy mood was seen more often after MST and hyoscine than after MST alone or with diazepam. It has been suggested that postoperative emesis occurs in 20-40% of all surgical patients [9]; however, in the present study, 57 % of patients suffered from nausea and vomiting after MST and placebo. The occurrence of emesis was not related to plasma morphine concentrations. Hyoscine premedication has been shown to reduce postoperative emesis [10], but its duration of action is short; the failure of hyoscine to reduce nausea and vomiting significantly in the present study may therefore have been a result of the prolonged action of MST. In conclusion, sedation was unpredictable and there was no anxiolysis when MST alone was used before operation; the addition of diazepam was necessary to improve the quality of premedication. The use of hyoscine with MST cannot be recommended, as it did not improve sedation, worsened mood and did not decrease the rather high incidence of emesis; it may also have delayed the absorption or morphine. (Since 1984 the perioperative use of MST has not been recommended by the manufacturers (Napp Laboratories).) ACKNOWLEDGEMENTS We are grateful to Mrs E. Hay and Mr P. Allam (University Department of Anaesthesia, St James's University Hospital) for the performance of catecholamine assays, and to Dr R. Evans and Dr Shapiro (Department of Chemical Pathology, St James's University Hospital) for provision of cortisol assays. We are indebted to Mrs Elizabeth Tonge, Clinical Research Associate, Napp Laboratories, for support, provision of MST used during the study and organization of the morphine assay. We also thank Dr A. Judd and the staff of the Yorkshire Regional Drug Information Centre for providing the placebo and randomizing the tablets for the study. REFERENCES 1. Leslie ST, Rhodes A, Black FM. Controlled release morphine sulphate tablets a study in normal volunteers. British Journal of Clinical Pharmacology 1980; 9: 531-534. 2. Vater M, Smith G, Aherne GW, Aitkenhead AR. Pharmacokinetics and analgesic effect of slow-release oral morphine sulphate in volunteers. British Journal of Anaesthesia 1984; 56: 821-827. 3. Kay B, Healy TEJ. Premedication by controlled-release morphine. Anaesthesia 1984; 39: 587-589. 4. Pinnock CA, Derbyshire DR, Elling AE, Smith G. Comparison of oral slow release morphine (MST) with intramuscular morphine for premedication. Anaesthesia 1985; 40: 1082-1085. 5. Hjemdahl P, Daleskog M, Kahan T. Determination of plasma catecholamines using liquid chromatography with electrochemical detection: comparison with radioenzymatic method. Life Sciences 1979; 25: 131-138. 6. Brahams A. Death of patient participating in trial of oral morphine for relief of postoperative pain. Lancet 1984; 1, 1083-1084. 7. Simpson KH, Stakes AF. Effect of anxiety on gastric emptying in preoperative patients. British Journal of Anaesthesia 1987; 59: 540-544. 8. Wassenaar W, Lancee WJ, Galloon S, Gale GD. The measurement of anxiety in the presurgical patient. British Journal of Anaesthesia 1977; 49: 605-608. 9. Palazzo MGA, Strunih L. Anaesthesia and emesis: prevention and management. Canadian Anaesthetists Society Journal 1984; 31: 407-415. 10. Clarke RSJ, Dundee JW, Love WJ. Studies of drugs given before anaesthesia VIII. Morphine 10 mg alone and with atropine or hyoscine. British Journal of Anaesthesia 1965; 37: 772-777.