Low-Dose Naltrexone: An Inexpensive Medicine for Many Ills?

Miriam E. Tucker

March 11, 2020

Low-dose naltrexone (LDN) could represent a low-cost and safe alternative treatment for several chronic neurologic, rheumatologic, psychiatric, and gastrointestinal inflammatory conditions, recent findings suggest.  

The opioid antagonist naltrexone is currently approved in 50 mg tablet doses for the treatment of opioid and alcohol dependence. But at much lower doses — typically 1.5 mg to 12 mg — it appears to operate uniquely as an anti-inflammatory agent in the central nervous system, via action on microglial cells. The low-dose version is not currently approved by the US Food and Drug Administration, so to be used it must be prescribed off-label and specially compounded.

Given that it's off-patent and costs only about $25 to $65 a month (at US compounding pharmacies), there's little financial incentive for pharmaceutical companies to conduct large randomized clinical trials of LDN.

However, accumulating data from a variety of sources suggest that it's relieving pain and other symptoms of several different chronic inflammatory conditions, with few side effects other than mild and transient nausea, insomnia, headache, and vivid dreams.

One recent three-patient series published in BMJ Case Reports is the latest to describe successful use of LDN in relieving not just pain, but also fatigue, cognitive impairment, and post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating neuroimmune condition for which there are no currently approved treatments.

Another case series published in November reports similar benefits in ME/CFS, and clinicians who specialize in the illness have endorsed its use based on their cumulative anecdotal experience.

Indirect evidence for LDN's benefits comes from a unique series of articles published in the last few years from Norway, reporting the impact of a surge in LDN prescribing in that country in 2013 following the airing of a television documentary about LDN.

According to Norway's nationwide prescribing database, about 15,297 patients, or 0.3% of the country's population, was prescribed LDN by physicians following the airing of the documentary. Over the next year, there were dramatic drops in prescriptions for high-cost drugs used in the treatment of rheumatoid and seropositive arthritis, inflammatory bowel disease, epilepsy, psychotic conditions, and depression.

Jarred W. Younger, PhD, who has studied LDN in fibromyalgia and is seeking funding to study it in ME/CFS, told Medscape Medical News, "We really need clinical trials to show what it works for [ME/CFS] and how to use it properly."

"A lot of clinicians are trying it without enough guidance," added Younger, who is director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama, Birmingham.

"They're giving it for conditions that don't make any sense, like knee pain. That's not in the brain. Also, the full naltrexone dose won't work because it blocks the endogenous opioid system. Since doctors are going to try it, we really need to give them information to do it well."

ME/CFS: Treatment for Some Where None Are Approved Now?

Myalgic encephalomyelitis/chronic fatigue syndrome is a chronic, multisystem disorder characterized by profound fatigue and loss of function lasting 6 months or longer, post-exertional malaise, unrefreshing sleep, and other symptoms varying across individuals, including widespread pain, cognitive dysfunction, and orthostatic intolerance. Prevalence ranges from 0.2% to 0.4% of the population, and about a quarter are partially or completely bedbound.

Clinical trials of any treatments in ME/CFS are difficult because of the lack of a single-best case definition and absence of biomarkers for diagnosis, or for objectively assessing response to interventions. Overall funding for the illness has been suboptimal.

The three cases in the current BMJ Case Reports article — two of which involved the article's coauthors — detailed patients with longstanding, severe ME/CFS who had tried many other treatments before starting LDN.

Responses to LDN varied from a "life-changing" full recovery of function to partial improvements in pain and sleep.

The lead author and Case #1 herself is Monica Bolton, a UK physician who contracted viral meningitis from a patient in 1988 when she was 33, and subsequently developed ME/CFS. She remained completely bed- and wheelchair-bound for most of the next three decades, her medical career derailed. Her symptoms included profound weakness, fatigue, light and sound sensitivity, cognitive impairment, and widespread pain, all worsening on exertion.  

She began taking LDN in 2010 at a starting dose of 1.5 mg/day, eventually titrating up to her current dose of 6 mg twice daily. She has now recovered to the point of near-normal health.

"The difference was just so amazing. I didn't have to try. It was the LDN that did it…I'm absolutely sure it's working by reducing inflammation in my brain," Bolton attests.

The other two cases — a woman diagnosed in 1989 at age 29 and a man who became ill as a teenager in the 1990s — have experienced partial relief and report improved quality of life despite persistence of some symptoms.

Younger says that range of response corresponds to what he's seen with fibromyalgia. "I think the people with the clearest evidence of prior, true inflammation probably respond best to LDN, as far as we can tell."

