Single dose oral ibuprofen for acute postoperative pain in adults

Christopher J Derry; Sheena Derry; R Andrew Moore; Henry J McQuay

doi:10.1002/14651858.CD001548.pub2

. 2009 Jul 8;2009(3):CD001548. doi: 10.1002/14651858.CD001548.pub2

Single dose oral ibuprofen for acute postoperative pain in adults

Christopher J Derry ¹, Sheena Derry ^2,^✉, R Andrew Moore ³, Henry J McQuay ¹

Editor: Cochrane Pain, Palliative and Supportive Care Group

PMCID: PMC4171980 EMSID: EMS57123 PMID: 19588326

Abstract

Background

This review updates a 1999 Cochrane review showing that ibuprofen at various doses was effective in postoperative pain in single dose studies designed to demonstrate analgesic efficacy. New studies have since been published. Ibuprofen is one of the most widely used non‐steroidal anti‐inflammatory (NSAID) analgesics both by prescription and as an over‐the‐counter medicine. Ibuprofen is used for acute and chronic painful conditions.

Objectives

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

Search methods

We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009.

Selection criteria

Randomised, double blind, placebo‐controlled trials of single dose orally administered ibuprofen (any formulation) in adults with moderate to severe acute postoperative pain.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number‐needed‐to‐treat‐to‐benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.

Main results

Seventy‐two studies compared ibuprofen and placebo (9186 participants). Studies were predominantly of high reporting quality, and the bulk of the information concerned ibuprofen 200 mg and 400 mg. For at least 50% pain relief compared with placebo the NNT for ibuprofen 200 mg (2690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6475 participants) it was 2.5 (2.4 to 2.6). The proportion with at least 50% pain relief was 46% with 200 mg and 54% with 400 mg. Remedication within 6 hours was less frequent with higher doses, with 48% remedicating with 200 mg and 42% with 400 mg. The median time to remedication was 4.7 hours with 200 mg and 5.4 hours with 400 mg. Sensitivity analysis indicated that pain model and ibuprofen formulation may both affect the result, with dental impaction models and soluble ibuprofen salts producing better efficacy estimates. Adverse events were uncommon, and not different from placebo.

Authors' conclusions

The very substantial amount of high quality evidence demonstrates that ibuprofen is an effective analgesic in treating postoperative pain. NNTs for 200 mg and 400 mg ibuprofen did not change significantly from the previous review even when a substantial amount of new information was added. New information is provided on remedication.

Plain language summary

A single dose of ibuprofen administered orally to treat acute postoperative pain in adults

Ibuprofen at 200 mg and 400 mg produces a high level of pain relief in about half of those with moderate or severe acute postoperative pain. This is a good result compared with most other analgesics tested in a very well researched model of pain used for demonstrating that drugs can actually produce pain relief. There were no more adverse events than with placebo.

Background

This review is an update of a previously published review in The Cochrane Database of Systematic Reviews on 'Single dose oral ibuprofen and diclofenac for postoperative pain' (Collins 1999). In this update it refers to ibuprofen only, and the title now states that the review is limited to adults. An updated review of single dose oral diclofenac in acute postoperative pain in adults has also been published (Derry P 2009).

Acute pain occurs as a result of tissue damage either accidentally due to an injury or as a result of surgery. Acute postoperative pain is a manifestation of inflammation due to tissue injury. The management of postoperative pain and inflammation is a critical component of patient care. This is one of a series of reviews whose aim is to present evidence for relative analgesic efficacy through indirect comparisons with placebo, in very similar trials performed in a standard manner, with very similar outcomes, and over the same duration. Such relative analgesic efficacy does not in itself determine choice of drug for any situation or patient, but guides policy‐making at the local level.

Recently published reviews include paracetamol (Toms 2008), celecoxib (Derry 2008), naproxen (Derry C 2009) and parecoxib (Lloyd 2009).

Single dose trials in acute pain are commonly short in duration, rarely lasting longer than 12 hours. The numbers of participants is small, allowing no reliable conclusions to be drawn about safety. To show that the analgesic is working it is necessary to use placebo (McQuay 2005). There are clear ethical considerations in doing this. These ethical considerations are answered by using acute pain situations where the pain is expected to go away, and by providing additional analgesia, commonly called rescue analgesia, if the pain has not diminished after about an hour. This is reasonable, because not all participants given an analgesic will have significant pain relief. Approximately 18% of participants given placebo will have significant pain relief (Moore 2006), and up to 50% may have inadequate analgesia with active medicines. The use of additional or rescue analgesia is hence important for all participants in the trials.

Clinical trials measuring the efficacy of analgesics in acute pain have been standardised over many years. Trials have to be randomised and double blind. Typically, in the first few hours or days after an operation, patients develop pain that is moderate to severe in intensity, and will then be given the test analgesic or placebo. Pain is measured using standard pain intensity scales immediately before the intervention, and then using pain intensity and pain relief scales over the following 4 to 6 hours for shorter acting drugs, and up to 12 or 24 hours for longer acting drugs. Pain relief of half the maximum possible pain relief or better (at least 50% pain relief) is typically regarded as a clinically useful outcome. For patients given rescue medication it is usual for no additional pain measurements to be made, and for all subsequent measures to be recorded as initial pain intensity or baseline (zero) pain relief (baseline observation carried forward). This process ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention. In some trials the last observation is carried forward, which gives an inflated response for the test intervention compared to placebo, but the effect has been shown to be negligible over 4 to 6 hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first 6 hours following the intervention, with measurements supervised, although they may then be allowed home to make their own measurements in trials of longer duration.

Clinicians prescribe non‐steroidal anti‐inflammatory drugs (NSAIDs) on a routine basis for a range of mild‐to‐moderate pain. NSAIDs are the most commonly prescribed analgesic medications worldwide, and their efficacy for treating acute pain has been well demonstrated (Moore 2003). They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins and thromboxane A2 (FitzGerald 2001). Prostaglandins mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive processes. However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cyclooxygenase‐dependent prostanoid formation (Hawkey 1999). Since NSAIDs do not depress respiration and do not impair gastro‐intestinal motility as do opioids (BNF 2002) they are clinically useful for treating pain after minor surgery and day surgery, and have an opiate‐sparing effect after more major surgery (Grahame‐Smith 2002).

Ibuprofen was developed in the 1960s and is used extensively throughout the world for relief of pain and inflammation in both acute and chronic conditions. It is available over the counter in most countries, usually as 200 mg tablets, with 1200 mg as the recommended maximum daily dose for adults. Under medical supervision, up to 3200 mg daily may be taken, divided into three doses. The lysine salt of ibuprofen is more soluble in water, with some theoretical advantage for faster onset after oral administration, and with the possibility that it could be used intravenously. Intravenous ibuprofen lysine has been used for closure of patent ductus arteriosis in newborns (Aranda 2006). Topical formulations are also available over the counter, and are dealt with in other separate reviews.

In UK primary care in 2007 there were 4.5 million prescriptions for ibuprofen, most commonly for 400 mg tablets (2.6 million), but only 6800 for ibuprofen lysine (PACT 2007). These numbers do not include over the counter sales, which are considerable, with over seven million packs sold annually in the UK in 2000, about 46,000 kg by weight (Sheen 2002).

A major concern regarding the use of conventional NSAIDs postoperatively is the possibility of bleeding from both the operative site (because of the inhibition of platelet aggregation) (Forrest 2002) and from the upper gastrointestinal tract, (especially in patients stressed by surgery, the elderly, frail, or dehydrated). Other potentially serious adverse events include acute liver injury, acute renal injury, heart failure, and adverse reproductive outcomes (Hernandez‐Diaz 2001). However, such complications are more likely to occur with chronic use and NSAIDs generally present fewer risks if used in the short term, as in the treatment of postoperative pain (Rapoport 1999).

The previous review included 35 studies in 34 reports with 3591 participants. Ibuprofen was shown to be an effective analgesic at 200 mg and 400 mg, with numbers‐needed‐to‐treat‐to‐benefit (NNTs) for at least 50% pain relief over 4 to 6 hours of 3.3 (95% confidence interval (CI) 2.8 to 4.0) and 2.7 (2.5 to 3.0) respectively. Adverse events were generally mild and transient and did not differ from placebo. A number of new studies are now available. The increased numbers of studies and participants gives more robust estimates of outcomes, and permits more detailed analysis of subgroups. This review has also looked at use of rescue medication as an additional measure of efficacy.

Objectives

To evaluate the analgesic efficacy and safety of oral ibuprofen in the treatment of acute postoperative pain, using methods that permit comparison with other analgesics evaluated in the same way, using criteria of efficacy recommended by an in‐depth study at the individual patient level (Moore 2005).

Methods

Criteria for considering studies for this review

Types of studies

Studies were included if they were full publications of double blind trials of a single dose oral ibuprofen against placebo for the treatment of moderate to severe postoperative pain in adults, with at least 10 participants randomly allocated to each treatment group. Multiple dose studies were included if appropriate data from the first dose were available, and cross‐over studies were included provided that data from the first arm were presented separately.

Studies were excluded if they were:

posters or abstracts not followed up by full publication;
reports of trials concerned with pain other than postoperative pain (including experimental pain);
studies using healthy volunteers;
studies where pain relief was assessed by clinicians, nurses or carers (i.e. not patient‐reported);
studies of less than 4 hours' duration or which failed to present data over 4 to 6 hours post‐dose.

Types of participants

Studies of adult participants (15 years old or above) with established moderate to severe postoperative pain were included. For studies using a visual analogue scale (VAS), pain of at least moderate intensity was assumed when the VAS score was greater than 30 mm (Collins 1997). Studies of participants with postpartum pain were included provided the pain investigated resulted from episiotomy or Caesarean section (with or without uterine cramp). Studies investigating participants with pain due to uterine cramps alone were excluded.

Types of interventions

Orally administered ibuprofen with matched placebo administered as a single oral dose for post‐operative pain.

Types of outcome measures

Data collected included the following.

characteristics of participants;
pain model;
patient‐reported pain at baseline (physician, nurse, or carer reported pain will not be included in the analysis);
patient‐reported pain relief and/or pain intensity expressed hourly over 4 to 6 hours using validated pain scales (pain intensity and pain relief in the form of visual analogue scales (VAS) or categorical scales, or both), or reported total pain relief (TOTPAR) or summed pain intensity difference (SPID) at 4 to 6 hours;
patient‐reported global assessment of treatment (PGE), using a standard five‐point scale;
number of participants using rescue medication, and the time of assessment;
time to use of rescue medication;
withdrawals ‐ all cause, adverse event;
adverse events ‐ participants experiencing one or more, and any serious adverse event, and the time of assessment.

Search methods for identification of studies

For the earlier review the following electronic databases were searched using a sensitive search strategy:

The Cochrane Library (August 1996);
The Specialised Register of the Cochrane Pain, Palliative and Supportive Care group (December 1996);
MEDLINE (1966 to December 1996);
EMBASE (1980 to January 1997);
Biological Abstracts (Jan 1985 to December 1996;
Oxford Pain database (Jadad 1996a).

For this update the following electronic databases were searched.

Cochrane CENTRAL (Issue 2, 2009);
MEDLINE via Ovid (1996 to May 2009);
EMBASE via Ovid (1996 to May 2009);

See Appendix 1 for the MEDLINE search strategy, Appendix 2 for the EMBASE search strategy and Appendix 3 for the CENTRAL search strategy.

Additional studies were sought in reference lists of retrieved articles and reviews.

Language

No language restriction was applied.

Unpublished studies

Abstracts, conference proceedings and other grey literature were not searched, but known unpublished studies from a different review were included.

Data collection and analysis

Selection of studies

Two review authors independently assessed and agreed the search results for studies that might be included in the updated review. Disagreements were resolved by consensus or referral to a third review author.

Quality assessment

Two review authors independently assessed the included studies for quality using a five‐point scale (Jadad 1996b).

