Single dose oral ibuprofen for acute postoperative pain in adults

  • Review
  • Intervention

Authors


Maura Moore, Pain Research and Nuffield Department of Anaesthetics, University of Oxford, West Wing (Level 6), John Radcliffe Hospital, Oxford, Oxfordshire, OX3 9DU, UK. maura.moore@pru.ox.ac.uk.

Abstract

Background

Ibuprofen and diclofenac are two widely used non-steroidal anti-inflammatory (NSAID) analgesics. It is therefore important to know which drug should be recommended for postoperative pain relief. This review seeks to compare the relative efficacy of the two drugs, and also considers the issues of safety and cost.

Objectives

To assess the analgesic efficacy of ibuprofen and diclofenac in single oral doses for moderate to severe postoperative pain.

Search methods

Randomised trials were identified by searching Medline (1966 to December 1996), Embase (1980 to January 1997), The Cochrane Library (Issue 3 1996), Biological Abstracts (January 1985 to December 1996) and the Oxford Pain Relief Database (1950 to 1994). Date of the most recent searches: July 1998.

Selection criteria

The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared either ibuprofen or diclofenac with placebo.

Data collection and analysis

Data were extracted by two independent reviewers, and trials were quality scored.

Summed pain relief or pain intensity difference over four to six hours was extracted, and converted into dichotomous information yielding the number of patients with at least 50% pain relief. This was then used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief.

Main results

Thirty-four trials compared ibuprofen and placebo (3591 patients), six compared diclofenac with placebo (840 patients) and there were two direct comparisons of diclofenac 50 mg and ibuprofen 400 mg (130 patients). In postoperative pain the NNTs for ibuprofen 200 mg were 3.3 (95% confidence interval 2.8 to 4.0) compared with placebo, for ibuprofen 400 mg 2.7 (2.5 to 3.0), for ibuprofen 600 mg 2.4 (1.9 to 3.3), for diclofenac 50 mg 2.3 (2.0 to 2.7) and for diclofenac 100 mg 1.8 (1.5 to 2.1).

Direct comparisons of diclofenac 50 mg with ibuprofen 400 mg showed no significant difference between the two.

Authors' conclusions

Both drugs work well. Choosing between them is an issue of dose, safety and cost.

Plain language summary

Single dose oral ibuprofen for postoperative pain

Ibuprofen and diclofenac are two widely used non-steroidal anti-inflammatory (NSAID) analgesics. This review seeks to compare the relative efficacy of the two drugs, and also considers the issues of safety and cost. The results confirm that both ibuprofen and diclofenac are effective analgesics for postoperative pain with a low incidence of adverse effects. This analysis indicates there is no real difference between the single dose efficacy of ibuprofen and diclofenac. The relative efficacy of the two drugs comes down to dose, 50 mg of diclofenac may provide better analgesia than 400 mg of ibuprofen but it is one third of the maximum daily dose whereas ibuprofen 400 mg is only one sixth. At 600 mg ibuprofen appears to work as well as diclofenac 50 mg yet the dose is still a lower proportion of the maximum daily allowance. Choosing between them therefore appears to be a matter of dose, safety and cost. Ibuprofen has been reported as having a lower incidence of adverse effect but this again may be a reflection of the dosage used, it is also usually cheaper.

Background

Ibuprofen and diclofenac are two of the most widely used non-steroidal anti-inflammatory (NSAID) analgesics. Ibuprofen is commonly available without prescription. In England in 1996, ibuprofen accounted for nearly five and a half million prescriptions (31% of total NSAID prescriptions) and diclofenac for nearly six million prescriptions (34%), although it is not known how much of this was for acute pain conditions (GSS 1997). With an increasing amount of surgery being performed as day case it is important to know which drug should be recommended for postoperative pain relief. We sought to compare the relative efficacy of the two drugs to allow a balanced decision to be made based on efficacy, safety and cost.

The lack of direct comparisons makes it hard to judge the relative efficacy of analgesics. Relative efficacy may be determined indirectly from comparisons of each analgesic with placebo. By using a measure of at least 50% pain relief as a common descriptor of analgesic effectiveness, we can then produce a rank order of analgesic efficacy.

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 (McQuay 1996b). The quantitative measure of effect size generated by pooling these means must therefore also be inappropriate as well as being difficult to interpret. A more easily understood measure, the number-needed-to-treat (NNT) (Cook 1995), can be calculated from dichotomous data. A validated method which allows for the skewed distribution has now been developed which reliably converts mean values for pain relief (percent of maximum total pain relief from pain relief scales, %maxTOTPAR or percent of maximum total pain intensity difference from pain intensity scales, %maxSPID) into dichotomous information (number of patients with at least 50%maxTOTPAR over four to six hours) (Moore 1996, Moore 1997a, Moore 1997b). This method has been used to produce a quantitative systematic review of the relative analgesic efficacy of single oral doses ibuprofen and diclofenac in postoperative pain, using the NNT as a descriptor of effectiveness.

Objectives

To quantitatively evaluate the analgesic efficacy of ibuprofen and diclofenac in postoperative pain. To compare the results with those for other analgesics assessed in the same way in order to provide evidence-based recommendations for clinical practice.

Methods

Criteria for considering studies for this review

Types of studies

Reports were included if they were a full journal publication of single dose, double-blind, randomised placebo controlled trials of ibuprofen or diclofenac over four to six hours in postoperative pain. Multiple dose studies were included if the appropriate data from the first dose was available.

We excluded reports that did not clearly state that the interventions had been randomly allocated. We also excluded reports of ibuprofen or diclofenac for the relief of other pain conditions, controlled release formulations, ibuprofen or diclofenac used in combination with other drugs, trials which reported data from a cross-over design as a single data set, trials with less than four hours of observations, and trials which included pain relief data collected after additional analgesia was given.

In postpartum pain, trials were included if the pain investigated was due to episiotomy or Caesarean section irrespective of the presence of uterine cramps but trials investigating pain due to uterine cramps alone were excluded.

Abstracts, review articles, case reports, clinical observations and unpublished data were not included. Neither pharmaceutical companies nor authors of papers were contacted for unpublished reports.

Full details of each study are given in the 'characteristics of included studies' section using the following abbreviations;
RCT = randomised controlled trial, DB = double blind, PI = pain intensity, PR = pain relief, AE = adverse effect

Types of participants

Only trials of adult patients with established postoperative pain of moderate to severe intensity were included. For studies using a visual analogue scale (VAS), pain of at least moderate intensity equates to >30 mm (Collins 1997). When the baseline pain is only presented as a mean VAS score with the corresponding standard deviation (SD), the study was only included if the mean minus 1.96 times the SD was >30 mm.

Types of interventions

Trials were included if they contained a treatment group allocated to either ibuprofen or diclofenac and placebo. Interventions were administered orally and were immediate release formulations (tablets, gel capsules or soluble).

Types of outcome measures

The derived pain relief outcomes extracted were TOTPAR (total pain relief) or SPID (summed pain intensity difference) over four to six hours or sufficient data to allow their calculation. The pain measures accepted for the calculation of TOTPAR or SPID were; five point categorical pain relief (PR) scales with comparable wording to "none, slight, moderate, good or complete", scales using percentages or money as anchors were not permitted; four point categorical pain intensity (PI) scales with comparable wording to "none, mild, moderate, severe"; visual analogue scales (VAS) for pain relief; VAS for pain intensity.

If TOTPAR or SPID were not available global evaluations of pain relief were used provided they were over four to six hours and measured on a five point scale by the patient, not an observer. Dichotomous information from these global evaluations (number of patients reporting the top two categories e.g. good or excellent) is comparable to the calculated dichotomous information from the method used (Oxford Pain Research Unit unpublished data).

Search methods for identification of studies

Medline (1966-December 1996), Embase (1980-Jan 1997), the Cochrane Library (August 1996), Biological Abstracts (Jan 1985-Dec 1996), and the Oxford Pain Relief Database (1950-1994) (Jadad 1996a) were searched for randomised controlled trials of ibuprofen or diclofenac.

Both search strategies used were highly sensitive, yielding 1500-2000 hits, all of which were then downloaded from each database and every abstract checked for relevance. If there was no abstract available the paper itself was obtained.

The search used for this review can be seen in Appendix 1.

These were free text searches across all fields on each database, no restriction on language was applied. Details of the 76 brand names used for diclofenac can be found on the internet at http://www.ebandolier.com.

Additional reports were identified from reference lists of retrieved articles, reviews and textbooks. Unpublished data were not sought.

