Adverse events associated with single dose oral analgesics for acute postoperative pain in adults ‐ an overview of Cochrane reviews Stable (no update expected for reasons given in 'What's new')



This is an update of a Cochrane overview published in Issue 9, 2011; that overview considered both efficacy and adverse events. This overview considers adverse events, with efficacy dealt with in a separate overview.

Thirty‐nine Cochrane reviews of randomised trials have examined the adverse events associated with individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews.


To provide an overview of adverse event rates associated with single‐dose oral analgesics, compared with placebo, for acute postoperative pain in adults.


We identified systematic reviews in The Cochrane Database of Systematic Reviews on The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group. We extracted information related to participants experiencing any adverse event, and reports of serious adverse events, and deaths from the individual reviews.

Main results

Information was available from 39 Cochrane reviews for 41 different analgesics or analgesic combinations (51 drug/dose/formulations) tested in single oral doses in participants with moderate or severe postoperative pain. This involved around 350 unique studies involving about 35,000 participants. Most studies involved younger participants with pain following removal of molar teeth.

For most nonsteroidal anti‐inflammatory drugs (NSAIDs), paracetamol, and combinations not containing opioids, there were few examples where participants experienced significantly more or fewer adverse events than with placebo. For aspirin 1000 mg and diflunisal 1000 mg, opioids, or fixed‐dose combination drugs containing opioids, participants typically experienced significantly more adverse events than with placebo. Studies of combinations of ibuprofen and paracetamol reported significantly fewer adverse events.

Serious adverse events were rare, occurring a rate of about 1 in 3200 participants.

Most reviews did not report specific adverse events.

Authors' conclusions

Despite ongoing problems with the measurement, recording, and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids.


R Andrew Moore, Sheena Derry, Dominic Aldington, Philip J Wiffen


Plain language summary

 Adverse events after single doses of oral analgesics for acute pain after operation in adults 

Acute pain is often felt soon after injury. Most people who have surgery have moderate or severe pain afterwards. Painkillers (analgesics) are tested in people with pain, often following the removal of wisdom teeth. In all these studies, the participants have to have at least moderate pain in order for there to be a sensitive measure of pain‐relieving properties. The pain is usually treated with painkillers taken by mouth. Results can be applied to other forms of acute pain.

In May 2015, we performed searches to update an overview review originally published in 2011. The Cochrane Library now has 39 reviews of oral analgesic interventions for pain immediately after operations, with 41 different painkillers at various doses. How well the drugs work is reported in a different overview.

In this overview, we used information from about 35,000 participants in about 350 studies to look specifically at the adverse events (unwanted effects) experienced with painkillers, and compared the results with those for placebo (dummy pill). Measuring adverse events is complicated because the particular method used to collect information influences how many adverse events are reported. Most people in the studies had wisdom teeth removed, were relatively young and fit, and were likely to take occasional painkillers. Adverse events may be different in people who are less well, older, or who take painkillers for several days or longer.

The results we have showed that for most nonsteroidal anti‐inflammatory drugs (painkillers like aspirin, ibuprofen, or diclofenac), paracetamol, and combinations of different painkillers that do not contain opioids (drugs like codeine), adverse events happened to the same proportion of people with painkillers and placebo. With aspirin 1000 mg, opioids, or fixed dose combinations containing opioids, people typically experienced significantly more adverse events than with placebo. A combination of ibuprofen and paracetamol resulted in significantly fewer adverse events than placebo.

Serious adverse events were rare, occurring a rate of about 1 in 3200 people.

The results are not unexpected for single dose studies, which are likely to be different from the situation when analgesics are taken over the medium or longer term.


R Andrew Moore, Sheena Derry, Dominic Aldington, Philip J Wiffen

Reviewer's Conclusions

Authors' conclusions

Implications for practice
For people with acute pain

The major implication for people with acute pain is the knowledge that there is a body of reliable evidence about the efficacy of 51 drug and dose combinations in acute pain. In most cases, there was no difference in terms of participants reporting adverse events taking single oral doses of the analgesics, and those taking placebo. The exceptions were high doses of aspirin and diflunisal, and combinations that included opioids. Serious adverse events were very rare.

For clinicians

Adverse events with single dose analgesics for acute pain are not generally more frequent than with placebo, with the exception of opioid combinations. Serious adverse events were very rare.

For policy makers

Adverse events with single dose oral analgesics occur no more frequently than with placebo, except for opioid combinations.

For funders

Opioid combination analgesics tend to have more frequent adverse events, and that is likely to come with greater costs. Other analgesics have the same or better analgesic efficacy and are without raised adverse event rates.

Implications for research

Studies in this overview were designed to measure efficacy, not adverse events. In this case that is unlikely to be a problem, since there is a great deal of evidence for the most relevant drugs.

The major implication for research is the different results likely using different methods of adverse event ascertainment. This is not currently a topic of much active research, despite numerous literature surveys commenting on the poor reporting of adverse events and the difference in absolute rates reported with different methods. There is an argument that we actually do not understand this area of importance to patients and to policy making well.


If adverse events were to become a principal topic of research, then study designs would have to change. In particular, considerable effort would be needed to determine which method of ascertainment provided results relevant to patient attitudes.

Measurement (endpoints)

The measurement of adverse events was varied, and they provided different rates. We do not know which is best.


There is probably a need for short‐term multiple dose studies over periods of one or two weeks, for adverse events as well as for efficacy.

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