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Injected 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 intra- muscular 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 pa- tients 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 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 calcu- lated only from dichotomous data. These methods have been used to produce a quanti- tative systematic review of the analgesic efficacy of single doses of intramuscular mor- phine in postoperative pain, using the NNT as a descriptor of effectiveness.

Judging the relative efficacy of has always been difficult because of the lack of direct comparisons. Relative efficacy can also be determined indirectly from compari- sons 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, subcuta- neous 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’, ‘’ 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 subcu- taneous) 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 pla- cebo 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 calcu- lated with their 95% confidence intervals (CI) using a random effect model13 for analge- sic 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% confi- dence 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 differ- ence 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 intra- muscular 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 pa- tients 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 assess- ments 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 intra- muscular 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 intra- muscular morphine was 7% to 93% (mean 46%; Figure 1). Of the 15 comparisons be- tween 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).

Minor adverse effects occurred in 34% of patients given intramuscular morphine com- pared with 23% of patients given placebo. This was a significantly increased rate with a relative risk of 1.49 (1.09 - 2.04). Major adverse effects (drug-related study withdrawal) were rare (overall 1.2%) and not different between morphine and placebo (Table 2). Discussion

Morphine is the archetypal analgesic for use in moderate or severe pain. It is also the ‘gold-standard’ against which other injected analgesics are tested. It was surprising, therefore, that rigorous searching revealed so few placebo-controlled trials in which morphine had been given by intravenous, intramuscular or subcutaneous injection, and with testing of single-dose analgesic efficacy using standard, validated methods. We found no subcutaneous studies, one intravenous study, and only for 10 mg intramuscu- lar morphine was there sufficient information (486 treated patients) for information to be pooled for analysis. We found no diamorphine studies which met the criteria.

A single intramuscular dose of morphine 10 mg had an NNT of 2.9 for at least 50% pain relief compared with placebo. This means that one out of every three patients with pain of moderate to severe intensity will experience at least 50% pain relief with morphine which they would not have had with placebo. Sensitivity analysis found that size of trial did not make a difference (Table 2). Sensitivity analysis was not performed for quality of trials, since all but two reports had quality scores of 3 or more. Over-estima- tion of the effect of treatment has been shown in trials with quality scores of 2 or less using the same validated quality scale as here.44

5 Because the trials comparing 10 mg intramuscular morphine were of high methodologi- cal quality, and were all randomised and double blind, this minimises the likelihood of bias over-emphasising treatment effect.45 Moreover, a funnel plot of the relative benefit against trial size (Figure 2) does not show gross asymmetry. Conventional interpretation is that ‘missing’ trials in the lower left quadrant of the graph (the left side of the in- verted funnel) would indicate missing data from small, negative trials, and hence publi- cation bias because such trials are believed to be less likely to be published.46 For this set of injected morphine trials there was no evidence of such a bias.

The NNT for morphine can be compared with those of other analgesics from similar meta-analyses which compared the efficacy of analgesics with placebo in patients with moderate or severe postoperative pain (Figure 3). While there is as yet no comparable information available for other injected analgesics, the NNT of 2.9 (2.6 - 3.8) for 10 mg intramuscular morphine can be compared with those obtained for oral 100 mg of 4.8 (3.4 - 8.2),8 for oral 1000 mg of 3.6 (3.0 - 4.4) and paracetamol 600/650 mg plus 60 mg of 3.1 (2.6 - 3.8),9 and 400 mg 400 mg of 2.7 (2.5 - 3.0; unpublished data) (Figure 3). At first sight the fact that the analgesia from 10 mg of intramuscular morphine is no better than the analgesia from a therapeutic dose of oral NSAID is surprising. We all think of injected drugs as more ‘powerful’ than oral drugs. In reality there is a considerable body of direct evidence that confirms the indirect rank- ing, because the equivalence of the NNTs for oral NSAID and 10 mg of intramuscular morphine is supported by the repeated failure to separate them in comparisons within the same trial and hence randomisation.46,47 A crucial issue here is dose. Clearly with there should be dose titration to effect.