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

The results are described in the 'Methodological quality of included studies' section below, and 'Characteristics of included studies' table.

Data management

Data were extracted by two review authors and recorded on a standard data extraction form. Data suitable for pooling were entered into RevMan 5.

Data analysis

QUOROM guidelines were followed (Moher 1999). For efficacy analyses we used the number of participants in each treatment group who were randomised, received medication, and provided at least one post‐baseline assessment. For safety analyses we used number of participants who received study medication in each treatment group. Analyses were planned for different doses. Sensitivity analyses were planned for pain model (dental versus other postoperative pain), trial size (39 or fewer versus 40 or more per treatment arm), and quality score (two versus three or more), and formulation (standard tablet versus more soluble tablet or liquid preparations). A minimum of two studies and 200 participants were required for any analysis (Moore 1998).

Primary outcome:

Number of participants achieving at least 50% pain relief

For each study, mean TOTPAR (total pain relief) or SPID (summed pain intensity difference) for active and placebo groups were converted to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). The proportion of participants 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 participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group. Information on the number of participants with at least 50%maxTOTPAR for active treatment and placebo was then used to calculate relative benefit (RB) and NNT.  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";
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 none of these measures were available, numbers of participants reporting "very good or excellent" on a five‐point categorical global scale with the wording "poor, fair, good, very good, excellent" were taken as those achieving at least 50% pain relief (Collins 2001).

Further details of the scales and derived outcomes are in the glossary (Appendix 4).

Secondary outcomes:

1. Use of rescue medication. Numbers of participants requiring rescue medication were used to calculate relative risk (RR) and numbers needed to treat to prevent (NNTp) use of rescue medication for treatment and placebo groups. Median (or mean) time to use of rescue medication was used to calculate the weighted mean of the median (or mean) for the outcome. Weighting was by number of participants.

2. Adverse events. Numbers of participants reporting adverse events for each treatment group were used to calculate RR and numbers needed to treat to harm (NNH) estimates for:

any adverse event;
any serious adverse event (as reported in the study);
withdrawal due to an adverse event.

3. Withdrawals. Withdrawals for reasons other than lack of efficacy (participants using rescue medication ‐ see above) and adverse events were noted, as were exclusions from analysis where data were presented.

RB or RR estimates were calculated with 95% Confidence Interval (CI) using a fixed‐effect model (Morris 1995). NNT, NNTp and NNH with 95% CI were calculated using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control was assumed when the 95% CI of the RB did not include the number one.

Homogeneity of studies was assessed visually (L'Abbé 1987). The z test (Tramèr 1997) was used to determine if there was a significant difference between NNTs for different doses of active treatment, or between groups in the sensitivity analyses.

Results

Description of studies

This review included 72 studies in abstract, 9186 participants. The previous review identified 34 reports of 35 studies, in which 2214 participants were treated with ibuprofen and 1377 with placebo. This updated review identified a total of 65 published reports of 67 studies, and one published report of five unpublished studies (Edwards 2002), in which a total of 5804 participants were treated with ibuprofen and 3382 with placebo. Details of the studies are in the 'Characteristics of included studies' table. Three new studies were excluded (Cooper 1996b; Doyle 2002; Schleier 2007), please see the 'Characteristics of excluded studies' table for further details.

In an new search in May 2009, four additional studies were identified. Two were subsequently excluded after reading the full text (Akural 2009; Chopra 2009), and two are awaiting classification (Daniels 2009; Kleinert 2008). These studies are not included in this analysis.

Ibuprofen 50 mg was used in three studies, 100 mg in four studies, 200 mg in 20 studies (25 treatment arms), 400 mg in 61 studies (67 treatment arms), 600 mg in three studies (four treatment arms), and 800 mg in one study.

Most studies had treatment arms using standard formulation tablets, but nine used tablets of a more soluble salt of ibuprofen (lysine or arginine) or a "soluble" or liquid preparation (De Miguel Rivero 1997; Hersh 2000; Laveneziana 1996; Mehlisch 1995; Nelson 1994; Olson 2001; Pagnoni 1996; Parker 1986; Wahl 1997). Six studies included treatment arms using both standard tablets and a more soluble preparation (Black 2002; Desjardins 2002; Mehlisch 2002; Seymour 1991 (study 1); Seymour 1991 (study 2); Seymour 1996).

Fifty‐seven studies were in participants with dental pain following surgical extraction of one or more impacted third molars, 10 studies were in participants with pain following obstetric or gynaecological surgery (seven), abdominal or gynaecological surgery (two), and abdominal or pelvic surgery (one), two studies were in participants with pain following orthopaedic surgery, and one study each in general surgery, tonsillectomy, and hernia repair.

Study duration was 4 hours in nine studies, 5 hours in two studies, 6 hours in 42 studies, 7 hours in one study, 8 hours in nine studies, 12 hours in six studies, and 24 hours in three studies.

Risk of bias in included studies

Methodological quality of included studies

All included studies were both randomised and double blind. Twenty‐one studies were given a score of five, 32 a score of four, 16 a score of three, and three a score of two. Details are in the 'Characteristics of included studies' table.

Effects of interventions

All studies contributed data for analysis of the primary efficacy outcome.

Number of participants achieving at least 50% pain relief

(Table 1; Summary of results A)