Data collection and analysis

From each report we took; the numbers of patients treated, the mean TOTPAR, SPID, VASTOTPAR or VASSPID, study duration and the dose given. Information on adverse events was also extracted. For each report, the mean TOTPAR, SPID, VASTOTPAR or VASSPID values for active and placebo were converted to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). The proportion of patients in each treatment group who achieved at least 50%maxTOTPAR was calculated using verified equations (Moore 1996, Moore 1997a, Moore 1997b). These proportions were then converted into the number of patients achieving at least 50%maxTOTPAR by multiplying by the total number of patients in the treatment group. Information on the number of patients with at least 50%maxTOTPAR for active and placebo was then used to calculate relative benefit (RB) and the NNT.

Information on adverse events was used, where possible, to calculate the relative risk (RR) and number-needed-to-harm (NNH).

Relative benefit (RB) and relative risk (RR) estimates were calculated with 95% confidence intervals (CI) using a fixed effects model (Gardner 1986). The NNT, NNH and 95% cCI were calculated by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control was assumed when the 95% CI of the relative benefit did not include one.

Calculations were performed using Excel v 5.0 on a Power Macintosh 7100/80.

Results

Description of studies

Ibuprofen

One hundred and seven published articles were identified from the search as potential double blind, RCTs of oral ibuprofen in postoperative pain. Of these, three reports did not state whether they were randomised and/or double blind, so had to be excluded and three were abstracts.

Of the remaining 101 RCTs, 67 were excluded. In 28 studies patients did not have baseline pain of at least moderate severity, this includes the studies which administered the intervention pre-operatively. This is methodologically important as testing the intervention on patients with established pain ensures adequate sensitivity (Lasagna 1962). Nineteen studies did not have a placebo control and in six studies the participants were children. In three studies pain scales other than those described in the selection criteria were used and in two, data was provided for less than four hours. As the method for generating dichotomous data has only been verified for the most commonly used pain scales, applied over four to six hours, other outcome measurements cannot be legitimately used with this technique. Three studies provided multiple dose data without analysing the first dose separately and two studies did not measure pain directly. In two studies patients continued to complete the diaries after re-medicating with rescue analgesics thus invalidating the results and one trial presented the data from a cross-over design as one data set. One study used a controlled release formulation of ibuprofen. Thirty four reports of 35 studies met our inclusion criteria and were included in the analysis. One was author contacted and kindly provided information on the number of patients in each treatment arm (Laska 1986).

Diclofenac

Although the search identified nearly 2000 trials the majority were in chronic pain or the intervention was administered before the patient experienced pain. Over 500 reports were found of trials involving rectal, intravenous and intramuscular diclofenac. Predominantly these reports were not placebo controlled, did not use standard pain outcome measures or the intervention was administered before the patient experienced any pain.

Only 47 published articles were identified as potential double blind, RCTs of oral diclofenac in postoperative pain. Of these, one report failed to state whether it was randomised, so had to be excluded and five were abstracts.

Of the remaining 41 RCTs, 35 were excluded. In 13 studies patients did not have baseline pain of at least moderate severity, this includes the studies which administered the intervention pre-operatively. Sixteen studies did not have a placebo control and one study only reported the first hour's data for the placebo group. Five reports identified by the search could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals (Joubert 1977, Vigneron 1977, Carlos 1984, Frezza 1985, Iqbal 1986).

Six reports of six studies met our inclusion criteria and were included in the analysis. One author was contacted for information on the number of patients in each treatment arm (Nelson 1994a); they were unable to provide this information and so an equal split of 50 patients per group was assumed.

Risk of bias in included studies

Each report was independently scored for quality by two of the authors using a three-item scale with a maximum score of five (see below) (Jadad 1996b); all of the authors then met to agree a 'consensus' score for each report.

The quality scores (QS) for individual trials are reported in the notes section of the included studies table. These scores were not used to weight the results in any way.

The scale used is as follows:
Is the study randomised ? If yes - 1 point
Is the randomisation procedure reported and is it appropriate ? If yes add 1 point, if no deduct 1 point
Is the study double blind ? If yes then add 1 point
Is the double blind method reported and is it appropriate ? If yes add 1 point, if no deduct 1 point
Are the reasons for patient withdrawals and dropouts described ? If yes add 1 point

Effects of interventions

Ibuprofen versus placebo

Thirty four reports of 35 trials fulfilled our inclusion criteria; 2214 patients were given ibuprofen and 1377 placebo.

Twenty five trials (71%) investigated oral surgery pain (predominantly third molar extraction with bone removal), five trials investigated postpartum pain (predominantly episiotomy and Caesarean section) and four trials investigated postoperative pain (one tonsillectomy, one inguinal hernia, one orthopaedic surgery and one general surgery). Median quality score was 4 (2 to 5), 70% scoring 4 or 5.

One trial (Parker 1986) used a syrup formulation of ibuprofen, two trials (Seymour 1991(study1), OR CHECK Seymour 1991(study2), Seymour 1996) used soluble ibuprofen and liquid in gelatin capsules, two trials (Nelson 1994a OR CHECK Nelson 1994b; Mehlisch 1995) used ibuprofen lysine and two trials (Laveneziana 1996; Pagnoni 1996) used soluble ibuprofen arginine. When these more readily absorbed formulations were pooled and the results compared with those of the standard tablet formulation, no difference was found in relative benefit or NNT. The NNT for a single dose of ibuprofen 400 mg standard formulation tablets (1356 patients) compared with placebo was 2.8 (2.5 to 3.1) and for ibuprofen 400 mg soluble formulations (250 patients) the NNT was 2.5 (2.1 to 3.1). All formulations were therefore pooled for the overall analysis.

The pooled relative benefits for ibuprofen 100 mg, 200 mg, 400 mg and 600 mg were significantly different from placebo, as were the single data sets for ibuprofen 50 mg and 800 mg. The relative benefit (RB) and number-needed-to-treat (NNT) for at least 50% pain relief over 4 to 6 hours compared with placebo in pain of moderate to severe intensity is given below - numbers in brackets are the 95% confidence intervals:

50 mg RB 30 (1.8 to >480) NNT 3.6(2.5 to 6.1) No. of patients: 108

100 mg RB 18 (2.5 to >135) NNT 5.6 (3.8 to 9.9) No. of patients: 186

200 mg RB 4.7 (3.2 to 6.9) NNT 3.3 (2.8 to 4.0) No. of patients: 707

400 mg RB 3.4 (3.0 to 3.9) NNT 2.7 (2.5 to 3.0) No. of patients: 2817

600 mg RB 2.0 (1.6 to 2.6) NNT 2.4 (1.9 to 3.3) No. of patients: 203

800 mg RB 2.6 (1.8 to 4) NNT 1.6 (1.3 to 2.2) No. of patients: 76

Adverse effects
Drug-related study withdrawals occurred rarely. One study (Fricke 1993) had one withdrawal on ibuprofen for vomiting which the authors did not attribute to the medication. One study (Seymour 1996) had three withdrawals on ibuprofen and one on placebo for vomiting soon after ingestion of study drug. Another study (Parker 1986) had one patient who withdrew on placebo. The studies reported a variable incidence of minor adverse events which were all mild and transient, with no difference in incidence between ibuprofen and placebo.

Relative risk estimates were calculated for ibuprofen 400 mg versus placebo for the most commonly reported adverse effects ('drowsiness'/'somnolence', 'dizziness', headache, nausea and vomiting). This pooled data showed no significant difference between ibuprofen and placebo for any adverse effect except drowsiness/somnolence which was significantly different, with an NNH of 19 (12 to 41).

Diclofenac versus placebo

Six trials fulfilled our inclusion criteria (528 patients were given diclofenac and 312 placebo). Five trials (83%) investigated oral surgery pain (third molar extraction with bone removal) and one pain following gynaecological surgery. Doses of diclofenac were 25 mg in one trial, 50 mg in six and 100 mg in three. Three trials used an immediate release diclofenac potassium formulation (Hebertson 1994; Mehlisch 1994; Nelson 1994b) and two used dispersible diclofenac (Ahlstrom 1993, Bakshi 1994). One trial used both the immediate release and enteric coated formulations (Bakshi 1992). To ensure comparability only the data from the immediate release formulation were included. Median quality score was 3 (2 to 4), four trials scoring 3.

Pooled relative benefit for diclofenac versus placebo was significant at all doses. The relative benefit (RB) and NNT for at least 50% pain relief over 4 to 6 hours compared with placebo in pain of moderate to severe intensity is given below - numbers in brackets are the 95% confidence intervals:

25 mg RB 5.8 (2.1 to 15) NNT 2.6 (1.9 to 4.5) No. of patients: 100

50 mg RB 3.4 (2.7 to 4.4) NNT 2.3 (2.1 to 2.7) No. of patients: 636

100 mg RB 7.7 (4.5 to 13) NNT 1.8 (1.5 to 2.1) No. of patients: 308

Adverse effects
Drug-related study withdrawals occurred rarely. One study (Hebertson 1994) had one withdrawal on diclofenac 100 mg for nausea and vomiting. The studies reported a variable incidence of minor adverse events none of which were serious and with no difference in incidence between diclofenac and placebo.

