Low-dose naltrexone
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Low-dose naltrexone (LDN) is the off-label,use of the medication naltrexone at low doses. LDN therapy has several mechanisms of action which work together to produce benefits for over 200 diseases, ranging from chronic pain, MS, Crohn's Disease, long covid, PTSD, weight loss, pediatric disorders and veterinarian conditions.[1][2]
Naltrexone is a class of drugs known as an opiate antagonist. It is commonly used to treat addiction to opiate drugs like heroin and morphine or to treat an acute overdose. The dosage usually varies between 50 mg to 300 mg daily, depending on the severity of the addiction.
Low-dose Naltrexone (LDN) has been used since 1985, by Harvard trained Dr. Bernard Bihari, a qualified Neurologist from New York, USA who devised and developed the use of LDN. Dr. Bihari was qualified in Internal Medicine and Psychiatry.[3]
Mechanism of action
[edit]Action of naltrexone at normal dose
[edit]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 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).[4]
How Low Dose Naltrexone Works
[edit]LDN increases the secretion of naturally occurring endorphins (feel good, runner’s high). Endorphins relieve pain, give a happy feeling and reduce inflammation.
General summary:
LDN increases the release of the Opioid Growth Factor which works powerfully to reduce inflammation, autoimmune responses and tumor cell growth.
LDN reduces inflammatory immune cell signaling (Toll-like Receptor-4). When these immune “lookout cells” get excited, they signal the immune system to get overly busy, which can cause or worsen auto0immune and inflammatory responses. These “lookout cells” are located throughout the body, including the gut and brain.
LDN calms glial cells in the nervous system. Glial cells make up over 70% of the nervous system and can either protect nerve pathways or cause inflammation of nerves. We want our Glial cells to remain in a calm and protective mode.
LDN increases dopamine levels. Dopamine is a neurotransmitter that makes us feel happy and rewarded, gives us energy and helps our brain solve problems. When dopamine is low, we feel depressed.[5]
A scientific summary:
Naltrexone is an example of a drug that exhibits pleiotropy - there are many effects of this compound other than those for which the agent was specifically developed. The first thing to understand is that Naltrexone, the drug in LDN, comes in a 50:50 mixture of 2 different shapes (called isomers). It has been discovered that one particular shape binds to immune cells whilst the other shape binds to opioid receptors.
Although consisting of exactly the same components, the two isomers appear to have different biological activity.
The LEVO (left-handed) version of naltrexone blocks opiate receptors. The DEXTRO (right-handed) version blocks receptors on immune cells. These include "Toll Like Receptors" (TLRs), which are heavily involved in immunity. LDN is an antagonist of TLR-4.
LDN has Immunomodulatory, opiate blocking, and anti-tumor effects and multiple Phase I and II trials have shown efficacy.
"Ultra-low dose" when given daily in microgram dosing - dosed twice daily
"Very low dose" when given in a daily dose of less than 0.1- 0.5 mg
"Low dose" when given in daily dose (or split doses) less than or equal to 4.5-10 mg
"Moderate dose" when the daily dose is between 10-25mg
"High dose" when given in daily amounts of 50mg or more[6]
Research
[edit]Multiple studies have shown that low-dose naltrexone has promise as a treatment for chronic pain, some autoimmune disorders and cancers.[7][8][9] As of 2014, no peer-reviewed studies supporting low-dose naltrexone for multiple sclerosis (MS) have been published.[10][11] Clinical trials for treatment of fibromyalgia were initiated in 2021.[12]
Prescription and medical formulations of low-dose naltrexone are not licensed or approved in the UK, EU and USA.[citation needed]
Low-dose naltrexone is also being studied in long COVID. However, efficacy has not been shown.[13][14]
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."[15]
A 2018 therapeutic utilization review concluded that low-dose naltrexone may be an appropriate option for treatment of fibromyalgia and irritable bowel disease, but that "Proper clinical trials are needed in order to establish evidence that could lead to correct indications, mode of administration, and other aspects necessary for effective clinical pharmacology of [low-dose naltrexone]."[16]
A 2023 systematic review published in the Australian Journal of General Practice found that preliminary research into the use of low-dose naltrexone as a treatment for fibromyalgia is promising. All clinical studies examined showed statistically significant improvements in pain and pain tolerance with mild side effects, however, sample sizes were small and further research is needed.[17]
As the UK's National Health Service noted in 2020, "...trials are necessary to draw firm conclusions on the efficacy of [low-dose naltrexone]."[11]
References
[edit]- ^ "LDN 2024 Patient Guide" (PDF). LDN Research Trust.org. LDN Research Trust.
- ^ "Prescribing information for veterinarians" (PDF). LDNResearchTrust.org.
- ^ Elsegood L (17 June 2024). New Horizons. UK: LDN Research Trust. p. xii. ISBN 978-1739107048.
- ^ a b Niciu MJ, Arias AJ (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.
- ^ "Compounding Low Dose Naltrexone (LDN)". https://dispensariesltd.ca/. 19 August 2023. Archived from the original on 5 June 2023. Retrieved 26 July 2024.
{{cite web}}: External link in|website= - ^ Elsegood L (17 June 2024). New Horizons. UK: LDN Research Trust. pp. xii to xiii. ISBN 978-1739107048.
- ^ Kim PS, Fishman MA (26 August 2020). "Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review". Current Pain and Headache Reports. 24 (10) (10 ed.): 64. doi:10.1007/s11916-020-00898-0. PMID 32845365. S2CID 221310708. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
- ^ Younger J, Parkitny L, McLain D (April 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology. 33 (4) (4 ed.): 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. S2CID 47009754. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
- ^ "Low-Dose Naltrexone". National MS Society. Archived from the original on 27 January 2022. Retrieved 9 January 2022.
- ^ a b Eve M (5 February 2020). "What is the evidence for low dose naltrexone for treatment of multiple sclerosis?" (PDF). Specialist Pharmacy Service. National Health Service. Archived (PDF) from the original on 10 February 2022. Retrieved 9 January 2022.
- ^ Bruun KD, Amris K, Vaegter HB, Blichfeldt-Eckhardt MR, Holsgaard-Larsen A, Christensen R, Toft P (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.
- ^ Steenhuysen J (18 October 2022). "Addiction drug shows promise lifting long COVID brain fog, fatigue". Reuters. Archived from the original on 19 October 2022. Retrieved 19 October 2022.
- ^ 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.
- ^ 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.
- ^ Toljan K, Vrooman B (2018). "Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization". Medical Sciences. 6 (4): 82. doi:10.3390/medsci6040082. PMC 6313374. PMID 30248938.
- ^ Aitcheson N, Lin Z, Tynan K (2023). "Low-dose naltrexone in the treatment of fibromyalgia: A systematic review and narrative synthesis". Australian Journal of General Practice. 52 (4). Royal Australian College of General Practitioners: 189–195. doi:10.31128/AJGP-09-22-6564. PMID 37021443.