Injected Morphine in Postoperative Pain: a Quantitative Systematic Review

Injected morphine in postoperative pain: a quantitative systematic review Henry J. McQuay, DM, Clinical Reader in Pain Relief Dawn Carroll, BA Hons, Research Sister R. Andrew Moore, DSc, Consultant Biochemist Pain Research & Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ UK This study was supported by grants from the NHS R&D Health Technology Evaluation programmes, European Union Biomed 2, and Pain Research Funds. Correspondence to Dr H J McQuay, Pain Research Tel: +44 1865 226161 Fax: +44 1865 226160 email: [email protected] Abstract This systematic review of single dose placebo randomised controlled trials assessed pain relief from subcutaneous, intramuscular or intravenous morphine compared with placebo in postoperative pain. Pain relief or pain intensity difference over four to six 1 hours was extracted and converted into the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. In 15 trials comparing intramuscular morphine 10 mg (486 patients) with placebo (460 patients) morphine had an NNT of 2.9 (95% confidence interval 2.6 - 3.6). This meant that one of every three patients with moderate or severe postoperative pain treated with 10 mg intramuscular morphine had at least 50% pain relief, who would not have done had they been given placebo. Minor adverse effects were more common with morphine (34%) than with placebo (23%) (relative risk 1.49 (1.09 - 2.04)), but drug-related study withdrawal was rare (1.2% overall) and no different from placebo. Key Words: Morphine / postoperative pain / quantitative systematic review / meta analysis / randomised control trials Running title: Injected morphine for postoperative pain Introduction Until recently combining data from different analgesic studies has been problematic. One reason is the historical use of mean values to describe the outcome measures. This has been shown to be inappropriate and potentially misleading as the distributions they describe are skewed.1 A method which allows for the skewed distribution has now been developed to reliably convert mean values for pain intensity or pain relief (for instance, the percent of maximum total pain relief from categorical pain relief scales, %maxTOTPAR) into dichotomous information (number of patients with >50%maxTOTPAR over 4 - 6 hours).2-4 The quantitative measure of effect size generated by pooling these means must also be inappropriate. Effect size is difficult to interpret. A more easily understood measure, the number-needed-to-treat (NNT),5-7 can be calculated only from dichotomous data. These methods have been used to produce a quantitative systematic review of the analgesic efficacy of single doses of intramuscular morphine in postoperative pain, using the NNT as a descriptor of effectiveness. Judging the relative efficacy of analgesics has always been difficult because of the lack of direct comparisons. Relative efficacy can also be determined indirectly from comparisons of each analgesic with placebo. By using at least 50% pain relief as a common descriptor of analgesic effectiveness, it is possible to produce a rank order of analgesic efficacy.8,9 Methods 2 Single dose randomised placebo controlled trials of injectable (intramuscular, subcutaneous and intravenous) morphine in acute postoperative pain were sought. A number of different search strategies were used to identify eligible reports in MEDLINE (1966 - 1997), EMBASE (1980 - 1997), the Cochrane Library (1997 issue 2) and the Oxford Pain Relief Database (1950 - 1994) .10 The last electronic search was conducted in March 1997. The words ‘morphine’, ‘diamorphine’, ‘heroin’ were used to identify relevant reports, using a combination of free text words and MeSH terms, and without restriction to language. Additional reports were identified from reference lists of retrieved reports, review articles, and specialist textbooks. Inclusion criteria were full journal publication of randomised controlled trials which included single dose treatment groups of injected (intravenous, intramuscular or subcutaneous) morphine and placebo, acute postoperative pain, blinded design, baseline pain of moderate to severe intensity, adult patients, and assessments of pain intensity or pain relief over four to six hours with results for total pain relief (TOTPAR), summed pain intensity difference (SPID), or their visual analogue equivalents (VASTOTPAR, VASSPID), or with data from which these could be calculated. Review articles, letters or abstracts were not included. We screened reports to eliminate those without pain outcomes, those which were defi- nitely not randomised, or were abstracts or reviews. Each report which could possibly be described as a randomised controlled trial was read independently by each of the authors and scored using a commonly-used three item, 1-5 