Wednesday, March 7, 2012

Low-Dose Naltrexone Eases Fibromyalgia Pain

Naltrexone Fibromyalgia is a common chronic pain disorder characterized by diffuse musculoskeletal pain, sensitivity to mechanical stimulation, and profound fatigue that primarily afflicts women. New research reported at the 2012 American Academy of Pain Medicine meeting suggests that low doses of the opioid antagonist naltrexone may help to relieve pain associated with fibromyalgia by targeting the immune pathway of pain. This is promising research, offering hope for patients, but more study is needed.

Jarred Younger, PhD, and colleagues at Stanford University had demonstrated in an earlier pilot study that daily low-dose naltrexone (LDN, 4.5 mg/day) reduced symptom severity in 10 women with fibromyalgia [Younger et al. 2009]. Because the earlier study was limited by a single-blind design, they conducted a more extensive investigation, which is the first placebo-controlled, double-blind trial of naltrexone for treating chronic pain.

In this crossover-design study, 30 women completed a protocol involving 2 weeks of baseline observation, followed by the treatment period — 12 weeks of daily LDN-4.5 mg and 4 weeks placebo — and, then, 4 weeks follow-up. A portion of the subjects were randomly assigned to first receive placebo and secondly were switched to active LDN therapy, another portion first received LDN then placeobo. Both the patients and treatment providers were blinded as to whether the women were receiving LDN or placebo at any given time. Each day, participants completed symptom severity reports via a handheld computer. The primary outcome was daily pain.

In a Medpage Today report on Younger’s presentation [here], pain was reduced significantly more during the LDN treatment condition (48.5%) versus the placebo condition (27.4%; P=0.006). In addition to the half of patients who reported feeling very much or much improved with LDN, an additional quarter reported small improvement; however, there was no impact on fatigue or sleep quality. Participants rated LDN equally as tolerable as placebo (89.2 versus 89.4, respectively, rated on a 100-point scale). The only side effects reported more often with LDN than placebo were vivid dreams (37% versus 13%) and mild headache (16% versus 3%).

This study was supported by the American Fibromyalgia Syndrome Association and other private donors. Younger and colleagues conclude that, while further randomized controlled trials are needed, LDN may be an effective, highly tolerable, and relatively inexpensive treatment for fibromyalgia.

COMMENTARY: This study was published as an abstract for presentation at a conference, so the data and results should be considered as preliminary. While the trial was adequately powered to detect a large effect of LDN for pain relief, data in the Medpage conference report (above) suggest only a medium effect size [h=0.46, as calculated by us] and somewhat different data appearing in the published abstract indicate a small effect size [h=0.21, calculated by us from data in Younger et al. 2012]. Either way, the results seem encouraging and the approach merits further testing in larger, well-designed trials.

We have previously discussed naltrexone for chronic pain conditions; for example, in an UPDATE [here] and a research overview [available here]. This agent is an oral opioid antagonist that also has been demonstrated to suppress the release of proinflammatory factors from glial cells — including microglia and astrocytes — such as by antagonizing, or blocking, effects of toll-like receptor 4 (TLR-4) on these cells [Hutchinson et al. 2008]. TLR-4 is a protein that plays an important role in activating the innate immune system; so, by ultimately restraining an exaggerated or overactive immune response, naltrexone may help to improve symptoms of fibromyalgia and other chronic pain conditions.

It should be noted that patients treated with LDN — eg, at the 4.5 mg naltrexone dose used in this study by Younger et al. — cannot simultaneously be administered opioid analgesics for pain, as it could block opioid effects or might precipitate withdrawal in persons already maintained on opioids. Hopefully, investigations of naltrexone will continue, since there could be an interesting and vital future for this opioid antagonist in pain management practice. However, this is one of those potentially important areas of medicine that seems to offer much promise but also appears to attract minimal funding for ongoing research.

> Hutchinson et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). European Journal of Neuroscience. 2008;28,20-29.
> Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Medicine. 2009;10, 663-672 [
article here].
> Younger J, McCue R, Noor N, et al. Low-dose naltrexone reduces the symptoms of fibromyalgia: A double-blind and placebo-controlled crossover study. In posters and abstracts, AAPM Annual Meeting, Palm Springs, CA; Feb 23-26, 2012; Abstract 251 [
available here].

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