Low-dose naltrexone

Low-dose naltrexone (LDN) refers to daily naltrexone dosages that are roughly one-tenth of the standard opioid addiction treatment dosage. Most published research suggests a daily dosage of 4.5 mg, but this can vary by a few milligrams.[1] Low-dose naltrexone has been studied for the treatment of multiple chronic pain disorders including fibromyalgia, multiple sclerosis, Crohn’s disease, and complex regional pain syndrome.[2]

Naltrexone is approved by the Food and Drug Administration (FDA) for medication-assisted treatment of alcoholism and opioid use disorders.[3] Bernard Bihari's initial off-label usage of naltrexone in doses ranging from 1.5 mg to 3 mg as an adjuvant therapy for acquired immune deficiency syndrome (AIDS) in the 1980s led to the introduction of LDN into clinical practice.[4] Due to a lack of large-scale clinical trials and standardized research aimed at determining appropriate indications for LDN, it has remained an off-label option.[5]

Mechanism of action

Naltrexone and its active metabolite 6-β-naltrexol are competitive antagonists at μ-opioid and κ-opioid receptors, and to a lesser extent at δ-opioid receptors.[6] Standard therapeutic doses of naltrexone block these receptors, which does two things; it prevents inhibition of GABA receptors (normally, signaling through the GABA receptors inhibits the activity of neurons; many recreational drugs inhibit GABA and thus "free up" neuronal activation; preventing inhibition of GABA allows GABA's normal inhibition activity to take place) and it blocks dopamine release (many recreational drugs stimulate dopamine release, which is part of the brain's reward system that creates pleasure).[6]

Research

Multiple studies have shown that low-dose naltrexone has promise as a treatment for chronic pain, some autoimmune disorders and cancers.[7][8][9] As of 2014, no peer-reviewed studies supporting low-dose naltrexone for multiple sclerosis (MS) have been published.[10][11] Clinical trials for treatment of fibromyalgia were initiated in 2021.[12]

Low-dose naltrexone is also being studied in long COVID. However, efficacy has not been shown.[13][14]

A 2018 therapeutic utilization review concluded that low-dose naltrexone may be an appropriate option for treatment of fibromyalgia and irritable bowel disease, but that "Proper clinical trials are needed in order to establish evidence that could lead to correct indications, mode of administration, and other aspects necessary for effective clinical pharmacology of [low-dose naltrexone]."[15] The UK’s National Health Service echoed this sentiment in 2020.[11]

A 2023 systematic review published in the Australian Journal of General Practice found that preliminary research into the use of low-dose naltrexone as a treatment for fibromyalgia is promising. All clinical studies examined showed statistically significant improvements in pain and pain tolerance with mild side effects, however, sample sizes were small and further research is needed.[16]

References

  1. ^ Younger J, Parkitny L, McLain D (15 February 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology. 33 (4). Springer Science and Business Media LLC: 451–459. doi:10.1007/s10067-014-2517-2. ISSN 0770-3198. PMC 3962576. PMID 24526250.
  2. ^ Kim PS, Fishman MA (2020). "Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review". Current Pain and Headache Reports. 24 (10): 64. doi:10.1007/s11916-020-00898-0. ISSN 1531-3433. PMID 32845365.
  3. ^ Sudakin D (6 November 2015). "Naltrexone: Not Just for Opioids Anymore". Journal of Medical Toxicology. 12 (1). Springer Science and Business Media LLC: 71–75. doi:10.1007/s13181-015-0512-x. ISSN 1556-9039. PMC 4781804. PMID 26546222.
  4. ^ Bihari B (2013). "Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function". Alternative Therapies in Health and Medicine. 19 (2): 56–65. ISSN 1078-6791. PMID 23594453.
  5. ^ Toljan K, Vrooman B (21 September 2018). "Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization". Medical Sciences. 6 (4). MDPI AG: 82. doi:10.3390/medsci6040082. ISSN 2076-3271. PMC 6313374. PMID 30248938.
  6. ^ a b Niciu MJ, Arias AJ (24 July 2013). "Targeted Opioid Receptor Antagonists in the Treatment of Alcohol Use Disorders". CNS Drugs. 27 (10): 777–787. doi:10.1007/s40263-013-0096-4. PMC 4600601. PMID 23881605.
  7. ^ Kim PS, Fishman MA (26 August 2020). "Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review". Current Pain and Headache Reports. 24 (10) (10 ed.): 64. doi:10.1007/s11916-020-00898-0. PMID 32845365. S2CID 221310708. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
  8. ^ Younger J, Parkitny L, McLain D (April 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology. 33 (4) (4 ed.): 451–9. doi:10.1007/s10067-014-2517-2. PMC 3962576. PMID 24526250.
  9. ^ Zijian Li, Yue You, Noreen Griffin, Juan Feng, Fengping Shan (August 2018). "Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy". International Immunopharmacology. 61: 178–184. doi:10.1016/j.intimp.2018.05.020. PMID 29885638. S2CID 47009754. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
  10. ^ "Low-Dose Naltrexone". National MS Society. Archived from the original on 27 January 2022. Retrieved 9 January 2022.
  11. ^ a b Eve M (5 February 2020). "What is the evidence for low dose naltrexone for treatment of multiple sclerosis?" (PDF). Specialist Pharmacy Service. National Health Service. Archived (PDF) from the original on 10 February 2022. Retrieved 9 January 2022.
  12. ^ Bruun KD, Amris K, Vaegter HB, Blichfeldt-Eckhardt MR, Holsgaard-Larsen A, Christensen R, Toft P (December 2021). "Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial". Trials. 22 (1): 804. doi:10.1186/s13063-021-05776-7. ISSN 1745-6215. PMC 8591911. PMID 34781989.
  13. ^ Steenhuysen J (18 October 2022). "Addiction drug shows promise lifting long COVID brain fog, fatigue". Reuters. Archived from the original on 19 October 2022. Retrieved 19 October 2022.
  14. ^ O'Kelly B, Vidal L, McHugh T, Woo J, Avramovic G, Lambert JS (October 2022). "Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study". Brain, Behavior, & Immunity — Health. 24: 100485. doi:10.1016/j.bbih.2022.100485. PMC 9250701. PMID 35814187.
  15. ^ Toljan K, Vrooman B (2018). "Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization". Medical Sciences. 6 (4): 82. doi:10.3390/medsci6040082. PMC 6313374. PMID 30248938.
  16. ^ Aitcheson N, Lin Z, Tynan K (2023). "Low-dose naltrexone in the treatment of fibromyalgia: A systematic review and narrative synthesis". Australian Journal of General Practice. 52 (4). Royal Australian College of General Practitioners: 189–195. doi:10.31128/AJGP-09-22-6564. PMID 37021443.