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Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: a systematic review

BMJ 1996; 313 doi: (Published 10 August 1996) Cite this as: BMJ 1996;313:321
  1. Anton J M de Craen, clinical epidemiologista,
  2. Giuseppe Di Giulio, research fellowb,
  3. Angela J E M Lampe-Schoenmaeckers, anaesthesiologistc,
  4. Alphons G H Kessels, clinical epidemiologistb,
  5. Jos Kleijnen, clinical epidemiologistd
  1. a Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, PO Box 22700, NL-1100 DE Amsterdam, Netherlands
  2. b Department of Epidemiology, University of Limburg, PO Box 616, NL-6200 MD Maastricht, Netherlands
  3. c Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam
  4. d Dutch Cochrane Centre, Academic Medical Centre, University of Amsterdam
  1. Correspondence to: Mr de Craen.
  • Accepted 11 July 1996


Objectives: To assess whether adding codeine to paracetamol has an additive analgesic effect; to assess the safety of paracetamol-codeine combinations versus paracetamol alone.

Design: Systematic literature review with meta-analysis, methodological quality of published trials being scored by means of 13 predefined criteria.

Trials: 24 of 29 trials that met the inclusion criteria. Models studied in the trials were postsurgical pain (21), postpartum pain (one), osteoarthritic pain (one), and experimentally induced pain (one).

Interventions: Dosages ranged from 400 to 1000 mg paracetamol and 10 to 60 mg codeine.

Main outcome measures: The sum pain intensity difference (efficacy analysis)and the proportion of patients reporting a side effect (safety analysis).

Results: Most trials were considered of good to very good quality. Only the single dose studies could be combined for analysis of analgesic efficacy. Pooled efficacy results indicated that codeine added to paracetamol provided a 5% increase in analgesia on the sum pain intensity difference. This effect was comparable to the difference in analgesic effect between codeine and placebo. The cumulative incidence of side effects with each treatment was comparable in the single dose trials. In the multidose studies a significantly higher proportion of side effects occurred with paracetamol-codeine preparations.

Conclusion: The difference in analgesic effect between paracetamol-codeine combinations and paracetamol alone was small but statistically significant. In the multidose studies the proportion of patients reporting a side effect was significantly higher with paracetamol-codeine combinations. For occasional pain relief a paracetamol-codeine combination might be appropriate but repeated use increases the occurrence of side effects.

Key messages

  • Paracetamol-codeine combinations are thought to bring more pain relief than that achieved with paracetamol alone

  • Single dose studies show a slightly increased analgesic effect when codeine is added to paraceta- mol

  • In single dosage the incidence of side effects with paracetamol alone and paracetamol plus codeine is similar; in multidosage side effects are significantly increased with paracetamol-codeine preparations

  • A paracetamol-codeine preparation is recom- mended when more pain relief is needed with a single dose of a drug; more side effects may occur with multiple dosage


  • Funding None

  • Conflict of interest None

  • Accepted 11 July 1996
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