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 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 suggested that LDN 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.[3]

Some proponents of low-dose naltrexone have brought forth unproven[2] claims about its efficacy in treating a wide range of diseases, including cancer, chronic fatigue syndrome and HIV/AIDS.

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.[4] 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).[4]

Hypothesised action of LDN

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.[3] 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;[5] it may also antagonize Toll-like receptor 4 that are found on macrophages, including microglia, and any reported anti-inflammatory effects might be due to that.[3][6]

These apparent effects have not been seen at standard doses or in major trials.[3] 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.[3]

Research

Multiple studies have been claimed to show that LDN has promise as a treatment for chronic pain, some autoimmune disorders and cancers. More research is needed.[7][8][9] As of 2014 no peer-reviewed studies that would justify clinical use of low-dose naltrexone in treating multiple sclerosis (MS) have been published.[1] Prescription and medical formulation of low-dose naltrexone in the UK are unlicensed in the treatment of multiple sclerosis.[5]

Criticisms

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.[2] 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 LDN... However, there is little incentive for pharmaceutical companies to conduct this research as naltrexone is inexpensive and off-patent."[5]

References

  1. 1 2 "Low-Dose Naltrexone". National MS Society. Retrieved 9 January 2022.
  2. 1 2 3 Novella, Steven (5 May 2010). "Low Dose Naltrexone – Bogus or Cutting Edge Science?". Retrieved 5 July 2011.
  3. 1 2 3 4 5 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.
  4. 1 2 Niciu, Mark J.; Arias, Albert J. (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.
  5. 1 2 3 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  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.
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