PALM SPRINGS, CALIF. – Off-label use of daily low-dose naltrexone hydrochloride reduced fibromyalgia pain severity by an average of 48%, compared with a 27% pain reduction on placebo in a double-blind crossover trial in 28 women.
"These are statistically significant results, and I think they are also clinically significant," said Jarred Younger, Ph.D., at the annual meeting of the American Academy of Pain Medicine.
Dr. Jarred W. Younger
Tolerability ratings of a regimen of 4.5 mg daily of naltrexone and placebo were statistically equivalent, with scores of 89 (of a possible 100, which represented perfectly tolerated treatment) for both naltrexone and placebo. Side effects associated with use of naltrexone were mild and transient, with significantly more patients reporting vivid dreams (37%) and headaches (16%) on the drug compared with placebo (13% and 3%, respectively).
Low-dose naltrexone, an opioid agonist, is not approved by the Food and Drug Administration and must be custom compounded, but the drug is generic and costs less than $40 per month, said Dr. Younger, director of the adult and pediatric pain laboratory at Stanford (Calif.) University.
"We know it’s cheap, and we know it’s easy to get ahold of," he said.
The 22-week study included women aged 23-65 years living near Stanford who fulfilled the American College of Rheumatology’s 1990 criteria for fibromyalgia, including having 11 of 18 tender points. They had had fibromyalgia for a mean of 12 years. Patients were allowed to continue taking their medications as normal, with the exclusion of opioid analgesics.
After a 2-week run-in period, patients were randomized to either 12 weeks of naltrexone or 4 weeks of placebo, taken daily with or without food or water approximately 1 hour before bedtime, in the form of an opaque gelatin capsule with microcrystalline cellulose filler and noncaloric sweetener. The treatment groups then switched to the other regimen for a total of 16 weeks of treatment or placebo, ending with a 4-week follow-up period.
Patients daily rated their pain, fatigue, and other symptoms on a handheld computer; they were assessed every 2 weeks in the laboratory for side effects and were given a new bottle of capsules. Investigators calculated the mean reduction in symptom severity based on measurements in the final 3 days on the drug or placebo.
Three other patients (for a total of 31) were randomized in the study but were excluded from the final analysis, two of them because they stopped taking the capsules.
"Global impression of change" ratings by 30 patients showed that after 12 weeks on naltrexone, 13% reported that their pain was very much improved, 37% said it was much improved, 20% reported minimal improvement, 20% said there was no change in pain, and 10% said pain was minimally worse.
By the end of the naltrexone phase, 57% of patients reported a 30% or greater reduction in pain, Dr. Younger and his associates reported.
Fatigue and sleep quality were not significantly improved on naltrexone, compared with placebo. Patients were not able to guess accurately whether they were receiving the drug or placebo.
The findings confirm results of a 10-patient pilot study by the same investigators (Pain Med. 2009;10:663-72). "We now have two studies" suggesting that low-dose naltrexone reduces the severity of fibromyalgia pain, he said.
Low-dose naltrexone deserves a larger, parallel-group, randomized, controlled trial to further confirm the results in a larger cohort, he added.
Naltrexone is microglia moderator, and the investigators hypothesized that this may be the mechanism of action in reducing fibromyalgia pain. Abnormal functioning of microglia may cause the central sensitivity seen in fibromyalgia and the subsequent overproduction of proinflammatory factors. In-vitro and animal studies have shown that naltrexone reduces microglia hyperexcitability, suppressing the production of proinflammatory cytokines, reducing pain, and serving a neuroprotective function, he said.
Dr. Younger said that future studies also should assess other potential microglia modulators, including ibudilast and 3-hydroxymorphinan. Fluorocitrate, minocycline, and dextromethorphan also are microglia modulators.
A physician in the audience noted that the current study showed a higher-than-usual placebo effect, and wondered about the cause. "I wondered about that very thing," Dr. Younger replied. The previous pilot study found a lower placebo effect, but the results of the pilot study became widely known and may have increased expectations and the effect of placebo in the women who were recruited to the current study, he speculated.
The study excluded women with abnormal or elevated levels of rheumatoid factor, antinuclear antibodies, erythrocyte sedimentation rate, or C-reactive protein; women who were taking opioid analgesics; and women with joint inflammation or a history of autoimmune disease.