|Trade names||ReVia, Vivitrol, others|
|Other names||EN-1639A; UM-792; N-Cyclopropyl-methylnoroxymorphone; N-Cyclopropylmethyl-14-hydroxydihydro-morphinone; 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one|
|By mouth, intramuscular injection, subcutaneous implant|
|Elimination half-life||Oral (ReVia):|
• Naltrexone: 4 hours
• 6β-Naltrexol: 13 hours
• Naltrexone: 5 hours
• Naltrexone: 5–10 days
• 6β-Naltrexol: 5–10 days
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||341.407 g·mol−1|
|3D model (JSmol)|
|Melting point||169 °C (336 °F)|
|(what is this?)|
Naltrexone, sold under the brand names ReVia and Vivitrol among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found to be 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. A decreased desire for opioids, though, may take a few weeks.
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, both those from inside and outside the body.
Naltrexone has been best studied as a treatment for alcoholism. Naltrexone has been shown to decrease the amount and frequency of drinking. It does not appear to change the percentage of people drinking. Its overall benefit has been described as "modest".
The Sinclair method is a method of using opiate antagonists such as naltrexone to treat alcoholism. The person takes the medication once, about an hour before drinking, to avoid side effects that arise from chronic use. The opioid antagonist is thought to block the positive-reinforcement effects of alcohol and may assist the person to stop or reduce drinking.
Long-acting injectable naltrexone decreases heroin use more than placebo. It has benefits over methadone and buprenorphine in that it is not a restricted medication. It may decrease cravings for opioids after a number of weeks, and decreases the risk of overdose, at least during the time period that naltrexone is still active. It is given once per month and has better compliance than the oral formulation.
A 2011 review found insufficient evidence to determine the effect of naltrexone taken by mouth in 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 disorders is limited by the low retention in treatment. Naltrexone by mouth 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.
Naltrexone is available and most commonly used in the form of an oral tablet (50 mg). Vivitrol, a naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available. 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.
Naltrexone should not be used by persons with acute hepatitis or liver failure, or those with recent opioid use (typically 7–10 days).
The most common side effects reported with naltrexone are gastrointestinal complaints such as diarrhea and abdominal cramping. These adverse effects are analogous to the symptoms of opioid withdrawal, as the μ-opioid receptor blockade will increase gastrointestinal motility.
Naltrexone has been reported to cause liver damage when given at doses higher than recommended. It carries an FDA boxed warning for this rare side effect. Due to these reports, some physicians may check liver function tests prior to starting naltrexone, and periodically thereafter. Concerns for liver toxicity initially arose from a study of nonaddicted obese patients receiving 300 mg of naltrexone. Subsequent studies have suggested limited or no toxicity in other patient populations and at typical recommended doses such as 50 to 100 mg/day.
Naltrexone should not be started until several (typically 7–10) days of abstinence from opioids have been achieved. This is due to the risk of acute opioid withdrawal if naltrexone is taken, as naltrexone will displace most opioids from their receptors. The time of abstinence may be shorter than 7 days, depending on the half-life of the specific opioid taken. Some physicians use a naloxone challenge to determine whether an individual has any opioids remaining. The challenge involves giving a test dose of naloxone and monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be started.
Whether or not naltrexone causes dysphoria, depression, anhedonia, or other aversive effects as side effects has been studied and reviewed. Surprisingly, naltrexone seems to have minimal to no untoward influence in these areas. According to one source:
- Naltrexone itself produces little or no psychoactive effect in normal research volunteers even at high doses, which is remarkable given that the endogenous opioid system is important in normal hedonic functioning. Because endogenous opioids are involved in the brain reward system, it would be reasonable to hypothesize that naltrexone might produce anhedonic or dysphoric effects. Although some evidence from small, early trials suggested that patients with a history of opiate dependence might be susceptible to dysphoric effects in response to naltrexone (Crowley et al. 1985; Hollister et al. 1981), reports of such effects have been inconsistent. Most large clinical studies of recovering opioid-dependent individuals have not found naltrexone to have an adverse effect on mood (Greenstein et al. 1984; Malcolm et al. 1987; Miotto et al. 2002; Shufman et al. 1994). Some studies have actually found improvements in mood during the course of treatment with naltrexone (Miotto et al. 1997; Rawlins and Randall 1976).
On the other hand, naltrexone has been found to reduce feelings of social connection. Reports on whether naltrexone can decrease the pleasurable effects of listening to music are conflicting.
|1.0 nM||3.9 nM||149 nM||1:4:149|||
|0.0825 nM||0.509 nM||8.02 nM||1:6:97|||
Naltrexone and its active metabolite 6β-naltrexol are competitive antagonists of the μ-opioid receptor (MOR), the κ-opioid receptor (KOR) to a lesser extent, and the δ-opioid receptor (DOR) to a much lesser extent. In one study, naltrexone was not a silent antagonist of these receptors but acted as a weak partial agonist, with Emax values of 29% at the MOR, 16% at the KOR, and 25% at the DOR. In combination with agonists of these receptors however, naltrexone appears to become an inverse agonist of the MOR and a neutral antagonist of the KOR and DOR. This may at least in part underlie its ability to precipitate withdrawal in opioid-dependent individuals.
