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Combination paracetamol and ibuprofen for pain relief after oral surgery: a dose ranging study

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Combined paracetamol and ibuprofen has been shown to be more effective than either constituent alone for acute pain in adults, but the dose-response has not been confirmed. The aim of this study was to define the analgesic dose-response relationship of different potential doses of a fixed dose combination containing paracetamol and ibuprofen after third molar surgery.


Patients aged 16 to 60 years with moderate or severe pain after the removal of at least two impacted third molars were randomised to receive double-blind study medication as two tablets every 6 h for 24 h of either of the following: two tablet, combination full dose (paracetamol 1000 mg and ibuprofen 300 mg); one tablet, combination half dose (paracetamol 500 mg and ibuprofen 150 mg); half a tablet, combination quarter dose (paracetamol 250 mg and ibuprofen 75 mg); or placebo. The primary outcome measure was the time-adjusted summed pain intensity difference over 24 h (SPID 24) calculated from the 100-mm VAS assessments collected over multiple time points for the study duration.


Data from 159 patients were included in the analysis. Mean (SD) time-adjusted SPID over 24 h were full-dose combination 20.1 (18.0), half dose combination 20.4 (20.8), quarter dose combination 19.3 (20.0) and placebo 6.6 (19.8). There was a significant overall effect of dose (p = 0.002) on the primary outcome. Planned pairwise comparisons showed that all combination dose groups were superior to placebo (full dose vs. placebo p = 0.004, half dose vs. placebo p = 0.002, quarter dose vs. placebo p = 0.002). The overall effect of dose was also significant for maximum VAS pain intensity score (p = 0.048), response rate (p = 0.0094), percentage of participants requiring rescue (p = 0.025) and amount of rescue (p < 0.001). No significant dose effect was found for time to peak reduction in VAS or time to meaningful pain relief. The majority of adverse events recorded were of mild (52.75 %) or moderate (40.16 %) severity and not related (30.7 %) or unlikely related (57.5 %) to the study medication.


All doses of the combination provide safe superior pain relief to placebo in adult patients following third molar removal surgery.

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We are most grateful to the participants who volunteered to take part in this research. We wish to thank Mr Christopher Seeley, Mrs Anneke Marais, Mrs Julia Matheson and Ms Ali Maoate for administration of the study protocol and data collection. We are grateful to Dr. Jennifer Zhang for trial monitoring, Dr. Amanda Potts for her assistance in drafting this manuscript and Mrs. Ioana Stanescu for reviewing the manuscript.

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Correspondence to Chris Frampton.

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Atkinson, H.C., Currie, J., Moodie, J. et al. Combination paracetamol and ibuprofen for pain relief after oral surgery: a dose ranging study. Eur J Clin Pharmacol 71, 579–587 (2015).

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