NSAIDS or paracetamol, alone or combined with opioids, for cancer pain: Cochrane systematic review


Assessed as up to date: 2004/11/19


NSAIDs are widely applied to treat cancer pain and are frequently combined with opioids in combination preparations for this purpose. However, it is unclear which agent is most clinically efficacious for relieving cancer-related pain, or even what may be the additional benefit of combining an NSAID with an opioid in this setting.


To assess the effects of NSAIDs, alone or combined with opioids, for the treatment of cancer pain.

Search methods

CENTRAL (Issue 2, 2002), MEDLINE (January 1966 to March 2003), EMBASE (January 1980 to December 2001), LILACS (January 1984 to December 2001) were searched.

Selection criteria

Randomized controlled trials (RCTs) and controlled clinical trials that compared NSAID versus placebo; NSAID versus NSAID; NSAID versus NSAID plus opioid; opioid versus opioid plus NSAID; or NSAID versus opioid.

Data collection and analysis

Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse event information was collected from trials. Where there was disagreement between reviewers, the opinion of an additional reviewer was sought to resolve the issue.

Main results

Forty-two trials involving 3084 patients were included. Clinical heterogeneity of study methods and outcomes precluded meta-analyses and only supported a qualitative systematic review. Seven of eight papers that compared NSAID with placebo demonstrated superior efficacy of NSAID with no difference in side effects. Thirteen papers compared one NSAID with another; four reported increased efficacy of one NSAID over another. Four different studies found that one NSAID had fewer side effects than one or more others. Twenty-three studies compared NSAIDs and opioids in combination or alone with NSAID/opioid combinations. Thirteen out of 14 studies found no difference, or low clinical difference, when combining an NSAID plus an opioid versus either drug alone. Comparisons between various NSAID/opioid combinations were inconclusive. Nine studies assessed the association between dose and efficacy and safety. Four papers demonstrated increased efficacy with increased dose, but no dose-dependent increase in side effects within the dose ranges studied. Study duration ranged from single dose studies performed over six hours to crossover studies lasting six weeks; however, the majority of studies were of less than seven days duration.

Authors' conclusions

Based upon limited data, NSAIDs appear to be more effective than placebo for cancer pain; clear evidence to support superior safety or efficacy of one NSAID over another is lacking; and trials of combinations of an NSAID with an opioid have disclosed either no difference (4 out of 14 papers), a statistically insignificant trend towards superiority (1 out of 14 papers), or at most a slight but statistically significant advantage (9 out of 14 papers), compared with either single entity. The short duration of studies undermines generalization of their findings on efficacy and safety of NSAIDs for cancer pain.


McNicol Ewan D, Strassels Scott, Goudas Leonidas, Lau Joseph, Carr Daniel B


Non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for the treatment of cancer pain

NSAIDs are commonly used, often in combination with an opioid, for treatment of cancer pain. Short-term studies have shown that NSAIDs alone are effective in managing cancer pain, with side effects similar to placebo and in about 50% of studies, increasing the dose of NSAID can increase efficacy without increasing the incidence of side effects. Similar studies have not demonstrated a large clinical difference when combining an opioid with an NSAID versus either medication alone. Insufficient long-term studies have been conducted to provide information on chronic safety and effectiveness of NSAIDs alone or with opioids in treating cancer pain.

Reviewer's Conclusions

Implications for practice

The World Health Organisation's ladder for cancer pain relief is considered the gold standard for practice in the management of this population of patients (WHO 1996). Regarding the first step of the ladder, the management of mild pain, our results strongly suggest that the use of NSAID alone is superior to placebo and adequate for this purpose, at least in short-term use. The second step of the ladder involves the treatment of mild to moderate pain. The WHO recommends the addition of a "weak" opioid to the patient's regimen. Our findings do not substantiate this recommendation. It may be advisable for a patient to increase to a maximum acceptable the dose of their NSAID (or adjuvant drug) before the addition of, or replacement with, an opioid.

The studies that we retrieved were of insufficient duration to demonstrate that the long-term use of NSAIDs is safe and effective in patients with cancer. Clinicians should be at least as cautious in using NSAIDs in this population as they would any other population, especially given the probability that a patient with cancer may be on a broad regimen of medications, some of which may increase NSAID-related toxicity.
The selection of a particular NSAID was not conclusively established. The majority of studies demonstrated no difference between different NSAIDs, and of those that did demonstrate a difference, clinical significance was mostly marginal. In the meantime, results from studies in other populations that have shown certain NSAIDs to be more effective and/or safer could be extrapolated for use in patients with cancer.

Implications for research

This review illustrates that, despite a proliferation of articles since the earlier systematic review by Eisenberg et al. (Eisenberg 1994), there remains a need for a substantial increase in the number of high quality trials of NSAIDs in patients with cancer. Studies that specifically address the question of whether addition of an opioid to an NSAID regimen actually increases efficacy and/or reduces side effects are required. In addition, the safety and efficacy of chronic NSAID use in patients with cancer needs to be established. Emerging questions regarding COX-2 inhibitors, such as their role in treating cancer pain and their potentially beneficial anti-angiogenic properties (Steinbach 2000) remain unanswered. Translation of emerging preclinical insights into distinct mechanisms for cancer-related pain of different etiologies (e.g., bone metastasis) would be another step towards rational selection of analgesics for cancer pain (Davar 2002). The availability of such studies could help clinicians to optimize analgesia in this large and underserved population of patients (Goudas 2001; Foley 2001).

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