Abstract

Background

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 mild to moderate cancer pain, and are recommended for this purpose in the 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for nonsteroidal anti‐inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005.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 NSAIDs, updates the evidence.

Objectives

To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries.

Selection criteria

We included randomised, double‐blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single‐blind and open studies were also eligible for inclusion. 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.

Main results

Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel‐group, and two had a cross‐over design. All used paracetamol as an add‐on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non‐paracetamol medication included non‐steroidal anti‐inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias.

None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference.

Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources.

Authors' conclusions

There is no high‐quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three‐step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Ewan D McNicol, Rae Frances Bell, Daniel B Carr, Mairead McIntyre, Bee Wee

Abstract

Plain language summary

Paracetamol for cancer pain

Bottom line

There is no evidence to show that paracetamol is useful in treating people with cancer pain, either alone or combined with a morphine‐like drug. Nor is there evidence to disprove that it is useful. There are no good studies evaluating paracetamol for management of cancer pain.

Background

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 recommended taking morphine‐like drugs (opioids) for moderate to severe pain from cancer, and non‐opioid drugs like paracetamol, alone for mild to moderate pain, or alongside opioids in people with moderate to severe pain.

Study characteristics

In this review we set out to examine all the evidence on how well paracetamol (alone or with morphine‐like drugs) worked in adults and children with cancer pain. We also wanted to know how many people had side effects, and how severe those side effects were, for example, whether they caused people to stop taking their medicines.

In March 2017, we found three studies with 122 participants. All compared paracetamol plus opioid with the same dose of opioid alone. The studies were small, and were of poor quality. They used different study designs and different ways of showing their pain results. Outcomes of importance to people with cancer pain were not reported.

Key findings

We found no evidence that taking paracetamol alone made any difference to the level of pain experienced. We found no evidence that taking paracetamol together with a morphine‐like drug was better than the morphine‐like drug alone. Paracetamol did not appear to improve quality of life. No conclusions could be reached about side effects. The amount of information and the differences in how studies were reported meant that no conclusions could be made.

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 paracetamol for treating cancer pain. We do not know whether using paracetamol alone, or in combination with an opioid such as codeine or morphine, is worthwhile.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Ewan D McNicol, Rae Frances Bell, Daniel B Carr, Mairead McIntyre, Bee Wee

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with cancer pain

The amount and quality of evidence around the use of paracetamol for treating cancer pain is low. The small amount of evidence we have does not indicate that it has any pain‐relieving effects or makes any improvement to quality of life. No judgement can be made about adverse events or withdrawals.

For clinicians

There is no evidence for paracetamol alone. The evidence we have is from add‐on studies with oral morphine doses of 60 mg daily or above, when any additional analgesic effect of oral paracetamol would be difficult to detect. It may be possible to reduce the drug burden for people with cancer pain taking such large amounts of oral morphine equivalents, but we have no evidence that this is the case.

The amount and quality of evidence around the use of paracetamol for treating cancer pain is low. There is no evidence supporting or refuting the use of paracetamol on the first and second steps of the WHO ladder. The small amount of evidence we have for the use of paracetamol combined with opioids does not indicate that it has any additional pain‐relieving effects or makes any improvement to quality of life. No judgement can be made about adverse events or withdrawals.

For policy makers

The amount and quality of evidence around the use of paracetamol for treating cancer pain is low. There is no evidence supporting or refuting the use of paracetamol on the first step of the WHO ladder. The small amount of evidence we have for the use of paracetamol combined with strong opioids does not indicate that it has any additional pain‐relieving effects or makes any improvement to quality of life. No judgement can be made about adverse events or withdrawals.

For funders

The amount and quality of evidence around the use of paracetamol for treating cancer pain is low. There is no evidence supporting or refuting the use of paracetamol on the first step of the WHO ladder. The small amount of evidence we have for the use of paracetamol combined with strong opioids does not indicate that it has any additional pain‐relieving effects or makes any improvement to quality of life. No judgement can be made about adverse events or withdrawals.

Implications for research 

General

This review on paracetamol 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 studies that clearly demonstrate how best to perform a study on the lower two steps, which relate to the treatment of mild and moderate pain with non‐opoid drugs like paracetamol, alone or in combination with weak opioids. As best we know there are no ongoing studies examining the use of paracetamol alone for mild to moderate pain for the first step of the WHO ladder. We know of one ongoing study examining paracetamol plus opioid for the second or third step of the ladder. In this study, participants with moderate to severe pain (3/10 to 9/10) who are taking daily opioid plus 4 x 1000 mg paracetamol are randomised to continued treatment with the combination or the opioid alone.

Design

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, and rarely how many individuals achieve satisfactory pain relief. In the situation where initial pain is mild or moderate, 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 paracetamol. 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 (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).

Measurement (endpoints)

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, outcomes identified previously as important (Wiffen 2014). The choice of measures to be used in cancer pain studies is not necessarily straightforward.

Other

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).

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