Only two studies (Bakshi 1992, Nelson 1994b) provided data which could allow calculation of the relative risk associated with the most commonly reported adverse effects. Diclofenac 50 mg was not significantly different from placebo for 'dizziness' (97 patients), headache (100), nausea (97) or vomiting (97). Neither of the studies reported 'drowsiness' or 'somnolence'.

Diclofenac versus ibuprofen
(Numbers in brackets are the 95% confidence intervals)

There were two direct comparisons of diclofenac 50 mg and ibuprofen 400 mg (Ahlstrom 1993, Bakshi 1994). Both trials were in dental pain (third molar removal); 118 patients received diclofenac and 112 ibuprofen. There was no significant difference between diclofenac 50 mg and ibuprofen 400 mg (relative benefit 1.0 (0.9 - 1.2)).

Sensitivity analyses for trial size and quality score
(Numbers in brackets are the 95% confidence intervals)

There were 34 studies of ibuprofen 400 mg. The NNT for trials with 30 or fewer patients given ibuprofen was 2.4 (2.0 to 3.0; 206 patients), compared with 2.8 (2.5 to 3.1; 1400 patients) for trials with more than thirty patients on ibuprofen (z = 1.1). The NNT for trials with quality score of less than 4 was 2.5 (2.2 to 3.0; 449 patients), compared with 2.8 (2.5 to 3.1; 1157 patients) for trials with quality score of 4 or 5 (z = 1.2).

Discussion

A single dose of ibuprofen 400 mg had an NNT of 2.7 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 ibuprofen which they would not have had with placebo. The equivalent NNTs for ibuprofen 200 and 600 mg were 3.3 and 2.4 and those for diclofenac 25, 50 and 100 mg were 2.6, 2.3 and 1.8 respectively. There was therefore, a dose-response for both drugs although the confidence intervals overlapped. Sensitivity analyses did not show significant bias from small trials or trials of lower quality (Khan 1996, Moore 1998).

Some of the problems of direct and indirect treatment comparisons have been highlighted recently by Bucher and colleagues (Bucher 1997). For two of the most frequently prescribed analgesics there appear to be few direct comparisons. However, indirect comparisons against placebo involved 3,591 patients for ibuprofen and 840 for diclofenac. Therefore, the weight of evidence seems to favour the indirect comparison, but our results suggest that there was no conflict between the results of the two approaches - there was no difference at standard doses.

Single trials of non-steroidal anti-inflammatories have often reported flat dose-response curves. With the much larger numbers of patients in the meta-analysis a dose-response of conventional shape is shown for these drugs (this is illustrated in the previous publication of this review (Collins 1998). Diclofenac is widely regarded as a more effective NSAID than ibuprofen, but our results suggest that dose must be taken into account, Diclofenac 50 mg was 'better' than ibuprofen 400 mg, but 'the same as' ibuprofen 600 mg. Both drugs were tested predominantly in oral surgery pain (over 70% of studies), so that type of surgery is unlikely to be a confounding factor. The issue of the relative efficacy of the two drugs therefore comes down to dose. 400 mg of ibuprofen is only one sixth of the maximum daily dose whilst 50 mg of diclofenac is one third. This difference in 'standard doses' may explain prescriber confusion.

These results came from single dose studies reporting minimal adverse effects. In chronic dosing ibuprofen has been shown to be safer than diclofenac (Henry 1996) but this may be a reflection of the dosage. What remains unknown is whether giving higher doses of oral NSAIDs to relieve pain after surgery is significantly less safe than giving smaller doses. In chronic dosing all current non-steroidal anti-inflammatories carry some gastrointestinal toxicity. If COX2 anti-inflammatories deliver their promise of reduced gastrointestinal toxicity we may be able to exploit higher doses safely to produce better pain relief. Analysis of specific adverse events indicated a significant difference in the occurrence of drowsiness/somnolence for ibuprofen 400 mg when compared with placebo. There appears to be no biological explanation for this finding and the absolute number of events was small (35/446 ibuprofen; 12/478 placebo). The effect was not due to general anaesthesia as nine of the ten trials reporting this adverse effect used a local anaesthetic. Central nervous system effects of single dose ibuprofen have been reported before (Furey 1992, Max 1988) and somnolence has also been reported for naproxen, again primarily in dental studies (DeArmond 1995). Whether this adverse effect may also occur with diclofenac remains unknown as there was insufficient data available from the six trials.

From this analysis there is no difference between the single dose efficacy of ibuprofen and diclofenac. Choosing between them is a matter of safety and cost. In the UK, generic ibuprofen 400 mg costs 1p (one pence), generic diclofenac 50 mg costs 6p (six pence). If all the generic diclofenac 50 mg tablets dispensed in 1996 had been supplied as ibuprofen 400 mg, the savings would have been £5.2 million (GSS 1997). This simplistic calculation excludes any brand to generic savings.

Finally, it is possible to compare the NNTs for ibuprofen and diclofenac with NNTs for other analgesics obtained from quantitative systematic reviews with identical inclusion criteria thus creating a ladder of analgesic efficacy.

A regularly updated version of this ladder is available from the authors and in 1999 will appear on the following web site: http://www.ebandolier.com. This evidence supports clinical experience showing paracetamol 1000 mg (NNT 4.6 (3.8 to 5.4)) has a similar analgesic efficacy to aspirin 1000 mg (NNT 4.0 (3.2 to 5.4)). Ibuprofen 400 mg and diclofenac 50 mg have a lower (better) NNT than both. These two NSAIDs are also more effective than several other commonly used analgesics including some with an opioid component eg dextropropoxyphene 65 mg plus paracetamol 650 mg (NNT 4.4 (3.5 to 5.6)), tramadol 100 mg (NNT 4.8 (3.8 to 6.1)) and dihydrocodeine 30 mg (NNT 9.7 (4.5 to >10000)).

(Numbers in brackets are the 95% confidence intervals).

Authors' conclusions

Implications for practice

The results confirm that both ibuprofen and diclofenac are effective analgesics for postoperative pain with a low incidence of adverse effects. This analysis indicates there is no real difference between the single dose efficacy of ibuprofen and diclofenac. The relative efficacy of the two drugs comes down to dose, 50 mg of diclofenac may provide better analgesia than 400 mg of ibuprofen but it is one third of the maximum daily dose whereas ibuprofen 400 mg is only one sixth. At 600 mg ibuprofen appears to work as well as diclofenac 50 mg yet the dose is still a lower proportion of the maximum daily allowance. Choosing between them therefore appears to be a matter of dose, safety and cost. Ibuprofen has been reported as having a lower incidence of adverse effects (Henry 1996) but this again may be a reflection of the dosage used, it is also usually cheaper.

Implications for research

Four studies which we suspected were RCTs were excluded from this review as the authors had failed to adequately describe their methods. This highlights the need to improve the quality of reporting. Unless the methods used are adequately described not only is meta-analysis hampered but the reader is unable to make an informed decision as to the validity and relevance of the reported results. Also, the standard of reporting of adverse effects was low, with often only a vague statement being made. However, from the papers adequately reporting adverse effects there appears to be a significantly increased incidence of 'drowsiness'/'somnolence' with ibuprofen when compared with placebo: currently there appears to be no biological explanation for this.

Acknowledgements

We would like to thank Clare Abbott at the Cairns Library, Churchill Hospital for her unstinting help and support; and Catherine Strong (Novartis medical information services) and Darren Bloore (Knoll library) for their help in obtaining papers which were not held at any UK location.

Data and analyses

Download statistical data

Comparison 1. Ibuprofen 50 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 1.1.

Comparison 1 Ibuprofen 50 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 2. Ibuprofen 100 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief2186Risk Ratio (M-H, Fixed, 95% CI)18.61 [2.47, 140.08]
Analysis 2.1.

Comparison 2 Ibuprofen 100 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 3. Ibuprofen 200 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief8707Risk Ratio (M-H, Fixed, 95% CI)4.73 [3.15, 7.10]
Analysis 3.1.

Comparison 3 Ibuprofen 200 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 4. Ibuprofen 400 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief312817Risk Ratio (M-H, Fixed, 95% CI)3.47 [3.02, 3.97]
2 No. pts. with drowsiness, sleepiness or somnolence11924Risk Ratio (M-H, Fixed, 95% CI)2.77 [1.57, 4.89]
3 No. pts. with dizziness6517Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.26, 2.30]
4 No. pts. with headache9723Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.53, 2.39]
5 No. pts. with nausea8688Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.53, 2.83]
6 No. pts. with vomiting2141Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.13, 3.64]
Analysis 4.1.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Analysis 4.2.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 2 No. pts. with drowsiness, sleepiness or somnolence.

Analysis 4.3.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 3 No. pts. with dizziness.

