Naltrexone

Not to be confused with Naloxone or Nalmexone.
Naltrexone
Names
Pronunciation/ˌnælˈtrɛksoʊn/
Trade namesReVia, Vivitrol, others
Other namesEN-1639A; UM-792; N-Cyclopropyl-methylnoroxymorphone; N-Cyclopropylmethyl-14-hydroxydihydro-morphinone; 17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
IUPAC name
  • (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one
Clinical data
Drug classOpioid antagonist[1]
Main usesAlcohol or opioid dependence[1]
Side effectsTrouble sleeping, anxiety, nausea, headaches[1]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, intramuscular injection, subcutaneous implant
    Defined daily dose50 mg[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa685041
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • CA: ℞-only
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability5–40%
    Protein binding21%
    MetabolismLiver
    Elimination half-lifeNaltrexone: 4 hours
    6β-Naltrexol: 13 hours
    ExcretionUrine
    Chemical and physical data
    FormulaC20H23NO4
    Molar mass341.407 g·mol−1
    3D model (JSmol)
    Melting point169 °C (336 °F)
    SMILES
    • O=C4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)CC6CC6
    InChI
    • InChI=1S/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19+,20-/m1/s1 checkY
    • Key:DQCKKXVULJGBQN-XFWGSAIBSA-N checkY

    Naltrexone, sold under the brand names ReVia and Vivitrol among others, is a medication primarily used to manage alcohol or opioid dependence.[1] An opioid-dependent person should not receive naltrexone before detoxification.[1] It is taken by mouth or by injection into a muscle.[1] Effects begin within 30 minutes.[1] A decreased desire for opioids, though, may take a few weeks.[1]

    Side effects may include trouble sleeping, anxiety, nausea, and headaches.[1] In those still on opioids, opioid withdrawal may occur.[1] Use is not recommended in people with liver failure.[1] It is unclear if use is safe during pregnancy.[1][3] Naltrexone is an opioid antagonist and works by blocking the effects of opioids, both those from inside and outside the body.[1]

    Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984.[1][4] It is on the World Health Organization's List of Essential Medicines.[5] As of 2019, the wholesale cost of tablets is about US$0.80 per day in the United States.[6] The extended-release injections cost about $1,267 per month ($41 per day).[6] Naltrexone, as naltrexone/bupropion, is also used to treat obesity.[7]

    Medical uses

    Alcoholism

    Naltrexone has been best studied as a treatment for alcoholism.[8] It decreases the amount and frequency of drinking in about 1 in 13 people.[9][10] It does not appear to change the percentage of people drinking.[11] Its overall benefit has been described as "modest".[12]

    Acamprosate may work better than naltrexone for eliminating drinking, while naltrexone may decrease the desire for alcohol to a greater extent.[13]

    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 continuous use.[14][15] This is proposed to block the positive-reinforcement of alcohol and allows the person to stop or reduce drinking.[15]

    Opioid use

    Long-acting injectable naltrexone decreases heroin use more than placebo.[16] It has benefits over methadone and buprenorphine in that it is not a restricted medication.[16] 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.[1][17] It is given once per month and has better compliance than the oral formulation.[18]

    A 2011 review found insufficient evidence to determine the effect of naltrexone taken by mouth in opioid dependence.[19] 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.[20]

    Others

    Naltrexone is not useful for quitting smoking.[21] It has been used in chronic pain such as fibromyalgia with tentative evidence of benefit.[22][23]

    Dosage

    The defined daily dose is 50 mg by mouth.[2] It is generally started at 12.5 to 25 mg by mouth once the person has no opiates on board.[1] This is than increased to 50 mg once per day.[1] Larger doses may also be used less frequently.[1] For alcohol dependence a dose of 50 mg once per day is generally used.[1]

    Naltrexone is available and most commonly used in the form of an by mouth tablet (50 mg).[24] A naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available.[24][25] Additionally, naltrexone subcutaneous implants that are surgically implanted.[26] While these are manufactured in Australia, they are not authorized for use within Australia, but only for export.[27]

    Contraindications

    Naltrexone should not be used by persons with acute hepatitis or liver failure, or those with recent opioid use (typically 7–10 days).

    Side effects

    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), for which it carries an FDA boxed warning. 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 people receiving 300 mg of naltrexone.[28] Subsequent studies have suggested limited toxicity in other populations.

    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.[29]

    Pharmacology

    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 generated via κ-opioid receptor antagonism,[30] which blocks the actions of the endogenous opioid peptide dynorphin.[31] Dynorphin typically instates drug-seeking behavior when it binds to the κ-opioid receptor, as well as decreasing dopaminergic signalling in the nucleus accumbens.[32]

    Pharmacodynamics

    Naltrexone at opioid receptors
    Affinities (Ki)RatioRef
    MORDORKORMOR:DOR:KOR
    1.0 nM
    0.0825 nM    		149 nM
    8.02 nM    		3.9 nM
    0.509 nM    		1:149:4
    1:97:6    		[33]
    [34]

    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 extent, at the δ-opioid receptor (DOR).[35]

    Pharmacokinetics

    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.

    Pharmacogenetics

    Tentative evidence suggests that family history and presence of the Asn40Asp polymorphism predicts naltrexone being effective.[36][37]

    Chemistry

    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.

    Analogues

    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.

    History

    Naltrexone was first synthesized in 1963 by Metossian at Endo Laboratories, a small pharmaceutical company in New York City.[38] 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.[38][39][40][4] 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.[4] It was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by DuPont in 1969.[41] 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.[41] 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.[41][24] 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.[25][24]

    Society and culture

    Generic names

    Naltrexone is the generic name of the drug and its INN, USAN, BAN, DCF, and DCIT, while naltrexone hydrochloride is its USP and BANM.[42][43][44][45]

    Brand names

    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.[42][43][44][45] It is also marketed in combination with bupropion (naltrexone/bupropion) as Contrave and Mysimbam, and was marketed with morphine (morphine/naltrexone) as Embeda.[45] A combination of naltrexone with buprenorphine (buprenorphine/naltrexone) has been developed, but has not been marketed.[46]

    Controversies

    The FDA authorized use of injectable naltrexone for opioid addiction using a single study[47] that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia,[48] 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.[49] A subsequent RCT in Norway did compare injectable naltrexone to buprenorphine and found them to be similar in outcomes.[50]

    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.[51] 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".[52] 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"[51] 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."[52]

    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".[51]

    Research

    Depersonalization

    Naltrexone is sometimes used in the treatment of dissociative symptoms such as depersonalization and derealization.[53][54] Some studies suggest it might help.[55] Other small, preliminary studies have also shown benefit.[53][54] Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization.[53][54] Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than typically used seem to be necessary.[53][54]

    Low-dose

    Main article: Low-dose naltrexone

    "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.[56] More research needs to be done before it can be recommended for clinical use.

    Although some scientific studies show its efficacy in some conditions such as fibromyalgia,[57] other, more dramatic claims for its use in conditions such as cancer and HIV have less scientific support.[56] This treatment has received significant attention on the Internet, especially through websites run by organizations promoting its use.[58]

    Self-injury

    One study suggests that self-injurious behaviors present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.[59] 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.[60] If the "rush" generated by self-injury is removed, the behavior may stop.

    Behavioral disorders

    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.[61][62][63] A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.[64]

    Interferon alpha

    Naltrexone is effective in suppressing the cytokine-mediated adverse neuropsychiatric effects of interferon alpha therapy.[65][66]

    See also

    References

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