Cochrane for Clinicians
Putting Evidence into Practice
NSAIDs Alone or with Opioids as Therapy for Cancer Pain
Am Fam Physician. 2005 Aug 1;72(3):436-437.
This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB005180.htm.
A 70-year-old woman is diagnosed with malignant melanoma that has metastasized to the liver and lungs. She has begun to experience abdominal pain, which you attribute to the liver metastases. She wants to know what you recommend for pain management.
What is the most effective therapy for the management of cancer pain?
Short-term trials indicate that cancer pain can be reduced with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as initial monotherapy. NSAIDs combined with opioids can result in slight short-term improvement in pain compared with either agent alone. Long-term efficacy and safety of NSAIDs for cancer pain have not been established.1
The World Health Organization’s (WHO’s) three-step analgesic ladder is a widely accepted framework for treating cancer pain.2 According to the WHO approach, treatment for mild cancer pain can begin with analgesics such as acetaminophen or NSAIDs. For patients in moderate pain, weak or episodic short-acting opioids can be added. For severe intractable cancer pain, more potent long-acting opioids are recommended. Adjuvant analgesics or therapies can be added at any point, and should be individualized according to the underlying cause of pain, the patient’s desires, and the available resources. For example, antidepressants and anticonvulsants commonly are prescribed for neuropathic pain. Corticosteroids have been used in a wide range of cancer pain syndromes. Radiotherapy and bisphosphonates may palliate bone metastases. Surgery and chemotherapy may palliate pain caused by tumor growth and encroachment on normal structures. A variety of physical and psychologic modalities also may be helpful adjuncts for cancer pain.
The main effect of the WHO guidelines has been to facilitate more liberal use of opioid therapy in cancer patients with intractable pain.3 However, there still is concern that opioids are underused or ineffectively prescribed for cancer pain.3,4 The National Cancer Institute Web site (http://www.cancer.gov/cancertopics/pdq/supportivecare/ pain) provides regularly updated information for health care professionals and their patients on the most common therapeutic options for the relief of cancer pain.
According to the results of the Cochrane review,1 NSAIDs should not be overlooked as a potential first-line treatment for cancer pain. They may provide additive pain relief for some patients who already are receiving opioids for moderate to severe cancer pain. Caution should be used in interpreting these results. Most studies reviewed were small and heterogeneous in terms of type of cancer or cancer pain, level of pain among participants, and specific medications used. In addition, none of the studies lasted more than two weeks, so potential adverse effects from prolonged use of these treatments individually or in combination could not be assessed or compared. Although it is possible that NSAIDs could be better tolerated than opioids in some situations, there certainly are situations in which the opposite is true. Therefore, it still is left to the physician to determine which therapies to offer each patient on an individual basis.
Background. NSAIDs are widely applied to treat cancer pain and frequently are 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.
Objectives. To assess the effects of NSAIDs, alone or combined with opioids, for the treatment of cancer pain.
Search Strategy. The authors1 searched the Cochrane Central Register of Controlled Trials (Issue 2, 2002), MEDLINE (January 1966 to March 2003), EMBASE (January 1980 to December 2001), LILACS (January 1984 to December 2001), and reference lists of articles.
Selection Criteria. Randomized controlled trials 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.
Primary Results. Forty-two trials involving 3,084 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.
Reviewers’ Conclusions. Based on 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 no difference (four out of 14 papers), a statistically insignificant trend towards superiority (one out of 14 papers), or at most a slight but statistically significant advantage (nine 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.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
The initial objectives of this review included determining the benefit of acetaminophen in treating cancer pain, but the authors were unable to find sufficient good-quality studies to analyze acetaminophen separately from NSAIDs. However, a recent randomized trial,5 published shortly after this review, demonstrated improved pain control with acetaminophen in patients with advanced cancer who already were receiving a strong opioid regimen. Like the NSAID studies, the sample size was small, the duration of the study brief, and improvement in pain scores modest.
1. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDs or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev. 2005;(2):CD005180.
2. World Health Organization: Cancer pain relief. 2d ed. Geneva, Switzerland: World Health Organization, 1996.
3. Meldrum M. The ladder and the clock: cancer pain and public policy at the end of the twentieth century. J Pain Symptom Manage. 2005;29:41-54.
4. Wiffen PJ, Edwards JE, Barden J, McQuay HJ. Oral morphine for cancer pain. Cochrane Database Syst Rev. 2003;(4):CD003868.
5. Stockler M, Vardy J, Pillai A, Warr D. Acetaminophen (Paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2004;22:3389-94.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Michael B. Potter, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.
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