Low-Dose Naltrexone Researcher Disputes Study Negativity

Neuroinflammation expert Jarred Younger, PhD, disputes a recent study commentary calling for clinicians to stop prescribing low-dose naltrexone for people with fibromyalgia.

Naltrexone is a nonselective µ-opioid receptor antagonist approved by the US Food and Drug Administration (FDA) at doses of 50-100 mg/day to treat opioid and alcohol dependence. Lower doses, typically 1-5 mg, can produce an analgesic effect via antagonism of receptors on microglial cells that lead to neuroinflammation. The low-dose version, available at compounding pharmacies, is not FDA-approved, but for many years it has been used off-label to treat fibromyalgia and related conditions.

Results from earlier small clinical trials have conflicted, but two conducted by Younger using doses of 4.5 mg/day showed benefit in reducing pain and other fibromyalgia symptoms. However, a new study from Denmark on 6 mg low-dose naltrexone versus placebo among 99 women with fibromyalgia demonstrated no significant difference in the primary outcome of change in pain intensity from baseline to 12 weeks.

On the other hand, there was a significant improvement in memory, and there were no differences in adverse events or safety, the authors reported in Lancet Rheumatology.

Nonetheless, an accompanying commentary called the study a “resoundingly negative trial” and advised that while off-label use of low-dose naltrexone could continue for patients already taking it, clinicians should not initiate it for patients who have not previously used it, pending additional data.

Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023.

During his talk, Younger said, “It looks like the study was very well done, and all the decisions made sense to me, so I don’t doubt the quality of their data or the statistics.”

But as for the commentary, he said, “I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people.”

Indeed, Anthony L. Komaroff, MD, who heard Younger’s talk but hadn’t seen the new study, told Medscape Medical News that he is a “fan” of low-dose naltrexone based on his own experience with one patient who had a “clearly beneficial response” and that of other clinicians he’s spoken with about it. “My colleagues say it doesn’t work for everyone because the disease is so heterogeneous…but it definitely works for some patients.”

Younger noted that the proportion of people in the Danish study who reported a clinically significant, that is 30% reduction, in pain scores was 45% versus 28% with placebo, not far from the 50% he found in his studies. “If they’d had 40 to 60 more people, they would have had statistically significant difference,” Younger said.

Indeed, the authors themselves pointed this out in their discussion, noting, “Our study was not powered to detect a significant difference regarding responder indices…Subgroups of patients with fibromyalgia might respond

differently to low-dose naltrexone treatment, and we intend to conduct a responder analysis based on levels of inflammatory biomarkers and specific biomarkers of glial activation, hypothesising that an inflammatory subgroup

might benefit from the treatment. Results will be published in subsequent papers.”

The commentary authors responded to that, saying that they “appreciate” the intention to conduct that subgroup analysis, but that it is “probable that the current sample size will preclude robust statistical comparisons but could be a

step to generate hypotheses.”

Those authors noted that a systematic review has described both pro-inflammatory (tumor necrosis factor, interleukin [IL]-6, and IL-8) and anti-inflammatory (IL-10) cytokines as peripheral inflammatory biomarkers in patients with fibromyalgia. “The specific peripheral biomarkers of glial activation are yet to be identified. The neuroinflammation hypothesis of fibromyalgia could be supported if a reduction of central nervous system inflammation would predict improvement of fibromyalgia symptoms. Subsequent work in this area is eagerly awaited.”

In the meantime, Younger said, “I do not think this should stop us from looking at low-dose naltrexone [or that] we shouldn’t try it. I’ve talked to over a thousand people over the last 10 years. It would be a very bad thing to give up on low-dose naltrexone now.”

Younger’s work is funded by the National Institutes of Health, Department of Defense, SolveME, the American Fibromyalgia Association, and ME Research UK. Komaroff has no disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on X (formerly known as Twitter) @MiriamETucker.