• Sheena Derry, Samuel M Karlin, and R Andrew Moore.
• Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
• Cochrane Db Syst Rev. 2013 Jan 1;3:CD010107.

BackgroundThere is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific effects are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations and when tested in the same and different trials. Some combinations of ibuprofen and codeine are available without prescription (but usually only from a pharmacy) where the dose of codeine is lower, and with a prescription when the dose of codeine is higher.ObjectivesTo assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus codeine for moderate to severe postoperative pain. We compared ibuprofen plus codeine with placebo and with the same dose of ibuprofen alone.Search MethodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. The date of the most recent search was 30 September 2012.Selection CriteriaRandomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus codeine for acute postoperative pain in adults.Data Collection And AnalysisTwo review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed ibuprofen plus codeine, placebo, or the same dose of ibuprofen alone with at least 50% pain relief over six hours, using validated equations. We calculated the relative risk (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. Analyses were planned for different doses of ibuprofen and codeine, but especially for codeine where we set criteria for low (< 10 mg), medium (10 to 20 mg), and high (> 20 mg) doses.Main ResultsInformation was available from six studies with 1342 participants, with a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% CI 1.8 to 2.6). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (95% CI 1.01 to 1.6). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies.Authors' ConclusionsThe combination of ibuprofen 400 mg plus codeine 25.6 to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone. Use of combination analgesics that contain codeine has been a source of some concern because of misuse from over-the-counter preparations.

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