Naltrexone, sold under the brand names ReVia and Vivitrol among others, is a medication primarily used to manage alcohol dependence and opioid dependence. In opioid dependence, it should not be started until people are detoxified. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes. A decreased desire for opioids however may take a few weeks.
|Trade names||ReVia, Vivitrol, others|
|Synonyms||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|
|Biological half-life||Naltrexone: 4 hours
6β-Naltrexol: 13 hours
|Chemical and physical data|
|Molar mass||341.401 g/mol|
|3D model (JSmol)|
|Melting point||169 °C (336 °F)|
|(what is this?)|
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 was first made in 1965 and was approved for medical use in the United States in 1984. As of 2017, the wholesale cost of tablets is about US$0.74 per day in the US. The extended-release injections cost about $1,267 per month ($41.20 per day). Naltrexone, as bupropion/naltrexone, is also used to treat obesity.
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 about an hour (and only then) before drinking to avoid side effects that arise from chronic use. The opioid antagonist blocks the positive reinforcement effects of alcohol and allows 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. It is given once per month and has better compliance than the by mouth formulation.
A 2011 review found insufficient evidence to determine the effect of naltrexone take 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 by mouth tablets (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 encouraging results.
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 mu receptor blockade will increase GI 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 non-addicted obese patients receiving 300 mg of naltrexone. Subsequent studies have suggested limited toxicity in other patient populations.
Naltrexone should not be started until several (typically 7-10) days of abstinence from opioids has 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.
Naltrexone and its active metabolite 6β-naltrexol are competitive antagonists at the μ-opioid receptor (MOR), the κ-opioid receptor (KOR) to a lesser extent, and to a far lesser and possibly insignificant extent, at the δ-opioid receptor (DOR). The Ki affinity values of naltrexone at the MOR, KOR, and DOR have been reported as 0.0825 nM, 0.509 nM, and 8.02 nM, respectively, demonstrating a MOR/KOR binding ratio of 6.17 and a MOR/DOR binding ratio of 97.2.
Mechanism of actionEdit
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 not fully understood, but as an opioid receptor antagonist is likely to be due to the modulation of the dopaminergic mesolimbic pathway (one of the primary centers for risk-reward analysis in the brain, and a tertiary "pleasure center") which is hypothesized to be a major center of the reward associated with addiction that all major drugs of abuse are believed to activate. Mechanism of action may be antagonism to endogenous opioids such as tetrahydropapaveroline, whose production is augmented in the presence of alcohol.
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 glucuronide. The plasma half-life of naltrexone and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively.
A naltrexone treatment study by Anton et al., released by the National Institutes of Health in February 2008 and published in the Archives of General Psychiatry, has shown that alcoholics having a certain variant of the opioid receptor gene (G polymorphism of SNP Rs1799971 in the gene OPRM1), known as Asp40, demonstrated strong response to naltrexone and were far more likely to experience success at cutting back or discontinuing their alcohol intake altogether, while for those lacking the gene variant, naltrexone appeared to be no different from placebo. The G allele of OPRM1 is most common in individuals of Asian descent, with 60% to 70% of people of Chinese, Japanese, and Indian ancestry having at least one copy, as opposed to 30% of Europeans and few Africans.
Because of the characteristics of the patient group in the US, the first study was done on white patients and the next without regard for ethnicity. Anton et al. found that patients of African descent did not have much success with naltrexone in treatment for alcohol dependence because of lacking the relevant gene.
As white patients with the gene had a five times greater rate of success in reducing drinking when given naltrexone than did patients without the gene, when used in a protocol of Medical Management (MM), Anton et al. concluded,
"Because almost 25% of the treatment-seeking population carries the Asp40 allele, genetic testing of individuals before naltrexone treatment might be worth the cost and effort, especially if structured behavioral treatment were not being considered." This would enable treatment to be targeted by genetics to patients for whom it would be most effective. They noted, "Naltrexone is relatively easy to administer and free of serious adverse effects and, as we observed in the Asp40 carriers we studied, it appears to be highly effective."
Studies have found naltrexone to be more efficacious among certain white subjects, because of the genetic basis, than among black subjects, who generally do not carry the relevant gene variant. A 2009 study of naltrexone as an alcohol dependence treatment among African Americans failed to find any statistically significant differences between naltrexone and a placebo. Studies have suggested that carriers of the G allele may experience higher levels of craving and stronger "high" upon alcohol consumption, compared to carriers of the dominant allele, and naltrexone somewhat blunts these responses, leading to a reduction in alcohol use in some studies.
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. 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 like 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. Clinical trials for opioid dependence began in 1973 and a developmental collaboration of DuPont with the National Institute on Drug Abuse (NIDA) 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, at which point 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 cultureEdit
Naltrexone is or has been marketed under a variety of brand names including Adepend, Antaxone, Celupan, Depade, Nalorex, Narcoral, Nemexin, Revia/ReVia, Trexan, and Vivitrol among others. It is also marketed in combination with bupropion (bupropion/naltrexone) 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 abuse submitting a letter to Price cautioning him about Vivitrol's "marketing tactics" and warning him that his comment "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 abuse. 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. It is thought that blockade of the KOR by naltrexone and naloxone is responsible for their effectiveness in ameliorating depersonalization and derealization. Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher dose 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. More research needs to be done before it can be recommended for clinical use.
Although there are scientific studies showing its efficacy in some conditions such as fibromyalgia, other, more dramatic claims for its use in conditions like cancer and HIV have less scientific support. This treatment has received significant attention on the Internet, especially through websites run by organizations promoting its use.
Some studies suggest that self-injurious behaviors present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone. In these cases, it is believed that the self-injury is being 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.
There are indications that naltrexone might be beneficial in the treatment of impulse control disorders such as kleptomania, compulsive gambling, or trichotillomania (compulsive hair pulling), but there is conflicting evidence of its effectiveness for gambling. A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.
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