Naltrexone has been best studied as a treatment foralcoholism.[12] Naltrexone has been shown to decrease the quantity and frequency ofethanol 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 foralcohol to a greater extent.[26]
A method pioneered (starting in the 1980s) by scientistJohn David Sinclair (dubbed commercially the "Sinclair Method") 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 themfound any significant benefit of naltrexone over placebo when combined with support for abstinence."[27]
Long-acting injectable naltrexone (under the brand nameVivitrol) is anopioid antagonist, blocking the effects ofheroin and otheropioids, and decreases heroin use compared to a placebo.[28] Unlikemethadone andbuprenorphine, it is not a controlled medication.[28] It may decrease cravings for opioids after a number of weeks, and decreases the risk ofoverdose, at least during the time period that naltrexone is still active, though concern about risk of overdose for those stopping treatment remains.[8][29][30] It is given once per month and has betteradherence 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naltrexone is that it requires patients with opioid use disorder and current physiological dependence to be fully withdrawn before it is initiated to avoid a precipitatedopioid withdrawal that may be quite severe.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]
The consequence of relapse when weighing the best course of treatment for opiate use disorder remains a concern. Methadone and buprenorphine administration maintain greaterdrug tolerance while naltrexone allows tolerance to fade, leading to higher instances of an overdose in people who relapse and thus highermortality.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 orally on 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 inopioid 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 additionalcontingency management support, naltrexone may be effective in a broader population.[36]
Unlikevarenicline (brand name Chantix), naltrexone is not useful forquitting smoking.[37] Naltrexone has also been under investigation for reducingbehavioral addictions such as gambling,NSSID (non-suicidal self-injury disorder), andkleptomania, 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 aslow-dose naltrexone (LDN), naltrexone may reduce pain and help to address neurological symptoms. Some patients report that LDN helps reduce their symptoms ofME/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.[40] LDN is also being considered as a potential treatment forlong COVID.[41]
Naltrexone is available and most commonly used in the form of anoraltablet (50 mg).[42] Vivitrol, a naltrexone formulation fordepot injection containing 380 mg of the medication per vial, is also available.[42][43] Additionally, naltrexonesubcutaneous 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]
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 acuteopioid 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 analoxone 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]
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.[48][49][50][51] It has been suggested that differences in findings between acute and longer-term studies of naltrexone treatment might be related to altered function in the opioid system with chronic administration of naltrexone.[50][48] For example, markedupregulation of opioid receptors and hyper-sensitivity to opioids have been observed with naltrexone inpreclinical 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 bypain orstress.[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 produceopioid 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 whodrop out of treatment.[59][48][58]
Naltrexone has been reported to causeliver damage when given at doses higher than recommended.[25] Due to these reports, some physicians may check liver function tests before starting naltrexone, and periodically thereafter. Concerns for liver toxicity initially arose from a study of nonaddicted obese patients receiving 300 mg of naltrexone.[68] 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]
Notoxic effects have been observed with naltrexone in doses of up to 800 mg/day in clinical studies.[6][3] The largest reportedoverdose 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.[69] No deaths are known to have occurred with naltrexone overdose.[70]
Naltrexone and itsactive metabolite6β-naltrexol arecompetitive antagonists of theopioid receptors.[81][82] Naltrexone is specifically an antagonist preferentially of theμ-opioid receptor (MOR), to a lesser extent of theκ-opioid receptor (KOR), and to a much lesser extent of theδ-opioid receptor (DOR).[81] However, naltrexone is not actually asilent antagonist of these receptors but instead acts as a weakpartial agonist, withEmax values of 14 to 29% at the MOR, 16 to 39% at the KOR, and 14 to 25% at the DOR in different studies.[82][79][80] 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.[82] In combination with agonists of the MOR such asmorphine however, naltrexone appears to become aninverse agonist of the MOR.[82] Conversely, the naltrexone remains a neutral antagonist (or weak partial agonist) of the KOR and DOR.[82] In contrast to naltrexone, 6β-naltrexol is purely a neutral antagonist of the opioid receptors.[83] The MOR inverse agonism of naltrexone, when it is co-present with MOR agonists, may in part underlie its ability to precipitatewithdrawal inopioid-dependent individuals.[83][82] This may be due to suppression of basal MOR signaling via inverse agonism.[83][82]