Analysis 4.4.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 4 No. pts. with headache.

Analysis 4.5.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 5 No. pts. with nausea.

Analysis 4.6.

Comparison 4 Ibuprofen 400 mg V placebo, Outcome 6 No. pts. with vomiting.

Comparison 5. Ibuprofen 600 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief3203Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.49, 2.46]
Analysis 5.1.

Comparison 5 Ibuprofen 600 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 6. Ibuprofen 800 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief176Risk Ratio (M-H, Fixed, 95% CI)2.59 [1.72, 3.89]
Analysis 6.1.

Comparison 6 Ibuprofen 800 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 7. Diclofenac 25 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief1100Risk Ratio (M-H, Fixed, 95% CI)5.75 [2.14, 15.42]
Analysis 7.1.

Comparison 7 Diclofenac 25 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Comparison 8. Diclofenac 50 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief6636Risk Ratio (M-H, Fixed, 95% CI)3.43 [2.69, 4.39]
2 No. pts. with dizziness197Risk Ratio (M-H, Fixed, 95% CI)2.71 [0.11, 64.96]
3 No. pts. with headache1100Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.05, 5.34]
4 No. pts. with nausea2197Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.17, 5.53]
5 No. pts with vomiting197Risk Ratio (M-H, Fixed, 95% CI)2.71 [0.11, 64.96]
Analysis 8.1.

Comparison 8 Diclofenac 50 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Analysis 8.2.

Comparison 8 Diclofenac 50 mg V placebo, Outcome 2 No. pts. with dizziness.

Analysis 8.3.

Comparison 8 Diclofenac 50 mg V placebo, Outcome 3 No. pts. with headache.

Analysis 8.4.

Comparison 8 Diclofenac 50 mg V placebo, Outcome 4 No. pts. with nausea.

Analysis 8.5.

Comparison 8 Diclofenac 50 mg V placebo, Outcome 5 No. pts with vomiting.

Comparison 9. Diclofenac 100 mg V placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No. pts. with >50% pain relief3308Risk Ratio (M-H, Fixed, 95% CI)7.69 [4.51, 13.11]
Analysis 9.1.

Comparison 9 Diclofenac 100 mg V placebo, Outcome 1 No. pts. with >50% pain relief.

Appendices

Appendix 1. Search strategy

Exact search strategy used for ibuprofen:
('ibuprofen' OR 'brufen' OR 'propionic acid' OR 'isobutylphenyl propionic acid')
AND
('random*' OR 'double blind' OR 'double-blind' OR 'clinical trial' OR 'trial' OR 'study' OR 'report' )
AND
('analgesi*' OR 'pain*' OR 'postoperative' OR 'post-operative')

Exact search strategy used for diclofenac:
('diclofenac' OR {76 brand names eg voltarol (Reynolds 1996)})
AND
('random*' OR 'double blind' OR 'double-blind' OR 'clinical trial' OR 'trial' OR 'study' OR 'report' )
AND
('analgesi*' OR 'pain*' OR 'postoperative' OR 'post-operative')

What's new

DateEventDescription
12 November 2008AmendedContact details updated

History

DateEventDescription
23 May 2008AmendedConverted to new review format.
25 January 2002AmendedNew studies found but not yet included or excluded

Declarations of interest

None known

Sources of support

Internal sources

  • Oxford Pain Research funds, UK.

External sources

  • NHS R&D Health Technology Evaluation programmes (#93/31/4 and #94/11/4), UK.

  • European Union Biomed 2 Grant no. BMH4 CT95 0172, UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ahlstrom 1993

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Evaluated at 0, 20, 40 mins 1hr then hourly intervals for 6 hrs. Medication taken when baseline pain was at least moderate intensity (>30mm).
ParticipantsThird Molar Extraction
n = 127
Age: 18 - 40
InterventionsIbuprofen (400mg) n= 32
Diclofenac (50mg) Drinkable n= 35
Placebo n= 30
OutcomesPI (VAS scale)
"no Pain at all"- "Agonising pain"
Global Rating by patient
Ibuprofen was significantly superior to Placebo by 40mins (p=0.01) this continued for 6hrs. TOTPI & SPID; Ibuprofen & diofenac were significantly superior to placebo (p<0.0001).
Notes

Patients were allowed to remedicate after 1 hr. After remedication PI = last score was carried forward for all further timepoints. 97 analysed. Exclusions: 30 for various protocol violations.

No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 3/32 with ? AE
Diclofenac 6/35 with ? AE
Placebo 2/30 with ? AE
QS = 4

Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Arnold 1990

MethodsRCT, DB, single oral dose, parallel groups. Assessed by single nurse observer at 0, 0.5, 1hr then hourly intervals for 6 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsGeneral surgery (inc. gynaecological & orthopaedic)
n= 59
Age: 22 - 70
InterventionsIbuprofen (400mg) n = 15
Placebo n = 14
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
Time to meaningful relief
Global Rating (5pt scale) by patient
Ibuprofen was not significantly superior to placebo for either SPID or TOTPAR.
NotesAfter remedication PR =0 and PI =baseline score for all further timepoints. No information given on any exclusions. The difference in occurrence of adverse events was not significant between groups. No patient withdrew from either the ibuprofen or placebo group as a result of adverse events.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Bakshi 1992

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Self-assessed at 0, 15, 30mins, 1hr then hourly intervals for 6 hrs. Medication taken when baseline pain was of at least moderate intensity.
ParticipantsThird Molar Extraction
n=180
Age: Adults
InterventionsDiclofenac potassium (50mg) - sugar coated n= 51
Diclofenac sodium (50mg) - enteric coated n= 54
Placebo n= 46
OutcomesPI (4pt scale) - Standard
PR (4pt scale) - Non standard
50% PR (y/n)
Global Rating (4pt scale) by patient
Diclofenac K was significantly superior to placebo for SPID, TOTPAR, MAXPID & MAXPAR (p<0.001). Diclofenac Na was significantly superior to placebo for SPID (p=0.023) and MAXPID (p=0.018)
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR =0 and PI = last score or baseline (whichever was greater) for all further timepoints. 151 analysed.
Exclusions: 26 did not require medication and 3 were lost to follow up. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Diclofenac K 3/51 with 5 AE
Diclofenac Na 1/54 with 1 AE
Placebo 3/46 with 3 AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Bakshi 1994

MethodsRCT, DB, single oral dose, parallel groups. LA. Self-assessed at 0, 20 mins, 40mins, 1hr, 1.5 hrs, 2 hrs then hourly intervals for 6 hrs. Medication taken when baseline pain was of at least severe intensity.
ParticipantsThird Molar Extraction
n=257
Age: Adults up to 65
InterventionsIbuprofen (400mg) n = 80
Diclofenac (50 mg) dispersible n = 83
Placebo n = 82
OutcomesPI (VAS scale) -"no Pain - pain could not be worse"
PR (5pt scale) - (none, poor, mod., sufficient, total)
Global Rating (5pt scale) by patient and by observer
Ibuprofen & diclofenac were significantly superior to placebo for TOTPAR and both global ratings (p<0.01).
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR =0 and PI = last score for all further timepoints. 245 analysed. Exclusions: 9 did not experience severe pain, 2 remedicated before 1 hr, 1 completed the diaries incorrectly. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 6/80 with ? AE
Diclofenac 4/83 with ? AE
Placebo 5/82 with ? AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Cooper 1977

MethodsRCT, DB, single oral dose, parallel groups. LA. Self-assessed at home at 0 then hourly intervals for 4 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 245
Age: ?
InterventionsIbuprofen (400mg) n= 40
Ibuprofen (200mg) n= 38
Placebo n= 40
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen at both doses was significantly superior to placebo for all measures of efficacy (p<0.05)
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline score for all further timepoints. 192 analysed. Exclusions: 17 provided uninterpretable data, 12 took confounding medication, 10 were lost to follow up, 9 did not need medication, 5 fell asleep. No serious adverse events were reported and no patient withdrew as a result of adverse events. No individual data was provided but there was no significant difference in occurrence between groups.
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Cooper 1982

MethodsRCT, DB, single oral dose, parallel groups. Mostly LA. Self-assessed at home at 0 then hourly intervals for 4 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 316
Age: 16 - 65
InterventionsIbuprofen (400mg) n=38
Placebo n=46
Ibuprofen (400mg) + Codeine (60mg)n= 41
Codeine (60mg) n= 41
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
All active treatments were significantly superior to placebo for SPID & TOTPAR (no p value given).
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline score for all further timepoints. 249 analysed. Exclusions: 30 were lost to follow up, 15 did not req. medication, 11 remedicated before 1 hr, 6 missed more than 1 evaluation, 3 medicated with slight pain, 1 did not take all the medication, 1 medicated over 24hrs after surgery. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 11/38 with 12 AE
Placebo 5/46 with 6 AE
Ibuprofen + Codeine 18/41 with 20 AE
Codeine 11/41 with 11 AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Cooper 1988a

