Opioids for osteoarthritis? Weighing benefits and risks: A Cochrane Musculoskeletal Group review

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Applied Evidence

Opioids for osteoarthritis? Weighing benefits and risks: A Cochrane Musculoskeletal Group review

J Fam Pract. 2011 April;60(4):206-212

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References

1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.

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8. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-167.

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14. Wilder-Smith C, Hill L, Spargo K, et al. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAIDs: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain. 2001;91:23-31.

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Physical function. Four of the 6 placebo-controlled tramadol studies included in the Cochrane review used the WOMAC Index score, which included the physical function subscale. The tramadol group had a larger reduction in the score than the placebo group, by 0.34 mm (95% CI, -0.49 to -0.19). While this was equivalent to an 8.5% relative reduction in mean baseline score, it is still small compared with the minimal perceptible clinical improvement level of 9.3 mm on a 0-100 scale needed for the WOMAC physical function subscale. A similar improvement was reported for those taking tramadol compared with diclofenac—the only one of the active-controlled studies to report on physical function.¹⁷

Other opioids relieve pain, improve function—but how much?

The review of oral and transdermal opioids for OA¹¹ encompassed 10 trials, with a total of 1541 patients receiving opioids and 727 on placebo. The opioids used in the trials were codeine, oxycodone, oxymorphone, morphine, and transdermal fentanyl. (For more details, see “How the reviews were conducted”.)

Pain. The trials included in the review used a variety of scales to measure pain, so the reviewers gauged results by the proportion of patients responding to treatment. Response was defined as a 50% improvement in pain score.

In the overall analysis, 35% of patients taking opioids responded to treatment, vs 31% of those on placebo—or 4 more patients in 100. That represents an NNT of 25. (A subgroup analysis did not demonstrate any significant differences in effect size among the opioids tested. In addition, the effect size was similar regardless of the potency of the opioid or the administration route.)

Function. Seven of the 10 trials (1794 participants, including both the treatment groups and controls) used validated function scores to measure physical function after 4 weeks of treatment. Here, too, the reviewers defined a treatment response as a 50% improvement in score.

Their finding? Opioids had a greater effect on function compared with placebo, equaling 0.7 on a WOMAC disability scale of 1 to 10. This means that about 3 more patients in 100 responded to treatment with opioids vs placebo—an NNT of 30.

But what about safety?

FAST TRACK

The data highlight the importance of making patients aware that the risks of opioids (including tramadol) for OA treatment may outweigh the benefits.

Opioids, including tramadol, are associated with adverse events (AEs), which may be minor or major. To determine when, or whether, the benefits outweigh the risks for treating patients with OA, both reviews reported on AEs and the number of participants who stopped taking the drug because of AEs.

AEs limit tramadol’s usefulness
While tramadol was more effective than placebo at reducing pain intensity, relieving symptoms, and improving function, the benefits were small—with an overall NNT of 6 (TABLE 1). This is similar to acetaminophen (NNT, 4-16),¹⁸ but with a greater downside.

Minor AEs. Four placebo-controlled trials reported on minor AEs.^19-22 Those most commonly reported by patients taking tramadol were nausea, vomiting, dizziness, constipation, somnolence, tiredness, and headache.

Overall, 39% of those who received tramadol experienced minor AEs, compared with 18% of patients receiving placebo—an NNH of 5.¹⁰ Thus, tramadol’s NNH for minor AEs is equivalent to its NNT for pain relief. In active-controlled studies, there was a higher risk of minor AEs in those receiving tramadol compared with diclofenac or dextropropoxyphene, but a lower risk compared with those taking pentazocine.¹⁰

FAST TRACK

One in 8 patients stopped taking tramadol because of a major adverse event.

Major AEs. An analysis of the placebo-controlled trials revealed that 21% of those who received tramadol had major AEs—defined as an event that resulted in cessation of treatment—compared with 8% of those taking placebo. By this measure, the NNH was 8: One in 8 patients stopped taking tramadol because of a major AE.¹⁰

Among the active-controlled trials, participants taking tramadol were more likely to report a major AE compared with those receiving either diclofenac or dextropropoxyphene (NNH=5), but less likely compared with patients taking pentazocine. In a trial that compared tramadol alone with paracetamol, 2 out of 10 in the tramadol group discontinued treatment; none in the paracetamol group did.¹³

TABLE 1
Tramadol and other opioids for OA pain: NNT and NNH

Treatment	NNT	NNH
Tramadol¹⁰	6	5
Opioids (overall)¹¹	25	12
NNH, number needed to harm; NNT, number needed to treat; OA, osteoarthritis.

Post-review RCTs provide further evidence
We identified 4 double-blind RCTs of tramadol for the treatment of OA that were of at least 6 weeks’ duration,^19-22 published after the 2006 review. The results of these studies (TABLE 2) were broadly consistent with those of the systematic review. Two of the 4 studies had active controls, with one comparing tramadol with diclofenac¹⁹ and the other with celecoxib.²¹ Tramadol and diclofenac were found to be equally effective; celecoxib appeared to be superior in terms of pain relief, global improvement, and physical function, but no statistical comparisons were reported.