Low-dose naltrexone

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Low-dose naltrexone (LDN) refers to daily naltrexone dosages that are roughly one-tenth of the standard opioid addiction treatment dosage. Most published research suggests a daily dosage of 4.5 mg, but this can vary by a few milligrams. [1] Low-dose naltrexone has been studied for the treatment of multiple chronic pain disorders including fibromyalgia, multiple sclerosis, Crohn’s disease, and complex regional pain syndrome. [2]

Contents

Naltrexone is approved by the Food and Drug Administration (FDA) for medication-assisted treatment of alcoholism and opioid use disorders. [3] Bernard Bihari's initial off-label usage of naltrexone in doses ranging from 1.5 mg to 3 mg as an adjuvant therapy for acquired immune deficiency syndrome (AIDS) in the 1980s led to the introduction of LDN into clinical practice. [4] Due to a lack of large-scale clinical trials and standardized research aimed at determining appropriate indications for LDN, it has remained an off-label option. [5]

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. [6] 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). [6]

Research

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]

Low-dose naltrexone is also being studied in long COVID. However, efficacy has not been shown. [13] [14]

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]." [15] The UK’s National Health Service echoed this sentiment in 2020. [11]

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. [16]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. 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">Tramadol</span> Medication of the opioid type, patented 1972

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

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

Fibromyalgia is a medical syndrome which causes chronic widespread pain, accompanied by fatigue, waking unrefreshed, and cognitive symptoms. Other symptoms can include headaches, lower abdominal pain or cramps, and depression. People with fibromyalgia can also experience insomnia and a general hypersensitivity. The cause of fibromyalgia is unknown, but is believed to involve a combination of genetic and environmental factors. Environmental factors may include psychological stress, trauma, and certain infections. Since the pain appears to result from processes in the central nervous system, the condition is referred to as a "central sensitization syndrome".

Depressants, colloquially known as "downers" or central nervous system (CNS) depressants, are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.

<span class="mw-page-title-main">Gabapentin</span> Anticonvulsant medication

Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.

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, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.

<span class="mw-page-title-main">Flumazenil</span> GABA receptor antagonist drug and benzodiazepine antidote

Flumazenil is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines, through competitive inhibition.

<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.

<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.

<span class="mw-page-title-main">Tiagabine</span> Anticonvulsant medication

Tiagabine is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.

<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">Milnacipran</span> Antidepressant

Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

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

Acamprosate, sold under the brand name Campral, is a medication which reduces alcoholism cravings. It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals, as it only addresses withdrawal symptoms and not psychological dependence. It facilitates a reduction in alcohol consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior.

Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is an uncommon condition of generalized pain caused by the long-term use of high dosages of opioids such as morphine, oxycodone, and methadone. OIH is not necessarily confined to the original affected site. This means that if the person was originally taking opioids due to lower back pain, when OIH appears, the person may experience pain in the entire body, instead of just in the lower back. Over time, individuals taking opioids can also develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). This means that if the person originally felt pain from twisting or from sitting too long, the person might now additionally experience pain from a light touch or from raindrops falling on the skin.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

<span class="mw-page-title-main">Gabapentinoid</span> Calcium channel blockers

Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.

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.

References

  1. ↑ Younger J, Parkitny L, McLain D (15 February 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology. 33 (4). Springer Science and Business Media LLC: 451–459. doi:10.1007/s10067-014-2517-2. ISSN   0770-3198. PMC   3962576 . PMID   24526250.
  2. ↑ Kim PS, Fishman MA (2020). "Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review". Current Pain and Headache Reports. 24 (10): 64. doi:10.1007/s11916-020-00898-0. ISSN   1531-3433. PMID   32845365.
  3. ↑ Sudakin D (6 November 2015). "Naltrexone: Not Just for Opioids Anymore". Journal of Medical Toxicology. 12 (1). Springer Science and Business Media LLC: 71–75. doi:10.1007/s13181-015-0512-x. ISSN   1556-9039. PMC   4781804 . PMID   26546222.
  4. ↑ Bihari B (2013). "Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function". Alternative Therapies in Health and Medicine. 19 (2): 56–65. ISSN   1078-6791. PMID   23594453.
  5. ↑ Toljan K, Vrooman B (21 September 2018). "Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization". Medical Sciences. 6 (4). MDPI AG: 82. doi: 10.3390/medsci6040082 . ISSN   2076-3271. PMC   6313374 . PMID   30248938.
  6. 1 2 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.
  7. ↑ 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.
  8. ↑ 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.
  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. S2CID   47009754. Archived from the original on 5 October 2021. Retrieved 5 October 2021.
  10. ↑ "Low-Dose Naltrexone". National MS Society. Archived from the original on 27 January 2022. Retrieved 9 January 2022.
  11. 1 2 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
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