The management of persistent pain in rheumatoid arthritis (RA) remains a major challenge, despite important therapeutic advances during the past 2 decades. Patients with RA report pain relief as a high priority and opioid analgesics are often prescribed, but existing RA-treatment guidelines provide little direction in this regard. A recent review found that weak opioids may be of some help short-term, but adverse effects may outweigh longer-term benefits; however, much further research is needed before valid conclusions can be reached.
Writing in the February 6, 2013 edition of JAMA (Journal of the American Medical Association), researchers from Australia summarize their earlier Cochrane review examining opioids for RA pain [Whittle et al. 2013; Whittle et al. 2011]. Their extensive literature search had discovered only 11 randomized controlled trials (RCTs) qualifying for inclusion, none of which were considered to be of high quality with a low risk of bias. The studies were published between 1969 and 2006, with 9 published prior to 2000.
Study durations were short, with 4 of the studies being less than 1 week. Of the remaining 7 studies, the longest was 6 weeks. Six different opioids were investigated, including codeine, dextropropoxyphene, tramadol, tilidine, and pentazocine (which are all relatively weak agents), and morphine, which was the only strong opioid studied.
Pooled analyses of data were complicated by a high degree of heterogeneity across studies. Of the 6 studies that were at least 1 week long and compared an opioid vs placebo, 5 reported superiority of the opioid on at least 1 efficacy measure. A global efficacy measure could be extracted from 3 placebo-controlled trials — describing patient-reported impression of clinical change — and opioids were superior to placebo, with an NNT (number needed to treat) of 6. That is, for every 6 patients treated with opioid rather than placebo, 1 extra patient achieved benefits rated as good or very good.
However on another measure — the number of withdrawals due to inadequate analgesia — pooled data from 4 studies showed that opioids were no better than placebo. Furthermore, opioids were shown to improve function in only 1 of the 3 studies that assessed this outcome.
The odds of adverse events (AEs) were nearly 4 times higher in patients receiving opioids compared with placebo. Serious AEs were rare; however, commonly occurring AEs — eg, nausea, vomiting, dizziness and constipation — resulted in trial withdrawal by nearly 19% of participants receiving opioids, although overall risks of withdrawal were statistically equivalent between intervention and control groups. The estimated NNH (number needed to harm) for AEs within the first 6 weeks of opioid therapy was 4; that is for every 4 patients treated with opioids there would be 1 additional AE reported, albeit of possible minor consequence.
The researchers performed a unique “Net Efficacy Adjusted for Risk,” or NEAR, analysis as a measure of the risk-benefit profile of opioids in RA. The NEAR is a composite relative risk (RR) measure considering both benefit (efficacy) and harm (safety) that estimates the relative proportion of study participants receiving either opioid or placebo who achieve an analgesic response and also avoid negative effects. In this study, patient-reported impression of clinical change as good or very good (efficacy) and the avoidance of AEs (safety) were factored into the equation and there was no significant difference between opioids and placebo (NEAR RR = 1.20; 95% CI, 0.89-1.61).
Based on their review and data analyses, the researchers conclude that there is limited evidence that weak oral opioids may be effective analgesics for some patients with RA, but adverse effects are common and may offset the benefits of this class of medications. However, they observe, there is insufficient evidence to draw conclusions regarding the use of weak opioids for longer than 6 weeks or for the potential beneficial role of strong opioids.
COMMENTARY: There appear to be many limitations of available evidence regarding benefits of opioid analgesics for treating RA, and these deficiencies are well-demonstrated in the systematic review and meta-analysis by Whittle and colleagues. It seems that in some cases, such as this, it might be more prudent to simply not draw any conclusions at all in the face of limited and insufficient research than to pursue analyses that may be incomplete or misleading.
Here are some points to consider:
- The weak opioids investigated in the systematic review are hardly representative of the full range of opioid analgesics and may have little relevance for the United States and many other parts of the world. Dextropropoxyphene has been discontinued, and tilidine — 1/5 the potency of morphine — is used in relatively few countries (and the U.S. in not among them). Pentazocine is a mixed agonist/antagonist with 1/5 the potency of morphine and is often combined with naloxone as an abuse deterrent. Depending on the formulation, codeine is among the least effective opioids and may not be properly metabolized by significant portions of patients. In this review, the sparse data on morphine were not analyzed in comparison with the other opioids, so potential benefits of a stronger opioid are undetermined.
- It is interesting that, even with such weak opioid analgesia, there was a short-term clinically important and significant NNT of 6 for favorable patient-rated global improvement. Unfortunately, this was roughly equalled and offset by occurrences of nonserious adverse effects (NNH=4; 95% CI, 3-6). Apparently, even modest pain relief afforded by relatively inadequate analgesia can be of importance to patients, but the accompaniment of typical opioid-related adverse effects may foster discontinuation of those agents.
- The researchers concede that there is a paucity of high-quality evidence in treating RA pain with sustained-release strong oral opioids such as morphine or oxycodone, or transdermal preparations of strong opioids such as fentanyl. And, there apparently are no adequate data for oxymorphone, hydromorphone, buprenorphine, or others. Along with that, there are no comparisons regarding benefits and risks of weak versus strong opioids used for RA, or for any type of opioid beyond 6 weeks.
- Studies included in this systematic review were performed between 1969 and 2006, before the current era of aggressive disease-modifying therapy for RA. None of the included studies attempted to describe RA disease activity or the specific nature of the pain suffered by participants. The use of concurrent DMARDs (Disease Modifying Antirheumatic Drugs) was incompletely reported and none of the participants were receiving biologic therapy; therefore, study results may not apply to current clinical practices in treating RA.
- The efficacy or safety of opioids, or the balance between the two, may not be the same for short-term versus longer-term use, or for pain of different mechanistic origins. Some unwanted effects, such as endocrinopathy and physical dependence, might increase with extended use, while other adverse effects may become better tolerated and less bothersome.
Since RA is a chronic disease, analgesic medications may be required both short-term (eg, during flares of inflammatory activity or while waiting for DMARDs to take effect) and long-term (eg, due to irreversible joint damage or the development of secondary pain syndromes). If anything, the review by Whittle et al. highlights how little is known about the appropriateness of opioid analgesia in patients with RA and stresses the need for well-designed research in such patients who also may be receiving modern disease-modifying treatment strategies.
> Whittle SL, Richards BL, Buchbinder R. Opioid Analgesics for Rheumatoid Arthritis Pain. JAMA. 2013;309(5):485-486 [abstract here].
> Whittle SL, Richards BL, Husni E, Buchbinder R. Opioid therapy for treating rheumatoid arthritis pain. Cochrane Database Syst Rev. 2011(11):CD003113 [abstract/summary here].
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