Low-Dose Naltrexone

Naltrexone is a long-acting, non-selective opioid receptor antagonist whose U.S. Food and Drug Administration-approved indications are opioid and alcohol dependence. ^{[1] [2]} Low-dose naltrexone (LDN) refers to naltrexone prescribed off-label at low doses, typically 0.5 to 6.0 mg, for a variety of therapeutic indications distinct from its approved use for alcohol or opioid use disorder. ^[3] LDN has been used off-label for pain and inflammation in conditions such as fibromyalgia, multiple sclerosis, Crohn's disease, and other chronic pain disorders. ^[1]

It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and anti-inflammatory effect. ^[1] The mechanism of LDN appears to be modulation of neuro-inflammation, specifically the modulation of glial cells and release of inflammatory chemicals in the central nervous system, and these effects appear unique at low dosage compared with the doses approved for alcohol and opioid dependence. ^[4] LDN transiently blocks the opioid receptor, resulting in increased ligand and receptor expression, favoring kappa over mu receptors and decreasing inflammatory mediators and itch. ^[5]

A narrative review of 105 studies, including 15 randomised controlled trials, found that across chronic pain, autoimmune, gastrointestinal, dermatological, post-infectious, mental-health and oncology fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials, and concluded that current evidence does not support routine clinical use. ^[3] A meta-analysis of randomized controlled trials found that LDN did not show a significant difference in pain response compared with control groups overall, but improved pain in fibromyalgia compared with placebo. ^[6] A separate systematic review and meta-analysis of fibromyalgia found that although LDN marginally reduced pain and symptom severity from baseline, these effects were not superior to placebo. ^[7] A Cochrane review of low-dose naltrexone for induction of remission in Crohn's disease identified only two studies with 46 participants and concluded there is insufficient evidence to allow any firm conclusions regarding its efficacy and safety. ^[8]

LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg, but its experimental status and uncertain efficacy should be clearly explained. ^[3] A meta-analysis of chronic pain trials found that adverse events were increased with LDN compared with placebo, though comparable to active comparators. ^[6] In the Cochrane Crohn's disease review, pooled data from two small studies showed no statistically significant differences in specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue, and no serious adverse events were reported. ^[8] Because LDN is commonly compounded by a pharmacy, this may pose barriers to access. ^[5]