1. Summary of outcomes: analgesia and use of rescue medication.

		Analgesia			Rescue medication
Study ID	Treatment	PI or PR	Number with 50% PR	PGE: v good or excellent	Median time to use (h)	% using
Ahlstrom 1993	(1) Ibuprofen 400 mg, n = 32 (3) Placebo n = 30	SPID 6:  (1) 188 mm (3) 32 mm	(1) 19/32 (3) 2/30	at 6 h: (1) 75% (3) 17%	No data	at 6 h: (1) 31 (3) 77
Arnold 1990	(1) Ibuprofen 400 mg, n = 15 (2) Ketoprofen 25 mg, n = 14 (3) Ketoprofen 100 mg, n = 16 (4) Placebo, n = 14	TOTPAR 6: (1) 4.2 (4) 1.5	(1) 2/15 (4) 0/14	No usable data	Mean: (1) 3.9 (4) 2.4	at 6 h: (1) 67 (4) 83
Bakshi 1994	(1) Ibuprofen 400 mg, n = 80 (2) Diclofenac (dispersible) 50 mg, n = 83 (3) Placebo, n = 82	TOTPAR 6: (1) 14.9 (3) 8.9	(1) 57/80 (3) 31/82	No usable data	Mean: (1) 5.3 (3) 3.4	at 6 h: (1) 28 (3) 65
Black 2002	(1) Ibuprofen 200 mg, n = 100 (2) Ibuprofen 400 mg, n = 100 (3) Ibuprofen arginate 200 mg, n = 100 (4) Ibuprofen arginate 400 mg, n = 99 (5) Placebo, n = 99	TOTPAR 6:  (1) 12.6 (2) 14.9 (3) 13.1 (4) 15.0 (5) 6.9	(1) 58/100 (2) 71/100 (3) 61/100 (4) 71/99 (5) 26/99	No usable data	(1) 4.2 (2) 5.2 (3) 4.0 (4) 4.5 (5) 1.3	No data
Cheung 2007	(1) Ibuprofen 440 mg, n = 57 (2) Celecoxib 400 mg, n = 57 (3) Placebo, n = 57	TOTPAR 6: (1) 14.9 (3) 3.7	(1) 40/57 (3) 5/57	No data	(1) 11 (3) 1.9	at 24 h: (1) 72 (3) 86
Cooper 1977	(1) Ibuprofen 200 mg n = 38 (2) Ibuprofen 400 mg, n = 40 (3) Aspirin 325 mg, n = 37 (4) Aspirin 650 mg, n = 37 (5) Placebo, n= 40	TOTPAR 4: (1) 7.32 (2) 6.27 (5) 3.32	(1) 17/38 (2) 20/40 (5) 6/40	No data	No data	No data
Cooper 1982	(1) Ibuprofen 400 mg, n =38 (2) Ibuprofen 400 mg + Codeine 60 mg, n = 41 (3) Aspirin 650 mg, n = 38 (4) Aspirin 650 mg + codeine 60 mg, n = 45 (5) Codeine 60 mg, n = 41 (6) Placebo, n = 46	TOTPAR 4: (1) 8.4 (6) 2.7	(1) 22/38 (2) 27/41 (6) 5/46	No usable data	Mean: (1) 3.8 (6) 2.4	No data
Cooper 1988a	(1) Ibuprofen 400 mg, n = 37 (2) Ketoprofen 100 mg, n = 39 (3) Ketoprofen 25 mg, n = 42 (4) Placebo, n = 43	TOTPAR 6: (1) 11.3 (4) 4.7	(1) 19/37 (4) 6/43	at 6 h: (1) 12/37 (4) 2/43	(1) 4.0 (4) 3.0	at 6 h: (1) 65 (4) 79
Cooper 1989	(1) Ibuprofen 400 mg, n = 61 (2) Paracetamol 1000 mg, n = 59 (3) Placebo, n = 64	TOTPAR 6: (1) 13.1 (3) 4.7	(1) 37/61 (3) 9/64	at 6 h: (1) 32/61 (3) 4/64	(1) 5.5 (3) 2.3 Mean: (1) 4.5 (3) 3.3	at 6 h: (1) 52 (3) 78
Cooper 1996a	(1) Ibuprofen 200 mg, n = 19 (2) Misoprostal 200 mg, n = 18 (3) Ibuprofen 200 mg + misoprostal 200 mg, n = 20 (4) Placebo, n = 13	TOTPAR 6: (1) 5.3 (3) 5.1 (4) 1.2	(1) 3/19 (3) 3/18 (4) 0/33	No usable data	Mean: (1) 3.0 (3) 2.8 (4) 1.8	No data
De Miguel Rivero 1997	(1) Ibuprofen arginine 400 mg, n = 36 (2) Magnesic dipyrone, 2 g (IM), n = 33 (3) Placebo, n = 34	VAS SPID 5: (1) 187 mm (3) 120 mm	(1) 24/36 (3) 15/34	at 5 h: (1) 20/36 (3) 7/34	Mean: (1) 3.5 (3) 1.8	at 5 h: (1) 14 (3) 12
Desjardins 2002	(1) Ibuprofen 200 mg, n = 50 (2) Ibuprofen 400 mg, n = 52 (3) Ibuprofen arginine 200 mg, n = 49 (4) Ibuprofen arginine 400 mg, n = 50 (5) Placebo, n = 24	TOTPAR 6: (1) 5.4 (2) 7.3 (3) 5.8 (4) 7.9 (5) 1.7	(1) 9/50 (2) 15/52 (3) 10/49 (4) 16/49 (5) 0/23	No data	(1) 2.6 (2) 4.0 (3) 3.0 (4) 4.0 (5) 1.5	No data
Dionne 1998	(1) S(+)‐Ibuprofen 200 mg, n = 51 (2) S(+)‐Ibuprofen 400 mg, n = 50 (3) Ibuprofen (racemic) 400 mg, n = 50 (4) Placebo, n = 25	TOTPAR 6: (1) 13.0 (2) 14.9 (3) 11.5 (4) 3.5	(1) 31/51 (2) 35/40 (3) 26/50 (4) 2/25	No data	(1) 5.8 (2) 6.1 (3) 5.4 (4) 1.8	No data
Ehrich 1999	(1) Ibuprofen 400 mg, n = 20 (2) Rofecoxib 50 mg, n = 32 (3) Rofecoxib 500 mg, n = 20 (4) Placebo, n = 32	TOTPAR 6: (1) 15.1 (4) 2.7	(1) 14/20 (4) 1/32	No usable data	(1) >6 (4) 1.6	No usable data
Forbes 1984	(1) Ibuprofen 400 mg, n = 28 (2) Fendosal 200 mg, n = 29 (3) Aspirin 650 mg, n = 24 (4) Placebo n = 28	TOTPAR 6: (1) 15.8 (4) 3.8	(1) 21/28 (4) 3/28	No usable data	(1) 8.3 (4) 2.7 Mean: (1) 8.5 (4) 4.5	at 12 h: (1) 75 (4) 89
Forbes 1990	(1) Ibuprofen 400 mg, n = 32 (2) Ketorolac 10 mg, n = 31 (3) Ketorolac 20 mg, n = 35 (4) Paracetamol 600 mg, n = 36 (5) Paracetamol 600 mg + codeine 60 mg, n = 38 (6) Placebo, n = 34	TOTPAR 6: (1) 10.5 (6) 1.9	(1) 15/32 (6) 0/34	No usable data	(1) 4.7 (6) 1.9 Mean: (1) 4.6 (6) 2.9	at 6 h: (1) 58 (6) 97
Forbes 1991a	(1) Ibuprofen 50 mg, n = 57 (2) Ibuprofen 100 mg, n = 49 (3) Ibuprofen 200 mg, n = 48 (4) Ibuprofen 100 mg + Caffeine 100 mg, n = 49 (5) Ibuprofen 200 mg + Caffeine 100 mg, n = 44 (6) Placebo n = 51	TOTPAR 6: (1) 7.0 (2) 7.0 (3) 8.7 (4) 9.3 (5) 12.6 (6) 2.2	(1) 16/57 (2) 13/49 (3) 18/48 (4) 19/49 (5) 26/44 (6) 0/51	No usable data	Mean: 1) 4.9 (2) 4.8 (3) 5.1 (4) 5.4 (5) 6.1 (6) 3.0	at 8 h: (1) 79 (2) 78 (3) 79 (4) 69 (5) 57 (6) 94
Forbes 1991b	(1) Ibuprofen 400 mg, n = 37 (2) Bromfenac 5 mg, n = 39 (3) Bromfenac 10 mg, n = 43 (4) Bromfenac 25 mg, n = 42 (5) Aspirin 650 mg, n = 41 (6) Placebo, n = 39	TOTPAR 6: (1) 11.0 (6) 2.5	(1) 18/37 (6) 3/39	No usable data	(1) 6.9 (6) 1.8 Mean: (1) 5.7 (6) 2.8	at 6 h: (1) 42 (6) 96 at 8 h: (1) 57 (6) 97
Forbes 1992	(1) Ibuprofen 400 mg, n = 38 (2) Bromfenac 10 mg, n = 43 (3) Bromfenac 25 mg, n = 41 (4) Bromfenac 50 mg, n = 42 (5) Bromfenac 100 mg, n = 40 (6) Aspirin 650 mg, n = 38 (7) Placebo, n = 38	TOTPAR 6: (1) 11.8 (7) 2.1	(1) 20/38 (7) 0/38	No usable data	(1) 7.3 (7) 1.8 Mean: (1) 6.3 (7) 2.7	at 6 h: (1) 38 (7) 92 at 8 h:  1) 58 (7) 97
Frame 1989	(1) Ibuprofen 400 mg, n = 42 (2) Dihydrocodeine 30 mg, n = 43 (3) Placebo, n = 38	TOTPAR 5: (1) 11.1 (3) 1.9	(1) 26/42 (3) 0/38	No data	No usable data	at 5 h: (1) 40 (3) 89
Fricke 1993	(1) Ibuprofen 400 mg, n = 81 (2) Naproxen Na 440 mg, n = 81 (3) Placebo, n = 39	TOTPAR 6: (1) 10.9 (3) 2.9	(1) 40/81 (3) 2/39	No usable data	(1) 6.0 (3) 1.1	at 12 h: (1) 78 (3) No data
Gay 1996	(1) Ibuprofen 400 mg, n = 41 (2) DKP.TRIS 5 mg, n = 41 (3) DKP.TRIS 10 mg, n = 42 (4) DKP.TRIS 20 mg, n = 41 (5) Placebo, n = 39	TOTPAR 6: (1) 13.6 (5) 5.2	(1) 26/41 (5) 7/39	No usable data	Mean: (1) 5.04 (5) 3.65	at 6 h: (1) 27 (5) 67
Heidrich 1985	(1) Ibuprofen 400 mg, n = 40 (2) Paracetamol 300 + codeine 30 mg, n = 40 (3) Placebo, n = 40	VAS TOTPAR 6: (1) 234 mm (3) 104 mm	(1) 15/40 (3) 5/40	No data	No data	No data
Hersch 1993a	(1) Ibuprofen 200 mg, n = 51 (2) Ibuprofen 400 mg, n = 49 (3) Meclofenamate 100 mg, n = 52 (4) Meclofenamate 50 mg, n = 51 (5) Placebo, n = 51	TOTPAR 6: (1) 10.3 (2) 8.0 (5) 1.7	(1) 17/51 (2) 22/49 (5) 0/51	at 8 h: (1) 24/51 (2) 14/49 (5) 6/51	Mean: (1) 3.1 (2) 4.2 (5) 1.5	at 8 h: (1) 94 (2) 94 (5) 98
Hersch 1993b	(1) Ibuprofen 400 mg, n = 12 (2) Codeine 60 mg, n = 16 (3) Placebo, n = 16	TOTPAR 6: (1) 15.7 (3) 9.0	(1) 9/12 (3) 6/16	No usable data	Mean: (1) 5.0 (3) 4.0	No data
Hersh 2000	(1) Ibuprofen liquigel 200 mg, n = 61 (2) Ibuprofen liquigel 400 mg, n = 59 (3) Paracetamol 1000 mg, n = 63 (4) Placebo, n = 27	TOTPAR 6: (1) 14.7 (2) 16.6 (4) 5.2	(1) 43/61 (2) 47/59 (4) 5/27	at 6 h: (1) 38/61 (2) 41/59 (4) 4/27	(1) > 6 (2) > 6 (4) 1.6	at 6 h: (1) 31 (2) 23 (4) 75
Hill 2001	(1) Ibuprofen 400 mg, n = 49 (2) Pregabalin 50 mg, n = 49 (3) Pregabalin 300 mg, n = 50 (4) Placebo, n = 50	TOTPAR 6: (1) 10.1 (4) 3.8	(1) 22/49 (4) 5/50	No usable data	(1) 4.1 (4) 2.0	at 6 h: (1) 61 (4) 81
Jain 1986	(1) Ibuprofen 100 mg, n = 39 (2) Ibuprofen 200 mg, n = 47 (3) Ibuprofen 400 mg, n = 49 (4) Aspirin 650 mg, n = 45 (5) Placebo, n = 47	SPID 6: (1) 1.5 (2) 2.3 (3) 3.0 (5) ‐1.7	(1) 3/39 (2) 7/47 (3) 9/49 (5) 0/47	No usable data	Mean: (1) 3.9 (2) 4.2 (3) 4.0 (5) 2.1	at 6 h: (1) 74 (2) 67 (3) 59 (5) 96
Jain 1988	(1) Ibuprofen 400 mg, n = 49 (2) Ibuprofen 200 mg + caffeine 100 mg, n = 50 (3) Placebo, n = 48	TOTPAR 6: (1) 14.4 (2) 13.9 (3) 8.6	(1) 33/49 (2) 33/50 (3) 17/48	No usable data	No data	at 6 h: (1) 20 (2) 24 (3) 49
Johnson 1997	(1) Ibuprofen 400 mg, n = 48 (2) Paracetamol 650 mg + oxycodone 10 mg, n = 47 (3) Bromfenac 100 mg, n = 48 (4) Bromfenac 50 mg, n = 47 (5) Placebo, n = 48	TOTPAR 6: (1) 7.7 (5) 5.5	(1) 15/48 (5) 9/48	No usable data	(1) 3.4 (5) 2.7	at 6 h: (1) 79 (5) 89
Kiersch 1993	(1) Ibuprofen 200 mg, n = 81 (2) Naproxen Na 220 mg, n = 80 (3) Placebo, n = 42	TOTPAR 6: (1) 10.3 (3) 3.7	(1) 37/81 (3) 4/42	at 12 h: (1) 34/81 (3) 4/42	(1) 8.0 (3) 2.0	at 12 h: (1) 63 (3) 90
Laska 1986	(1) Ibuprofen 400 mg, n = 39 (2) Ibuprofen 600 mg, n = 36 (3) Ibuprofen 800 mg, n = 39 (4) Aluminium ibuprofen 400 mg, n = 39 (5) Placebo, n = 37	SPID 6: (1) 13.9 (2) 14.1 (3) 13.4 (5) 5.3	(1) 39/39 (2) 36/36 (3) 39/39 (5) 14/37	No data	No data	No usable data
Laveneziana 1996	(1) Ibuprofen arginine soluble 400 mg, n = 42 (2) Ketorolac 30 mg, n = 41 (3) Placebo, n = 41	VAS SPID 6: (1) 233 mm (3) 204 mm	(1) 29/42 (3) 24/41	No usable data	(1) 1.2 (3) 1.2	at 6 h: (1) 36 (3) 41