Occupancy of the opioid receptors in the brain by naltrexone has been studied usingpositron emission tomography (PET).[25][84] Naltrexone at a dose of 50 mg/day has been found to occupy approximately 90 to 95% of brain MORs and 20 to 35% of brain DORs.[25] Naltrexone at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies.[85][84][86] 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.[84] In a study of the duration of MOR blockade with naltrexone, the drug with a single 50 mg dose showed 91% blockade of brain[11C]carfentanil (a selective MOR ligand) binding at 48 hours (2 days), 80% blockade at 72 hours (3 days), 46% blockade at 120 hours (5 days), and 30% blockade at 168 hours (7 days).[9][10] The half-time of brain MOR blockade by naltrexone in this study was 72 to 108 hours (3.0 to 4.5 days).[9][10] Based on these findings, doses of naltrexone of even less than 50 mg/day would be expected to achieve virtually complete brain MOR occupancy.[9][10] Blockade of brain MORs with naltrexone is much longer-lasting than with otheropioid antagonists likenaloxone (half-time of ~1.7 hoursintranasally) ornalmefene (half-time of ~29 hours).[9][87][88]
The half-life of occupancy of the brain MOR and duration of clinical effect of naltrexone are much longer than suggested by itsplasma elimination half-life.[9][89][10][90] 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.[89][10][91] 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).[9][10][48] As an alternative possibility, the prolonged brain MOR occupancy by opioid antagonists like naltrexone and nalmefene may be due to slow dissociation from MORs consequent to their very high MORaffinity (<1.0 nM).[88][92]
Naltrexoneblocks the effects of MOR agonists likemorphine,heroin, andhydromorphone in humans via its MOR antagonism.[6][11] Following a single 100 mg dose of naltrexone, the subjective and objective effects of heroin were blocked by 90% at 24 hours, with blockade then decreasing up to 72 hours.[6] Similarly, 20 to 200 mg naltrexone dose-dependently antagonized the effects of heroin for up to 72 hours.[6] Naltrexone alsoblocks the effects of KOR agonists likesalvinorin A,pentazocine, andbutorphanol in humans via its KOR antagonism.[93][94][95][74] In addition to opioids, naltrexone has been found to block or reduce the rewarding and other effects of othereuphoriant drugs includingalcohol,[57]nicotine,[96] andamphetamines.[97]
Blockade of MORs is thought to be themechanism 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.[98][99]
Naltrexone levels following a 50 mg oral dose of naltrexone atsteady state during treatment with 50 mg/day naltrexone[104][105]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[106][107][108][109]
Theabsorption of naltrexone withoral administration is rapid and nearly complete (96%).[3] Thebioavailability of naltrexone with oral administration is 5 to 60% due to extensivefirst-pass metabolism.[6][7]Peak concentrations of naltrexone are 19 to 44 μg/L after a single 100 mg oral dose andtime to peak concentrations of naltrexone and6β-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]
Theplasma protein binding of naltrexone is about 20% over a naltrexone concentration range of 0.1 to 500 μg/L.[6][3] Its apparentvolume 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 ismetabolized in the liver mainly bydihydrodiol dehydrogenases into6β-naltrexol (6β-hydroxynaltrexone).[6][7] Levels of 6β-naltrexol are 10- to 30-fold higher than those of naltrexone with oral administration due to extensivefirst-pass metabolism.[110] Conversely, 6β-naltrexol exposure is only about 2-fold higher than that of naltrexone withintramuscular injection of naltrexone inmicrospheres (brand name Vivitrol).[106] 6β-Naltrexol is an opioid receptor antagonist similarly to naltrexone and shows a comparable binding profile to the opioid receptors.[111] However, 6β-naltrexol isperipherally selective and crosses into the brain much less readily than does naltrexone.[111] In any case, 6β-naltrexol does still show some central activity and may contribute significantly to the central actions of oral naltrexone.[111][6] Othermetabolites of naltrexone include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxynaltrexone.[6] Following their formation, the metabolites of naltrexone are further metabolized byconjugation withglucuronic acid to formglucuronides.[6] Naltrexone is not metabolized by thecytochrome P450 system and has low potential fordrug interactions.[11]
Theelimination of naltrexone isbiexponential and rapid over the first 24 hours followed by a third extremely slow decline after 24 hours.[6] The fastelimination half-lives of naltrexone and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively.[3] In Contrave oral tablets, which also containbupropion and are described asextended-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]
The closely related medication,methylnaltrexone (N-methylnaltrexone), is used to treat opioid-induced constipation but does not treat addiction as it does not cross theblood–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 withnaloxone (N-allylnoroxymorphone), which is used in emergency cases of opioidoverdose. Other opioid antagonists related to naltrexone include6β-naltrexol (6β-hydroxynaltrexone),samidorphan (3-carboxamido-4-hydroxynaltrexone),β-funaltrexamine (naltrexone fumarate methyl ester),nalodeine (N-allylnorcodeine),nalorphine (N-allylnormorphine), andnalbuphine (N-cyclobutylmethyl-14-hydroxydihydronormorphine).
