Naltrexone

Alcohol use disorder Naltrexone has been best studied as a treatment for alcoholism. Naltrexone has been shown to decrease the quantity and frequency of ethanol consumption by reducing the dopamine release from the brain after consuming alcohol. Studies comparing naltrexone to a placebo show a small but statistically significant decrease in relapse. Its overall benefit has been described as "modest". A method pioneered (starting in the 1980s) by scientist John David Sinclair (dubbed commercially the "") advocates "pharmacological extinction" of problem drinking behavior by administering naltrexone alongside controlled alcohol consumption. In effect, he argues that naltrexone-induced opioid antagonism sufficiently disrupts reflexive reward mechanisms inherent in the consumption of alcohol and, given enough repetition, will dissociate positive associations formerly made with the consumption of alcohol. A review of eight naltrexone trials concluded, "Although all found benefits from naltrexone with the coping therapy, none of them found any significant benefit of naltrexone over placebo when combined with support for abstinence." Opioid use disorder Long-acting injectable naltrexone (under the brand name Vivitrol) is an opioid antagonist, blocking the effects of heroin and other opioids, and decreases heroin use compared to a placebo. Unlike methadone and buprenorphine, it is not a controlled medication. A drawback of injectable naltrexone is that it requires patients with opioid use disorder and current physiological dependence to be fully withdrawn before it is initiated to avoid a precipitated opioid withdrawal that may be quite severe. In contrast, initiation of buprenorphine only requires delay of the first dose until the patient begins to manifest at least mild opioid withdrawal symptoms. Among patients able to successfully initiate injectable naltrexone, long-term remission rates were similar to those seen in clinical buprenorphine/naloxone administration. The consequence of relapse when weighing the best course of treatment for opiate use disorder remains a concern. Methadone and buprenorphine administration maintain greater drug tolerance while naltrexone allows tolerance to fade, leading to higher instances of an overdose in people who relapse and thus higher mortality. World Health Organization guidelines state that most patients should be advised to use opioid agonists (e.g., methadone or buprenorphine) rather than opioid antagonists like naltrexone, citing evidence of superiority in reducing mortality and retaining patients in care. A 2011 review found insufficient evidence to determine the effect of naltrexone taken orally on opioid dependence. While some do well with this formulation, it must be taken daily, and a person whose cravings become overwhelming can obtain opioid intoxication simply by skipping a dose. Due to this issue, the usefulness of oral naltrexone in opioid use disorder is limited by the low retention in treatment. Naltrexone taken orally remains an ideal treatment for a small number of people with opioid use, usually those with a stable social situation and motivation. With additional contingency management support, naltrexone may be effective in a broader population. Others Unlike varenicline (brand name Chantix), naltrexone is not useful for quitting smoking. Naltrexone has also been under investigation for reducing behavioral addictions such as gambling, NSSID (non-suicidal self-injury disorder), and kleptomania, as well as compulsive sexual behaviors in both offenders and non-offenders (e.g. compulsive porn viewing and masturbation). The results were promising. In one study, the majority of sexual offenders reported a strong reduction in sexual urges and fantasies which reverted to baseline once the medication was discontinued. Case reports have also shown cessation of gambling and other compulsive behaviors, for as long as the medication was taken. When taken at much smaller doses, a regimen known as low-dose naltrexone (LDN), naltrexone may reduce pain and help to address neurological symptoms. Some patients report that LDN helps reduce their symptoms of ME/CFS, multiple sclerosis (MS), fibromyalgia, or autoimmune diseases. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory. LDN is also being considered as a potential treatment for long COVID. Available forms Naltrexone is available and most commonly used in the form of an oral tablet (50 mg). Additionally, naltrexone subcutaneous implants that are surgically implanted are available. While these are manufactured in Australia, they are not authorized for use within Australia, but only for export. By 2009, naltrexone implants showed superior efficacy in the treatment of heroin dependence when compared to the oral form. ==Side effects==

The most common side effects reported with naltrexone are gastrointestinal complaints such as diarrhea and abdominal cramping. Adverse effects Whether naltrexone causes dysphoria, depression, anhedonia, or other aversive effects has been studied and reviewed. In early studies of normal and opioid-abstinent individuals, acute and short-term administration of naltrexone was reported to produce a variety of aversive effects including fatigue, loss of energy, sleepiness, mild dysphoria, depression, lightheadedness, faintness, confusion, nausea, gastrointestinal disturbances, sweating, and occasional derealization. However, these studies were small, often uncontrolled, and used subjective means of assessing side effects. : The side-effect profile [of naltrexone], at least on the recommended dose of 50 mg per day, is generally benign, although 5 to 10 percent of detoxified opioid addicts experience immediate, intolerable levels of withdrawal-like effects including agitation, anxiety, insomnia, light-headedness, sweating, dysphoria, and nausea. Most patients on naltrexone experience few or no symptoms after the first 1 to 2 weeks of treatment; for a substantial minority (20 to 30 percent) protracted discomfort is experienced. Persisting affective distress related to naltrexone may account for individuals taking the drug who drop out of treatment. The μ-opioid receptor has been found to play a major role in social reward in animals and the μ-opioid receptor knockout mouse is an animal model of autism. Studies on whether naltrexone can decrease the pleasurable effects of listening to music are conflicting. Besides humans, naltrexone has been found to produce aversive effects in rodents as assessed by conditioned place aversion. Subsequent studies have suggested limited or no toxicity in other patient populations and at typical recommended doses such as 50 to 100 mg/day. ==Overdose==