Malmstrom 1999	(1) Ibuprofen 400 mg, n = 46 (2) Rofecoxib 50 mg, n = 90 (3) Celecoxib 200 mg, n = 91 (4) Placebo, n = 45	TOTPAR 6: (1) 15.2 (4) 3.7	(1) 33/46 (4) 4/45	No usable data	(1) 8.9 (4) 1.5	at 24 h: (1) 76 (4) 91
Malmstrom 2002	(1) Ibuprofen 400 mg, n = 45 (2) Rofecoxib 50 mg, n = 151 (3) Celecoxib 400 mg, n = 151 (4) Celecoxib 200 mg, n = 90 (5) Placebo, n = 45	TOTPAR 6: (1) 11.7 (5) 1.0	(1) 24/45 (5) 0/45	No usable data	(1) 10.0 (5) 1.6	at 24 h: (1) 87 (5) 98
Malmstrom 2004	(1) Ibuprofen 400 mg, n = 48 (2) Etoricoxib 60 mg, n = 75 (3) Etoricoxib 120 mg, n = 76 (4) Etoricoxib 180 mg, n = 74 (5) Etoricoxib 240 mg, n = 76 (6) Placebo, n = 49	TOTPAR 6: (1) 14.1 (6) 3.4	(1) 32/48 (6) 4/49	No usable data	(1) 10.1 (6) 2.1	at 24 h: (1) 81 (6) 82
McQuay 1996	(1) Ibuprofen 200 mg, n = 31 (2) Ibuprofen 400 mg, n = 30 (3) Ibuprofen 200 mg + caffeine 50 mg, n = 30 (4) Ibuprofen 200 mg + caffeine 100 mg, n = 30 (5) Ibuprofen 200 mg + caffeine 200 mg, n = 29 (6) Placebo, n = 11	TOTPAR 6: (1) 3.0 (2) 7.0 (3) 10.3 (4) 9.5 (5) 5.5 (6) 0	(1) 2/31 (2) 6/30 (3) 8/30 (4) 14/30 (5) 12/29 (6) 0/11	No usable data	No data	No data
Medve 2001	(1) Ibuprofen 200 mg, n = 240 (2) Tramadol 37.5 mg, n = 238 (3) Paracetamol 325 mg, n = 240 (4) Tramadol 37.5 mg + paracetamol 325 mg, n = 240 (5) Placebo, n = 239		Data taken from IPMA: (1) 114/240 (5) 5/239	No usable data	(1) 5.4 (5) 2.0	No data
Mehlisch 1990	(1) Ibuprofen 400 mg, n = 306 (2) Paracetamol 1000 mg, n = 306 (3) Placebo, n = 85	SPID 6: (1) 5.8 (3) 1.2	(1) 124/306 (3) 5/85	No data	No data	at 6 h: (1) 41 (3) 75
Mehlisch 1995	(1) Ibuprofen lysine 400 mg, n = 98 (2) Paracetamol 1000 mg, n = 101 (3) Placebo, n = 40	TOTPAR 6: (1) 14.4 (3) 2.6	(1) 67/98 (3) 1/40	at 6 h: (1) 65/98 (3) 1/40	(1) > 6 (3) 1.4	at 6 h: (1) 26 (3) 88
Mehlisch 2002	(1) Ibuprofen 200 mg, n = 100 (2) Ibuprofen 400 mg, n = 100 (3) Ibuprofen arginine 200 mg, n = 100 (4) Ibuprofen arginine 400 mg, n = 100 (5) Placebo, n = 100	TOTPAR 6: (1) 10.0 (2) 12.4 (3) 13.6 (4) 13.3 (5) 4.5	(1) 44/100 (2) 57/100 (3) 64/100 (4) 62/100 (5) 13/100		(1) 3.8 (2) 4.2 (3) 4.5 (4) 4.4 (5) 2.3	at 4 h: (1) 32 (2) 47 (3) 27 (4) 33 (5) No data
Morrison 1999	(1) Ibuprofen 400 mg, n = 51 (2) Rofecoxib 50 mg, n = 50 (3) Placebo, n = 50	TOTPAR 6: (1) 9.3 (3) 4.2	(1) 20/51 (3) 6/50	No usable data	(1) 6.1 (3) 2.4	at 24 h: (1) 82 (3) 92
Nelson 1994	(1) Ibuprofen lysine 200 mg, n = 77 (2) Aspirin 500 mg, n = 65 (3) Placebo, n = 40	TOTPAR 6: (1) 12.3 (3) 5.6	(1) 44/77 (3) 8/40	at 6 h: (1) 39/77 (3) 6/40	(1) >6 (3) 2.9	at 6 h: (1) 44 (3) 70
Nørholt 1998	(1) Ibuprofen 400 mg, n = 26 (2) Placebo, n = 31	TOTPAR 4: (1) 11.7 (2) 4.5	(1) 22/26 (2) 8/31	No data	No data	at 4 h: (1) 15 (2) 71
Olson 2001	(1) Ibuprofen liquigel 400 mg, n = 67 (2) Ketoprofen 25 mg, n = 67 (3) Paracetamol 1000 mg, n = 66 (4) Placebo, n = 39	TOTPAR 6: (1) 17.4 (4) 4.3	(1) 57/67 (4) 5/39	at 6 h: (1) 52/67 (4) 4/49	(1) > 6 (4) 1.3	at 6 h: (1) 21 (4) 79
Pagnoni 1996	(1) Ibuprofen arginine soluble 400 mg, n = 30 (2) Ketorolac (IM) 30 mg, n = 30 (3) Placebo, n = 32	VAS SPID 6: (1) 279 (3) 114	(1) 13/30 (3) 5/32	at 6 h: (1) 5/30 (3) 0/32	(1) 2.1 (3) 1.9	at 6 h: (1) 43 (3) 66
Parker 1986	(1) Ibuprofen syrup 600 mg, n = 44 (2) Aspirin syrup 600 mg, n = 33 (3) Placebo, n = 33	TOTPAR 4: (1) 10.4 (3) 8.8	(1) 33/44 (3) 20/33	No data	No data	No data
Schachtel 1989	(1) Ibuprofen 400 mg, n = 36 (2) Paracetamol 1000 mg, n = 37 (3) Placebo, n = 38	TOTPAR 4: (1) 10.4 (3) 5.5	(1) 27/36 (3) 13/38	No data	No data	at 4 h: (1) 22 (3) 58
Schou 1998	(1) Ibuprofen 50 mg, n = 51 (2) Ibuprofen 100 mg, n = 53 (3) Ibuprofen 200 mg, n = 49 (4) Ibuprofen 400 mg, n = 49 (5) Placebo, n = 56	TOTPAR 6: (1) 11.8 (2) 11.2 (3) 15.5 (4) 17.2 (5) 7.3	(1) 27/51 (2) 27/53 (3) 36/49 (4) 41/49 (5) 16/56	No data	(1) 5.5 (2) >6 (3) >6 (4) >6 (5) 3.7	Up to 6 h: (1) 54 (2) 48 (3) 36 (4) 16 (5) 66
Schwartz 2007	(1) Ibuprofen 400 mg, n = 15 (2) MK‐0703 12.5 mg, n = 31 (3) MK‐0703 50 mg, n = 28 (4) MK‐0703 100 mg, n = 31 (5) Placebo, n = 16	No data	Not available	at 8 h: (1) 5/15 (5) 0/16	(1) 7.1 (5) 1.6	at 8 h: (1) 80 (5) 100
Seymour 1991 (study 1)	(1) Ibuprofen tablets 400 mg, n = 31 (2) Ibuprofen liquid in gelatin capsules 400 mg, n = 32 (3) Placebo n = 32	VAS SPID 6: (1) 243 mm (2) 233 mm (3) 120 mm	(1) 20/31 (2) 22/32 (3) 10/32	No usable data	Mean: (1) 3.6 (2) 3.5 (3) 2.1	at 6 h: (1) 39 (2) 44 (3) 69
Seymour 1991 (study 2)	(1) Ibuprofen tablets 400 mg, n = 30 (2) Ibuprofen soluble 400 mg, n = 32 (3) Placebo, n = 30	VAS SPID 6: (1) 214 mm (2) 228 mm (3) 86 mm	(1) 20/30 (2) 8/30 (3) 7/30	No usable data	Mean: (1) 3.24 (2) 3.15 (3) 1.40	at 6 h: (1) 60 (2) 72 (3) 93
Seymour 1996	(1) Ibuprofen tablets 200 mg, n = 18 (2) Ibuprofen soluble 200 mg, n = 17 (3) Ibuprofen tablets 400 mg, n = 15 (4) Ibuprofen soluble 400 mg, n = 16 (5) Ibuprofen tablets 600 mg, n = 17 (6) Ibuprofen soluble 600 mg, n = 17 (7) Placebo, n = 19	VAS SPID 6: (1) 230 mm (2) 148 mm (3) 258 mm (4) 238 mm (5) 140 mm (6) 198 mm (7) 44 mm	(1) 7/18 (2) 9/17 (3) 11/15 (4) 11/16 (5) 11/17 (6) 8/17 (7) 2/19	No usable data	(1) 3.0 (2) 1.6 (3) 2.8 (4) 2.1 (5) 2.0 (6) 1.5 (7) 0.8	at 6 h: (1) 88 (2) 88 (3) 67 (4) 81 (5) 100 (6) 88 (7) 100
Seymour 1998	(1) Ibuprofen 400 mg, n = 76 (2) Aceclofenac 150 mg, n = 71 (3) Placebo, n = 70	VAS TOTPAR 4: (1) 151 mm (3) 46 mm	(1) 27/76 (3) 3/70	No usable data	(1) 3.5 (3) 1.6	at 6 h: (1) 55 (3) 86
Seymour 1999	(1) Ibuprofen 400 mg, n = 41 (2) WAG 994 1 mg, n = 42 (3) Placebo, n = 39	TOTPAR 6: (1) 10.4 (3) 5.1	(1) 19/41 (3) 7/39	No usable data	(1) 5.2 (3) 2.0	at 6 h: (1) 56 (3) 100
Seymour 2000	(1) Ibuprofen 200 mg, n = 59 (2) Buffered ketoprofen 12.5 mg, n = 61 (3) Placebo, n = 60	TOTPAR 6: (1) 6.4 (3) 4.1	(1) 14/59 (3) 7/60	No usable data	(1) 2.0 (3) 1.9	at 6 h: (1) 83 (3) 98
Singla 2005	(1) Ibuprofen 400 mg, n = 175 (2) Ibuprofen 400 mg + oxycodone 5 mg, n = 169 (3) Oxycodone 5 mg, n = 52 (4) Placebo, n = 60	TOTPAR 6: (1) 10.0 (4) 6.4	(1) 77/175 (4) 14/60	No usable data	(1) 4.0 (4) 2.3	at 6 h: (1) 71 (4) No data
Sunshine 1983	(1) Ibuprofen 400 mg, n = 30 (2) Aspirin 600 mg, n = 30 (3) Zomepirac 100 mg, n = 30 (4) Placebo, n = 30	SPID 4: (1) 6.0 (4) 1.0	(1) 21/30 (4) 3/30	No data	No data	at 4 h: (1) 0 (4) 17
Sunshine 1987	(1) Ibuprofen 400 mg, n = 38 (2) Ibuprofen 200 mg + codeine 30 mg, n = 40 (3) Ibuprofen 400 mg + codeine 60 mg, n = 40 (4) Codeine 60 mg, n = 37 (5) Placebo, n = 40	SPID 4: (1) 4.8 (5) 3.4	(1) 16/38 11/40	No usable data	No usable data	at 4 h: (1) 13 (5) 50
Sunshine 1996	(1) Ibuprofen 50 mg, n = 51 (2) Ibuprofen 100 mg, n = 51 (3) Ibuprofen 200 mg, n = 50 (4) Ibuprofen 100 mg + caffeine 100 mg, n = 50 (5) Ibuprofen 200 mg + caffeine 100 mg, n = 50 (6) Placebo, n = 50	TOTPAR 6: (1) 4.7 (2) 8.2 (3) 13.9 (4) 10.9 (5) 14.9 (6) 2.2	(1) 7/51 (2) 17/51 (3) 33/50 (4) 24/50 (5) 36/50 (6) 0/50	No usable data	No data	at 6 h: (1) 4 (2) 0 (3) 0 (4) 0 (5) 2 (6) 32
Sunshine 1997	(1) Ibuprofen 400 mg, n = 40 (2) Ibuprofen 400 mg + hydrocodone 15 mg, n = 40 (3) Placebo, n = 39	TOTPAR 6: (1) 9.7 (3) 2.7	(1) 17/40 (3) 1/39	No usable data	No usable data	at 6 h: (1) 25 (3) 82
Sunshine 1998	(1) Ibuprofen 200 mg, n = 35 (2) Ketoprofen 6.25 mg, n = 35 (3) Ketoprofen 12.5 mg, n = 35 (4) Ketoprofen 25 mg, n = 35 (5) Placebo, n = 35	TOTPAR 6: (1) 12.5 (5) 3.6	(1) 20/35 (5) 3/35	No usable data	No usable data	No usable data
Unpublished from Edwards 2002	(1) Ibuprofen 400 mg, n = 339 (2) Placebo, n = 339	Individual patient meta‐analysis	(1) 145/339 (2) 11/339	No usable data	No usable data	at 8 h: (1) 43/339 (2) 121/337
Van Dyke 2004	(1) Ibuprofen 400 mg, n = 186 (2) Ibuprofen 400 mg + oxycodone 5 mg, n = 187 (3) Oxycodone 5 mg, n = 63 (4) Placebo, n = 62	TOTPAR 6: (1) 12.9 (4) 4.8	(1) 112/186 (4) 9/62	No usable data	1) > 6 (4) 2.0	at 6 h: (1) 38 (4) 84
Wahl 1997	(1) Ibuprofen lysinate 342 mg (= 200 mg Ibu), n = 74 (2) Paracetamol 200 mg + aspirin 250 mg + caffeine 50 mg, n = 73 (3) Placebo, n = 42	TOTPAR 6: (1) 11.6 (3) 2.5	(1) 39/74 (3) 1/42	No usable data	No data	at 6 h: (1) 42 (3) 81
Wideman 1999 (study 1)	(1) Ibuprofen 200 mg, n = 60 (2) Ibuprofen 200 mg, + hydrocodone 7.5 mg, n = 59 (3) Hydrocodone 7.5 mg, n = 61 (4) Placebo, n = 60	TOTPAR 6: (1) 4.9 (4) 3.5	(1) 9/60 (4) 5/60	No data	No data	No data
Wideman 1999 (study 2)	(1) Ibuprofen 400 mg, n = 50 (2) Ibuprofen 400 mg + hydrocodone 15 mg, n = 50 (3) Hydrocodone 15 mg, n = 50 (4) Placebo, n = 51	TOTPAR 6: (1) 9.7 (4) 3.0	(1) 21/50 (4) 3/51	No data	(1) 4.2 (4) 1.8	at 8 h: (1) 69 (4) 100
Zelenakas 2004	(1) Ibuprofen 400 mg, n = 51 (2) Lumiracoxib 100 mg, n = 51 (3) Lumiracoxib 400 mg, n = 50 (4) Placebo, n = 50	TOTPAR 6: (1) 11.6 (4) 4.2	(1) 27/51 (4) 6/50	No usable data	(1) ˜8 (4) ˜2	at 12 h: (1) 73 (4) 92

