Low-dose naltrexone (LDN) describes the off-label use of the medication naltrexone at low doses for diseases such as multiple sclerosis. Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is a strong opioid antagonist. Preliminary research has been promising for use of LDN in treating chronic medical conditions such as chronic pain, but at this stage the use of LDN as a treatment is still experimental and more research needs to be done before it can be widely recommended.
Some proponents of low-dose naltrexone have brought forth claim about its efficacy in treating a wide range of diseases, including cancer and HIV/AIDS. Low-dose naltrexone organizations have promoted its use on their webpages.
Approved uses of naltrexone
Naltrexone is an opioid receptor antagonist, meaning it binds to opioid receptors in cells. These receptors bind endogenous pain relieving compounds such as endorphins as well as opioids such as morphine. Naltrexone also works to bind against the effects of heroin, which is synthesized from morphine, and is useful to alleviate opioid dependence.
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. 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 at about 1/10th the size of the dose used normally. One hypothesis behind low-dose naltrexone's mechanism of action is that inhibiting opioid receptors at low doses might 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, and any reported anti-inflammatory effects might be due to that. 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.
Organizations promoting low-dose naltrexone have advocated it as a treatment for a variety of medical conditions. However, currently no peer-reviewed studies that would justify clinical use of low-dose naltrexone in treating Multiple Sclerosis (MS) have been published.
Low-dose naltrexone may relieve certain symptoms in people with multiple sclerosis, although medical practitioners often advise against using it as a substitute to proven therapies, and the evidence supporting its use in MS is not robust, as different studies have come to conflicting conclusions. Writing for the National MS Society in 2009, neurologist Alan Bowling called research into low-dose naltrexone "encouraging" but further research needed to be done before any definitive conclusions could be reached. Bowling noted that safety of low-dose naltrexone treatment for multiple sclerosis has not been assessed, and that patients who chose to undergo the treatment should be fully informed of the limited research backing its use. Personal testimonials describing low-dose naltrexone as a cure for multiple sclerosis are not supported by high quality evidence in large randomised, double-blind, placebo-controlled clinical trials. The UK National Health Service concluded that small pilot studies indicate low-dose naltrexone can improve symptoms in multiple sclerosis patients, but that more thorough studies are needed to determine its efficacy and safety. There is not enough evidence to prove it is effective in treating multiple sclerosis. Prescription and medical formulation of low-dose naltrexone in the UK are unlicensed in the treatment of multiple sclerosis.
Although preliminary studies have been published on Crohn's disease, the small size and preliminary nature of the studies prevent drawing "any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease."
One small pilot study found a reduction in fibromyalgia symptoms in patients treated with low-dose naltrexone. There is a website at www.lowdosenaltrexone.org giving a great deal of information. Mentioned there is a TV program made in Norway about lowdosenaltrexone with the result that it has been prescribed by 70% of GPs in that country since 2014. A recent website www.ldnscience.org covers new research. An interesting piece from Harvard suggests that it has a mild antidepressant effect. Reports from other well-known institutions are slowly building a great deal of useful information. It is particularly helpful in autoimmune conditions and chronic pain.
In addition to proposed uses for low-dose naltrexone that have been studied in clinical research, low-dose naltrexone advocates make unproven claims of its efficacy in treating other conditions, including: various types of cancer, Alzheimer's disease, HIV/AIDS, rheumatoid arthritis, and others. Steven Novella of the Yale University School of Medicine disputed these claims as unsupported by rigorous clinical research, calling many applications pseudoscientific. He further argues that the claim that low-dose naltrexone as an effective treatment for both immune dysfunction and autoimmune diseases is contradictory, and that improving the immune system could make the autoimmune disease worse.
- 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 . PMID 24526250.
- Bowling, Allen C. "Low-dose naltrexone (LDN) The "411" on LDN". National Multiple Sclerosis Society. pp. 44–46. Archived from the original on 29 September 2009. Retrieved 14 May 2014.
- Bourdette, Dennis (December 2009). "Spotlight on low dose naltrexone (LDN)". US Department of Veteran Affairs. Archived from the original on 25 February 2012.
- 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 . PMID 23881605.
- Smith, Katie (6 November 2015). "What is the evidence for low dose naltrexone for treatment of multiple sclerosis?". Specialist Pharmacy Service, National Health Service. Retrieved 12 November 2016.
- Ngian GS, Guymer EK, Littlejohn GO (February 2011). "The use of opioids in fibromyalgia" (PDF). Int J Rheum Dis. 14 (1): 6–11. doi:10.1111/j.1756-185X.2010.01567.x. PMID 21303476.
- "Low-Dose Naltrexone". National MS Society. Retrieved 12 May 2014.
- Novella, Steven (5 May 2010). "Low Dose Naltrexone – Bogus or Cutting Edge Science?". Retrieved 5 July 2011.
- Segal, D; Macdonald, JK; Chande, N 9 (Feb 21, 2014). "Low dose naltrexone for induction of remission in Crohn's disease". The Cochrane Database of Systematic Reviews. 2 (2): CD010410. doi:10.1002/14651858.CD010410.pub2. PMID 24558033.