Naltrexone

Source: Wikipedia, the free encyclopedia.
Not to be confused with Naloxone or Nalmexone.
"Revia" redirects here. For the cantillation mark, see Revia (Hebrew cantillation mark).

Naltrexone
Clinical data
Pronunciation/ˌnælˈtrɛksoʊn/
Trade namesRevia, Vivitrol, Depade, others
Other namesEN-1639A; UM-792; ALKS-6428; N-cyclopropylmethylnoroxymorphone; N-cyclopropylmethyl-14-hydroxydihydromorphinone; 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one
AHFS/Drugs.comMonograph
MedlinePlusa685041
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, intramuscular injection, subcutaneous implant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5–60%[6][7]
Protein binding20%[6][3]
MetabolismLiver (non-CYP450)[11]
Metabolites6β-Naltrexol, others[6]
Onset of action30 minutes[8]
Elimination half-lifeOral (Revia):[3]
• Naltrexone: 4 hours
• 6β-Naltrexol: 13 hours
Oral (Contrave):[4]
• Naltrexone: 5 hours
IMTooltip Intramuscular injection (Vivitrol):[5]
• Naltrexone: 5–10 days
• 6β-Naltrexol: 5–10 days
Duration of action>72 hours[6][9][10]
ExcretionUrine[3]
Identifiers
  • (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
JSmol)
Melting point169 °C (336 °F)
  • O=C4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)CC6CC6
  • 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
  (verify)

Naltrexone, sold under the brand name Revia among others, is a

injection into a muscle.[8] Effects begin within 30 minutes,[8] though a decreased desire for opioids may take a few weeks to occur.[8]
Side effects may include
trouble sleeping, anxiety, nausea, and headaches.[8] In those still on opioids, opioid withdrawal may occur.[8] Use is not recommended in people with liver failure.[8] It is unclear if use is safe during pregnancy.[8][13] Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain.[8]

Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984.[8][14] Naltrexone, as naltrexone/bupropion (brand name Contrave), is also used to treat obesity.[15] It is on the World Health Organization's List of Essential Medicines.[16] In 2021, it was the 254th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[17][18]

Medical uses

Alcohol use disorder

Naltrexone has been best studied as a treatment for alcoholism.[12] Naltrexone has been shown to decrease the quantity and frequency of ethanol consumption by reducing the dopamine release from the brain after consuming alcohol.[19][20][21] It does not appear to change the percentage of people drinking.[22] Its overall benefit has been described as "modest".[23][19][24][25]

Acamprosate may work better than naltrexone for eliminating alcohol abuse, while naltrexone may decrease the desire for alcohol to a greater extent.[26]

A method pioneered by scientist John David Sinclair (dubbed commercially the “Sinclair Method”) advocates for “pharmacological extinction” of problem drinking behavior by administering naltrexone alongside controlled alcohol consumption. In effect, he argues naltrexone induced opiate antagonism sufficiently disrupts reflexive reward mechanisms inherent in the consumption of alcohol and, given enough repetition, will disassociate positive associations formerly made with the consumption of alcohol. The Sinclair Method has a clinically proven success rate of 78%.[27]

Opioid use

Long-acting injectable naltrexone (under the brand name Vivitrol) is an opioid receptor antagonist, blocking the effects of heroin and other opioids, and decreases

compliance and effect for opioid use than the oral formulation.[31]

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.[32] Among patients able to successfully initiate injectable naltrexone, long-term remission rates were similar to those seen in clinical buprenorphine/naloxone administration.[33]

Consequence of relapse when weighting best course of treatment for opiate use disorder remains a concern. Methadone and buprenorphine administration maintains greater drug tolerance while naltrexone allows tolerance to fade, leading to higher instances of 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.[34]

A 2011 review found insufficient evidence to determine the effect of naltrexone taken by mouth in opioid dependence.[35] 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.[36]

Others

Unlike varenicline (brand name Chantix), naltrexone is not useful for quitting smoking.[37] Naltrexone has also been under investigation for reducing behavioral addictions such as gambling or 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.[38][39]

When taken at much smaller doses, a regimen known as

ME/CFS, multiple sclerosis (MS), fibromyalgia (FMS), or autoimmune disease. Although its mechanism of action is unclear, some have speculated that it may act as an anti-inflammatory.[40] LDN is also being considered as a potential treatment for long COVID.[41]

Available forms

See also:
Bupropion/naltrexone, Morphine/naltrexone, and Buprenorphine/naltrexone

Naltrexone is available and most commonly used in the form of an oral tablet (50 mg).[42] Vivitrol, a naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available.[42][43] Additionally, naltrexone subcutaneous implants that are surgically implanted are available.[44] While these are manufactured in Australia, they are not authorized for use within Australia, but only for export.[45] By 2009, naltrexone implants showed superior efficacy in the treatment of heroin dependence when compared to the oral form.[46]

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 motility
.

