Monday, September 9, 2013

Are Opioids Ineffective for Neuropathic Pain?

Neuropathic PainNeuropathic pain associated with various types of nerve involvement can be difficult to diagnose and treat. The use of opioid analgesic therapy is controversial due to concerns that this type of pain does not always respond well to these agents and there is potential for adverse effects. An updated systematic review examined 31 studies, involving 1,237 patients with neuropathic pain, and found intermediate-term effectiveness of opioids, but longer-term benefits for chronic conditions seem uncertain.

In this present study, Ewan D McNicol — of the Tufts Medical Center, Boston — and colleagues updated their original Cochrane systematic review first published in 2006 [McNicol et al. 2013]. As before, their assessment included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Research trials were excluded if nonopioid drugs were combined with opioids or if opioids were administered epidurally or intrathecally.

This new review included 31 trials meeting inclusion criteria, studying 10 different opioids: 23 studies were from the original 2006 review and 8 additional studies were discovered for the update. Of the total, 17 studies — 392 participants with neuropathic pain, average 22 participants per study — provided efficacy data for acute exposure to opioids during less than 24 hours.

Most of these short-term studies (16) reported pain outcomes, and with contradictory results: 8 studies reported less pain with opioids than placebo; 2 reported that some but not all participants benefited; 5 reported no differences; and, 1 reported equivocal results. Six studies, with about 170 participants, found that mean pain scores with opioid were only about 15/100 points less than with placebo.

The remaining 14 studies — 845 participants, average 60 participants per study — were of intermediate duration, lasting 12 weeks or less; however, most studies lasted <6 weeks. While these trials did demonstrate opioid efficacy for treating spontaneous neuropathic pain, many of them also had flaws that likely overestimated treatment effects; such as, small sample sizes and inadequate handling of missing data from study dropouts.

Meta-analyses of intermediate-duration trial data demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. Effect sizes were statistically significant but modest, with an absolute risk difference of 0.25 (95% Confidence Interval [CI] 0.13 to 0.37, p<0.0001). This translated to a number needed to treat (NNT) of 4.0; ie, for every 4 patients treated with opioid rather than placebo, 1 additional patient would have 33% pain relief.

When the number of participants achieving at least 50% pain relief was analyzed, the absolute risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, p=0.03). This translated to an NNT of about 6.0, but the 95% CI of 3.0 to 50.0 was very imprecise.

Furthermore, in this updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various questionnaires. Constipation was the most common adverse event (34% opioid vs 9% placebo), followed by drowsiness, nausea, dizziness, and vomiting. As might be expected, more participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%). Conversely, lack of efficacy resulted in study withdrawal by more participants receiving placebo (12%) than among those receiving opioids (2%).

The new study data available for this updated review did not substantially alter the researchers’ conclusions from their earlier Cochrane review. Namely, short-term studies (<24 hrs) provide at best only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrate significant pain-relief efficacy of opioids over placebo, but the results may be influenced by considerable bias because of small study size, inadequate duration, and potentially flawed handling of data from dropouts. Reported adverse events of opioids were common but not life-threatening. Future RCTs are needed to establish unbiased estimates of long-term opioid efficacy, safety, and effects on quality of life in the treatment of chronic neuropathic pain conditions.


Trials included in the systematic review by McNicol and colleagues examined various painful neuropathies, but predominantly postherpetic neuralgia and peripheral diabetic neuropathy. Few trials included patients with back pain primarily of neuropathic origin, which may be common in some patient populations.

This could be important, since it often is difficult to diagnose back pain as being purely neuropathic in origin, without also including a nociceptive component that might be amenable to opioid therapy. Along with that, in the current review, there were insufficient numbers of participants diagnosed with each type of neuropathy to perform subanalysis of efficacy or safety, which lessens the precision and clinical usefulness of the conclusions.

McNicol et al. suggest several other points of some importance….

  • The lack of efficacy found with short-term opioid administration should not be interpreted as predictive of whether administration of opioid analgesics could be helpful longer-term for neuropathic pain in individual patients.

  • Despite study limitations and possible sources of bias, the NNT outcomes (as noted above) do suggest that opioids may reduce various forms of neuropathic pain. Therefore, McNicol and colleagues suggest that “opioids at low-to-moderate doses are suitable for use over periods of weeks to months in the treatment of neuropathic pain.”

  • The use of a single dimension (eg, pain scales) for efficacy assessment in the available studies is problematic, since neuropathic pain is a multidimensional phenomenon that varies from one patient to the next. Also, it is important to demonstrate improvements in specific features of neuropathic pain (eg, evoked or burning pain, etc), in emotional or physical aspects of functioning, and/or in health-related quality of life that might be expected of truly effective analgesic therapy.

  • The meta-analyses conducted in this review showed similar opioid responsiveness for neuropathic pain of central and peripheral etiologies, but data were insufficient to resolve any debate regarding the differential efficacy of opioids for these two types of pain.

  • A dose-dependent analgesic effect was found in 2 studies examined in the review; however, the dose ranges tested were still in the low-to-intermediate range and may not necessarily reflect clinical practice in some countries. McNicol et al. state, “This, along with increasing concerns about opioid toxicity, especially at higher dose ranges (greater than the daily equivalent of 200 mg of oral morphine), does not support the use of high doses of opioids for the relief of neuropathic pain.”

It is always amazing, yet important, that so many persons with pain are willing to participate in placebo-controlled trials, knowing (due to informed consent) that there is a chance they will not be administered active-drug therapy. Despite this, only 12% of participants receiving placebo withdrew due to a lack of analgesic efficacy, which suggests a considerable placebo effect in such trials. At the same time, NcNicol et al. concede that participants willing to enter these trials may not always be typical of those in everyday clinical practice.

Furthermore, the researchers observe, “intermediate-term studies are more clinically relevant than short-term studies because they assess the benefits and risks associated with opioid treatments for weeks to months; that is, they reflect how opioids are administered for neuropathic pain in clinical practice.” They conclude that intermediate-term opioid treatment has a beneficial effect over placebo for spontaneous neuropathic pain as measured by both number of participants with at least 33% and at least 50% pain relief and in mean differences in post-intervention pain intensity.

At present, however, there are inadequate data to demonstrate improvements in many aspects of emotional or physical functioning afforded by opioids in treating neuropathic pain. And, despite the favorable intermediate-term outcomes regrading pain relief, research data are lacking to verify whether opioids may provide relief of chronic neuropathic pain during administration periods longer than 6 to 12 weeks.

REFERENCE: McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews. 2013, Issue 8, Art. No. CD006146 [abstract here].

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