No toxic effects have been observed with naltrexone in doses of up to 800 mg/day in clinical studies. No deaths are known to have occurred with naltrexone overdose. ==Pharmacology==

Pharmacodynamics Opioid receptor blockade Naltrexone and its active metabolite 6β-naltrexol are competitive antagonists of the opioid receptors. However, naltrexone is not actually a silent antagonist of these receptors but instead acts as a weak partial agonist, with Emax values of 14 to 29% at the MOR, 16 to 39% at the KOR, and 14 to 25% at the DOR in different studies. Naltrexone at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies. Per simulation, a lower dose of naltrexone of 25 mg/day might be expected to achieve around 60% brain occupancy of the KOR but still close to 90% occupancy of the MOR. The half-time of brain MOR blockade by naltrexone in this study was 72 to 108 hours (3.0 to 4.5 days). The half-life of occupancy of the brain MOR and duration of clinical effect of naltrexone are much longer than suggested by its plasma elimination half-life. A single 50 mg oral dose of naltrexone has been found to block brain MORs and opioid effects for at least 48 to 72 hours. The half-time of brain MOR blockade by naltrexone (72–108 hours) is much longer than the fast plasma clearance component of naltrexone and 6β-naltrexol (~4–12 hours) but was reported to correspond well to the longer terminal phase of plasma naltrexone clearance (96 hours). Naltrexone blocks the effects of MOR agonists like morphine, heroin, and hydromorphone in humans via its MOR antagonism. and amphetamines. The opioid receptors are involved in neuroendocrine regulation. Other activities In addition to the opioid receptors, naltrexone binds to and acts as an antagonist of the opioid growth factor receptor (OGFR) and toll-like receptor 4 (TLR4) and interacts with high- and low-affinity binding sites in filamin A (FLNA). It is said that very low doses of naltrexone (<0.001–1 mg/day) interact with FLNA, low doses (1 to 5 mg/day) produce TLR4 antagonism, and standard clinical doses (50 to 100 mg/day) exert opioid receptor and OGFR antagonism. Absorption The absorption of naltrexone with oral administration is rapid and nearly complete (96%). Peak concentrations of naltrexone are 19 to 44 μg/L after a single 100 mg oral dose and time to peak concentrations of naltrexone and 6β-naltrexol (metabolite) is within 1 hour. Conversely, 6β-naltrexol exposure is only about 2-fold higher than that of naltrexone with intramuscular injection of naltrexone in microspheres (brand name Vivitrol). However, 6β-naltrexol is peripherally selective and crosses into the brain much less readily than does naltrexone. ==Chemistry==

Naltrexone, also known as N-cyclopropylmethylnoroxymorphone, is a derivative of oxymorphone (14-hydroxydihydromorphinone). It is specifically the derivative of oxymorphone in which the tertiary amine methyl substituent is replaced with methylcyclopropane. Analogues The closely related medication, methylnaltrexone (N-methylnaltrexone), is used to treat opioid-induced constipation but does not treat addiction as it does not cross the blood–brain barrier. Nalmefene (6-desoxy-6-methylenenaltrexone) is similar to naltrexone and is used for the same purposes as naltrexone. Naltrexone should not be confused with naloxone (N-allylnoroxymorphone), which is used in emergency cases of opioid overdose. Other opioid antagonists related to naltrexone include 6β-naltrexol (6β-hydroxynaltrexone), samidorphan (3-carboxamido-4-hydroxynaltrexone), β-funaltrexamine (naltrexone fumarate methyl ester), nalodeine (N-allylnorcodeine), nalorphine (N-allylnormorphine), and nalbuphine (N-cyclobutylmethyl-14-hydroxydihydronormorphine). ==History==

Naltrexone was first synthesized in 1963 by Metossian at Endo Laboratories, a small pharmaceutical company in New York City. It was characterized by Blumberg, Dayton, and Wolf in 1965 and was found to be an orally active, long-acting, and very potent opioid antagonist. Clinical trials for opioid dependence began in 1973, and a developmental collaboration of DuPont with the National Institute on Drug Abuse for this indication started the next year in 1974. A depot formulation for intramuscular injection was approved by the FDA under the brand name Vivitrol for alcohol dependence in 2006 and opioid dependence in 2010. ==Society and culture==