Rank ordering the analgesics in this way is potentially less accurate than having the relative efficacy of the individual drugs from within one very large trial with a single randomisation. In the absence of such “head-to-head” comparisons, we would argue that this indirect ranking, the relative efficacy of the drugs against placebo, is helpful for our clinical decisions. In Figure 3 the trials used to produce NNTs for analgesics com- pared with placebo are all single-dose, postoperative, randomised and double-blind. The patients must have had moderate to severe pain before being treated and standard measures of pain are required. These uniform quality standards and patient selection criteria allow us to make a credible indirect ranking of efficacy. Internal validity is dem- onstrated in the ranking by the dose-response relationships obtained for analgesics, with better analgesia (lower NNT) obtained with higher doses (Figure 3). External validity will come when there are direct (head-to-head) comparisons which confirm the rank order in the indirect table. The trials from which Figure 3 is derived include both oral surgery and other postoperative models. Opioids perform slightly less well relative to NSAIDs in oral surgery than in other postoperative models.8 Morphine efficacy

6 relative to NSAID might improve marginally if Figure 3 was restricted to trials which were not conducted in oral surgery.

This is a clinically helpful observation for patients who can swallow and who have no contraindication to NSAID; oral NSAID appears to be the best analgesic choice. There is no advantage to giving that dose of NSAID by suppository.49 If the patient can swallow, but speedy analgesia is required, then intravenous rather than intramuscular injection seems more logical. 49 If the patient cannot swallow, then we know that 10 mg of intra- muscular morphine gives analgesia equivalent to oral NSAID, and that doubling the dose does indeed increase the analgesia.32 We do not yet have the ranking of injected NSAID compared with injected .

