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

Abstract 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

[1]  P. Kjaersgaard-Andersen.  Evaluating codeine plus paracetamol for pain. , 1991, Nursing times.

[2]  Boelen-van der Loo Wj,et al.  Prevention and control of pain in (adeno)tonsillectomy , 1992 .

[3]  K. White,et al.  Clinical epidemiology. , 1983, International journal of epidemiology.

[4]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[5]  J A Forbes,et al.  Evaluation of Flurbiprofen, Acetaminophen, an Acetaminophen‐Codeine Combination, and Placebo in Postoperative Oral Surgery Pain , 1989, Pharmacotherapy.

[6]  Miller Jm,et al.  Acetaminophen with codeine for the relief of severe pain in postpartum patients. , 1974 .

[7]  W. Beaver.  Combination analgesics. , 1984, The American journal of medicine.

[8]  T. Reisine.  Opioid analgesics and antagonists , 1996 .

[9]  P. Skjelbred,et al.  Codeine added to paracetamol induced adverse effects but did not increase analgesia. , 1982, British journal of clinical pharmacology.

[10]  T. Hedner,et al.  Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P , 1994, Pain.

[11]  Cooper Sa,et al.  The relative efficacy of indoprofen compared with opioid-analgesic combinations. , 1981 .

[12]  E. Laska,et al.  The Design of Analgesic Clinical Trials , 1991, Annals of Internal Medicine.

[13]  B. J. Meadows.  Codeine combinations in clinical practice , 1984 .

[14]  H. Levin,et al.  Acetaminophen with codeine for the relief of severe pain in postpartum patients. , 1974, Current therapeutic research, clinical and experimental.

[15]  S. Cooper,et al.  The relative efficacy of indoprofen compared with opioid-analgesic combinations. , 1981, Journal of oral surgery.

[16]  S. Honig,et al.  An Appraisal of Codeine as an Analgesic: Single‐Dose Analysis , 1984, Journal of clinical pharmacology.

[17]  R. W. White,et al.  Diflunisal. A new oral analgesic with an unusually long duration of action. , 1982, JAMA.

[18]  S. Cooper,et al.  The analgesic efficacy of flurbiprofen compared to acetaminophen with codeine. , 1991, The Journal of clinical dentistry.

[19]  L. Pedersen,et al.  Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis of the hip. A randomised, double-blind, multi-centre study , 1990, Pain.

[20]  S. Cooper.  Five studies on ibuprofen for postsurgical dental pain. , 1984, The American journal of medicine.

[21]  J. Cornett,et al.  Acetaminophen: a practical pharmacologic overview. , 1984, Canadian Medical Association journal.

[22]  F. Mosteller,et al.  Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  L. A. Skoglund,et al.  Analgesic Efficacy of Acetaminophen 1000 mg, Acetaminophen 2000 mg, and the Combination of Acetaminophen 1000 mg and Codeine Phosphate 60 mg versus Placebo in Acute Postoperative Pain , 1991, Pharmacotherapy.

[24]  J. Egle.  The pharmacological basis of therapeutics, 7th ed. Edited by Alfred Goodman Gilman, Louis S. Goodman, Theodore W. Rail, and Ferid Murad. Macmillan, New York, NY 10022. 1985. 1839 pp. 18 × 26 cm. ISBN 0‐02‐344710‐9. $65.00 , 1986 .

[25]  A. Kolodny,et al.  A 12‐Hour Evaluation of the Analgesic Efficacy of Diflunisal, Acetaminophen, an Acetaminophen‐Codeine Combination, and Placebo in Postoperative Pain , 1983, Pharmacotherapy.

[26]  W. Beaver,et al.  Evaluation of Ketorolac, Ibuprofen, Acetaminophen, and an Acetaminophen‐Codeine Combination in Postoperative Oral Surgery Pain , 1990, Pharmacotherapy.

[27]  A Sunshine,et al.  Comparative study of flurbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain. , 1986, The American journal of medicine.

[28]  Peter Bjerring,et al.  Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine , 1990, Clinical pharmacology and therapeutics.

[29]  P. Dayer,et al.  Central analgesic effect of acetaminophen but not of aspirin , 1991, Clinical pharmacology and therapeutics.

[30]  J. R. Snyder,et al.  Analgesic efficacy of flurbiprofen in comparison with acetaminophen, acetaminophen plus codeine, and placebo after impacted third molar removal. , 1994, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[31]  J. Kleijnen,et al.  Acupuncture and chronic pain: a criteria-based meta-analysis. , 1990, Journal of clinical epidemiology.

[32]  J. Kellam,et al.  Analysis of the Analgesic Efficacy of Acetaminophen 1000 mg, Codeine Phosphate 60 mg, and the Combination of Acetaminophen 1000 mg and Codeine Phosphate 60 mg in the Relief of Postoperative Pain , 1986, Pharmacotherapy.

[33]  M. Torabinejad,et al.  Effectiveness of various medications on postoperative pain following root canal obturation. , 1994, Journal of endodontics.

[34]  S. Cooper,et al.  Double-blind comparison of meclofenamate sodium with acetaminophen, acetaminophen with codeine and placebo for relief of postsurgical dental pain. , 1988, The Journal of clinical dentistry.

[35]  T. Head,et al.  The additive analgesic efficacy of acetaminophen,1000 mg, and codeine, 60 mg, in dental pain , 1987, Clinical pharmacology and therapeutics.

[36]  S. Cooper,et al.  A model to evaluate mild analgesics in oral surgery outpatients , 1976, Clinical pharmacology and therapeutics.

[37]  M. Torabinejad,et al.  Effectiveness of various medications on postoperative pain following complete instrumentation. , 1994, Journal of endodontics.