MethodsRCT, DB, single oral dose, parallel groups. LA + sedative. Self-assessed at home at 0 then hourly intervals for 6 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n=201
Age: Adults
InterventionsIbuprofen (400mg) n=37
Placebo n=43
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of efficacy (p<0.01).
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline score for all further timepoints. 161 analysed. Exclusions: 20 did not req. medication, 13 were lost to follow up, 7 for various protocol violations. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 10/40 with 14 AE
Placebo 7/45 with 7 AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Cooper 1989

MethodsRCT, DB, single oral dose, parallel groups. LA. Self-assessed at home at 0, 0.5, 1hrs then hourly intervals for 6 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 194
Age: 16 +
InterventionsIbuprofen (400mg) n= 61
Placebo n= 64
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of efficacy (p<0.001)
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. No details on how the data was handled for remedication. 184 analysed. Exclusions: 2 were lost to follow up, 2 did not req. medication, 4 missed more than 1 evaluation, 1 had insufficient baseline pain, 1 failed to complete the diary at the appropriate time. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 5/63 with 6 AE
Placebo 7/64 with 7 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Forbes 1984

MethodsRCT, DB, single oral dose, parallel groups. GA. Self-assessed at home at 0 then hourly intervals for 12 hrs. Medication taken when baseline pain was of moderate to severe intensity. Follow up 5 days post surgery with the research nurse.
ParticipantsThird Molar Extraction
n= 136
Age: 15 +
InterventionsIbuprofen (400mg) n= 28
Placebo n= 28
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of efficacy (p<0.01)
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 109 analysed. Exclusions: 21 did not req. medication, 2 took rescue medication instead of the trial medication, 2 remedicated despite having some relief, 2 remedicated before 2 hrs. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Ibuprofen 5/28 with 6 AE
Placebo 3/28 with 3 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Forbes 1990

MethodsRCT, DB, single then multiple oral dose, parallel groups. GA / LA - unclear. Self assessed at home at 0,1 then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity. Follow up 5 days post surgery.
ParticipantsThird Molar Extraction
n=269
Age 15 +
InterventionsIbuprofen (400mg) n= 32
Placebo n= 34
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of analgesia (p<0.05 at least).
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 206 analysed. Exclusions; 3 lost to follow up, 1 lost report card, 22 did not req. med., 8 remed despite having relief from study med., 6 remed with only slight pain, 13 remed < 2hrs, 7 failed to follow instructions , 3 did not complete the forms. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 8/43 with 9 AE
Placebo 0/38 with 0 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Forbes 1991a

MethodsRCT, DB, single oral dose, parallel groups. LA. 4hr caffeine washout prior to start. Self-assessed at 0, 0.5,1hr then hourly intervals for 8 hrs. Med taken when baseline pain was mod-severe. Follow up 5 days post surgery . Multi-centre (2 sites).
ParticipantsThird Molar Extraction
n= 395
Age: 15 +
InterventionsIbuprofen (50mg) n= 57
Ibuprofen (100mg) n= 49
Ibuprofen (200mg) n= 48
Placebo n= 51
Ibuprofen (100mg) + Caffeine(100mg) n= 49
Ibuprofen (200mg) + Caffeine(100mg) n= 44
OutcomesPI (4pt scale) - Standard
PR (5pt scale) - Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
All Ibuprofen treatments were sig. superior to placebo for all measures (p<0.05 at least)
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 298 analysed. Exclusions: 33 did not req. med, 14 remed < 2 hrs, 1 ate caffeine containing food, 2 med for a headache, 1 rated only one side of mouth, 1 form completed by relative, 3 lacked consistency, 22 evaluated at incorrect time, 3 incomplete forms. No serious AE were reported and no patient withdrew as a result of adverse events.
Ibu 50 10/63 with 15 AE
Ibu 100 5/62 with 6 AE
Ibu 200 6/60 with 6 AE
Placebo 8/61 with 8 AE
100mg Caff Combo 12/58 with 15 AE
200mg Caff Combo 8/58 with 9 AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Forbes 1991b

MethodsRCT, DB, single oral dose, parallel groups. LA. Self assessed at home at 0,1 then hourly for 8 hours. Medication taken when baseline pain was of moderate to severe intensity. Follow up 5 days post surgery.
ParticipantsThird Molar Extraction
n= 288
Age 15 +
InterventionsIbuprofen (400mg) n= 37
Placebo n= 39
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of efficacy(p<0.05 at least)
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 241 analysed. Exclusions: 7 were lost to follow up, 12 did not req. med., 4 remed with some relief, 1 remed with slight pain, 19 remed before 2 hours, 2 lacked consistency, 1 did not complete the form, 1 took only part of the med. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 7/43 with 8 AE
Placebo 3/47 with 3 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Forbes 1992

MethodsRCT, DB, single oral dose, parallel groups. LA. Self assessed at home at 0,1 then hourly for 8 hours. Medication taken when baseline pain was of moderate to severe intensity. Follow up 5 days post surgery.
ParticipantsThird Molar Extraction
n= 338
Age 15 +
InterventionsIbuprofen (400mg) n= 38
Placebo n= 38
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of efficacy(p<0.01).
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 280 analysed. Exclusions; 3 did not return form, 14 did not req. med., 4 remed despite some relief, 6 remed with slight pain, 18 remed before 2 hrs, 2 lacked consistency, 2 did not complete form, 2 took only part of med., 5 took back up med., 2 were off the evaluation schedule. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 4/45 with 8 AE
Placebo 2/46 with 5 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Frame 1989

MethodsRCT, DB, single oral dose, parallel groups. LA. Self assessed at home at 0, 0.5, 1 then hourly for 5 hours. Medication taken when baseline pain was of at least moderate intensity.
ParticipantsThird Molar Extraction
n= 148
Age 16 +
InterventionsIbuprofen (400mg) n= 42
Placebo n= 38
OutcomesPI (9pt scale)- Non Standard
PR (5pt scale)- Standard
50% PR (y/n)
At 2 and 3 hours Ibuprofen was significantly superior to placebo.
NotesPatients were allowed to remedicate after 2 hrs.
No information provided on how data was handled for patients who remedicated. 123 analysed. Exclusions: 9 did not take the medication, 7 were lost to follow up, 1 was asleep so did not complete the forms, 1 had complications so did not complete the form, 7 had slight pain. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 2/42 with 2 AE
Placebo 1/38 with 3 AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Fricke 1993

MethodsRCT, DB, single oral dose, parallel groups. 72 hr washout prior to start. LA. Self assessed at home at 0, 20, 30, 40, 60min then hourly for 12 hours. Medication taken when baseline pain was of moderate intensity. Review 1/2 days after the trial.
ParticipantsThird Molar Extraction
n= 207
Age 15 +
InterventionsIbuprofen (400mg) n= 81
Placebo n= 39
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
50% PR (y/n)
PI (VAS) - no pain to worst pain imaginable
Ibuprofen was significantly superior to placebo for all measures after 30 mins.
NotesPatients were allowed to remedicate after 2 hrs. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 201 analysed. Exclusions: 1 took the medication twice, 5 had insufficient pain. No serious AE were reported and 1 patient in the ibuprofen group withdrew as a result of vomiting which the investigators did not attribute to the medication.
# patients reporting AE;
Ibuprofen 8/81 with 13 AE
Placebo 1/39 with 1 AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Gay 1996

MethodsRCT, DB, single oral dose, parallel groups. 12 hr washout prior to start. LA. Self assessed at "regular intervals" for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 206
Age 18 - 60
InterventionsIbuprofen (400mg) n= 41
Placebo n= 39
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
PI (VAS) - no pain to worst pain imaginable
Ibuprofen was significantly superior to placebo for all summary measures of analgesia (p< 0.05).
NotesPatients were allowed to remedicate after 1 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 194 analysed. Exclusions: 2 remedicated before 1 hour, 10 failed to complete the assessments within 15 mins of the scheduled time. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 3/41 with 3 AE
Placebo 4/41 with 7 AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Hebertson 1994

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Assessed by observer at 0, 0.5, 1hr then hourly intervals for 8 hrs. Medication taken when baseline pain was of moderate to severe intensity and groups stratified by baseline PI.
ParticipantsGynaecological Surgery
n= 217
Age 16+
InterventionsDiclofenac (50 mg) n= 52
Diclofenac (100 mg) n= 52
Placebo n= 52
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
Both diclofenac doses were significantly superior to placebo for pain relief at each timepoint from 1hr onwards.
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before their data was excluded from the efficacy analysis. After remedication the patients were discontinued but no information was given on how their data was then handled. 209 analysed for at least 1 efficacy analysis. 194 analysed for 8 hr SPID & TOTPAR.
No information given on any exclusions. All AE’s were Gastro-intestinal except 1 in the placebo group (not defined), 1 withdrew from Diclo 100mg for nausea and vomiting.
# Patients reporting AE;
Diclofenac 50mg 3/54 with ? AE
Diclofenac 100mg 2/55 with ? AE
Placebo 2/54 with ? AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Heidrich 1985