References

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11 3 4 4 3 4 4 4 Score Quality Adverse Effects (morphine vs. placebo) Analgesic Outcome Results 1. IM morphine 8 mg n = 24 2. placebo n = 24 3. IM hydroxyzine 100 mg n = 24 4. IM hydroxyzine + morphine n = 24 1. IM morphine 10 mg n = 30 2. placebo n = 30 3. PO naproxen 550 mg n = 30 1. IM morphine 10 mg n = 30 2. placebo n = 30 3. PO anirolac 600 mg n = 30 4. PO anirolac 125 mg n = 30 5. PO anirolac 5 mg n = 30 1. IM morphine 10 mg n = 30 2. placebo n = 30 3. IM nefopam 20 mg n = 30 4. IM diphenhydramine 20 mg n = 30 1.IV Morphine 8 mg n = 30 2. placebo n = 30 3. PO fenoprofen 200 mg n = 30 1. IM morphine 10 mg n = 51 2. IM morphine 5 mg n = 50 3. placebo n = 25 4. PO ketorolac 10 mg n = 50 1. IM morphine 10 mg n = 30 2. placebo n = 30 3. PO flurbiprofen 50 mg n = 30 Outcome MeasuresGroups Treatment standard 4 pt PI; 5 PR; 9 item tension/anxiety questionnaire PI (5 point) none, slight, moderate, severe, very severe PR (5 point) none, poor, fair, good, very good 50% pain relief at 6 hours Time to next analgesic PI (5 point) 1 = none, 2 slight, 3 moderate, 4 = severe, 5 very severe PR (5 point) 5 = none, 4 poor, 3 fair, 2 = good, 1 very good Pain half gone at end of study, or time of withdrawal standard 4 pt PI; Pain relief 50% VASPI 10 cm PI (5 point) 0 = none, 1 mild, 2 moderate, 3 = severe, 4 very severe VASPI 100 mm 0-99 PR (5 point) 0 = none, 1 a little, 2 some, 3 = a lot, 4 complete patient & investigator global evaluation end of study standard 4 pt PI; investigator rating end of treatment poor/fair = no effect, good/excellent effective pain relief derived score half gone need for additional analgesia Follow Up Design, Study Duration & RCT, double-blind, single dose, parallel group. Assessments by single nurse observer, hourly assessments up to 6 hr. Moderate severe baseline pain RCT, double-blind, single dose, parallel group, double-dummy. Assessed by single nurse observer at 0, 0.5, 1 hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate Study 3 only. RCT, double-blind, single dose, double-dummy, parallel group. Assessed by single nurse observer at 0, 0.5, 1 hr then hourly intervals for 6 hours. Medication taken when baseline pain was at least moderate RCT, single dose, parallel group, double-blind, Assessments by single nurse observer at 0, 30 min, 1, 2, 3, 4, 5 & 6 hr. Baseline pain at least moderate RCT, single dose, parallel group, double-blind, Assessments by single observer at 0, 30 min, 1, 2, 3, 4, 5 & 6 hr. Baseline pain at least moderate RCT, double-blind, single dose, parallel group, double-dummy? Assessed by patients at 0, 0.5, 1hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single dose, parallel group, double-dummy. Assessed by patients at 0, 1hr then hourly intervals for 6 hours. Medication taken when baseline pain was at least moderate Table 1: Details of patients, methods, outcomes, treatments and results for included studies Patients Condition & No. of general & gynaecological surgery n = 96 age: not given various surgical procedures n = 90 age: adults 18-68 yr various surgical procedures n = 150 age: 18-66 yr various acute and medical patients (2 part studies) n = 120 (each study) age: adults various day surgery procedures n = 90 age: 23-69 yr orthopaedic surgery (hip and knee replacement) n = 176 age: adults gynaecological surgery n = 92 age: not stated Author Beaver & Feise, 1976 Brown et al, 1984 Brown et al, 1991 Campos & Solis, 1980 Davie et al, 1982 DeAndrade et al, 1994 De Lia et al, 1986 12 3 3 3 4 2 3 No study withdrawals reported due to adverse effects NSD reported between groups total side effects per dose M n=14/50 34 p n=4/49 9 n=12/50 cod n=11/50 25 n=2/49 3 not given not reported 1. IM morphine 10 mg n = 36 2. placebo n = 35 3. IM ciramadol 30 mg n = 34 4. IM ciramadol 60 mg n = 34 1. IM morphine 10 mg n = 40 2. placebo n = 40 4. IM Dezocine 10 mg n = 40 5. IM Dezocine 15 mg n = 40 1. IM morphine 10 mg n = 9 2. placebo n = 9 3. oral cocaine 10 mg n = 9 3. oral cocaine 10 mg + morphine n = 9 1. IM morphine 12.5 mg n = 50 2. placebo n = 49 3. PO codeine 90 mg n = 50 4. PO pentazocine 75 mg n = 50 5. PO oxycodone compound (oxycodone hydrochloride 4.5 mg, oxycodone terepthalate 0.30 mg, aspirin 224 160 mg, caffeine 32 mg) n = 49 1. IM morphine 10 mg n = 30 2. IM placebo n = 30 3. IM tonazocine 2 mg n = 29 4. IM tonazocine 4 mg n = 30 5. IM tonazocine 2 mg n = 31 1. IM morphine 10 mg n = 51 2. placebo n = 55 3. PO flurbiprofen 50 mg n = 53 4. PO 100 mg n = 22 standard 4 pt PI; PR (5 point) -1 = worse, 0 none, 1= a little, 2= moderate, 3= a lot, 4= complete VASPI 10 cm patient rating end of treatment (4 point) 1= poor, 2= fair, 3= good, 4= excellent 50% relief (derived) standard 4 pt PI; PR (6 point) -1 = worse, 0 none, 1 slight, 2 = moderate, 3 substantial, 4 = complete VASPI 100 mm patient rating of treatment (4 point) poor, fair, good, excellent investigator rating of treatment (satisfactory/unsatisfactory) standard 4 pt PI; PR (5 point) VASPI VASPR VAS mood standard 4 pt PI; # patients with =>50% pain relief PI (4 point) 0= none, 1= slight, 2= moderate, 3= severe PR (scale not described) additional analgesia treatment effective/partially effective/ineffective (derived score) standard 4 pt PI; PR 1= unchanged/worse, 2=< half gone, 3= half 4= > 5= completely gone investigator global 1= no effect, 2= poor, 3= fair, 4= good, 5= excellent need for supplementary analgesia RCT, double-blind, single dose, parallel group, double-dummy. Assessed by single observer at 0, 15, 30 min, 1 hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate. Injections into deltoid muscle RCT, double-blind, single dose, parallel group. Assessed by more than 1 observer at 0, 15, 30 min, 1hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single dose, cross- over design. Assessed by nurse observer at 0, 30 mins,1hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, 4 doses of same drug given over 2 days. Nurse observers, assessments at 0, 30 min, 1 hr then hourly intervals for 4 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single dose, parallel group. Assessments at 0, 30 min, 1hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single dose, parallel group. Assessments at 0, 30 min, 1 hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate orthopaedic & major gynaecological surgery n = 139 age: 18-65 yr post-operative wound pain n = 160 age: 19-70 yr acute post-operative pain n = 9/17 (completed cross- over each treatment) age: 22-65 post operative & acute traumatic pain n = 250 age: 21-75 yr major abdominal and orthopaedic surgery n = 151 age: 18-65 yr major obstetric & gynaecological surgery n = 181 age: 19-65 yr Fragen et al, 1983 Gravenstein et al, 1984 Kaiko et al, 1987 Kantor et al, 1981 Lippmann et al, 1989 Morrison et al, 1986 13 5 4 4 4 2 % patients reporting AE M 10% P 8 % not stated , 4 = complete difference; M - morphine; P placebo; SD single dose; SPID summed pain intensity intensity difference using visual analogue scale; VASSPID - summed pain difference; PO oral 1. IM morphine 10 mg n = 37 2. IM morphine 20 mg n = 37 3. IM placebo n = 37 4. IM lornoxicam 4 mg n = 33 5. IM lornoxicam 8 mg n = 38 6. IM lornoxicam 16 mg n = 38 7. IM lornoxicam 20 mg n = 37 1. IM morphine 10 mg n = 14 2. IM placebo n = 12 3. IM enadoline 15 mg n = 14 (kappa ) 4. IM enadoline 25 mg n = 13 1. IM morphine 10 mg n = 39 2. IM placebo n = 38 3. IM dezocine 5 mg n = 38 4. IM dezocine 10 mg n = 37 5. IM dezocine 15 mg n = 38 1. IM morphine 10 mg n = 40 2. IM placebo n = 40 3. IM ciramadol 30 mg n = 40 4. IM ciramadol 60 mg n = 40 1. IM morphine 5 mg n = 20 2. IM morphine 10 mg n = 20 3. IM placebo n = 20 4. IM ciramadol 30 mg n = 40 5. IM ciramadol 60 mg n = 40 PI (5 point) 0=gone, 1=slight, 2=moderate, 3=severe, 4=unbearable PI (11 point) 0-10 PR (5 point) 0= none to 4= complete Patient rating of treatment 4 & 8 hours 1-5 onset of relief duration of relief remedication time PI 0-3 4hr & 8 hr SPID PR 0-4 pain reduced by half patient rating of treatment at end study PI (3 point) mild, moderate, severe % PR 0= none, 1= <50%, 2=50%, 3=>50%, 4= 100% pain reduced by half standard 4 pt PI; PR -1 worse, 0= none, 1= a little, 2= moderate, 3= a lot, 4= complete patient rating end of treatment 1= poor, 2= fair 3= good 4= excellent standard 4 pt PI; PR -1= worse, 0= none, 1= a little, 2= moderate, 3= a lot, 4= complete VAS PI 10 cm sedation 0-3 patient & investigator rating of treatment poor, fair, good, excellent standard 4 pt PI; 0 = none, 1 slight, 2 moderate, 3 =severe. Standard 5 PR; good RCT, double-blind, single dose, double dummy , parallel group. assessments at 0, 15, 30, 45 min, 1 hr then hourly intervals for 8 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single dose, parallel group. assessments at 0, 15, 30 mins,1hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate. RCT, double-blind, single dose, parallel group. Single observer, assessments at 0, 15, 30 mins,1 hr then hourly intervals for 4 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, multiple dose, parallel group, more than one observer, assessments at 0, 15, 30 mins,1 hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate RCT, double-blind, single, parallel group, medical observer, assessments at 0, 15, 30 mins,1 hr then hourly intervals for 6 hr. Medication taken when baseline pain was at least moderate third molar extraction n = 252 age: 18-40 yr obstetric & gynaecological surgery n = 53 age: 26-61 yr orthopaedic, gynaecological & general surgery n = 190 age: 26-61 yr orthopaedic, gynaecological & general surgery n = 160 age: 18-65 yr orthopaedic, gynaecological & general surgery n = 100 age: 18-65 yr Abbreviations: RCT - randomised controlled trial; PI pain intensity; PR relief; im intramuscular; PID intensity TOTPAR - total pain relief ; AE adverse effects; NSD no significant difference; F fenoprofen # number; VASPI Nørholt et al, 1996 Pande et al, 1996 2 studies in this report, use study 2 only Pandit et al, 1985 Powell,1985 Van Den Abeele & Camu,1985 14 Table 2: Analgesia and adverse effects of 10 mg intramuscular morphine

