Chemistry:Naltrexone

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Short description: Medication
Naltrexone
Naltrexone skeletal.svg
Naltrexone-from-xtal-3D-bs-17.png
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%[4][5]
Protein binding20%[4][1]
MetabolismLiver (non-CYP450)[9]
Metabolites6β-Naltrexol, others[4]
Onset of action30 minutes[6]
Elimination half-lifeOral (Revia):[1]
• Naltrexone: 4 hours
• 6β-Naltrexol: 13 hours
Oral (Contrave):[2]
• Naltrexone: 5 hours
IM (Vivitrol):[3]
• Naltrexone: 5–10 days
• 6β-Naltrexol: 5–10 days
Duration of action>72 hours[4][7][8]
ExcretionUrine[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC20H23NO4
Molar mass341.407 g·mol−1
3D model (JSmol)
Melting point169 °C (336 °F)
  (verify)

Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder.[6] It has also been found effective in the treatment of other addictions and may be used for them off-label.[10] An opioid-dependent person should not receive naltrexone before detoxification.[6] It is taken by mouth or by injection into a muscle.[6] Effects begin within 30 minutes,[6] though a decreased desire for opioids may take a few weeks to occur.[6] Side effects may include trouble sleeping, anxiety, nausea, and headaches.[6] In those still on opioids, opioid withdrawal may occur.[6] Use is not recommended in people with liver failure.[6] It is unclear if use is safe during pregnancy.[6][11] 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.[6]

Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984.[6][12] Naltrexone, as naltrexone/bupropion (brand name Contrave), is also used to treat obesity.[13] It is on the World Health Organization's List of Essential Medicines.[14] In 2021, it was the 254th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[15][16]

Medical uses

Alcohol use disorder

Naltrexone has been best studied as a treatment for alcoholism.[10] Naltrexone has been shown to decrease the quantity and frequency of ethanol consumption by reducing the dopamine release from the brain after consuming alcohol.[17][18][19] It does not appear to change the percentage of people drinking.[20] Its overall benefit has been described as "modest".[21][17][22][23]

Acamprosate may work better than naltrexone for eliminating alcohol abuse, while naltrexone may decrease the desire for alcohol to a greater extent.[24]

A method pioneered by scientist John David Sinclair (dubbed commercially the “Sinclair Method”) advocates for “psychological 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.[25]

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 heroin use compared to a placebo.[26] Unlike methadone and buprenorphine, it is not a controlled medication.[26] 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, though concern about risk of overdose for those stopping treatment remains.[6][27][28] It is given once per month and has better compliance and effect for opioid use than the oral formulation.[29]

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.[30] Among patients able to successfully initiate injectable naltrexone, long-term remission rates were similar to those seen in clinical buprenorphine/naloxone administration.[31]

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.[32]

A 2011 review found insufficient evidence to determine the effect of naltrexone taken by mouth in opioid dependence.[33] 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.[34]

Others

Unlike varenicline (brand name Chantix), naltrexone is not useful for quitting smoking.[35] 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.[36][37]

When taken at much smaller doses, a regimen known as low-dose naltrexone (LDN), naltrexone may reduce pain and help to address neurological symptoms. Some patients report that LDN helps reduce their symptoms of 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.[38] LDN is also being considered as a potential treatment for long COVID.[39]

Available forms

Naltrexone is available and most commonly used in the form of an oral tablet (50 mg).[40] Vivitrol, a naltrexone formulation for depot injection containing 380 mg of the medication per vial, is also available.[40][41] Additionally, naltrexone subcutaneous implants that are surgically implanted are available.[42] While these are manufactured in Australia, they are not authorized for use within Australia, but only for export.[43] By 2009, naltrexone implants showed superior efficacy in the treatment of heroin dependence when compared to the oral form.[44]

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.[1] These adverse effects are analogous to the symptoms of opioid withdrawal, as the μ-opioid receptor blockade will increase gastrointestinal motility.

The side effects of naltrexone by incidence are as follows:[1]

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.[45]

Adverse effects

Whether naltrexone causes dysphoria, depression, anhedonia, or other aversive effects as side effects has been studied and reviewed.[46][47][48][49] In early studies of normal and opioid-abstinent individuals, acute and short-term administration of naltrexone was reported to produce a variety of aversive effects including fatigue, loss of energy, sleepiness, mild dysphoria, depression, lightheadedness, faintness, mental confusion, nausea, gastrointestinal disturbances, sweating, and occasional feelings of unreality.[48][50][51][52][53] However, these studies were small, often uncontrolled, and used subjective means of assessing side effects.[53][46] 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.[48][54][53] According to one source:[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, .[46][47][48][49] 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.[48][46] For example, marked upregulation of opioid receptors and hyper-sensitivity to opioids have been observed with naltrexone in preclinical studies.[4][46][55] 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.[55] 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.[46][55] It is notable in this regard that most studies of naltrexone have been in people with substance dependence.[46]