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Assessed by trained nurse observer at 0, 0.5, 1hr then hourly intervals for 6 hrs. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsOrthopaedic Surgery
n= 120
Age 18 - 65
InterventionsIbuprofen (400mg) n= 40
Placebo n= 40
OutcomesPI (4pt scale)
PR (5pt scale)
PI VAS "no relief" - "complete relief"
PI (VAS) - "no pain" - "worst pain imaginable"
Orthogonal analyses of variance showed ibuprofen produced greater relief from pain than placebo.
NotesNo information was given on patients who remedicated. No information given on any exclusions. "There were no differences among treatments in terms of side effects. No patient withdrew because of adverse events".
QS = 2
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Hersch 1993a

MethodsRCT, DB, single oral dose, parallel groups. 4 hr washout prior to start. LA. Self assessed at 0, 0.5, 1 then hourly for 8 hours (for the first 2 hours this was in the clinic). Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 254
Age 16 +
InterventionsIbuprofen (400mg) n= 49
Ibuprofen (200mg) n= 51
Placebo n= 51
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
Ibuprofen at both doses was significantly superior to placebo for all measures of analgesia (p< 0.05).
NotesPatients were allowed to remedicate after 1 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 254 analysed. No Exclusions. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 400 mg 6/49 with 7 AE
Ibuprofen 200 mg 4/51 with 4 AE
Placebo 9/51 with 9 AE
QS = 2
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Hersch 1993b

MethodsRCT, DB, pre-surgery placebo then single oral dose, parallel groups. LA. Self assessed at 0, 0.5, 1 then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 114
Age: Did not say
InterventionsPlacebo then Ibuprofen (400mg) n= 12
Placebo then Placebo n= 16
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all summary measures of analgesia.
NotesPatients were allowed to remedicate after 1 hrs. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. Patients were allowed to remedicate after 1 hrs. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 81 analysed.
Exclusions: 19 lost to follow up, 11 did not req. medication, 3 excluded for various protocol violations. No information was given on Adverse Events.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Jain 1986

MethodsRCT, DB, single oral dose, parallel groups. Self-assessed at home at 0, 1 then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 260
Age 18 - 65
InterventionsIbuprofen (400mg) n= 49
Ibuprofen (200mg) n= 47
Ibuprofen (100mg) n= 39
Placebo n= 47
OutcomesPI (4pt scale)- Standard wording but scale 1-4
PR (5pt scale)- Non Standard
Global Rating (5pt scale) by patient
PI (VAS) - "no pain" - "worst ever pain"
All doses of ibuprofen were significantly superior to placebo (p<0.001).
NotesPatients were allowed to remedicate after 1 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = last score for all further timepoints. 227 analysed. Exclusions: 10 remedicated before 1 hr, 19 did not take the medication or were lost to follow up, 2 had mild baseline pain, 1 missed >2 evaluations and 1 used confounding drugs. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 400 mg 10/? with 12 AE
Ibuprofen 200 mg 6/? with 8 AE
Ibuprofen 100 mg 13/? with 15 AE
Placebo 12/? with 15 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Jain 1988

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Assessed by trained nurse observer at 0, 0.5, 1 then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsEpisiotomy
n= 161
Age 18 +
InterventionsIbuprofen (400mg) n= 49
Placebo n= 48
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Time to meaningful relief
Global Rating (5pt scale) by patient
Overall improvement (7pt scale) by patient
Ibuprofen was significantly superior to placebo for most summary measures of analgesia (p<0.01).
NotesPatients were allowed to remedicate after 2 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 147 analysed. Exclusions: 11 remedicated before 2 hrs, 2 received confounding agents, 1 was under 18 yrs old. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 2/49 with 2 AE
Placebo 1/48 with 1 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Kiersch 1993

MethodsRCT, DB, single oral dose, parallel groups. 72 hr washout prior to start. Self assessed at home at 0, 20, 30, 40, 60min then hourly for 12 hours. Medication taken when baseline pain was of at least moderate intensity. Review 1/2 days after the trial.
ParticipantsThird Molar Extraction
n= 205
Age 15 +
InterventionsIbuprofen (200mg) n= 81
Placebo n= 42
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
PI (VAS) - no pain to worst pain imaginable
Ibuprofen was significantly superior to placebo for all summary measures of analgesia (p< 0.001).
NotesPatients were allowed to remedicate after 2 hrs. no information was given on how the data was then handled. 203 analysed. Exclusions: 2 for protocol violations. No serious AE were reported and no patient withdrew as a result of adverse events. # patients reporting AE;
Ibuprofen 16/81 with 20 AE
Placebo 5/43 with 5 AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Laska 1986

MethodsRCT, DB, single oral dose, parallel groups. 4hr washout prior to start. Self-assessed at 0, 0.5, 1 then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 200
Age 16 +
InterventionsIbuprofen (400mg) n= 39
Ibuprofen (600mg) n= 36
Ibuprofen (800mg) n= 39
Placebo n= 37
OutcomesPI (4pt scale)- Standard
PR (5pt scale)
Global Rating by patient
Blood serum levels
All three doses of ibuprofen were significantly superior to placebo for %SPID.
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline or last score (whichever was greater) for all further timepoints. 195 analysed. Exclusions: 4 remedicated before 1 hour and 1 vomited within 5 mins of taking the study medication. No patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 400mg 1/? with1 AE
Placebo 3/? with 3 AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Laveneziana 1996

MethodsRCT, DB, single oral dose, parallel groups. 6hr washout prior to start. Assessed in hospital at 0, 15, 30, 45, 60, 90mins, 2hrs then hourly for up to 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsPost-operative (inguinal hernia)
n= 125
Age 18 - 75
InterventionsIbuprofen arginine soluble (400mg) n= 42
Placebo n= 41
OutcomesPI (VAS) -"no pain" - "unbearable pain"
Global Rating (5pt scale) by patient
Patients with 61-80mm baseline pain - were significantly superior to placebo (p<0.05).Patients with >81mm baseline pain - no significant difference.
NotesPatients were allowed to remedicate after 1 hr. Patients were asked to wait until their pain returned to baseline intensity before remedicating but no information was given on how the data was then handled. 124 analysed. Exclusions: 1 patient for insufficient pain. No AE were reported.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

McQuay 1996a

MethodsRCT, DB, single oral dose, parallel groups. 12 hr washout prior to start. LA. Self assessed for 6 hours (did not say at what points). Medication taken if baseline pain was of moderate to severe intensity within 2 hours of surgery.
ParticipantsThird Molar Extraction
n= 218
Age 16 - 53
InterventionsIbuprofen (400mg) n= 30
Ibuprofen (200mg) n= 31
Placebo n= 11
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
PI (VAS) - no pain to worst pain imaginable
PR (VAS) - no relief to complete relief
Random 8 word scale
Mood (VAS)
Stopwatch to meaningful relief
Ibuprofen at both doses was significantly superior to placebo for all measures of analgesia.
NotesPatients were allowed to remedicate after 45 mins If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = baseline for all further timepoints. 161 analysed. Exclusions: 15 no pain, 10 concurrent illness, 7 analgesics within 48 hrs, 4 withdrew before study began, 4 did not attend, 3 previous NSAID allergy, 1 possible pregnancy, 1 migraine after surgery, 1 surgery cancelled, 3 remed before 45 mins. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 400 mg 2/30 with 3 AE
Ibuprofen 200 mg 4/31 with 4 AE
Placebo 1/11 with 1 AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mehlisch 1990

MethodsRCT, DB, single oral dose, parallel groups. 6hr washout prior to start. Self-assessed at 0, 0.5, 1hr then hourly for up to 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsVarious oral surgery procedures
n=706
Age 18 - 64
InterventionsIbuprofen (400mg) n= 306
Placebo n= 85
OutcomesPI (4pt scale)- Standard wording scale 1-4
PR (4pt scale)- Non standard
Ibuprofen was significantly superior for most summary measures of efficacy.
NotesPatients were allowed to remedicate. After remedication PR = 0 and PI=baseline score for all further timepoints. 697 analysed. Exclusions: 4 were lost to follow up, 4 were entered in the trial twice (1st entry only was analysed for efficacy but both were included in safety analysis) and 1 was excluded for failing to meet inclusion criteria.No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 31/310 with ? AE
Placebo 12/85 with ? AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mehlisch 1994