The side effects of naltrexone by incidence are as follows:[3]

Opioid withdrawal

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.[47]

Adverse effects

Whether naltrexone causes

feelings of unreality.[50][52][53][54][55] However, these studies were small, often uncontrolled, and used subjective means of assessing side effects.[55][48] Most subsequent longer-term studies of naltrexone for indications like alcohol or opioid dependence have not reported dysphoria or depression with naltrexone in most individuals.[50][56][55] According to one source:[49]

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).

Based on available evidence, naltrexone seems to have minimal untoward effects in the aforementioned areas, at least with long-term therapy.

preclinical studies.[6][48][57] Another possibility is that the central opioid system may have low endogenous functionality in most individuals, becoming active only in the presence of exogenously administered opioid receptor agonists or with stimulation by endogenous opioids induced by pain or stress.[57] A third possibility is that normal individuals may experience different side effects with naltrexone than people with addictive disease such as alcohol or opioid dependence, who may have altered opioid tone or responsiveness.[48][57] It is notable in this regard that most studies of naltrexone have been in people with substance dependence.[48]

Naltrexone may also initially produce opioid withdrawal-like symptoms in a small subset of people not dependent on opioids:[58]

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.[59][48][58]

Naltrexone has been reported to reduce feelings of

conditioned place aversion.[48]

Liver damage

Naltrexone has been reported to cause

liver damage when given at doses higher than recommended.[25] 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.[67] Subsequent studies have suggested limited or no toxicity in other patient populations and at typical recommended doses such as 50 to 100 mg/day.[25][12]

Overdose

No

overdose of naltrexone, which was 1,500 mg in a female patient and was equivalent to an entire bottle of medication (30 × 50 mg tablets), was uneventful.[68] No deaths are known to have occurred with naltrexone overdose.[69]

Pharmacology

Pharmacodynamics

Opioid receptor blockade

Naltrexone at human opioid receptors
Ki
Tooltip Inhibitor constant)		 Ratios Refs
MOR
Tooltip μ-Opioid receptor
KOR
Tooltip κ-Opioid receptor
DOR
Tooltip δ-Opioid receptor		 MOR:KOR:DOR
1.0 nM 3.9 nM 149 nM 1:4:149 [70]
0.0825 nM 0.509 nM 8.02 nM 1:6:97 [71]
0.2 nM 0.4 nM 10.8 nM 1:2:54 [72][73]
0.23 nM 0.25 nM 38 nM 1:1.1:165 [74][57]
0.62 nM 1.88 nM 12.3 nM 1:3:20 [75][76]
0.11 nM 0.19 nM 60 nM 1:1.7:545 [77][78][79]

Naltrexone and its

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.[81][78][79] In accordance with its partial agonism, although naltrexone is described as a pure opioid receptor antagonist, it has shown some evidence of weak opioid effects in clinical and preclinical studies.[6]

By itself, naltrexone acts as an antagonist or weak partial agonist of the opioid receptors.

opioid-dependent individuals.[82][81] This may be due to suppression of basal MOR signaling via inverse agonism.[82][81]

intranasally) or nalmefene (half-time of ~29 hours).[9][86][87]

The half-life of occupancy of the brain MOR and duration of clinical effect of naltrexone are much longer than suggested by its

affinity (<1.0 nM).[87][91]

Naltrexone blocks the effects of MOR agonists like

euphoriant drugs including alcohol,[57] nicotine,[95] and amphetamines.[96]

The opioid receptors are involved in

endorphins.[6]

Blockade of MORs is thought to be the mechanism of action of naltrexone in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. It is also thought to be involved in the effectiveness of naltrexone in alcohol dependence by reducing the euphoric effects of alcohol. The role of KOR modulation by naltrexone in its effectiveness for alcohol dependence is unclear but this action may also be involved based on theory and animal studies.[97][98]

Other activities

In addition to the

affinity binding sites in filamin A (FLNA).[99][100][101][102] 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.[99][101] The interactions of naltrexone with FLNA and TLR4 are claimed to be involved in the therapeutic effects of low-dose naltrexone.[99]

Pharmacokinetics

steady state during treatment with 50 mg/day naltrexone[103][104]
Naltrexone levels following a 380 mg dose of naltrexone in microspheres (Vivitrol) by intramuscular injection at steady state during monthly treatment with 380 mg naltrexone in microspheres[105][106][107][108]

The

6β-naltrexol (metabolite) is within 1 hour.[6][7][3] Linear increases in circulating naltrexone and 6β-naltrexol concentrations occur over an oral dose range of 50 to 200 mg.[6] Naltrexone does not appear to be accumulated with repeated once-daily oral administration and there is no change in time to peak concentrations with repeated administration.[6]