Occupancy of the opioid receptors by naltrexone has been studied using positron emission tomography (PET). Naltrexone at a dose of 50 mg/day has been found to occupy approximately 90 to 95% of MORs and 20 to 35% of DORs. Naltrexone at a dose of 100 mg/day with the last dose 2 hours before testing has been found to achieve 92.4 ± 1.3% occupancy of the KOR. Per simulation, a lower dose of 25 mg/day would be expected to achieve around 60% occupancy of the KOR but still close to 90% occupancy of the MOR.
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.
Mechanism of action
The blockade of opioid receptors is the basis behind naltrexone's action in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. Its mechanism of action in alcohol dependence is thought to be generated via KOR antagonism, which blocks the actions of the endogenous opioid peptide dynorphin. Dynorphin typically instates drug-seeking behavior when it binds to the KOR, as well as decreasing dopaminergic signalling in the nucleus accumbens.
Naltrexone is metabolized in the liver mainly to 6β-naltrexol by the enzyme dihydrodiol dehydrogenase. Other metabolites include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. These are then further metabolized by conjugation with glucuronic acid to form a glucuronide. The elimination half-life of naltrexone and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively. In Contrave oral tablets, which are extended-release, the half-life of naltrexone is 5 hours. As Vivitrol, which is a suspension of microspheres for intramuscular injection, the half-life of both naltrexone and 6β-naltrexol is 5 to 10 days and is suitable for administration once every 4 weeks or once a month. The half-life of occupancy of the MOR and duration of clinical effect of naltrexone appear to be longer than suggested by its plasma half-life. A single 50 mg oral dose of naltrexone has been found to block MORs and opioid effects for 48 to 72 hours.
Naltrexone can be described as a substituted oxymorphone – here the tertiary amine methyl-substituent is replaced with methylcyclopropane. Naltrexone is the N-cyclopropylmethyl derivative of oxymorphone.
The closely related medication, methylnaltrexone, is used to treat opioid-induced constipation, but does not treat addiction as it does not cross the blood–brain barrier. Nalmefene is similar to naltrexone and is used for the same purposes as naltrexone. Naltrexone should not be confused with naloxone, which is used in emergency cases of opioid overdose. Other related opioid antagonists include nalodeine and samidorphan.
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. The drug showed advantages over earlier opioid antagonists such as cyclazocine, nalorphine, and naloxone, including its oral activity, a long duration of action allowing for once-daily administration, and a lack of dysphoria, and was selected for further development. It was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by DuPont in 1969.[self-published source?] 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. The drug was approved by the FDA for the oral treatment of opioid dependence in 1984, with the brand name Trexan, and for the oral treatment of alcohol dependence in 1995, when the brand name was changed by DuPont to ReVia. 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
Naltrexone is or has been marketed under a variety of brand names, including Adepend, Antaxone, Celupan, Depade, Nalorex, Narcoral, Nemexin, Nodict, Revia/ReVia, Trexan, and Vivitrol. 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.
The FDA authorized use of injectable naltrexone 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. A 2011 article reported that this single trial of naltrexone was performed not by comparing it to the best available, evidence-based treatment (methadone or buprenorphine), but by comparing it with a placebo. A subsequent RCT in Norway did compare injectable naltrexone to buprenorphine and found them to be similar in outcomes.
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. His remarks set off sharp criticism with almost 700 experts in the field of substance use submitting a letter to Price cautioning him about Vivitrol's "marketing tactics" and warning him that his comments "ignore widely accepted science". 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. To briefly summarize, 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."
According to a June 11, 2017, The New York Times article, Alkermes "has spent years coaxing, with a deft lobbying strategy that has targeted lawmakers and law enforcement officials. The company has spent millions of dollars on contributions to officials struggling to stem the epidemic of opioid use disorder. It has also provided thousands of free doses to encourage the use of Vivitrol in jails and prisons, which have by default become major detox centers".
Naltrexone is sometimes used in the treatment of dissociative symptoms such as depersonalization and derealization. Some studies suggest it might help. Other small, preliminary studies have also shown benefit. Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization. Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than typically used seem to be necessary.
"Low-dose naltrexone" (LDN) describes the off-label use of naltrexone at low doses for diseases not related to chemical dependency or intoxication, such as multiple sclerosis. Evidence for recommending such use is lacking.
One study suggests that self-injurious behaviors present 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.
Some indications exist that naltrexone might be beneficial in the treatment of impulse-control disorders such as kleptomania, compulsive gambling, or trichotillomania (compulsive hair pulling), but evidence of its effectiveness for gambling is conflicting. A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.
Critical addiction studies
Some historians and sociologists have suggested that the meanings and uses attributed to anti-craving medicine, such as naltrexone, is 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.
- Opioid antagonist § List of opioid antagonists
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