Meanwhile, in a retrospective examination of medical records from 218 patients with ME/CFS seen from 2010 to 2014 in Finland and taking LDN at doses of 3.0 to 4.5 mg/day, 73.9% reported positive responses. These included improved vigilance/alertness and improved physical and cognitive performance. Some reported less pain and fever, while 18.3% reported no treatment response. 

Mild insomnia and nausea were common at the beginning of treatment, but no severe or long-term adverse effects were reported with LDN.

"The high frequency of treatment response and good safety profile observed in this retrospective, open-label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms," write lead author Olli Polo, of the Unesta Sleep and Breathing Center, Tampere, Finland, and colleagues.

Bolton, who no longer practices medicine as a result of all the lost time, now focuses on raising awareness about LDN's potential for ME/CFS in efforts to acquire funding for a proper clinical trial, noting "The problem for all of us is funding."

The Norway Experience: A Medicine for Many Ills?

In February 2013, the largest commercial television channel in Norway aired a documentary called "Vårt lille land" ("Our Small Country"), in which patients with severe multiple sclerosis and other ailments — including one with ME/CFS and fibromyalgia — attested to how LDN had nearly normalized their function. The program included interviews with physicians who prescribe LDN.

Viewed by a large proportion of the Norwegian public, the program created a "natural experiment" for pharmacoepidemiologists Guttorm Raknes, MD, PhD, of the Regional Medicines and Information and Pharmacovigilance Centre at University Hospital of North Norway, and Lars Småbrekke, PhD, of the Department of Pharmacy at the Arctic University of Norway, both in Tromsø.

Raknes and Småbrekke examined data from the Norwegian Prescription Database and found that the number of naltrexone users increased from 14 in 2012 to more than 11,000 in 2013.

Further analysis showed that 71% of the country's GPs had prescribed LDN, at a median daily dose of 3.7 mg, to 15,297 individuals (0.3% of the entire population), during 2013–2014. The median patient age was 52 years, and 74% were female.   

They then conducted a series of substudies to analyze the impact of that surge in LDN prescribing by comparing prescribing patterns in the year prior to the documentary's broadcast to those in the year following it.

Among individuals with rheumatoid and seropositive arthritis who filled four or more LDN prescriptions, there was a significant 13% reduction in the total number of doses dispensed of all examined medicines and a significant 13% relative reduction in the number of users of disease-modifying antirheumatic drugs (DMARDs).

Among persistent LDN users with inflammatory bowel disease, a significant 12% overall reduction occurred in the number of users for all examined drugs, and also in the numbers of users of intestinal anti-inflammatory agents, other immunosuppressants, intestinal corticosteroids, and aminosalicylates, with reductions ranging from 17% to 32%.

In the psychiatry/neurology category, significant reductions were seen in use of antipsychotics between the highest and lowest LDN use (P = .007), and in the number of users of antiepileptics (P < .001), antipsychotics (P < .001), and antidepressants (P = .001).

And across disease categories among patients who had at least one dispensed opioid prescription during the year prior to their first LDN prescription, there was a 46% reduction in opioid use among those who became persistent LDN users, and that use that was not compensated by an increase in other painkillers.

Of interest, there were no differences in either dispensed cumulative doses or number of prevalent users of medications used in multiple sclerosis, the condition featured in the televised documentary, thereby providing at least some evidence against a placebo effect.

"Our research does not prove that LDN is efficacious, but some results indicate that there is an association between persistent use of LDN and decreased consumption of use of relevant approved medications," Raknes and Småbrekke told Medscape Medical News in a jointly written email.

Although it wasn't possible to reliably identify ME/CFS patients, "Anecdotally, from what we have seen in Norwegian LDN Facebook groups, we have reason to believe that a large proportion of the more than 15,000 individuals that started LDN in 2013 and 2014 were [ME/CFS] patients," they said.

Taken together, all the Norwegian data "in addition to other available, but limited, evidence might be sufficient for some doctors to justify the off-label prescribing of LDN," they conclude.

Asked whether they believe that large-scale randomized trials of LDN will be undertaken so as to obtain regulatory approval, Raknes and Småbrekke replied, "We believe it is unlikely that 'Big Pharma'-scale randomized studies will be conducted. The profit potential is very limited, and public funding is probably the only way to enable conduct of sufficiently large studies."

"Hypothetically, if robust studies would show that LDN is at least as efficacious as expensive biological medicines, it is quite obvious that LDN should replace them for both economic and safety reasons," Raknes and Småbrekke explained. "However, we believe this is a highly speculative and an unlikely scenario."

Younger, Bolton, Raknes, and Småbrekke have disclosed no relevant financial relationships.

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