MethodsRCT, DB, single oral dose, parallel groups. LA. 4hr washout prior to start. Self-assessed at 0, 0.5, 1hr then hourly for up to 8 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 208
Age 16-70
InterventionsDiclofenac (50 mg) n= 53
Diclofenac (100 mg) n= 52
Placebo n= 52
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
NotesBoth Diclofenac groups were significantly superior to placebo for all timepoints with regard to pain relief. Patients were allowed to remedicate after 2hrs. After remedication PR = 0 and PI = last score for all further timepoints. There were no exclusions. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Diclofenac 50mg 2/53 with ? AE
Diclofenac 100mg 2/52 with ? AE
Placebo 2/52 with ? AE
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Mehlisch 1995

MethodsRCT, DB, single oral dose, parallel groups. 12 hr washout prior to start. LA. Self assessed at 0, 15, 30, 45, 60, 90 mins, 2 hrs then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 205
Age 15 +
InterventionsIbuprofen (400mg) n=98
Placebo n= 40
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of analgesia (p< 0.05).
NotesPatients were allowed to remedicate after 1 hrs (but were encouraged to wait for 4 hrs). If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR and PID = 0 for all further timepoints. 239 analysed. Exclusion: 1 patient only had 1 molar removed and failed to complete the diary. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 12/98 with ? AE
Placebo 4/40 with ? AE
QS = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Nelson 1994a

MethodsRCT, DB, single oral dose, parallel groups. 12 hr washout prior to start. LA. Self assessed at 0, 15, 30, 45, 60, 90 mins, 2 hrs then hourly for 6 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 183
Age 15 +
InterventionsIbuprofen (200mg) n= 75
Placebo n= 40
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
50% PR (y/n)
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for PR and PID from 30 mins to the end.
NotesPatients were allowed to remedicate after 1 hrs If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = 0 for all further timepoints. 180 analysed. Exclusions: 2 remed before 1 hour, 1 did not record baseline pain intensity. No serious AE were reported and no patient withdrew as a result of adverse events.
# patients reporting AE;
Ibuprofen 16/77 with ? AE
Placebo 11/41 with ? AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Nelson 1994b

MethodsRCT, DB, single oral dose, parallel groups. LA. 4hr washout prior to start. Self-assessed at 0, 0.5, 1hr then hourly for up to 8 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsThird Molar Extraction
n= 255
Age 16-70
InterventionsDiclofenac (25 mg) n= 51
Diclofenac (50 mg) n= 51
Diclofenac (100 mg) n= 51
Placebo n= 51
NB assumed an equal distribution 51 per group (inc aspirin group)
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
All diclofenac groups were significantly superior to placebo for pain relief from 1 hr onwards.
NotesPatients were allowed to remedicate at 1 hr, no information was given as to how their data was then handled. 252 analysed for at least 1 efficacy analysis. No exclusions other than remedicators were given. No serious adverse events were reported and no patient withdrew as a result of adverse events.
# Patients reporting AE;
Diclofenac 25mg 5 with ? AE
Diclofenac 50mg 4 with ? AE
Diclofenac 100mg 4 with ? AE
Placebo 6 with ? AE
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Pagnoni 1996

MethodsRCT, DB, single oral dose, parallel groups. 6 hr washout prior to start. GA. Assessed in hospital at 0, 15, 30, 45, 60, 90 mins, 2 hrs then hourly for 6 hours. Medication taken when baseline pain was >55mm.
ParticipantsCaesarean section
n= 92
Age 18+
InterventionsIbuprofen arginine soluble (400mg) n= 30
Placebo n= 32
OutcomesPI (VAS) -"no pain" - "unbearable pain"
Global Rating (5pt scale) by patient
The sum of PID and the mean AUC showed ibuprofen to be significantly superior to placebo (p<0.001) the mean peak PID value was also significantly superior to placebo (p<0.05).
NotesPatients were allowed to remedicate after 1 hr. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PI = last recorded value for all further timepoints. 92 analysed. Exclusions: none. No adverse events were reported.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Parker 1986

MethodsRCT, DB, single oral dose then multiple doses, parallel groups. GA. Assessed in hospital at 0, 0.5, 1 then hourly for 4 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsTonsillectomy
n= 139
Age: 16 - 66
InterventionsIbuprofen syrup (600mg) n= 44
Placebo n= 33
OutcomesPI (9pt scale)- Non Standard
PR (5pt scale)- Standard
50% PR (y/n)
Ibuprofen was significantly superior to placebo at 30mins and 1 hour.
NotesNo information was given on patients who remedicated. 110 analysed. No information was given on the 29 exclusions. No details were given on the adverse events occurring during the single dose. For the multiple doses 1 patient in the placebo group withdrew as a result of AE. The number of AE reported was similar for both groups.
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Schachtel 1989

MethodsRCT, DB, single oral dose then multiple doses, parallel groups. 4 hr washout prior to start. Assessed in hospital at 0, 0.5, 1 then hourly for 4 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsEpisiotomy
n= 115
Age: 16 - 37
InterventionsIbuprofen (400mg) n= 36
Placebo n= 38
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Standard
Global Rating (5pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of analgesia (p< 0.05) at least.
NotesPatients were allowed to remedicate after 1 hrs If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = last or baseline (which ever was greater) for all further timepoints. 111 analysed. Exclusions: 4 remedicated before 1 hour. No adverse events were reported.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Seymour 1991(study1)

MethodsRCT, DB, single oral dose, parallel groups. GA. Assessed in hospital by the same observer at 0, 10, 20, 30, 45, 60, 90 mins, 2 hrs then hourly for 6 hours. Medication taken when baseline pain was >30mm.
ParticipantsThird Molar Extraction
n= 205
Age Adults
InterventionsIbuprofen (400mg) tablets n= 31
Ibuprofen (400mg) liquid in gelatin capsules n= 32
Placebo n= 32
OutcomesPI (VAS) -"no pain" - "unbearable pain"
Global Rating (5pt scale) by patient
Both Ibuprofen were sig superior to placebo; no sig dif between the 2 active groups
NotesPatients were allowed to remedicate. After remedication PI = last score for all further timepoints. 187 analysed but claimed to have enrolled only 180? No serious AE were reported and no patient withdrew as a result of adverse events. Only 1 patient reported an adverse event, they were in the placebo group.
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Seymour 1991(study2)

MethodsRCT, DB, single oral dose, parallel groups. GA. Assessed in hospital by the same observer at 0, 10, 20, 30, 45, 60, 90 mins, 2 hrs then hourly for 6 hours. Medication taken when baseline pain was >30mm.
ParticipantsThird Molar Extraction
n= 205
Age Adults
InterventionsIbuprofen (400mg) tablets n= 30
Ibuprofen (400mg) soluble n= 32
Placebo n=30
OutcomesPI (VAS) -"no pain" - "unbearable pain"
Global Rating (5pt scale) by patient
Soluble Ibuprofen was sig superior to placebo from 20 mins; tablets from 30 mins.
NotesPatients were allowed to remedicate. After remedication PI = last score for all further timepoints. 187 analysed but claimed to have enrolled only 180? No serious AE were reported and no patient withdrew as a result of adverse events.
QS = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Seymour 1996

MethodsRCT, DB, single oral dose, parallel groups. GA. Assessed in hospital by nurse observer at 0, 10, 20, 30, 45, 60, 75, 90,120, 150 mins, 3 hrs then hourly for 6 hours. Medication taken when baseline pain was >30mm.
ParticipantsThird Molar Extraction
n= 148
Age Adults
InterventionsIbuprofen (600mg) tablets n= 17
Ibuprofen (600mg) soluble n= 17
Ibuprofen (400mg) tablets n= 15
Ibuprofen (400mg) soluble n= 16
Ibuprofen (200mg) tablets n= 18
Ibuprofen (200mg) soluble n= 17
placebo = 19
OutcomesPI (VAS) -"no pain" - "unbearable pain"
Global Rating (5pt scale) by patient
All Ibuprofen treatments except Ibuprofen 200mg resulted in significantly less pain than placebo for all efficacy measures (p<0.05).
NotesPatients were allowed to remedicate. After remedication PI = last score for all further timepoints. 199 analysed. Exclusions: 4 were excluded for "unwanted effects" and 25 failed to reach a sufficient baseline pain intensity. 4 patients reported adverse effects, 3 had received ibuprofen (did not clarify which dose) and 1 had taken placebo.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Sunshine 1983

MethodsRCT, DB, single oral dose, parallel groups. 4 hr washout prior to start. Assessed in hospital by the same observer at 0, 0.5, 1hrs then hourly for 4 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsEpisiotomy
n= 115
Age 18+
InterventionsIbuprofen (400mg) n= 30
Placebo n= 30
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Non-standard (percentages not descriptive wording)
Global Rating of medication (4pt scale) by patient
Global Rating of personal improvement (7pt scale) by patient
Ibuprofen was significantly superior to placebo for all measures of analgesia from 1 hr onwards.
NotesPatients were allowed to remedicate after 1 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = last for all further timepoints. 120 analysed. Exclusions: none. No patient reported any adverse effects.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Sunshine 1987

