Low-dose naltrexone describes the off-label, experimental use of the medication naltrexone at low doses for diseases such as Crohn's disease and multiple sclerosis, but evidence for recommending such use is lacking.
Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is a strong opioid antagonist. It has been suggested that low-dose naltrexone might operate as an anti-inflammatory agent and therefore be used to treat some chronic conditions such as chronic pain, but the research is still highly experimental and few studies have been replicated.
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. Standard therapeutic doses of naltrexone blocks these receptors, which does two things; it prevents inhibition of GABA receptors (normally, signalling 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).
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. It is hypothesised that low-dose naltrexone may inhibit opioid receptors and therefore cause the body to increase production of endorphins and upregulate the immune system; it may also antagonize Toll-like receptor 4 that are found on macrophages, including microglia, possibly resulting in the reported anti-inflammatory effects.
These apparent effects have not been seen at standard doses or in major trials. 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.
Multiple studies have been claimed to show that low-dose naltrexone has promise as a treatment for chronic pain, some autoimmune disorders and cancers. More research is needed. As of 2014 no peer-reviewed studies that would justify clinical use of low-dose naltrexone in treating multiple sclerosis (MS) have been published. Prescription and medical formulation of low-dose naltrexone in the UK are unlicensed in the treatment of multiple sclerosis. Clinical trials for treatment of fibromyalgia were initiated in 2021.
In addition to proposed uses for low-dose naltrexone that have been studied in clinical research, low-dose naltrexone advocates make claims of its efficacy in treating other conditions, including: various types of cancer, Alzheimer's disease, HIV/AIDS, rheumatoid arthritis, and others. In 2010 Steven Novella of the Yale University School of Medicine disputed these claims as unsupported by rigorous clinical research, calling many applications pseudoscientific. More research is needed: however, as the UK's National Health Service noted in 2020, "...trials are necessary to draw firm conclusions on the efficacy of [low-dose naltrexone]... However, there is little incentive for pharmaceutical companies to conduct this research as naltrexone is inexpensive and off-patent."
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- Eve, Marianne (5 February 2020). "What is the evidence for low dose naltrexone for treatment of multiple sclerosis?" (PDF). Specialist Pharmacy Service. National Health Service. Retrieved 9 January 2022.
- Ngian, Gene-Siew; Guymer, Emma K.; Littlejohn, Geoffrey O (February 2011). "The use of opioids in fibromyalgia". International Journal of Rheumatic Diseases. 14 (1): 6–11. doi:10.1111/j.1756-185X.2010.01567.x. PMID 21303476. S2CID 29000267.
- Kim, Phillip S; Fishman, Michael A (26 August 2020). "Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review". Current Pain and Headache Reports (10 ed.). 24. doi:10.1007/s11916-020-00898-0. PMID 32845365.
- Younger, Jarred; Parkitny, Luke; McLain, David (April 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology (4 ed.). 33: 451–9. doi:10.1007/s10067-014-2517-2. PMC 3962576. PMID 24526250.
- 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.
- Bruun, Karin Due; Amris, Kirstine; Vaegter, Henrik Bjarke; Blichfeldt-Eckhardt, Morten Rune; Holsgaard-Larsen, Anders; Christensen, Robin; Toft, Palle (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.