Low-dose naltrexone

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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 and multiple sclerosis, but evidence for recommending such use is lacking. [1] [2]

Contents

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.

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]

Criticisms

Low-dose naltrexone advocates make numerous efficacy claims for myriad conditions, including those listed above, as well as; various types of cancer and immunocompromising conditions, Alzheimer's disease, HIV/AIDS, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, and Hashimoto’s thyroiditis.[ citation needed ]

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]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Any member of the group of drugs used to achieve analgesia, relief from pain

An analgesic drug, also called simply an analgesic, pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Myalgia</span> Muscle pain

Myalgia is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, especially when there has been no trauma.

<span class="mw-page-title-main">Fibromyalgia</span> Chronic pain of unknown cause

Fibromyalgia is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hypersensitivity.

<span class="mw-page-title-main">Pain management</span> Interdisciplinary approach for easing pain

Pain management is an aspect of medicine and health care involving relief of pain in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals provide some pain control in the normal course of their practice, and for the more complex instances of pain, they also call on additional help from a specific medical specialty devoted to pain, which is called pain medicine.

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for treatment of anxiety and chronic pain

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

A paradoxical reaction is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

<span class="mw-page-title-main">Opioid use disorder</span> Medical condition

Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder.

Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health-care provider.

<span class="mw-page-title-main">Baclofen</span> Medication for muscle movement disorders

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms. It is taken orally or by intrathecal pump. It is also sometimes used transdermally in combination with gabapentin and clonidine prepared at a compounding pharmacy.

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.

<span class="mw-page-title-main">Naltrexone</span> Medication

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur. Side effects may include trouble sleeping, anxiety, nausea, and headaches. In those still on opioids, opioid withdrawal may occur. Use is not recommended in people with liver failure. It is unclear if use is safe during pregnancy. Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain.

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">Ibudilast</span> Chemical compound

Ibudilast is an anti-inflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE4 subtype to the greatest extent, but also showing significant inhibition of other PDE subtypes.

<span class="mw-page-title-main">(+)-Naloxone</span> Drug

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (-)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

Tildrakizumab, sold under the brand names Ilumya and Ilumetri, is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders. It is approved for the treatment of adult patients with moderate-to-severe plaque psoriasis in the United States and the European Union.

An analgesic adjuvant is a medication that is typically used for indications other than pain control but provides control of pain (analgesia) in some painful diseases. This is often part of multimodal analgesia, where one of the intentions is to minimize the need for opioids.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

References

  1. 1 2 "Low-Dose Naltrexone". National MS Society. Retrieved 9 January 2022.
  2. ↑ Parker, Claire E; Nguyen, Tran M; Segal, Dan; MacDonald, John K; Chande, Nilesh (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. 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.
  4. 1 2 3 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. 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. ↑ 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 (10): 64. doi:10.1007/s11916-020-00898-0. PMID   32845365. S2CID   221310708.
  7. ↑ 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 (4): 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.
  9. ↑ 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.
  10. ↑ Steenhuysen, Julie (18 October 2022). "Addiction drug shows promise lifting long COVID brain fog, fatigue". Reuters.
  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.
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