Summary of results A: Number of participants with ≥ 50% pain relief over 4 to 6 hours
Dose	Studies	Participants	Ibuprofen (%)	Placebo (%)	NNT (95%CI)
50 mg	3	316	31	10	4.7 (3.3 to 8.0)
100 mg	4	396	31	8	4.3 (3.2 to 6.4)
200 mg	20	2690	46	9	2.7 (2.5 to 3.0)
400 mg	61	6475	54	14	2.5 (2.4 to 2.6)
600 mg	3	203	77	40	2.7 (2.0 to 4.2)
800 mg	1	76	100	38	1.6 (1.3 to 2.2)

Summary of results B: Sensitivity analyses using number of participants with ≥ 50% pain relief over 4 to 6 hours
Criterion	Studies	Participants	Ibuprofen (%)	Placebo (%)	NNT (95%CI)
Dental surgery 200 mg	18	2470	47	10	2.7 (2.5 to 3.0)
Other surgery 200 mg	2	220	39	5	3.0 (2.3 to 4.2)
Dental surgery 400 mg	49	5428	55	12	2.3 (2.2 to 2.4)
Other surgery 400 mg	12	1047	48	22	3.9 (3.2 to 5.0)
Dental 600/800 mg	2	165	86	29	1.7 (1.4 to 2.3)
Standard 200 mg, all surgery	17	2103	41	7	2.9 (2.6 to 3.2)
"Soluble" salts 200 mg, all surgery	7	828	56	10	2.1 (1.9 to 2.4)
Standard 400 mg, all surgery	55	5604	52	11	2.5 (2.4 to 2.7)
"Soluble" salts 400 mg, all surgery	12	1124	65	18	2.1 (1.9 to 2.4)
Standard 200 mg, dental surgery	15	1883	41	7	2.9 (2.6 to 3.2)
"Soluble" salts 200 mg, dental surgery	7	828	56	10	2.1 (1.9 to 2.4)
Standard 400 mg, dental surgery	46	4772	53	11	2.3 (2.2 to 2.5)
"Soluble" salts 400 mg, dental surgery	9	959	66	10	1.8 (1.7 to 2.0)
40 + participants, dental surgery 200 mg	11	1953	49	10	2.5 (2.3 to 2.8)
< 40 participants, dental surgery 200 mg	4	229	32	5	3.9 (2.8 to 6.1)
40 + participants, dental surgery 400 mg	19	3086	54	12	2.4 (2.2 to 2.6)
< 40 participants, dental surgery 400 mg	14	856	60	14	2.2 (1.9 to 2.5)

Summary of results C: Weighted mean proportion using rescue medication over 6 hours
Dose	Studies	Participants	Ibuprofen (%)	Placebo (%)	NNTp (95%CI)
50 mg	2	208	29	50	4.9 (3.0 to 13)
100 mg	3	296	38	64	3.8 (2.7 to 6.5)
200 mg	8	794	48	76	3.6 (2.9 to 4.6)
400 mg	28	2983	42	79	2.7 (2.5 to 3.0)
100 mg, dental surgery	2	195	59	80	4.8 (2.3 to 12)
200 mg, dental surgery	7	694	53	83	3.4 (2.8 to 4.3)
400 mg, dental surgery	22	2554	41	80	2.5 (2.3 to 2.8)
Standard 200 mg, dental surgery,	4	345	67	87	5.0 (3.5 to 8.7)
"Soluble" salts 200 mg, dental surgery	4	349	43	78	2.9 (2.3 to 4.1)
Standard 400 mg, dental surgery,	18	1857	43	80	2.7 (2.5 to 3.1)
"Soluble" salts 400 mg, dental surgery	6	449	34	82	2.1 (1.8 to 2.5)

Summary of results D: Weighted median and mean time to use of rescue medication
			Median time
Dose	Studies	Participants	Ibuprofen	Placebo
200 mg	10	1807	4.7	2.1
400 mg	31	3548	5.6	1.9
			Mean time
200 mg	4	345	3.9	2.2
400 mg	16	1313	4.6	2.8

