Naltrexone may lessen chronic pain

Low doses of the opioid antagonist naltrexone  may relieve pain associated with fibromyalgia compared with placebo by targeting the immune pathway of pain, researchers said.

In a small, randomised crossover trial, fibromyalgia patients reported significantly greater reductions in pain with naltrexone than with placebo, Jarred Younger, PhD, of Stanford University School of Medicine, and colleagues reported at the American Academy of Pain Medicine meeting here.

“The key here is not in its opioid antagonistic effects, but in a separate action on microglia,” Younger said during an oral presentation.

Interest has been growing in the immune pathways involved in pain. At the heart of the research are the body’s glial cells — including microglia and astrocytes — which disperse inflammatory cytokines when activated by certain biological triggers, such as opioids.

These cytokines can send messages to neurons that counter analgesia, explained Linda Watkins, PhD, of the University of Colorado in Denver, who delivered a keynote address at the meeting that was not related to Younger’s presentation.

To hamper that inflammatory response, researchers have been targeting the toll-like-receptor-4 (TLR-4) on glial cells.

Indeed, Younger said naltrexone can stifle the immune response and, ultimately, symptoms of fibromyalgia by blocking TLR-4 on microglia.

In an earlier pilot study, he and his colleagues demonstrated that low doses of naltrexone (4.5 mg/day) reduced pain and fatigue in 10 women with fibromyalgia (Pain Med 2009; 10: 663-672).

Expanding on that earlier research, they conducted a placebo-controlled, double-blind, crossover trial of 30 women who spent two weeks at baseline, followed by some combination of 12 weeks on low-dose naltrexone, four weeks on placebo, and four weeks of follow-up. The women completed symptom reports every day and the primary outcome was daily pain.

Younger and colleagues found that patients reported an overall greater reduction in pain when they were on low-dose naltrexone than when they took placebo (48.5% versus 27.4%, P=0.006).

In addition to the half of patients who reported feeling very much or much improved when on low-dose naltrexone, an additional quarter felt minimally improved, Younger said.

He added that there was no impact on fatigue or sleep quality, and patients reported low-dose naltrexone to be as tolerable as placebo (89.2% versus 89.4% rated on a 100-point scale).

Side effects reported more commonly with low-dose naltrexone were vivid dreams (37% versus 13% on placebo) and headache (16% versus 3%).

Other drugs may have also improved pain via the immune pathway, including naloxone, fluorocitrate, minocycline, and dextromethorphan, Younger said. Generic versions of some of these drugs are available, which would make them significantly less expensive, he added.

But Watkins said companies have been looking to develop new compounds targeting glial cells to treat chronic pain. A main area of research has been on the effects of (+)-naloxone on inhibiting TLR-4 to reduce pain, though it’s only been studied in animal models to date, she said.

“Immunologists have ignored pain, and pain people have ignored immunology,” Watkins said. “That has to end. They are intertwined.”

Younger said that although low-dose naltrexone appears to be an effective, tolerable, and inexpensive treatment for fibromyalgia, further randomized controlled trials are needed.

Disclosure:
The study was supported by the American Fibromyalgia Syndrome Association and other private donors.

The researchers reported no conflicts of interest.

Reference:
Younger J, et al “Low-dose naltrexone reduces the symptoms of fibromyalgia: A double-blind and placebo-controlled crossover study” AAPM 2012; Abstract 251.