Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non‐opioid drugs are commonly used to treat cancer pain, and are recommended for this purpose in the World Health Organization (WHO) cancer pain treatment ladder, either alone or in combination with opioids.
A previous Cochrane review that examined the evidence for nonsteroidal anti‐inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on paracetamol, updates the evidence.
To assess the efficacy of oral NSAIDs for cancer pain in adults, and the adverse events reported during their use in clinical trials.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to April 2017, together with reference lists of retrieved papers and reviews, and two online study registries.
We included randomised, double‐blind, single‐blind, or open‐label studies of five days' duration or longer, comparing any oral NSAID alone with placebo or another NSAID, or a combination of NSAID plus opioid with the same dose of the opioid alone, for cancer pain of any pain intensity. The minimum study size was 25 participants per treatment arm at the initial randomisation.
Data collection and analysis
Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table.
Eleven studies satisfied inclusion criteria, lasting one week or longer; 949 participants with mostly moderate or severe pain were randomised initially, but fewer completed treatment or had results of treatment. Eight studies were double‐blind, two single‐blind, and one open‐label. None had a placebo only control; eight compared different NSAIDs, three an NSAID with opioid or opioid combination, and one both. None compared an NSAID plus opioid with the same dose of opioid alone. Most studies were at high risk of bias for blinding, incomplete outcome data, or small size; none was unequivocally at low risk of bias.
It was not possible to compare NSAIDs as a group with another treatment, or one NSAID with another NSAID. Results for all NSAIDs are reported as a randomised cohort. We judged results for all outcomes as very low‐quality evidence.
None of the studies reported our primary outcomes of participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). With NSAID, initially moderate or severe pain was reduced to no worse than mild pain after one or two weeks in four studies (415 participants in total), with a range of estimates between 26% and 51% in individual studies.
Adverse event and withdrawal reporting was inconsistent. Two serious adverse events were reported with NSAIDs, and 22 deaths, but these were not clearly related to any pain treatment. Common adverse events were thirst/dry mouth (15%), loss of appetite (14%), somnolence (11%), and dyspepsia (11%). Withdrawals were common, mostly because of lack of efficacy (24%) or adverse events (5%).
There is no high‐quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three‐step WHO cancer pain ladder. There is very low‐quality evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within one or two weeks.
Sheena Derry, Philip J Wiffen, R Andrew Moore, Ewan D McNicol, Rae Frances Bell, Daniel B Carr, Mairead McIntyre, Bee Wee
Plain language summary
Oral nonsteroidal anti‐inflammatory drugs (NSAIDs) for cancer pain in adults
There is no high‐quality evidence to prove that NSAIDs are useful in treating people with cancer pain. Nor is there evidence to disprove that they are useful. Very low‐quality evidence shows that some people with moderate or severe cancer pain have pain much reduced within one or two weeks.
One person in two or three who gets cancer will suffer from pain that becomes moderate or severe in intensity. The pain tends to get worse as the cancer progresses. In 1986, the World Health Organization (WHO) recommended taking morphine‐like drugs (opioids) for moderate to severe pain from cancer, and non‐opioid drugs like NSAIDs, alone for mild to moderate pain, or alongside opioids in people with moderate to severe pain. There are many different types of NSAIDs. Common NSAIDs are ibuprofen and diclofenac.
In this review we set out to examine the evidence on how well NSAIDs worked (alone or with morphine‐like drugs) in adults with cancer pain. We also wanted to know how many people had side effects, and how severe they were.
In April 2017, we found 11 studies with 949 participants. They compared NSAID with NSAID, or NSAID with opioid drug (morphine or codeine). No studies looked at using NSAID together with an opioid‐like morphine, which is how they are often used. The studies were small and of poor quality. They used different designs and different ways of showing their pain results. Outcomes important to people with cancer pain were often not reported. Many different NSAIDs were tested, and it was not possible to make sensible comparisons.
With an NSAID, initially moderate or severe cancer pain was reduced to no worse than mild pain after one or two weeks in 1 in 4 (26%) to 1 in 2 (51%) people in four studies.
Side‐effect reporting was poor. Two serious side effects were reported with NSAIDs, and 22 deaths, but these were not related to pain treatment. Common side effects were thirst/dry mouth (1 in 7; 15%), loss of appetite (1 in 7; 14%), sleepiness (1 in 10; 11%), and heartburn (1 in 10; 11%). One in four people stopped taking NSAIDs because the drug did not work, and 1 in 20 stopped because of side effects.
Quality of the evidence
The quality of the evidence was very low. Very low‐quality evidence means that we are very uncertain about the impact of an NSAID alone for treating cancer pain. We do not know whether using NSAIDs together with an opioid such as codeine or morphine is worthwhile.
