Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly.
Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events.
We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update.
Randomised, double‐blind, placebo‐controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults.
Data collection and analysis
Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four‐to‐six hours, using validated equations. Number‐needed‐to‐treat‐to‐benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.
Twenty‐six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four‐to‐six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.
Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four‐to‐six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups.
This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
Laurence Toms, Sheena Derry, R Andrew Moore, Henry J McQuay
Plain language summary
Single dose oral paracetamol (acetaminophen) plus codeine for postoperative pain relief in adults
Pain is commonly experienced after surgical procedures, and is not always well controlled. Combining analgesics from different classes has the potential to provide adequate pain relief with reduced dose‐dependent adverse events. This review assessed data from twenty‐six studies comparing paracetamol plus codeine with placebo, and fourteen studies comparing paracetamol plus codeine with the same dose of paracetamol alone. The combination provided effective pain relief for about 40% of participants experiencing moderate to severe pain after an operation with 600 to 650 mg paracetamol plus 60 mg codeine, the dose most commonly used in these studies, and about 50% of participants with 800 to 1000 mg paracetamol plus 60 mg codeine, the dose most commonly used in clinical practice. The addition of codeine provided effective pain relief to about 10% more participants than the same dose of paracetamol alone. These single dose studies did not associate paracetamol plus codeine with any serious side effects.
Laurence Toms, Sheena Derry, R Andrew Moore, Henry J McQuay
Implications for practice
The data found in this update for Issue 1, 2009 further supports previous findings although more research is still required. The combination of paracetamol and codeine is an effective analgesic in postoperative pain with a low incidence of adverse events. At a dose of 1000 mg paracetamol plus 60 mg codeine it provides effective analgesia for over half of patients with moderate to severe postoperative pain following various types of surgery. The addition of codeine increases the proportion of patients with effective pain relief by over 10%, but increases the number of patients experiencing adverse events. Associated adverse events were of mild or moderate intensity, and did not lead to withdrawal.
Implications for research
Additional data for the higher dose is needed to confirm the dose response demonstrated in this review, and provide a more robust estimate of efficacy. More consistent data on use of rescue medication would provide better estimates of duration of analgesia, which in turn may help to decide which analgesics are most effective in the clinical setting. While more recent studies were generally of good quality, and efficacy data, where collected, was well reported, the quality of adverse event reporting remains problematical.