  1. a

    QS - quality score
    AE - adverse events
    PI - pain intensity
    PR - pain relief
    # - number

MethodsRCT, DB, single oral dose, parallel groups. 4 hr washout prior to start. Assessed in hospital by the same observer at 0, 0.5, 1hrs then hourly for 4 hours. Medication taken when baseline pain was of moderate to severe intensity.
ParticipantsEpisiotomy , caesarean section or gynaecological surgery
n= 200
Age Did not say
InterventionsIbuprofen (400mg) n= 38
Placebo n= 40
OutcomesPI (4pt scale)- Standard
PR (5pt scale)- Non-standard (percentages not descriptive wording)
Global Rating of medication (4pt scale) by patient
Global Rating of personal improvement (7pt scale) by patient
All active treatments were significantly superior to placebo for TOTPAR & all except Codeine for SPID.
NotesPatients were allowed to remedicate after 1 hrs. If they remedicated before then their data was excluded from the efficacy analysis. After remedication PR = 0 and PI = last for all further timepoints. 195 analysed. Exclusions: 1 had not complied with the washout period and 4 did not complete the evaluations. No adverse events were reported in either the placebo or ibuprofen groups.
QS = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment?Low riskA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ahlstrom 1989No placebo control.
Anaokar 1993No placebo control.
Apaydin 1994No placebo control.
Apiou 1988No placebo control.
Aranda 1989No placebo control.
Bailey 1993No placebo control.
Behotas 1992Baseline pain intensity was not moderate to severe.
Berthold 1993Intervention administered preoperatively. Therefore inadequate baseline pain.
Bertin 1991Participants included children.
Bhounsule 1990Did not state whether patients had a baseline pain of at least moderate intensity.
Biehl 1981No placebo control.
Bloomfield 1974Used 5 point pain intensity scale which is not validated for the data extraction method.
Bostrom 1994No placebo control.
Bridgman 1996No placebo control.
Calanchini 1991No placebo control.
Carlos 1984Could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals.
Carrillo 1990Did not state when the interventions were administered but as the pain levels were recorded for the first 4 hours following surgery it may be assumed that they were given immediately postoperatively. Therefore insufficient baseline pain.
Cooper 1984Inadequate description of method. Did not state whether interventions were randomly allocated or studies were double-blind.
Cooper 1988bInadequate description of method. Did not state whether interventions were randomly allocated.
Cooper 1993No placebo control.
Dahl 1994Intervention administered preoperatively. Therefore inadequate baseline pain.
Dahl 1995Baseline pain intensity not moderate to severe.
Darsow 1988No direct pain outcome measured over the first 4-6 hours (recorded motility etc in the days following surgery).
Dionne 1978Intervention administered preoperatively. Therefore inadequate baseline pain.
Dionne 1983Intervention administered preoperatively. Therefore inadequate baseline pain.
Dorfmann 1991Inadequate description of method. Did not say whether the allocation was randomised, did not say when the interventions were administered postoperatively, no mention of the level of baseline pain and did not define the pain measurement used.
El-Tanany 1993No placebo control.
Fell 1991Abstract
Fleiss 1979Take medication "if experience pain". Cannot assume that all the patients included had a baseline pain of >moderate intensity.
Forbes 1991Used a controlled release formulation of ibuprofen.
Frezza 1985Could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals.
Gallardo 1980Baseline pain intensity not moderate to severe.
Gallardo 1981Data was only collected for three hours.
Garwood 1983No placebo control.
Giles 1981No placebo control.
Giles 1985Did not state which scale was used.
Giles 1986Patients continued to complete the diaries following re-medication with rescue analgesics, thus invalidating the results.
Gillberg 1991Abstract.
Gillberg 1993Intervention administered preoperatively. Therefore inadequate baseline pain.
Habib 1990No placebo control.
Hay 1985Multiple dose study with no separate analysis of the first dose.
Hazra 1982Baseline pain intensity not moderate to severe.
Hellman 1992No placebo control.
Henderson 1994No placebo control.
Henrikson 1982Only presented the data for the placebo arm for the first hour.
Henrikson 1985No placebo control.
Higgins1994Intervention administered preoperatively. Therefore inadequate baseline pain.
Hill 1987Intervention administered preoperatively. Therefore inadequate baseline pain.
Hopkinson 19805 point pain intensity scale and 5 point pain relief scale (including "worse") neither of which are validated for the data extraction method used. Global evaluation was the opinion of the investigators rather than the patient.
Hultin 1978Cross-over study with the first dose administered exactly 1 hour after the local anaesthetic rather than when the patient experienced at least moderate pain.
Hyrkas 1992Intervention administered preoperatively. Therefore inadequate baseline pain.
Hyrkas 1993Intervention administered preoperatively. Therefore inadequate baseline pain.
Hyrkas 1994Intervention administered preoperatively. Therefore inadequate baseline pain.
Iles 1980Data was only presented for one hour after administration of the interventions.
Iqbal 1986Could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals.
Iwabuchi 1980No placebo control.
Joubert 1977Could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals.
Kantor 1991Abstract.
Katharia 1992Multiple dose study with no separate analysis of the first dose.
Khan 1992No placebo control.
Kittala 1972Intervention routinely administered to all participants irrespective of level of baseline pain.
Klein 1994Abstract.
Kokki 1994Participants included children.
Lokken 1975aIntervention administered preoperatively. Therefore inadequate baseline pain.
Lokken 1975bIntervention administered preoperatively. Therefore inadequate baseline pain.
Mastronardi 1988No placebo control.
Matthews 1984First dose was administered immediately postoperatively irrespective of patients level of pain.
McEvoy 1996No placebo control.
McGraw 1987Participants included children.
McQuay 1989No placebo control.
McQuay 1992No placebo control.
McQuay 1993No placebo control.
Moore 1985Participants included children.
Morrison 1994No placebo control.
Movilia 1990First dose was administered immediately postoperatively irrespective of patients level of pain.
Naidu 1994No placebo control.
Nakanishi 1990No placebo control.
Needle 1976Abstract.
Negm 1989Included participants who took the medication when they were experiencing only mild pain.
Ngan 1994Baseline pain intensity not moderate to severe.
Norman 1985Patients continued to complete the questionaires following re-medication with rescue analgesics, thus invalidating the results.
Olstad 1986Baseline pain intensity not moderate to severe.
Pandit 1987No placebo control.
Petersen 1993Baseline pain intensity not moderate to severe.
Rondeau 1980Baseline pain intensity not moderate to severe.
Rosenblum 1991Intervention administered preoperatively. Therefore inadequate baseline pain.
Rossi 1981Inadequate description of method. Did not state whether study was double blind. Also data was only recorded for three hours.
Schachtel 1993Participants included children.
Seymour 1990Abstract.
Shimura 1981No placebo control.
Squires 1981Intervention administered preoperatively. Therefore inadequate baseline pain.
Sunshine 1990Abstract.
Tai 1992No placebo control.
Taina 1981Multiple dose study with no separate analysis of the first dose.
Tani 1974No placebo control.
Tesseroli 1986The only measure of pain which was in the opinion of the patient rather than the investigator was the pain intensity VAS. At baseline, the mean VAS minus 1.96xSD was less than 30mm, therefore some patients included may have had a baseline pain intensity of less than moderate.
Torabinejad 1994Baseline pain intensity not moderate to severe.
Troullos 1990Intervention administered preoperatively. Therefore inadequate baseline pain.
Turcotte 1986Baseline pain intensity not moderate to severe.
Van Der Zwan 1982No direct pain outcome measurement used, pain assessed by analgesic intake.
Van Wering 1972No placebo control.
Vigneron 1977Could not be obtained despite attempts to contact the authors, ordering through the British Library and help from the librarians at Novartis and Knoll pharmaceuticals.
Vogel 1984Combined the data from separate arms of a cross-over trial into one data set.
Vogel 1992Baseline pain intensity not moderate to severe.
Von Mayer 1980Multiple dose study with no mention of the level of baseline pain.
Walker 1976No placebo control.
Walter 1987Abstract.
Walton 1990Intervention administered preoperatively. Therefore inadequate baseline pain.
Walton 1993First dose was given im during surgery, then oral doses were given postoperatively at specified times rather than when patients had baseline pain of at least moderate intensity.
Weber 1990No placebo control.
Wiebe 1995Intervention administered preoperatively. Therefore inadequate baseline pain.
Wilson 1991Participants included children.
Winter 1978Baseline pain intensity not moderate to severe.
Wuolijoki 1987Interventions were administered either pre-operatively or immediately post-operatively. Therefore insufficient baseline pain.

Ancillary