		Adverse events		Withdrawals
Study ID	Treatment	Any	Serious	Adverse event	Other
Ahlstrom 1993	(1) Ibuprofen 400 mg, n = 32 (2) Diclofenac (drinkable) 50 mg, n = 35 (3) Placebo n = 30	at 6 h: (1) 3/32 (3) 2/30	None	None	30 excluded for various protocol violations
Arnold 1990	(1) Ibuprofen 400 mg, n = 15 (2) Ketoprofen 25 mg, n = 14 (3) Ketoprofen 100 mg, n = 16 (4) Placebo, n = 14	at 6 h: (1) 6/15 (4) 3/14	None	None	No data
Bakshi 1994	(1) Ibuprofen 400 mg, n = 80 (2) Diclofenac (dispersible) 50 mg, n = 83 (3) Placebo, n = 82	at 6 h: (1) 6/80 (3) 5/82	None	None	12 exclusions: 9 with insufficient baseline pain, 2 remedicated early, 1 completed diary incorrectly
Black 2002	(1) Ibuprofen 200 mg, n = 100 (2) Ibuprofen 400 mg, n = 100 (3) Ibuprofen arginate 200 mg, n = 100 (4) Ibuprofen arginate 400 mg, n = 99 (5) Placebo, n = 99	at 6 h: (1) 31/100 (2) 41/100 (3) 51/100 (4) 36/99 (5) 48/99	(3) 1/100 (dysphagia and pharyngitis after 60 min assessment)	(3) 1/100	4 exclusions from efficacy analysis: 2 from Ibu Arg groups vomited soon after taking drug, 1 ibu arg 200 mg and 1 placebo took prohibited medication
Cheung 2007	(1) Ibuprofen 440 mg, n = 57 (2) Celecoxib 400 mg, n = 57 (3) Placebo, n = 57	at 24 h: (1) 35/57 (3) 39/57	None	(3) 3/57 (vomiting and anxiety)	(3) 1/57 (withdrew consent)
Cooper 1977	(1) Ibuprofen 200 mg n = 38 (2) Ibuprofen 400 mg, n = 40 (3) Aspirin 325 mg, n = 37 (4) Aspirin 650 mg, n = 37 (5) Placebo, n = 40	No data	None	None	Exclusions: 17 provided uninterpretable data, 12 took confounding medication, 10 were lost to follow up, 9 did not need medication, 5 fell asleep
Cooper 1982	(1) Ibuprofen 400 mg, n =38 (2) Ibuprofen 400 mg + Codeine 60 mg, n = 41 (3) Aspirin 650 mg, n = 38 (4) Aspirin 650 mg + codeine 60 mg, n = 45 (5) Codeine 60 mg, n = 41 (6) Placebo, n = 46	at 4 h: (1) 11/38 (6) 5/46	None	None	Exclusions: 30 were lost to follow up, 15 did not need medication, 11 remedicated early, 6 missed more the 1 evaluation, 3 medicated with slight pain, 1 did not take all the medication, 1 medicated over 24 hrs after surgery
Cooper 1988a	(1) Ibuprofen 400 mg, n = 37 (2) Ketoprofen 100 mg, n = 39 (3) Ketoprofen 25 mg, n = 42 (4) Placebo, n = 43	at 6 h: (1) 10/40 (4) 7/45	None reported	None reported	Exclusions: 20 did not need medication, 13 were lost to follow up, 7 had various protocol violations
Cooper 1989	(1) Ibuprofen 400 mg, n = 61 (2) Paracetamol 1000 mg, n = 59 (3) Placebo, n = 64	at 6 h: (1) 5/63 (3) 7/64	None	None	Exclusions: 2 were lost to follow up, 2 did not need medication, 4 missed more than 1 evaluation, 1 had insufficient baseline pain, 1 failed to complete the diary at the appropriate time
Cooper 1996a	(1) Ibuprofen 200 mg, n = 19 (2) Misoprostal 200 mg, n = 18 (3) Ibuprofen 200 mg + misoprostal 200 mg, n = 20 (4) Placebo, n = 13	No usable data All transient and mild	None reported	No data	No data
De Miguel Rivero 1997	(1) Ibuprofen arginine 400 mg, n = 36 (2) Magnesic dipyrone, 2 g (IM), n = 33 (3) Placebo, n = 34	at 5 h: (1) 1/36 (3) 1/34	None	None	Exclusions: 3 did not need medication
Desjardins 2002	(1) Ibuprofen 200 mg, n = 50 (2) Ibuprofen 400 mg, n = 52 (3) Ibuprofen arginine 200 mg, n = 49 (4) Ibuprofen arginine 400 mg, n = 50 (5) Placebo, n = 24	at 6 h: (1) 4/50 (2) 4/52 (3) 3/49 (4) 7/50 (5) 1/24	None	None	Exclusions from efficacy analysis: 1 (placebo) for protocol violation, 1 (placebo) for vomiting after receiving study drug and 1 (Ibu arg 400) for having a seizure 11 hours post‐dose
Dionne 1998	(1) S(+)‐Ibuprofen 200 mg, n = 51 (2) S(+)‐Ibuprofen 400 mg, n = 50 (3) Ibuprofen (racemic) 400 mg, n = 50 (4) Placebo, n = 25	No usable data	None reported	None	Exclusions: 4 had neither partial or bony impaction, 1 remedicated early
Ehrich 1999	(1) Ibuprofen 400 mg, n = 20 (2) Rofecoxib 50 mg, n = 32 (3) Rofecoxib 500 mg, n = 20 (4) Placebo, n = 32	No usable data Any events mild and transient	None	No data	No data Exclusions: 2 remedicated early
Forbes 1984	(1) Ibuprofen 400 mg, n = 28 (2) Fendosal 200 mg, n = 29 (3) Aspirin 650 mg, n = 24 (4) Placebo n = 28	at 12 h: (1) 5/29 (4) 3/30 All transitory and did not require treatment	None	None	Exclusions: 2 remedicated early, 2 remedicated with some pain relief, 2 took rescue medication not test drug
Forbes 1990	(1) Ibuprofen 400 mg, n = 32 (2) Ketorolac 10 mg, n = 31 (3) Ketorolac 20 mg, n = 35 (4) Paracetamol 600 mg, n = 36 (5) Paracetamol 600 mg + codeine 60 mg, n = 38 (6) Placebo, n = 34	at 6 h: (1) 8/43 (6) 0/38 All transitory and did not require treatment	None	None	Exclusions; 3 were lost to follow up, 1 lost report card, 27 remedicated early or while still experiencing some pain relief from study medication, 7 failed to follow instructions, 3 did not complete the forms
Forbes 1991a	(1) Ibuprofen 50 mg, n = 57 (2) Ibuprofen 100 mg, n = 49 (3) Ibuprofen 200 mg, n = 48 (4) Ibuprofen 100 mg + Caffeine 100 mg, n = 49 (5) Ibuprofen 200 mg + Caffeine 100 mg, n = 44 (6) Placebo n = 51	at 8 h: (1) 10/63 (2) 5/62 (3) 6/60 (4) 12/58 (5) 8/58 (6) 8/61 All transitory and did not require treatment	None	None	Exclusions from efficacy analysis: 33 did not need medication, 14 remedicated early, 1 ate caffeine containing food, 2 medicated 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
Forbes 1991b	(1) Ibuprofen 400 mg, n = 37 (2) Bromfenac 5 mg, n = 39 (3) Bromfenac 10 mg, n = 43 (4) Bromfenac 25 mg, n = 42 (5) Aspirin 650 mg, n = 41 (6) Placebo, n = 39	at 8 h: (1) 7/43 (6) 3/47 All transitory and did not require treatment	None	None	Exclusions: 7 were lost to follow up, 12 did not need medication, 24 remedicated early or while still experiencing some pain relief from study medication, 2 lacked consistency, 1 did not complete the form, 1 took only part of the med
Forbes 1992	(1) Ibuprofen 400 mg, n = 38 (2) Bromfenac 10 mg, n = 43 (3) Bromfenac 25 mg, n = 41 (4) Bromfenac 50 mg, n = 42 (5) Bromfenac 100 mg, n = 40 (6) Aspirin 650 mg, n = 38 (7) Placebo, n = 38	at 8 h: (1) 4/45 (7) 2/46 All transitory and did not require treatment	None	None	Exclusions; 3 did not return form, 14 did not need medication, 28 remedicated early or while still experiencing some pain relief from study medication, 2 lacked consistency, 2 did not complete form, 2 took only part of medication, 5 took back up medication, 2 evaluated at incorrect time
Frame 1989	(1) Ibuprofen 400 mg, n = 42 (2) Dihydrocodeine 30 mg, n = 43 (3) Placebo, n = 38	at 5 h: (1) 4/42 (3) 3/38	None reported	(3) 1/38 (postoperative bleed)	Exclusions: 9 did not take the medication, 7 were lost to follow up, 1 was asleep so did not complete the forms, 1 had postoperative complications so did not complete the form
Fricke 1993	(1) Ibuprofen 400 mg, n = 81 (2) Naproxen Na 440 mg, n = 81 (3) Placebo, n = 39	at 12 h: (1) 8/81 (3) 1/39	None	(1) 1/81 (soreness and swelling at 8 hrs)	Exclusions: 5 did not need medication, 1 took study medication twice ‐ excluded from efficacy analysis
Gay 1996	(1) Ibuprofen 400 mg, n = 41 (2) DKP.TRIS 5 mg, n = 41 (3) DKP.TRIS 10 mg, n = 42 (4) DKP.TRIS 20 mg, n = 41 (5) Placebo, n = 39	at 6 h: (1) 3/41 (5) 4/41	None	None	Exclusion from efficacy analysis: 2 remedicated early
Heidrich 1985	(1) Ibuprofen 400 mg, n = 40 (2) Paracetamol 300 + codeine 30 mg, n = 40 (3) Placebo, n = 40	No usable data Overall occurrence ±15%, no difference between groups	None reported	None	No data
Hersch 1993a	(1) Ibuprofen 200 mg, n = 51 (2) Ibuprofen 400 mg, n = 49 (3) Meclofenamate 100 mg, n = 52 (4) Meclofenamate 50 mg, n = 51 (5) Placebo, n = 51	at 8 h: (1) 6/49 (2) 4/51 (5) 9/51    All transitory and did not require treatment	None reported	None	No data
Hersch 1993b	(1) Ibuprofen 400 mg, n = 12 (2) Codeine 60 mg, n = 16 (3) Placebo, n = 16	No data	None reported	None reported	Exclusions: 19 lost to follow up, 11 did not need medication, 3 excluded for various protocol violations
Hersh 2000	(1) Ibuprofen liquigel 200 mg, n = 61 (2) Ibuprofen liquigel 400 mg, n = 59 (3) Paracetamol 1000 mg, n = 63 (4) Placebo, n = 27	at 6 h: (1) 7/61 (2) 4/59 (4) 7/27	None	None	None
Hill 2001	(1) Ibuprofen 400 mg, n = 49 (2) Pregabalin 50 mg, n = 49 (3) Pregabalin 300 mg, n = 50 (4) Placebo, n = 50	at 12 h: (1) 6/49 (4) 8/50	None	None	None
Jain 1986	(1) Ibuprofen 400 mg, n = 49 (2) Ibuprofen 200 mg, n = 47 (3) Ibuprofen 100 mg, n = 39 (4) Aspirin 650 mg, n = 45 (5) Placebo, n = 47	at 6 h: (1) 10/49 (2) 6/47 (3) 13/39 (5) 12/47	None reported	None reported	None
Jain 1988	(1) Ibuprofen 400 mg, n = 49 (2) Ibuprofen 200 mg + caffeine 100 mg, n = 50 (3) Placebo, n = 48	at 6 h: (1) 2/49 (2) 5/50 (3) 1/48	None reported	None reported	Exclusions: 11 remedicated early, 2 received confounding agents, 1 was under 18 yrs old
Johnson 1997	(1) Ibuprofen 400 mg, n = 48 (2) Paracetamol 650 mg + oxycodone 10 mg, n = 47 (3) Bromfenac 100 mg, n = 48 (4) Bromfenac 50 mg, n = 47 (5) Placebo, n = 48	No usable data CNS AEs at 8 h: (1) 5/48 (5) 2/48	None reported	None reported	Exclusions: 2 had invalid data
Kiersch 1993	(1) Ibuprofen 200 mg, n = 81 (2) Naproxen Na 220 mg, n = 80 (3) Placebo, n = 42	at 12 h: (1) 16/81 (3) 5/43	None	(1) 1/81	Exclusions: 2 had protocol violations
Laska 1986	(1) Ibuprofen 400 mg, n = 39 (2) Ibuprofen 600 mg, n = 36 (3) Ibuprofen 800 mg, n = 39 (4) Aluminium ibuprofen 400 mg, n = 39 (5) Placebo, n = 37	at 6 h: (1) 0/39 (2) 1/36 (3) 0/39 (4) 1/39 (5) 3/37	None reported	None	Exclusions: 4 remedicated early, 1 vomited within 5 mins of taking the study medication. 4 with moderate pain dropped to keep populations homogeneous (author letter)
Laveneziana 1996	(1) Ibuprofen arginine soluble 400 mg, n = 42 (2) Ketorolac 30 mg, n = 41 (3) Placebo, n = 41	None	None	None	Exclusions: 1 had insufficient pain
Malmstrom 1999	(1) Ibuprofen 400 mg, n = 46 (2) Rofecoxib 50 mg, n = 90 (3) Celecoxib 200 mg, n = 91 (4) Placebo, n = 45	No usable data	None reported	(4) 1/45 (excessive bleeding)	None 4 patients lost to follow up at post‐study visit
Malmstrom 2002	(1) Ibuprofen 400 mg, n = 45 (2) Rofecoxib 50 mg, n = 151 (3) Celecoxib 400 mg, n = 151 (4) Celecoxib 200 mg, n = 90 (5) Placebo, n = 45	at 24 h: (1) 8/45 (5) 12/45	None	None	None
Malmstrom 2004	(1) Ibuprofen 400 mg, n = 48 (2) Etoricoxib 60 mg, n = 75 (3) Etoricoxib 120 mg, n = 76 (4) Etoricoxib 180 mg, n = 74 (5) Etoricoxib 240 mg, n = 76 (6) Placebo, n = 49	Up to 14 days: (1) 17/48 (6) 24/49	None	(1) 1/48 (vomiting)	None
McQuay 1996	(1) Ibuprofen 200 mg, n = 31 (2) Ibuprofen 400 mg, n = 30 (3) Ibuprofen 200 mg + caffeine 50 mg, n = 30 (4) Ibuprofen 200 mg + caffeine 100 mg, n = 30 (5) Ibuprofen 200 mg + caffeine 200 mg, n = 29 (6)Placebo, n = 11	at 8 h: (1) 4/31 (2) 1/30 (3) 2/30 (4) 0/29 (5) 2/30 (6) 1/11	None reported	None	Exclusions: 3 with protocol violations
Medve 2001	(1) Ibuprofen 200 mg, n = 240 (2) Tramadol 37.5 mg, n = 238 (3) Paracetamol 325 mg, n = 240 (4) Tramadol 37.5 mg + paracetamol 325 mg, n = 240 (5) Placebo, n = 239	No usable data Generally transient and mild to moderate in severity	None reported	No data	No details for 3 exclusions
Mehlisch 1990	(1) Ibuprofen 400 mg, n = 306 (2) Paracetamol 1000 mg, n = 306 (3) Placebo, n = 85	at 6 h: (1) 31/306 (3) 12/85	None reported	None	Exclusions: 4 were lost to follow up, 4 entered in the trial twice (1st entry only was analysed for efficacy but both were included in safety analysis) and 1 excluded for failing to meet inclusion criteria
Mehlisch 1995	(1) Ibuprofen lysine 400 mg, n = 98 (2) Paracetamol 1000 mg, n = 101 (3) Placebo, n = 40	at 6 h: (1) 12/98 (3) 4/40	None	None	Exclusions: 1 failed to complete diary
Mehlisch 2002	(1) Ibuprofen 200 mg, n = 100 (2) Ibuprofen 400 mg, n = 100 (3) Ibuprofen arginine 200 mg, n = 100 (4) Ibuprofen arginine 400 mg, n = 100 (5) Placebo, n = 100	at 6 h: (1) 28/100 (2) 27/100 (3) 27/100 (4) 26/100 (5) 27/100	None	None	Exclusions: 3 from efficacy analysis for protocol violation
Morrison 1999	(1) Ibuprofen 400 mg, n = 51 (2) Rofecoxib 50 mg, n = 50 (3) Placebo, n = 50	at 24 h: (1) 13/51 (3) 17/50	None	None	None
Nelson 1994	(1) Ibuprofen lysine 200 mg, n = 77 (2) Aspirin 500 mg, n = 65 (3) Placebo, n = 40	at 6 h: (1) 16/75 (3) 11/40	None	None	Exclusions: 2 remedicated early, 1 did not record baseline pain intensity
Nørholt 1998	(1) Ibuprofen 400 mg, n = 26 (2) Placebo, n = 31	No data	No data	None	None
Olson 2001	(1) Ibuprofen liquigel 400 mg, n = 67 (2) Ketoprofen 25 mg, n = 67 (3) Paracetamol 1000 mg, n = 66 (4) Placebo, n = 39	at 6 h: (1) 7/67 (4) 2/39	None	None	None
Pagnoni 1996	(1) Ibuprofen arginine soluble 400 mg, n = 30 (2) Ketorolac (IM) 30 mg, n = 30 (3) Placebo, n = 32	None	None	None	None
Parker 1986	(1) Ibuprofen syrup 600 mg, n = 44 (2) Aspirin syrup 600 mg, n = 33 (3) Placebo, n = 33	No usable data	None reported	(3) 1/33 (probably in multiple dose phase)	Exclusions: 29 for which there is no further data
Schachtel 1989	(1) Ibuprofen 400 mg, n = 36 (2) Paracetamol 1000 mg, n = 37 (3) Placebo, n = 38	at 4 h: None	None	None	Exclusions: 4 remedicated early
Schou 1998	(1) Ibuprofen 50 mg, n = 51 (2) Ibuprofen 100 mg, n = 53 (3) Ibuprofen 200 mg, n = 49 (4) Ibuprofen 400 mg, n = 49 (5) Placebo, n = 56	No usable data 18 patients reported mild transient AEs ‐ no details of groups	None	None	Exclusions: 46 due to insufficient baseline pain, 3 withdrew (reasons not related to AE), 5 failed to attend follow‐up, 5 lost self‐report measure, 3 took study prohibited additional analgesia, 3 did not require surgery, 2 remedicated early, 1 had concomitant surgical removal of maxillary third molar
Schwartz 2007	(1) Ibuprofen 400 mg, n = 15 (2) MK‐0703 12.5 mg, n = 31 (3) MK‐0703 50 mg, n = 28 (4) MK‐0703 100 mg, n = 31 (5) Placebo, n = 16	No usable data 38 patients in total reported AEs, no details of groups	None	None	None
Seymour 1991 (study 1)	(1) Ibuprofen tablets 400 mg, n = 31 (2) Ibuprofen liquid in gelatin capsules 400 mg, n = 32 (3) Placebo n = 32	at 6 h: (1) 0/31 (2) 0/32 (3) 1/32	None	None	No data
Seymour 1991 (study 2)	(1) Ibuprofen tablets 400 mg, n = 30 (2) Ibuprofen soluble 400 mg, n = 32 (3) Placebo, n = 30	at 6 h: None	None	None	No data
Seymour 1996	(1) Ibuprofen tablets 200 mg, n = 18 (2) Ibuprofen soluble 200 mg, n = 17 (3) Ibuprofen tablets 400 mg, n = 15 (4) Ibuprofen soluble 400 mg, n = 16 (5) Ibuprofen tablets 600 mg, n = 17 (6) Ibuprofen soluble 600 mg, n = 17 (7) Placebo, n = 19	No data	No data	No usable data 4 reported adverse effects, 3 had received ibuprofen (did not clarify which dose) and 1 had taken placebo	25 had inadequate baseline pain intensity
Seymour 1998	(1) Ibuprofen 400 mg, n = 76 (2) Aceclofenac 150 mg, n = 71 (3) Placebo, n = 70	at 6 h: (1) 5/76 (3) 3/68	None reported	None reported	Exclusions: 2 patients in group 2 and 2 patients in group 3 not accounted for
Seymour 1999	(1) Ibuprofen 400 mg, n = 41 (2) WAG 994 1 mg, n = 42 (3) Placebo, n = 39	No data	None	No data	No data
Seymour 2000	(1) Ibuprofen 200 mg, n = 59 (2) Buffered ketoprofen 12.5 mg, n = 61 (3) Placebo, n = 50	at 6 h: (1) 5/59 (3) 3/60	None	None	Exclusions: 2 remedicated early, one in Ibuprofen group and one in placebo group
Singla 2005	(1) Ibuprofen 400 mg, n = 175 (2) Ibuprofen 400 mg + oxycodone 5 mg, n = 169 (3) Oxycodone 5 mg, n = 52 (4) Placebo, n = 60	at 6 h: (1) 74/175 (4) 33/60	None	(1) 1/175 (4) 0/60	1 patient in Ibu group excluded due to protocol violation
Sunshine 1983	(1) Ibuprofen 400 mg, n = 30 (2) Aspirin 600 mg, n = 30 (3) Zomepirac 100 mg, n = 30 (4) Placebo, n = 30	None	None	None	None
Sunshine 1987	(1) Ibuprofen 400 mg, n = 38 (2) Ibuprofen 200 mg + codeine 30 mg, n = 40 (3) Ibuprofen 400 mg + codeine 60 mg, n = 40 (4) Codeine 60 mg, n = 37 (5) Placebo, n = 40	at 4 h: (1) 0/38 (5) 0/40	None	None	Exclusions: 1 had not complied with the washout period, 4 did not complete the evaluations
Sunshine 1996	(1) Ibuprofen 50 mg, n = 51 (2) Ibuprofen 100 mg, n = 51 (3) Ibuprofen 200 mg, n = 50 (4) Ibuprofen 100 mg + caffeine 100 mg, n = 50 (5) Ibuprofen 200 mg + caffeine 100 mg, n = 50 (6) Placebo, n = 50	at 6 h: (1) 1/51 (2) 4/51 (3) 1/50 (4) 2/50 (5) 4/50 (6) 0/50	None	None	Exclusions: 3 for protocol violations
Sunshine 1997	(1) Ibuprofen 400 mg, n = 40 (2) Ibuprofen 400 mg + hydrocodone 15 mg, n = 40 (3) Placebo, n = 39	at 6 h: (1) 5/40 (3) 4/40	None	None	Exclusions: One from placebo group refused to cooperate and was excluded from the study
Sunshine 1998	(1) Ibuprofen 200 mg, n = 35 (2) Ketoprofen 6.25 mg, n = 35 (3) Ketoprofen 12.5 mg, n = 35 (4) Ketoprofen 25 mg, n = 35 (5) Placebo, n = 35	Up to 6 h: (1) 2/35 (5) 3/35	None	None	Exclusions: 2 remedicated early, 1 vomited study drug, 1 withdrew consent
Unpubl 2002 (Edwards 2002)	(1) Ibuprofen 400 mg, n = 339 (2) Placebo, n = 339	at 6 h: (1) 41/339 (2) 58/337	None	No usable data	Total withdrawals not due to lack of efficacy (1) 2/339 (2) 3/337
Van Dyke 2004	(1) Ibuprofen 400 mg, n = 186 (2) Ibuprofen 400 mg + oxycodone 5 mg, n = 187 (3) Oxycodone 5 mg, n = 63 (4) Placebo, n = 62	at 6 h: (1) 20/186 (4) 7/62	None	None	Exclusions: 1 had inadequate baseline pain (1) 1/186 no reason given
Wahl 1997	(1) Ibuprofen lysinate 342 mg (= 200 mg Ibu), n = 74 (2) Paracetamol 200 mg + aspirin 250 mg + caffeine 50 mg, n = 73 (3) Placebo, n = 42	at 6 h: (1) 7/74 (3) 5/42	None	None	Exclusions: 12 withdrew consent, 13 did not require analgesia after surgery, 6 failed to complete their study lists, and 1 may not have taken study medication correctly
Wideman 1999 (study 1)	(1) Ibuprofen 200 mg, n = 60 (2) Ibuprofen 200 mg, + hydrocodone 7.5 mg, n = 59 (3) Hydrocodone 7.5 mg, n = 61 (4) Placebo, n = 60	at 8 h: (1) 6/60 (4) 1/60	None	None	None
Wideman 1999 (study 2)	(1) Ibuprofen 400 mg, n = 50 (2) Ibuprofen 400 mg + hydrocodone 15 mg, n = 50 (3) Hydrocodone 15 mg, n = 50 (4) Placebo, n = 51	at 8 h: (1) 7/50 (4) 6/51	None	None	None
Zelenakas 2004	(1) Ibuprofen 400 mg, n = 51 (2) Lumiracoxib 100 mg, n = 51 (3) Lumiracoxib 400 mg, n = 50 (4) Placebo, n = 50	at 12 h: (1) 5/51 (4) 10/50	(1) 0/51 (4) 1/50 (deep vein thrombosis)	(1) 1/51 (postoperative bleed)	(1) 1/51 (? withdrew consent)

