Low Dose Naltrexone for Fibromyalgia Pain - Use it or Lose it? Save

Medscape recently reviewed off-label use of low dose naltrexone (LDN) in fibromyalgia (FM) and found it is deemed effective by some clinicians and patients, but 1) there is no FDA indication for LDN use in FM and 2) the data supporting its use is limited.

Most recent reviews have come to the same conclusion - LDN appears safe and is modestly effective (compared to placebo) in treating FM, but the strength of evidence is low. More importantly recent larger trials have not confirmed significant benefits.  One advantage is that naltrexone is an old, cheap drug. When prepared by compounding pharmacies it may cost between $20 and $60 per month. 

Limited Controlled Trial Data  

• Metanalyses and reviews suggest modest efficacy for pain reduction over placebo (Cohen’s d = -0.34), but not versus active comparator treatments.
• A 2013 RCT of 31 women with found that LDN better at pain reduction (29% vs 18% on placebo). Younger et al. Arthritis Rheum. 2013 Feb;65(2):529-38.
• A 2023 cohort study of LDN for pain conditions included 115 people, most having fibromyalgia. The study found that 65% reported a benefit in their pain and other symptoms.
• Bruun et al., 2023. A double-blind, crossover RCT, of 52 FM patients used 4.5 mg LDN daily. They found no significant analgesic effect of LDN over placebo was found. The study was underpowered (target n=140 not reached).
• FINAL Study - (Bruun et al., 2024) was a larger RCT (n=99), using 6 mg LDN daily and found LDN was not superior to placebo for pain reduction (mean difference -0.34, p=0.27), but more in the LDN group achieved ≥30% pain reduction (45% vs 28%). Memory problems improved with LDN, but clinical relevance is unclear. Adverse events were similar between groups, with no safety concerns.
• IN PROCESS: INNOVA Trial - is a 120 patient phase III RCT to assess LDN (4.5 mg) vs placebo over 12 months, with endpoints including pain, quality of life, cost-utility, and neurobiological effects. Results are pending.

MOA: How does LDN work in FM?  LDN is thought to act peripherally by binding to opioid receptors on glial cells, abrogating pain and secondarily lessening FM symptoms (fatigue, malaise, brain fog, etc.).  Some claim that LDN is antiinflammatory, and while this may be biologically plausible, there is no good evidence of antiinflammatory effects. 

Dosing: When naltrexone is used to treat opioid and alcohol use disorders, usual doses are 50-100 mg daily. But much lower doses have been used to treat FM, usually starting low (as low as 0.5 mg) and slowly increasing to 1.5 mg to 4.5 mg once daily, until pain control is achieved. It can be taken at night, or switched to the morning if sleep is disrupted by vivid dreams.

Caveats:

• Side effects are generally not a problem with the most frequently reported being vivid dreams/nightmares and headaches. Nausea, diarrhea, and anxiety can also occur infrequently.
• Naltrexone is an opioid antagonist and can block the effects of opioid pain medications. Patients must avoid or stop taking opioids when starting LDN (except in specific ultra-low dose protocols under medical supervision).
• LDN is not available in low-dose tablets from standard pharmacies and must be custom-prepared by a compounding pharmacy. This means it is typically not covered by insurance. The out-of-pocket cost is usually around $20-$100 per month.