At least At least Relative benefit or Number needed to Trial 50% pain 50% pain risk treat (date order) relief with relief with (95%CI) (95%CI) morphine placebo Campos et al, 1980 28/30 14/30 2.0 1.4 3.0 2.1 1.5 3.7 van den Abeele & Camu, 1983 15/20 2/20 7.5 2.0 28.6 1.5 1.1 2.4 Fragen et al, 1983 17/36 4/35 4.1 1.5 11.1 2.8 1.8 6.1 Brown et al, 1984 23/30 11/29 2.0 1.2 3.4 2.6 1.6 6.5 Gravenstein, 1984 10/40 0/40 101 0.2 >250 4.0 2.6 8.8 Pandit et al, 1985 8/39 2/38 3.9 0.9 17.2 6.7 3.4 138 Powell, 1985 11/39 0/40 114 0.2 >250 3.6 2.4 7.1 deLia et al, 1986 15/30 5/30 3.0 1.3 7.2 3.0 1.8 9.1 Morrison et al, 1986 47/51 25/55 2.0 1.5 2.7 2.1 1.6 3.2 Kaiko et al, 1987 2/9 1/9 2.0 0.2 18.8 9.1 2.2 ∞ Lippmann et al, 1989 4/30 0/30 41 0.1 >250 7.7 3.9 85 Brown et al, 1991 17/30 6/30 2.8 1.3 6.2 2.7 1.7 7.2 DeAndrade et al, 1994 34/51 4/25 4.2 1.7 10.5 2.0 1.4 3.2 Nørholt et al, 1996 9/37 0/37 91 0.2 >250 4.2 2.6 9.5 Pande et al, 1996 1/14 0/12 9.4 0.0 >250 14.3 4.9 ∞