score, quality scale.11 Con- sensus was then achieved. The maximum score of an included study was 5 and the minimum score was 1. Data extracted from the reports were the pain setting, study treatment groups, numbers of patients treated, study duration, the route and dose of morphine, and mean or de- rived TOTPAR, SPID, VASTOTPAR or VASSPID or any dichotomous global pain relief outcome. Information on minor and major adverse events as defined by the authors of the original reports was also extracted. Full details of analytic methods are given elsewhere.7 For each report with mean TOTPAR, SPID, VASTOTPAR or VASSPID values for morphine and placebo, the data was converted to percentage of maximum by division into the calculated maximum value.12 The proportion of patients in each treatment group who achieved at least 50%maxTOTPAR was calculated using verified equations.2-4 These proportions were then converted into the number of patients achieving at least 50%maxTOTPAR by mul- tiplying by the total number of patients in the treatment group.2 3 Information on the number of patients with >50%maxTOTPAR for morphine and placebo was used to calculate relative risk (or benefit) and NNT by pooling data when available from at least three studies including both morphine and placebo groups with the same dose and route of administration. Relative risk or benefit estimates were calculated with their 95% confidence intervals (CI) using a random effect model13 for analgesic data which were not homogenous (P < 0.1) and a fixed effects model14 for adverse effect data which were homogenous (P >0.1). Homogeneity of the analgesic results was also explored graphically.15 Number-needed-to-treat16 was calculated with 95% confidence interval.5 A statistically significant difference from control was assumed when the 95% confidence intervals of the relative risk/benefit did not include 1. Statistical difference between NNTs was assumed when confidence intervals did not overlap. Calcula- tions were performed using Excel v 5.0 on a Macintosh 8500/150. Results Thirty-eight reports were excluded for a variety of reasons. These included lack of placebo (10), not in acute postoperative pain (8), unvalidated methods used (7), obser- vations for less than four hours (3), drugs not given as a single dose (3), not randomised (3), duplicate publications (2), morphine not given (1), and not a full report (1). Eighteen reports of 20 trials did fulfil the inclusion criteria; 696 patients were given morphine and 563 placebo. No trials of subcutaneous morphine or of diamorphine by any route of administration met the inclusion criteria. Morphine was given by intramuscular injection in all reports except one17 in which it was given intravenously. Mor- phine doses were 5 mg,18,19 8 mg,17,20 10 mg,18, 19, 21-33 12.5 mg34 and 20 mg.32 Details of these studies are given in Table 1. Two studies22,34 included a mixed population of patients with postoperative and other acute pain. Trials otherwise investigated pain relief predominantly after orthopaedic and gynaecological surgery. Pain outcomes were over six hours except for two studies in which they were over four hours.26,34 Quality scores were 2 for two reports, 3 for six, 4 for nine and 5 for one. Nine reports which appeared to fulfil inclusion criteria were omitted. Three studies35-37 had pain relief or intensity information for one hour or less. Two reports38,39 appeared to duplicate previously published information. Four reports40-43 used non standard assessments which could not be used. Only for 10 mg of intramuscular morphine was data available from at least three trials to be pooled for meta-analysis. In 15 comparisons 486 patients were given 10 mg intramuscular morphine and 460 placebo (Table 2). The size of the active treatment group in 4 these trials varied between 9 and 51 patients (mean 33 patients, median 30). The placebo response rate (i.e. the proportion of patients given placebo experiencing at least 50% pain relief) varied from 0% to 47% (mean 15%), and the response rate with 10 mg intramuscular morphine was 7% to 93% (mean 46%; Figure 1). Of the 15 comparisons between 10 mg intramuscular morphine and placebo, eight were statistically superior to placebo and had a lower confidence interval of the relative benefit above 1 (Table 2). The pooled relative benefit was 2.8 (95%CI 2.0 - 3.8). The pooled NNT for 10 mg intramuscular morphine compared with placebo was 2.9 (2.6 - 3.6). Omitting the trial which included acute non surgical pain22 did not affect the result. The pooled NNT without this study was 3.1 (2.7 - 3.8). Trials which had fewer than the median number of patients given morphine (fewer than 32 patients treated) gave an NNT of 2.9 (2.3 - 4.1), the same as larger trials (32 patients or more) with an NNT of 3.0 (2.5 - 3.8).

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