Sheena Derry, Philip J Wiffen, R Andrew Moore, Ewan D McNicol, Rae Frances Bell, Daniel B Carr, Mairead McIntyre, Bee Wee
Implications for practice
For people with cancer pain
The amount and quality of evidence around the use of NSAIDs for treating cancer pain is very low. The amount of evidence we have indicates that oral NSAIDs may have pain‐relieving effects in some people with cancer pain, but we are very unsure of this. No judgement can be made about adverse events or withdrawals.
The amount and quality of evidence around the use of NSAIDs for treating cancer pain is very low. There is very limited evidence supporting the use of NSAIDs as part of the WHO ladder, and none on any additional pain‐relieving effects when combined with strong opioids. The small amount of evidence we have indicates that NSAIDs may have pain‐relieving effects in some people with cancer pain, but we are very unsure of this. No judgement can be made about adverse events or withdrawals. We have no evidence about which drug at which dose may be more or less effective.
For policy makers
The amount and quality of evidence around the use of NSAIDs for treating cancer pain is very low. There is very limited evidence supporting the use of NSAIDs as part of the WHO ladder, and none on any additional pain‐relieving effects when combined with oral strong opioids. The small amount of evidence we have indicates that NSAIDs may have pain‐relieving effects in some people with cancer pain, but we are very unsure of this. No judgement can be made about adverse events or withdrawals. We have no evidence about which drug at which dose may be more or less effective.
The amount and quality of evidence around the use of NSAIDs for treating cancer pain is very low. There is very limited evidence supporting or refuting the use of NSAIDs as part of the WHO ladder, and none on any additional pain‐relieving effects when combined with oral strong opioids. The small amount of evidence we have indicates that NSAIDs may have pain‐relieving effects in some people with cancer pain, but we are very unsure of this. No judgement can be made about adverse events or withdrawals. We have no evidence about which drug at which dose may be more or less effective.
Implications for research
This review on NSAIDs for cancer pain reveals major problems with the evidence available. The WHO pain ladder is now over 30 years old, and remains probably the most‐used and best‐understood pain guidance worldwide. Despite its obvious importance there are few exemplars for how best to perform cancer pain studies with non‐opoid drugs like NSAIDs, alone or in combination with opioids. We know of no ongoing studies.
Several methodological issues stand out.
The first is the use of outcomes of value to people with cancer pain. Existing trials are designed more for purposes of registration and marketing than informing and improving clinical practice, often because the outcomes chosen are average pain scores, or statistical differences, rather than how many individuals achieve satisfactory pain relief. In the situation where initial pain is mild or moderate initially, some consideration needs to be given to what constitutes a satisfactory outcome. The situation is somewhat different to that of strong opioids in cancer pain that are used for moderate to severe pain.
The second is the time taken to achieve good pain relief. We have no information about what constitutes a reasonable time to achieve a satisfactory result. Initially this may best be approached with a Delphi methodology.
The third is design. Studies with cross‐over design often have significant attrition. Parallel group designs may be preferable, and while this is a matter of debate (Bell 2006), considerable thinking has already gone into study design.
The fourth is size. The studies were small, and, combined with cross‐over design and consequent attrition, ended up reporting on very few participants. Much larger studies of several hundred participants or more are needed.
The fifth is the dose of opioid allowable in add‐on studies to test the analgesic efficacy or effectiveness of oral NSAIDs. In the circumstance of high oral opioid doses, additional benefit is unlikely to be measurable, and some upper limit of opioid dose may be needed.
The sixth is that in the current era of precision medicine investigator may have an opportunity to conduct clinical trials involving specific aetiologies of cancer pain, or accrue sufficient numbers of participants to conduct well‐powered subgroup analyses.
There are some other design issues that might be addressed. Most important might be a clear decision concerning the gold‐standard treatment comparator. Placebo‐controlled studies in cancer pain are unlikely to be ethically feasible unless rescue morphine is freely available (Bell 2006). It may be that low‐dose oral morphine is a suitable comparator, as a suggested alternative treatment for mild to moderate pain (Twycross 2014).
Trials need to consider the additional endpoints of no worse than mild pain and the impact of morphine on symptoms that raise serious concerns such as consciousness, appetite, and thirst. The choice of measures to be used in cancer pain studies is not necessarily straightforward.
Prospective randomised trials are the obvious design of choice, but other pragmatic designs may be worth considering. Studies could incorporate initial randomisation but a pragmatic design in order to provide immediately‐relevant information on effectiveness and costs. Such designs in pain conditions have been published (Moore 2010b).Get full text at The Cochrane Library
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