The plasma protein binding of naltrexone is about 20% over a naltrexone concentration range of 0.1 to 500 μg/L.[6][3] Its apparent volume of distribution at 100 mg orally is 16.1 L/kg after a single dose and 14.2 L/kg with repeated doses.[6]

Naltrexone is

conjugation with glucuronic acid to form glucuronides.[6] Naltrexone is not metabolized by the cytochrome P450 system and has low potential for drug interactions.[11]

The

extended-release, the half-life of naltrexone is 5 hours.[4] The slow terminal-phase elimination half-life of naltrexone is approximately 96 hours.[10] As microspheres of naltrexone by intramuscular injection (Vivitrol), the elimination half-lives of naltrexone and 6β-naltrexol are both 5 to 10 days.[5] Whereas oral naltrexone is administered daily, naltrexone in microspheres by intramuscular injection is suitable for administration once every 4 weeks or once per month.[5]

Naltrexone and its metabolites are excreted in urine.[3]

Pharmacogenetics

Tentative evidence suggests that family history and presence of the Asn40Asp polymorphism predicts naltrexone being effective.[111][24]

Chemistry

Naltrexone, also known as N-cyclopropylmethylnoroxymorphone, is a

methyl substituent is replaced with methylcyclopropane
.

Analogues

The closely related medication,

β-funaltrexamine (naltrexone fumarate methyl ester), nalodeine (N-allylnorcodeine), nalorphine (N-allylnormorphine), and nalbuphine
(N-cyclobutylmethyl-14-hydroxydihydronormorphine).

History

Naltrexone was first

duration of action allowing for once-daily administration, and a lack of dysphoria, and was selected for further development.[14] It was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by DuPont in 1969.[115][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.[115] 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.[115][42] 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.[43][42]

Society and culture

Generic names

Naltrexone is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and DCITTooltip Denominazione Comune Italiana, while naltrexone hydrochloride is its USPTooltip United States Pharmacopeia and BANMTooltip British Approved Name.[116][117][118][119]

Brand names

Naltrexone is or has been sold under a variety of brand names, including Adepend, Antaxone, Celupan, Depade, Nalorex, Narcoral, Nemexin, Nodict, Revia, Trexan, Vivitrex, and Vivitrol.[116][117][118][119] It is also marketed in combination with bupropion (naltrexone/bupropion) as Contrave,[120] and was marketed with morphine (morphine/naltrexone) as Embeda.[119][121] A combination of naltrexone with buprenorphine (buprenorphine/naltrexone) has been developed, but has not been marketed.[122]

Controversies

The FDA authorized use of injectable naltrexone (Vivitrol) for opioid addiction using a single study[123] that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia,[124] 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 .[125] 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 prior to naltrexone administration.[126] Nearly 30% of patients in the US trial did not complete induction.[33] In real world settings, a review of more than 40,000 patient records found that while methadone and buprenorphine reduced risk of fatal overdose, naltrexone administration showed no greater effect on overdose or subsequent emergency care than counseling alone.[30]

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.[127] The technique has been successful, with the criminal justice system in 43 states now incorporating long-acting naltrexone. Many do this through Vivitrol courts that offer only this option, leading some to characterize this as "an offer that cannot be refused."[128][129] The company's marketing techiques have led to a Congressional investigation,[130] and warning from the FDA about failure to adequately state risks of fatal overdose to patients receiving the medicine.[131]

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.[127] 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".[132] 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"[127] 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."[132]

Film

One Little Pill was a 2014 documentary film about use of naltrexone to treat alcohol use disorder.[133]

Four Good Days is a 2020 film about the four days a drug addict woman has to stay sober to get a shot of naltrexone in a detox facility.

Research

Depersonalization

Naltrexone is sometimes used in the treatment of dissociative symptoms such as depersonalization and derealization.[134][135] Some studies suggest it might help.[136] Other small, preliminary studies have also shown benefit.[134][135] Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization.[134][135] Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than typically used seem to be necessary.[134][135]

Low-dose naltrexone

Naltrexone has been used off-label at low doses for diseases not related to chemical dependency or intoxication, such as multiple sclerosis.[137] Evidence for recommending low-dose naltrexone is lacking.[138][139] This treatment has received attention on the Internet.[140] In 2022, four studies (in a few hundred patients) were conducted on naltrexone for long COVID.[141]

Self-injury

One study suggests that self-injurious behaviors present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.[142] 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.[143]
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.[144][145][146] A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.[147]

Interferon alpha

Naltrexone is effective in suppressing the

interferon alpha therapy.[148][149]

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.[150] Studies have suggested the use of naltrexone in drug courts or healthcare rehabs is a form of "post-social control,"[151] or "post-disciplinary control,"[152] 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.[153][154]

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