Combined analgesic data 241/486 74/460 2.8 2.0 3.8 2.9 2.6 3.6

Trials with <32 treated patients 101/293 40/198 2.2 1.8 2.8 2.9 2.3 4.1 Trials with >32 treated patients 136/293 35/270 4.0 1.6 9.8 3.0 2.5 3.8

Minor adverse effects 108/320 68/295 1.49 1.09 2.04 9.1 5.6 27.7

Major adverse effects 2/334 6/304 0.31 0.07 1.38

Values for relative benefit (risk) and number-needed-to-treat are given as the point estimate, followed by lower and higher confidence interval.

15 Figure 1: Relation between the proportion of patients achieving at least 50% pain relief with 10 mg intramuscular morphine in 15 trials

100

80

Percent wit h at least 60 50% pain relief wit h 10 mg int ramuscular morphine 40

20

0 020406080100 Percent with at least 50% pain relief with placebo

16 Figure 2: Funnel plot of relative benefit against total number of patients in the morphine/placebo comparison

125

100

75 Number of patients in morphine- placebo comparison 50

25

0 0.1 1 10 100 1000

Relative benefit

17 Figure 3: Relative efficacy of single doses of analgesics com- pared with placebo to produce at least 50% pain relief in moderate or severe postoperative pain (oral doses except for morphine)

Number given treatment

Codeine 60 mg 649 Tramadol 50 mg 409 Paracetamol 300 mg/Codeine 30 mg 246 Aspirin 650/Codeine 60 mg 305 Paracetamol 600/650 mg 634 Tramadol 100 mg 468 Paracetamol 650/Propoxyphene 100 mg 478 Paracetamol 1000 mg 595 Paracetamol 600 mg/ Codeine 60 mg 415 Ibuprofen 200 mg 324 Morphine 10 mg i.m. 486 Ibuprofen 400 mg 844

2468101214161820 Number-needed-to-treat (95% confidence intervals)

Data for drugs other than morphine is from other published systematic reviews,8,9 and for ibuprofen see reference 7.

18