Single dose oral analgesics for acute postoperative pain in adults ‐ an overview of Cochrane reviews
This is an updated version of the original Cochrane overview published in Issue 9, 2011. That overview considered both efficacy and adverse events, but adverse events are now dealt with in a separate overview.
Thirty‐nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews and assesses the reliability of available data.
To summarise the efficacy of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery who have been given a single dose of oral analgesic.
We identified systematic reviews in the Cochrane Database of Systematic Reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews, we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, and the percentage of participants remedicating by six, eight, 12, or 24 hours. Where there was adequate information for pairs of drug and dose (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable.
The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high‐quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken.
Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours.
Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg.
There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence).
There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long‐lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.
R Andrew Moore, Sheena Derry, Dominic Aldington, Philip J Wiffen
Plain language summary
Comparing single doses of oral analgesics for acute pain in adults after operation
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 medicines, with 41 different medicines at various doses. These involved about 50,000 participants in about 450 studies. This overview sought to bring all the high quality information together about how well the medicines work; side effects are reported in a different overview.
For some medicines there were no published trials. For other medicines there was inadequate information. For some medicines, there was adequate information, but the results could be overturned by just a few unpublished studies in which there was no effect. None of these could be regarded as reliable. There remained 53 pairs of medicine and dose with reliable evidence.
The range of results with single dose analgesics in participants with moderate or severe acute pain was from 7 out of 10 (70%) achieving good pain relief with the best medicine to about 3 out of 10 (30%) with the worst medicine. No medicine produced high levels of pain relief in all participants.
The period over which pain was relieved also varied, from about two hours to about 20 hours. Good results were found for medicines combined in a fixed dose in a single tablet, or medicines made for rapid absorption from the stomach.
Commonly used analgesic medicines at the recommended or licensed doses produce good pain relief in many, but not all, people with acute pain. The reasons for this are varied, but people in pain should not be surprised if medicines they are given do not work for them. Alternative analgesic medicines or methods should be found that do work.
R Andrew Moore, Sheena Derry, Dominic Aldington, Philip J Wiffen
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 53 pairs of drug and dose in acute pain. Not every person will achieve good pain relief even with the most effective drugs, and analgesic failure is to be expected with a single dose, or perhaps with particular drugs in particular people. Failure to achieve good pain relief should not be acceptable because it is likely that failure with any one drug could be reversed with another.
The major implication for clinicians is the knowledge that there is a body of reliable evidence about the efficacy of 53 pairs of drug and dose in acute pain. These results include information of immediate practical relevance including the percentage of people likely to benefit in the short term, and comparative information about the likely duration of effect ‐ a matter of pragmatic importance. However, not every person will achieve good pain relief even with the most effective drugs, and analgesic failure is to be expected with a single dose, or perhaps with particular drugs in particular people. Failure to achieve good pain relief should be actively and regularly sought and rectified.
There is also a clear message that simple drug combinations and fast acting formulations can deliver good analgesia in many people with acute pain at relatively low doses.
While much of the information in the overview derives from the third molar extraction model, previous analyses have shown no difference between efficacy in that pain model in typically younger participants, and other postsurgical models where the participants are older, and probably less healthy.
For policy makers
The issue is not which drug, but achieving success ‐ good pain relief is the goal of treatment. Surveys over a long period have shown that acute pain generally, and particularly in hospital, is poorly treated, and that many people experience moderate or severe pain.
Simple drug combinations and fast acting formulations can deliver good analgesia at relatively low doses in many people with acute pain. Acute pain treatment is often part of a complex of interactions between the person, condition, and desired outcome; the overview helps by presenting evidence from which rational choices and decisions can be made. The evidence linking short term benefit with longer duration of action is particularly important in this regard.
Very high levels of efficacy are available from a number of drugs and formulations, at relatively low doses, that are relatively inexpensive. This contrasts with anecdotal evidence that less effective drugs and formulations are frequently used because they are considered less expensive. It is not clear that this is sensible.
Implications for research
The studies in this overview have been single dose studies designed to demonstrate that analgesic drugs work in reducing pain. These trials were principally performed for regulatory purposes. An arguably more appropriate approach is to have studies examining treatment of acute pain over days rather than hours. Studies of that type are rare. Average pain, as reported in most individual studies, is unhelpful.
There are no main issues over the design of single dose studies, but considerable issues over reporting and outcomes. Despite calls over at least a decade to use participant‐centred outcomes such as number of participants with no worse than mild pain, the principal outcomes reported are still statistical.
Measurement (end points)
Pain measurement is not an issue.
Many of the improvements in understanding acute pain have been derived from individual participant level analyses. These can only come from close cooperation with the pharmaceutical industry, which overwhelmingly funds the studies and 'owns' the data. Industry has a responsibility to perform more useful analyses than just those required for regulatory purposes.
Possibly the main implication for research is methodological. There will be few circumstances where such a body of information exists in such a clinically homogeneous data set and it might appear to be an ideal opportunity to test new methods in meta‐analyses, such as network meta‐analyses.