Low-dose Naltrexone Explored as Option for Chronic Pain

SALT LAKE CITY, UT — Low-dose naltrexone (LDN) holds promise for treating chronic pain associated with a wide range of conditions, including fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

In fact, pending further study, LDN might offer a low-cost, nonaddictive opioid alternative for patients with chronic pain, according to Jarred W. Younger, PhD, director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama, Birmingham.

"Opioids work fast, but they may cause pain sensitivity when used long-term, so I think they should be used for only short periods of time. LDN lowers pain sensitivity over time, so may be a better choice for chronic pain," Younger told Medscape Medical News.

Naltrexone is an opiate antagonist currently available in a daily 50-mg tablet dose for the treatment of alcohol and opioid dependence. But in addition to opioid receptor antagonism, the drug also appears to exert anti-inflammatory effects via a separate mechanism targeting microglial cells.

Paradoxically, the dosage found to reduce pain is roughly one tenth the substance abuse treatment dose, around 4.5 mg per day. The low-dose version is not approved by the US Food and Drug Administration and must be specially compounded.

In studies of several known inflammatory conditions, including inflammatory bowel disease and multiple sclerosis, LDN reduced both self-reported pain and objective markers of inflammation and disease severity, Younger noted in a 2014 review article.

Evidence Supports LDN for Fibromyalgia, and Anecdotally for ME/CFS

At a 2-day summit held March 2 and 3, 2018, at the Bateman-Horne Center here in Salt Lake City, a panel of 13 clinicians who specialize in ME/CFS selected LDN as a top drug for that patient population, based on their clinical experience using it in their patients with ME/CFS who have hyperalgesia. The panel also placed LDN at the top of a wish list for randomized clinical trials of treatments for ME/CFS specifically.

There is currently no drug approved by the US Food and Drug Administration for ME/CFS, and treatment of the condition focuses on relief of symptoms including widespread pain. Many patients with ME/CFS also meet clinical criteria for fibromyalgia, for which LDN has shown benefit in several of Younger's studies.

Lucinda Bateman, MD, who directs the Bateman-Horne Center and chaired the ME/CFS summit, said she uses LDN frequently in her patients with fibromyalgia and those with ME/CFS for whom pain is a top complaint. "I'm totally convinced that in patients with pain amplification/hyperalgesia as their primary problem, it's great. It's as good as all the [approved fibromyalgia drugs], but cheaper."

However, she also noted, "The real unanswered question is, does LDN help cognition, fatigue, and other things related to neuroinflammation? We know that glial cells are involved in hyperalgesia, and we know LDN downregulates [microglia]. But that's not the same as downregulating everything about neuroinflammation."

Susan M. Levine, MD, an infectious disease and ME/CFS specialist in New York City, also prescribes LDN. "People think of it more for fibromyalgia, but it's definitely in our armamentarium for ME/CFS patients. I find it helps with both pain and sleep."

A typical protocol, Younger said, would be to start at 1.5 mg daily for 1 week, then titrate up to 3.0 mg for another week and then 4.5 mg daily. But as individual responses vary, it may take a bit of adjusting to find the right dose for a given patient. Some may respond better to 6.0 to 7.0 mg/day.

Levine explained that she starts at a much lower LDN dose, as low as 0.1 to 0.5 mg, as she is concerned about sensitivity in these patients.

Patients should be advised that it could take up to 2 months before they notice any changes with LDN, so they "should not give up too soon if they are not noticing beneficial effects right away," Younger noted.

Well-Tolerated, Lower Cost

Younger told Medscape Medical News that LDN is very well-tolerated in his studies, with the only common adverse effect being particularly vivid dreams in about 20% of patients. Smaller numbers have reported anxiety after taking LDN, or trouble falling asleep if they take it at bedtime.

"Everyone responds differently to medications, so patients and clinicians should track responses to any new medication carefully," he cautioned.

Although the low dosage of naltrexone used won't necessarily interact with opioid analgesics, care should be taken in combining the two, as naltrexone might block the effectiveness of hydrocodone and oxycodone.

Also, "There is also a small chance that LDN could interact with alcohol to make the person feel nauseated. After starting LDN, individuals should test alcohol before consuming a large amount," Younger advised.

As a generic medication, LDN is far less expensive than currently approved fibromyalgia drugs, at roughly $30 a month (including the cost of compounding) compared with approximately $500/month for Lyrica. In contrast, insurance doesn't currently cover LDN, as it's not yet approved for any indication.

Companies are currently working to secure US Food and Drug Administration approval for naltrexone in 1.0- and 4.5-mg versions. And in the United Kingdom, an entity called The LDN Research Trust is pushing for inclusion of LDN on the National Health Service's medical formulary list so it can be easily prescribed.

Meanwhile, Younger is hoping to conduct a clinical trial of LDN specifically for ME/CFS, but has not yet received grant money.

"So, as of now, we have no research data showing whether LDN is as effective in ME/CFS as it is in fibromyalgia. This trial is still a high priority for the lab and it needs to be conducted.... It is hard to determine from anecdotal reports whether the medication is truly beneficial. My hypothesis is that it will significantly help a good percentage of ME/CFS patients, but we cannot know for sure until a study is completed."

Younger, Bateman, and Levine have disclosed no relevant financial relationships.

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