Naltrexone was firstsynthesized in 1963 by Metossian at Endo Laboratories, a smallpharmaceutical company inNew York City.[113] It was characterized by Blumberg, Dayton, and Wolf in 1965 and was found to be anorally active, long-acting, and verypotent opioid antagonist.[113][114][115][14] The drug showed advantages over earlier opioid antagonists such ascyclazocine,nalorphine, and naloxone, including its oral activity, a longduration of action allowing for once-daily administration, and a lack ofdysphoria, and was selected for further development.[14] It waspatented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired byDuPont in 1969.[116][self-published source?]Clinical trials for opioid dependence began in 1973, and a developmental collaboration of DuPont with theNational Institute on Drug Abuse for this indication started the next year in 1974.[116] 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.[116][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]
Naltrexone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andDCITTooltip Denominazione Comune Italiana, while naltrexone hydrochloride is itsUSPTooltip United States Pharmacopeia andBANMTooltip British Approved Name.[117][118][119][120]
The FDA authorized use of injectable naltrexone (Vivitrol) for opioid addiction using a single study[124] that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia,[125] 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 biotechAlkermes 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.[126] 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.[127] 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 whilemethadone andbuprenorphine 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.[128] 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."[129][130] The company's marketing techniques have led to a Congressional investigation,[131] and warning from the FDA about failure to adequately state risks of fatal overdose to patients receiving the medicine.[132]
In May 2017,United States Secretary of Health and Human ServicesTom Price praised [Vivitrol] as the future of opioid addiction treatment after visiting the company's plant in Ohio.[128] 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".[133] 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"[128] 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."[133]
Naltrexone is sometimes used in the treatment ofdissociative symptoms, such as thedepersonalization andderealization ofdepersonalization-derealization disorder.[135][136] Some studies suggest it might help, but conclusions are limited by a small evidence base.[137][138][135][136] Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization.[135][136] Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than used in opioid dependence therapy seem to be necessary.[135][136]
Naltrexone has been usedoff-label at low doses for conditions unrelated to chemical dependency or intoxication, such asmultiple sclerosis.[139] Evidence for recommendinglow-dose naltrexone is lacking.[140][141] This treatment has received attention on theInternet.[142] In 2022, four studies (with a few hundred patients) were conducted on naltrexone in the setting oflong COVID.[143]
One study suggested thatself-harming behavior in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.[144]In these cases, the self-injury is believed to be done to releasebeta-endorphin, which binds to the same receptors as heroin and morphine.[145] If the "rush" generated by self-injury is removed, the behavior may stop.
Some studies exist that naltrexone might be beneficial in the treatment ofimpulse-control disorders such askleptomania, compulsive gambling, andtrichotillomania (compulsive hair pulling); evidence for its effectiveness for gambling is conflicting.[146][147][148] A 2008 case-study reported successful use of naltrexone in suppressing and treating an internetpornography addiction.[149]
Some historians and sociologists have suggested that the meanings and uses attributed to anti-craving medicine, such as naltrexone, are context-dependent.[152] Studies have suggested the use of naltrexone in drug courts or healthcare rehabs is a form of "post-social control,"[153] or "post-disciplinary control,"[154] whereby control strategies for managing offenders and addicts shift from imprisonment and supervision toward more direct control over biological processes.
Naltrexone is used in wild and zoo animals to reverse the effects ofcarfentanil andetorphine. Naltrexone has a longer duration of action thannaloxone 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.[157]
Aquaternary ammonium compound, methlynaltrexone is still being investigated for use in veterinary medicine. Naltrexone antagonises theμ-,κ-, andδ-, 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 theblood-brain barrier, which allows methlynaltrexone to treat peripheral effects of opioids such asgastrointestinal ileus whilst maintaining analgesia.[157] However, methlynaltrexone may not treat the side effects ofbuprenorphine.[158][157]
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