Summary of results E: Participants with at least one adverse event
Dose	Studies	Participants	Ibuprofen (%)	Placebo (%)	NNH (95%CI)
50 mg	2	225	10	7	not calculated
100 mg	3	310	14	13	not calculated
200 mg	14	1808	19	19	not calculated
400 mg	40	4867	17	16	not calculated

Date	Event	Description
29 May 2019	Amended	Contact details updated.
7 July 2017	Review declared as stable	See Published notes.

Date	Event	Description
25 April 2012	Review declared as stable	Although new studies on Ibuprofen may be published, they are unlikely to impact on the results of this review and so the authors suggest there should be no need to update this review for at least five years.
8 February 2011	Amended	Contact details updated.
6 October 2010	Amended	Contact details updated.
11 May 2009	New citation required and conclusions have changed	Information from 37 new studies with 5595 participants was added, giving a total of 72 studies and 9186 participants. NNTs for at least 50% pain relief over 4 to 6 hours were not significantly changed. Additional information on the proportion of participants requiring rescue medication, and median or mean time to use of rescue medication, are provided, with higher doses giving slightly better results. Pain model and ibuprofen formulation may both affect the result, with dental impaction models and soluble ibuprofen salts producing better efficacy estimates. A dose response was demonstrated in dental pain.
11 May 2009	New search has been performed	The original review published in 1999 was updated and an additional updated search was run prior to publication from January 2009 to May 2009 which found four new studies; two were subsequently excluded, and two are awaiting classification.
23 May 2008	Amended	Converted to new review format.
25 January 2002	Amended	New studies found but not yet included or excluded

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with at least 50% pain relief over 4 to 6 hours	3	316	Risk Ratio (M‐H, Fixed, 95% CI)	3.15 [1.94, 5.12]
2 Participants using rescue medication over 6 hours	2	208	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.44, 0.84]
3 Participants with any adverse event	2	225	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.57, 3.00]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with at least 50% pain relief over 4 to 6 hours	4	396	Risk Ratio (M‐H, Fixed, 95% CI)	3.68 [2.29, 5.92]
2 Participants using rescue medication over 6 hours	3	296	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.57, 0.84]
3 Participants with any adverse event	3	310	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.71, 2.07]

Methods	RCT, DB, DD, single oral dose, 3 parallel groups Medication administered when baseline pain was of least moderate intensity Pain assessed at 0, 20, 40, 60 mins then hourly up to 6 hours.
Participants	Third molar extraction N = 127 (97 valid for analysis) M/F not given Mean age 25 years
Interventions	Ibuprofen 400 mg, n = 32 Diclofenac (drinkable) 50 mg, n= 35 Placebo n= 30
Outcomes	PI: std 100 mm VAS PGE: std 5 point scale Numbers of participants using rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication permitted after 1 hour.

Methods	RCT, DB, single oral dose, 4 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 30, 60 mins then hourly up to 6 hours.
Participants	General surgery (including gynaecological and orthopaedic) N = 59 M = 35, F = 24 Age: 22 ‐ 70 years
Interventions	Ibuprofen 400 mg, n = 15 Ketoprofen 25 mg, n = 14 Ketoprofen 100 mg, n = 16 Placebo, n = 14
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals due to AE
Notes	Oxford Quality Score: R2, DB2, W0 Rescue medication permitted ‐ no further details.

Methods	RCT, DB, single oral dose, 3 parallel groups Medication administered when baseline pain was of severe intensity Pain assessed at 0, 20, 40, 60, 90, 120 mins, then hourly up to 6 hours.
Participants	Third molar extraction N = 257 (245 valid for analysis) M = 151, F = 94 Mean age 28 years
Interventions	Ibuprofen 400 mg, n = 80 Diclofenac (dispersible) 50 mg, n = 83 Placebo, n = 82
Outcomes	PI: std 100 mm VAS PR: std 5 point scale PGE: non‐std 4 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB1, W1 Rescue medication of patient's choice permitted after 1 hour.

Methods	RCT, DB, DD, single then multiple oral dose, 5 parallel groups multicentre Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120 mins, then hourly up to 6 hours.
Participants	Third molar extraction N = 498 M = 219, F = 279 Mean age 22 years
Interventions	Ibuprofen 200 mg, n = 100 Ibuprofen 400 mg, n = 100 Ibuprofen arginate 200 mg, n = 100 Ibuprofen arginate 400 mg, n = 99 Placebo, n = 99
Outcomes	PI: std 5 point scale PR: std 5 point scale PGE: std 5 point scale Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication was 2nd dose (or active treatment if in placebo group) as required.

Methods	RCT, DB, single oral dose, 5 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at baseline then hourly up to 4 hours.
Participants	Third molar extraction N = 245 (192 analysed) M = 83, F = 109 Age 16‐35 years
Interventions	Ibuprofen 200 mg n = 38 Ibuprofen 400 mg, n = 40 Aspirin 325 mg, n = 37 Aspirin 650 mg, n = 37 Placebo, n= 40
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Withdrawals
Notes	Oxford Quality Score: R2, DB2, W1 Rescue medication permitted after 2 hours.

