Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study

PLoS One. 2019 Feb 14;14(2):e0212460. doi: 10.1371/journal.pone.0212460. eCollection 2019.


In recent years, low dose naltrexone (LDN) has been used as an off-label therapy for several chronic diseases. Results from small laboratory and clinical studies indicate some beneficial effects of LDN in autoimmune diseases, but clinical research on LDN in rheumatic disease is limited. Using a pharmacoepidemiological approach, we wanted to test the hypothesis that starting LDN leads to reduced dispensing of medicines used in the treatment of rheumatic disease. We performed a controlled before-after study based on the Norwegian Prescription Database (NorPD) to compare prescriptions to patients one year before and one year after starting LDN in 2013. The identified patients (n = 360) were stratified into three groups based on LDN exposure. Outcomes were differences in dispensing of medicines used in rheumatic disease. In persistent LDN users, there was a 13% relative reduction in cumulative defined daily doses (DDD) of all medicines examined corresponding to -73.3 DDD per patient (95% CI -120,2 to -26.4, p = 0.003), and 23% reduction of analgesics (-21.6 DDD (95% CI -35.5 to -7.6, p<0.009)). There was no significant DDD change in patients with lower LDN exposure. Persistent LDN users had significantly reduced DDDs of NSAID and opioids, and a lower proportion of users of DMARDs (-6.7 percentage points, 95% CI -12.3 to-1.0, p = 0.028), TNF-α antagonists and opioids. There was a decrease in the number of NSAID users among patients with the least LDN exposure. Important limitations are that prescription data are proxies for clinical effects and that a control group unexposed to LDN is lacking. The results support the hypothesis that persistent use of LDN reduces the need for medication used in the treatment of rheumatic and seropositive arthritis. Randomised clinical trials on LDN in rheumatic disease are warranted.

MeSH terms

  • Aged
  • Antirheumatic Agents / administration & dosage
  • Arthritis / drug therapy*
  • Arthritis, Rheumatoid / drug therapy*
  • Controlled Before-After Studies
  • Drug Prescriptions
  • Female
  • Humans
  • Male
  • Middle Aged
  • Naltrexone / administration & dosage*
  • Narcotic Antagonists / administration & dosage
  • Norway
  • Off-Label Use
  • Pharmacoepidemiology
  • Registries


  • Antirheumatic Agents
  • Narcotic Antagonists
  • Naltrexone

Grants and funding

The author(s) received no specific funding for this work.