Low-dose naltrexone

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.^[1]

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.^[2]

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.

The U.S. Food and Drug Administration have approved the use of naltrexone for chronic treatment of opioid dependence and for drug detoxification.^[3]

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.^[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]

Low-dose naltrexone refers to doses at about 1/10th the size of the dose used normally.^[1] As of 2015, the theory behind low-dose naltrexone's mechanism of action is that inhibiting opioid receptors at low doses causes the body to increase production of endorphins and upregulates the immune system;^[5] it also appears to antagonize Toll-like receptor 4 that are found on macrophages, including microglia, and its apparent anti-inflammatory effects might be due to that.^[1][6] These apparent effects have not been seen at standard doses.^[1] 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.^[1]

Research

Organizations promoting low-dose naltrexone have advocated it as a treatment for a variety of medical conditions.^[2] However, currently no peer-reviewed studies that would justify clinical use of low-dose naltrexone have been published.^[7]

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,^[3][8] and the evidence supporting its use in MS is not robust, as different studies have come to conflicting conclusions.^[1] 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.^[2] 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.^[5]

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."^[9]

One small pilot study found a reduction in fibromyalgia symptoms in patients treated with low-dose naltrexone.^[6]

Ultra-low-dose naltrexone can reverse or prevent the development of tolerance to opioids, and its use is being investigated in the combination drug Oxytrex, which combines oxycodone with ultra-low-dose naltrexone.^[10] There is some evidence that very low doses of opioid antagonists such as naltrexone reduce the severity of opioid withdrawal.^[11]

Criticisms

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.^[8]

References