Generic names Naltrexone is the generic name of the drug and its , , , , and , while naltrexone hydrochloride is its and . It is also marketed in combination with bupropion (naltrexone/bupropion) as Contrave, and was marketed with morphine (morphine/naltrexone) as Embeda. A combination of naltrexone with buprenorphine (buprenorphine/naltrexone) has been developed, but has not been marketed. Controversies The FDA authorized use of injectable naltrexone (Vivitrol) for opioid addiction using a single study that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia, a country where opioid agonists such as methadone and buprenorphine are not available. The study was a "double-blind, placebo-controlled, randomized", 24-week trial running "from July 3, 2008, through October 5, 2009" with "250 patients with opioid dependence disorder" at "13 clinical sites in Russia" on the use of injectable naltrexone (XR-NTX) for opioid dependence. The study was funded by the Boston-based biotech Alkermes firm which produces and markets naltrexone in the United States. Critics charged that the study violated ethical guidelines since it compared the formulation of naltrexone not to the best available, evidence-based treatment (methadone or buprenorphine), but to a placebo. Further, the trial did not follow patients who dropped out of the trial to evaluate subsequent risk of fatal overdose, a major health concern. Subsequent trials in Norway and the US did compare injectable naltrexone to buprenorphine and found them to be similar in outcomes for patients willing to undergo the withdrawal symptoms required before naltrexone administration. Nearly 30% of patients in the US trial did not complete induction. Despite these findings, naltrexone's manufacturer and some health authorities have promoted the medicine as superior to methadone and buprenorphine since it is not an opioid and does not induce dependence. The manufacturer has also marketed directly to law enforcement and criminal justice officials, spending millions of dollars on lobbying and providing thousands of free doses to jails and prisons. The company's marketing techniques have led to a Congressional investigation, and warning from the FDA about failure to adequately state risks of fatal overdose to patients receiving the medicine. In May 2017, United States Secretary of Health and Human Services Tom Price praised [Vivitrol] as the future of opioid addiction treatment after visiting the company's plant in Ohio. The experts pointed out that Vivitrol's competitors, buprenorphine and methadone, are "less expensive", "more widely used", and have been "rigorously studied". Price had claimed that buprenorphine and methadone were "simply substitute[s]" for "illicit drugs" whereas according to the letter, "the substantial body of research evidence supporting these treatments is summarized in guidance from within your own agency, including the Substance Abuse and Mental Health Services Administration, the US Surgeon General, the National Institute on Drug Abuse, and the Centers for Disease Control and Prevention. Buprenorphine and methadone have been demonstrated to be highly effective in managing the core symptoms of opioid use disorder, reducing the risk of relapse and fatal overdose, and encouraging long-term recovery." ==Research==

Depersonalization Naltrexone is sometimes used in the treatment of dissociative symptoms, such as the depersonalization and derealization of depersonalization-derealization disorder. Some studies suggest it might help, but conclusions are limited by a small evidence base. Evidence for recommending low-dose naltrexone is lacking. This treatment has received attention on the Internet. In 2022, four studies (with a few hundred patients) were conducted on naltrexone in the setting of long COVID. Self-injury One study suggested that self-harming behavior in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone. In these cases, the self-injury is believed to be done to release beta-endorphin, which binds to the same receptors as heroin and morphine. If the "rush" generated by self-injury is removed, the behavior may stop. Behavioral disorders Some studies exist that naltrexone might be beneficial in the treatment of impulse-control disorders such as kleptomania, compulsive gambling, and trichotillomania (compulsive hair pulling); evidence for its effectiveness for gambling is conflicting. A 2008 case-study reported successful use of naltrexone in suppressing and treating an internet pornography addiction. Interferon alpha Naltrexone is effective in suppressing the adverse cytokine-mediated neuropsychiatric effects of interferon alpha therapy. Critical addiction studies Some historians and sociologists have suggested that the meanings and uses attributed to anti-craving medicine, such as naltrexone, are context-dependent. Studies have suggested the use of naltrexone in drug courts or healthcare rehabs is a form of "post-social control," or "post-disciplinary control," whereby control strategies for managing offenders and addicts shift from imprisonment and supervision toward more direct control over biological processes. Sexual addiction Small studies have shown a reduction of sexual addiction and problematic sexual behaviours from naltrexone. ==Veterinary use==

Naltrexone is used in wild and zoo animals to reverse the effects of carfentanil and etorphine. Naltrexone has a longer duration of action than naloxone in most species, although not the dog, making it more desirable than naloxone which requires more frequent administration. Although typically used for high strength opioids like carfentanil and etorphine naltrexone can be used for other opioids and is suitable for use of reversing strong opioid doses in the cat. A quaternary ammonium compound, methlynaltrexone is still being investigated for use in veterinary medicine. Naltrexone antagonises the μ-, κ-, and δ-, but methlynaltrexone does not bind to the δ-opioid receptor and binds to the μ-opioid receptor at greater potency than the κ-opioid receptor and it does not cross the blood-brain barrier, which allows methlynaltrexone to treat peripheral effects of opioids such as gastrointestinal ileus whilst maintaining analgesia. == References ==