Methods	RCT, DB, single oral dose, 6 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at baseline then hourly up to 4 hours.
Participants	Third molar extraction N = 316 (249 analysed) M = 83, F = 166 Mean age 23 years
Interventions	Ibuprofen 400 mg, n =38 Ibuprofen 400 mg + Codeine 60 mg, n = 41 Aspirin 650 mg, n = 38 Aspirin 650 mg + codeine 60 mg, n = 45 Codeine 60 mg, n = 41 Placebo, n = 46
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication permitted after 1 hour.

Methods	RCT, DB, DD, single oral or intramuscular dose, 3 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 10, 20, 30, 45, 60, 90, 120 mins, then hourly up to 5 hours.
Participants	Total hip replacement N = 103 (106 randomised, 3 did not need medication) M = 47, F = 56 Mean age 62 years
Interventions	Ibuprofen arginine 400 mg, n = 36 Magnesic dipyrone, 2 g (IM), n = 33 Placebo, n = 34
Outcomes	PI: std 100 mm VAS PGE: std 5 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication permitted after 1 hour.

Methods	Five RCTs, DB, single oral dose, parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 30, 60 mins, then hourly up to 8 hours.
Participants	Third molar extraction N = 339 M/F nor given Age not given
Interventions	Ibuprofen 400 mg, n = 338 Placebo, n = 339
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Numbers of participants using rescue medication Numbers with any adverse event Withdrawals
Notes	R2, DB2, W1 Rescue medication permitted ‐ no further details.

Methods	RCT, DB, single then multiple oral dose, 6 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at baseline, then hourly up to 6 hours
Participants	Third molar extraction N = 269 (206 analysed for efficacy, 244 for safety) M = 104, F = 102 Mean age 23 years
Interventions	Ibuprofen 400 mg, n = 32 Ketorolac 10 mg, n = 31 Ketorolac 20 mg, n = 35 Paracetamol 600 mg, n = 36 Paracetamol 600 mg + codeine 60 mg, n = 38 Placebo, n = 34
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R2, DB2, W1 Rescue medication permitted after 2 hours.

Methods	RCT, DB, single oral dose, 7 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at baseline, then hourly up to 8 hours.
Participants	Third molar extraction N = 324 (280 analysed for efficacy, 317 for safety) M = 119, F = 161 Mean age 23 years
Interventions	Ibuprofen 400 mg, n = 38 Bromfenac 10 mg, n = 43 Bromfenac 25 mg, n = 41 Bromfenac 50 mg, n = 42 Bromfenac 100 mg, n = 40 Aspirin 650 mg, n = 38 Placebo, n = 38
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R2, DB2, W1 Rescue medication permitted after 2 hours.

PERMALINK

Single dose oral ibuprofen for acute postoperative pain in adults

Christopher J Derry

Sheena Derry

R Andrew Moore

Henry J McQuay

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Language

Unpublished studies

Data collection and analysis

Selection of studies

Quality assessment

Data management

Data analysis

Primary outcome:

Number of participants achieving at least 50% pain relief

Secondary outcomes:

Results

Description of studies

Risk of bias in included studies

Methodological quality of included studies

Effects of interventions

Number of participants achieving at least 50% pain relief

1. Summary of outcomes: analgesia and use of rescue medication.

Ibuprofen 50 mg versus placebo

1.1. Analysis.

Ibuprofen 100 mg versus placebo

2.1. Analysis.

Ibuprofen 200 mg versus placebo

3.1. Analysis.

1.

Ibuprofen 400 mg versus placebo

4.1. Analysis.

2.

Ibuprofen 600 mg versus placebo

5.1. Analysis.

6.1. Analysis.

Sensitivity analysis of primary outcome

Methodological quality

Pain model; dental versus other surgery

Ibuprofen 200 mg

3.2. Analysis.

Ibuprofen 400 mg

4.2. Analysis.

3.

Dose response in dental studies

Salt preparation: standard ibuprofen versus ibuprofen lysine, arginine and "soluble"

Ibuprofen 200 mg

3.3. Analysis.

3.4. Analysis.

Ibuprofen 400 mg

4.3. Analysis.

4.

4.4. Analysis.

5.

Study size: 40 or more participants per treatment arm versus fewer than 40

Ibuprofen 200 mg

3.5. Analysis.

Ibuprofen 400 mg

4.5. Analysis.

Use of rescue medication

Proportion of participants using rescue medication (Summary of results C)

1.2. Analysis.

Methods	RCT, DB, pre‐surgery placebo then single oral dose, 3 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 30 60 mins, then hourly up to 6 hours.
Participants	Third molar extraction N = 103 (81 analysed) M/F not given Age not given
Interventions	All participants received preoperative placebo, then: Ibuprofen 400 mg, n = 12 Codeine 60 mg, n = 16 Placebo, n = 16
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Time to use of rescue medication Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication permitted after 1 hour.

Methods	RCT, DB, DD, single oral dose, 4 parallel groups Medication administered when baseline pain was of moderate to severe intensity (≥50 mm) Pain assessed at 0, 15, 30, 45, 60, 90, 120 mins, then hourly up to 6 hours.
Participants	Third molar extraction N = 210 M = 66, F = 144 Mean age 24 years
Interventions	Ibuprofen liquigel 200 mg, n = 61 Ibuprofen liquigel 400 mg, n = 59 Paracetamol 1000 mg, n = 63 Placebo, n = 27
Outcomes	PI: std 4 point scale PR: std 5 point scale PGE: std 5 point scale Numbers of participants using rescue medication Time to use of rescue medication Numbers with any adverse event Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication (paracetamol+hydrocodone) permitted after 1 hour

Methods	RCT, DB, single oral dose, 2 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at baseline, then hourly up to 4 hours.
Participants	Third molar extraction N = 57 M = 21, F = 36 Mean age 24 years
Interventions	Ibuprofen 400 mg, n = 26 Placebo, n = 31
Outcomes	PI: non‐std 5 point scale PR: 5 point scale ‐ reverse wording Numbers of participants using rescue medication Withdrawals
Notes	Oxford Quality Score: R1, DB2, W1 Rescue medication (paracetamol) permitted.

Methods	RCT, DB, single oral dose then multiple doses, 3 parallel groups Medication administered when baseline pain was of moderate to severe intensity Pain assessed at 0, 30, 60 mins, then hourly up to 4 hours.
Participants	Tonsillectomy N = 139 (110 analysed) M/F not given Age range 16 ‐ 66 years
Interventions	Ibuprofen syrup 600 mg, n = 44 Aspirin syrup 600 mg, n = 33 Placebo, n = 33
Outcomes	PI: non‐std 9 point scale PR: std 5 point scale PGE: std 5 point scale Withdrawals
Notes	Oxford Quality Score: R1, DB2, W0 Rescue medication (oral or IM) permitted.

Study	Reason for exclusion
Ahlstrom 1989	No placebo control.
Akural 2009	Medication administered preoperativley.
Anaokar 1993	No placebo control.
Apaydin 1994	No placebo control.
Apiou 1988	No placebo control.
Aranda 1989	No placebo control.
Averbuch 2000	Not an original report of trials, and unable to ensure that participants (total of 75 treated with ibuprofen) were not in another included study.
Bailey 1993	No placebo control.
Behotas 1992	Baseline pain intensity was not moderate to severe.
Bhounsule 1990	Did not state whether patients had a baseline pain of at least moderate intensity.
Biehl 1981	No placebo control.
Bloomfield 1974	Used 5 point pain intensity scale which is not validated for the data extraction method.
Calanchini 1991	No placebo control.
Carlos 1984	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.
Carrillo 1990	Did 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.
Chopra 2009	Medication administered at 1 hour, irrespective of baseline pain.
Cooper 1984	Inadequate description of method. Did not state whether interventions were randomly allocated or studies were double‐blind.
Cooper 1988b	Inadequate description of method. Did not state whether interventions were randomly allocated.
Cooper 1993	No placebo control.
Cooper 1996b	Intervention administered irrespective of postoperative baseline pain.
Darsow 1988	No direct pain outcome measured over the first 4‐6 hours (recorded motility etc in the days following surgery).
Dorfmann 1991	Inadequate 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.
Doyle 2002	No usable data for ibuprofen treatment arm.
El‐Tanany 1993	No placebo control.
Fleiss 1979	Take medication "if experience pain". Cannot assume that all the patients included had a baseline pain of >moderate intensity.
Forbes 1991	Used a controlled release formulation of ibuprofen.
Frezza 1985	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.
Gallardo 1980	Baseline pain intensity not moderate to severe.
Gallardo 1981	Data was only collected for three hours.
Garwood 1983	No placebo control.
Giles 1981	No placebo control.
Giles 1985	Did not state which scale was used.
Hazra 1982	Baseline pain intensity not moderate to severe.
Henderson 1994	No placebo control.
Henrikson 1982	Only presented the data for the placebo arm for the first hour.
Henrikson 1985	No placebo control.
Hopkinson 1980	Five 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 1978	Cross‐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 1992	Intervention administered preoperatively. Therefore inadequate baseline pain.
Hyrkas 1993	Intervention administered preoperatively. Therefore inadequate baseline pain.
Hyrkas 1994	Intervention administered preoperatively. Therefore inadequate baseline pain.
Iles 1980	Data was only presented for one hour after administration of the interventions.
Iqbal 1986	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.
Iwabuchi 1980	No placebo control.
Joubert 1977	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.
Katharia 1992	Multiple dose study with no separate analysis of the first dose.
Khan 1992	No placebo control.
Kittala 1972	Intervention routinely administered to all participants irrespective of level of baseline pain.
Klein 1994	Abstract.
Mastronardi 1988	No placebo control.
Matthews 1984	First dose was administered immediately postoperatively irrespective of patients level of pain.
McEvoy 1996	No placebo control.
McQuay 1993	No placebo control.
Movilia 1990	First dose was administered immediately postoperatively irrespective of patients level of pain.
Nakanishi 1990	No placebo control.
Negm 1989	Included participants who took the medication when they were experiencing only mild pain.
Rondeau 1980	Baseline pain intensity not moderate to severe.
Rossi 1981	Inadequate description of method. Did not state whether study was double blind. Also data was only recorded for three hours.
Schleier 2007	No placebo control.
Shimura 1981	No placebo control.
Squires 1981	Intervention administered preoperatively. Therefore inadequate baseline pain.
Tai 1992	No placebo control.
Tani 1974	No placebo control.
Tesseroli 1986	The 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 1.96 x SD was less than 30 mm, therefore some patients included may have had a baseline pain intensity of less than moderate.
Troullos 1990	Intervention administered preoperatively. Therefore inadequate baseline pain.
Turcotte 1986	Baseline pain intensity not moderate to severe.
Van Der Zwan 1982	No direct pain outcome measurement used, pain assessed by analgesic intake.
Van Wering 1972	No placebo control.
Vigneron 1977	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.
Vogel 1984	Combined the data from separate arms of a cross‐over trial into one data set.
Von Mayer 1980	Multiple dose study with no mention of the level of baseline pain.
Walker 1976	No placebo control.
Walton 1990	Intervention administered preoperatively. Therefore inadequate baseline pain.
Walton 1993	First 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 1990	No placebo control.
Winter 1978	Baseline pain intensity not moderate to severe.
Wuolijoki 1987	Interventions were administered either pre‐operatively or immediately post‐operatively. Therefore insufficient baseline pain.

Methods	RCT, DB, DD single dose
Participants	Third molar extraction, experiencing moderate to severe postoperative pain
Interventions	Sodium ibuprofen 512 mg, ibuprofen/poloxamer 400 mg/60 mg, paracetamol 1000 mg, placebo
Outcomes	Pain intensity and pain relief, onset of pain relief, tolerability
Notes

Methods	RCT, DB, single dose
Participants	Mandibular third molar extraction, experiencing moderate to severe postoperative pain
Interventions	Tapentodol HCl 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, morphine sulphate 60 mg, ibuprofen 400 mg, placebo
Outcomes	Pain relief, adverse events
Notes