Low-dose naltrexone

Low-dose naltrexone (LDN) describes the off-label, experimental use of the medication naltrexone at low doses for diseases such as Crohn's disease, Hashimoto's disease, and multiple sclerosis, but evidence for recommending such use is lacking.^[1][2]

Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is a strong opioid antagonist. It has been hypothesized that low-dose naltrexone might operate as an anti-inflammatory agent and therefore could be used to treat some chronic conditions involving immune system dysregulation.

Mechanism of action

Action of naltrexone at normal dose

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.^[3] 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).^[3]

Hypothesized action at low doses

Low-dose naltrexone refers to doses about 1/10th the size of the dose used normally, typically 4.5 mg or within a couple of milligrams of that value.^[4] It is hypothesized that if there are any effects, low-dose naltrexone may inhibit opioid receptors and therefore cause the body to increase production of endorphins and upregulate the immune system;^[5] it may also antagonize Toll-like receptor 4 that are found on macrophages, including microglia, possibly resulting in the reported anti-inflammatory effects.^[4] Researchers have also examined "ultra-low-doses" of naltrexone at microgram, nanogram, and picogram doses, that are co-administered with opioid analgesics with the goal of increasing pain relief and reducing side effects.^[4]

Research

Multiple studies have shown that low-dose naltrexone has promise as a treatment for chronic pain, some autoimmune disorders and cancers.^[6][7][8] As of 2014, no peer-reviewed studies supporting low-dose naltrexone for multiple sclerosis (MS) have been published.^[1][5] Clinical trials for treatment of fibromyalgia were initiated in 2021.^[9]

Prescription and medical formulations of low-dose naltrexone are not licensed or approved in the UK, EU and USA.^{[citation needed]}

Low-dose naltrexone is also being studied in long COVID. However, efficacy has not been shown.^[10][11]

In 2017, Raknes and Småbrekke published a drug utilization cohort study on Norwegian patient and prescriber characteristics, and dispense patterns, following a 2013 television documentary on low-dose naltrexone. They reported drawing upon the Norwegian Prescription Database and sales data not recorded in NorPD from the only Norwegian LDN manufacturer, with the caveat that these sources could not encompass the total. Their findings included that "Twenty percent of all doctors and 71% of general medicine practitioners registered in Norway in 2014 prescribed LDN at least once."^[12]

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.^[13]

As the UK's National Health Service noted in 2020, "...trials are necessary to draw firm conclusions on the efficacy of [low-dose naltrexone]."^[5]

References

1. "Low-Dose Naltrexone". National MS Society. from the original on 27 January 2022. Retrieved 9 January 2022.
2. Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N (1 April 2018). "Low dose naltrexone for induction of remission in Crohn's disease". Cochrane Database of Systematic Reviews. 4 (4): CD010410. doi:10.1002/14651858.CD010410.pub3. PMC 6494424. PMID 29607497.
3. 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.
4. Younger J, Parkitny L, McLain D (April 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clirheumatology. 33 (4): 451–9. doi:10.1007/s10067-014-2517-2. PMC 3962576. PMID 24526250.
5. 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. (PDF) from the original on 10 February 2022. Retrieved 9 January 2022.
6. 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. from the original on 5 October 2021. Retrieved 5 October 2021.
7. 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.
8. 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. from the original on 5 October 2021. Retrieved 5 October 2021.
9. 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.
10. Steenhuysen J (18 October 2022). "Addiction drug shows promise lifting long COVID brain fog, fatigue". Reuters. from the original on 19 October 2022. Retrieved 19 October 2022.
11. 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.
12. Raknes G, Småbrekke L (2016). "A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study". Pharmacoepidemiology and Drug Safety. 26 (2): 136–142. doi:10.1002/pds.4110. PMC 5298009. PMID 27670755.
13. 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.

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