Naltrexone may also initially produce opioid withdrawal-like symptoms in a small subset of people not dependent on opioids:[56]

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.[57][46][56]

Naltrexone has been reported to reduce feelings of social connection.[58][59][60][61] Studies on whether naltrexone can decrease the pleasurable effects of listening to music are conflicting.[62][63][64] Besides humans, naltrexone has been found to produce aversive effects in rodents as assessed by conditioned place aversion.[46]

Liver damage

Naltrexone has been reported to cause liver damage when given at doses higher than recommended.[23] 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.[65] Subsequent studies have suggested limited or no toxicity in other patient populations and at typical recommended doses such as 50 to 100 mg/day.[23][10]

Overdose

No toxic effects have been observed with naltrexone in doses of up to 800 mg/day in clinical studies.[4][1] The largest reported 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.[66] No deaths are known to have occurred with naltrexone overdose.[67]

Pharmacology

Pharmacodynamics

Opioid receptor blockade

Naltrexone at human opioid receptors
Affinities (Ki) Ratios Refs
MOR KOR DOR MOR:KOR:DOR
1.0 nM 3.9 nM 149 nM 1:4:149 [68]
0.0825 nM 0.509 nM 8.02 nM 1:6:97 [69]
0.2 nM 0.4 nM 10.8 nM 1:2:54 [70][71]
0.62 nM 1.88 nM 12.3 nM 1:3:20 [72][73]
0.11 nM 0.19 nM 60 nM 1:1.7:545 [74][75][76]

Naltrexone and its active metabolite 6β-naltrexol are competitive antagonists of the opioid receptors.[77][78] Naltrexone is specifically an antagonist preferentially of the μ-opioid receptor (MOR), to a lesser extent of the κ-opioid receptor (KOR), and to a much lesser extent of the δ-opioid receptor (DOR).[77] However, naltrexone is not actually a 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.[78][75][76] 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.[4]

By itself, naltrexone acts as an antagonist or weak partial agonist of the opioid receptors.[78] In combination with agonists of the MOR such as morphine however, naltrexone appears to become an inverse agonist of the MOR.[78] Conversely, naltrexone remains a neutral antagonist (or weak partial agonist) of the KOR and DOR.[78] In contrast to naltrexone, 6β-naltrexol is purely a neutral antagonist of the opioid receptors.[79] The MOR inverse agonism of naltrexone when it is co-present with MOR agonists may in part underlie its ability to precipitate withdrawal in opioid-dependent individuals.[79][78] This may be due to suppression of basal MOR signaling via inverse agonism.[79][78]

Occupancy of the opioid receptors in the brain by naltrexone has been studied using positron emission tomography (PET).[23][80] 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.[23] Naltrexone at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies.[81][80][82] 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.[80] 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).[7][8] The half-time of brain MOR blockade by naltrexone in this study was 72 to 108 hours (3.0 to 4.5 days).[7][8] Based on these findings, doses of naltrexone of even less than 50 mg/day would be expected to achieve virtually complete brain MOR occupancy.[7][8] Blockade of brain MORs with naltrexone is much longer-lasting than with other opioid antagonists like naloxone (half-time of ~1.7 hours intranasally) or nalmefene (half-time of ~29 hours).[7][83][84]

The half-life of occupancy of the brain MOR and duration of clinical effect of naltrexone are much longer than suggested by its plasma elimination half-life.[7][85][8][86] 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.[85][8][87] 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).[7][8][46] 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 MOR affinity (<1.0 nM).[84][88]

Naltrexone blocks the effects of MOR agonists like morphine, heroin, and hydromorphone in humans via its MOR antagonism.[4][9] 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.[4] Similarly, 20 to 200 mg naltrexone dose-dependently antagonized the effects of heroin for up to 72 hours.[4] Naltrexone also blocks the effects of KOR agonists like salvinorin A, pentazocine, and butorphanol in humans via its KOR antagonism.[89][90][91][71] In addition to opioids, naltrexone has been found to block or reduce the rewarding and other effects of other euphoriant drugs including alcohol,[55] nicotine,[92] and amphetamines.[93]

The opioid receptors are involved in neuroendocrine regulation.[4] MOR agonists produce increases in levels of prolactin and decreases in levels of luteinizing hormone (LH) and testosterone.[4] Doses of naltrexone of 25 to 150 mg/day have been found to produce significant increases in levels of β-endorphin, cortisol, and LH, equivocal changes in levels of prolactin and testosterone, and no significant changes in levels of adrenocorticotrophic hormone (ACTH) or follicle-stimulating hormone (FSH).[4] Naltrexone influences the hypothalamic–pituitary–adrenal axis (HPA axis) probably through interference with opioid receptor signaling by endorphins.[4]

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.[94][95]

Other activities

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).[96][97][98][99] 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.[96][98] The interactions of naltrexone with FLNA and TLR4 are claimed to be involved in the therapeutic effects of low-dose naltrexone.[96]

Pharmacokinetics

Naltrexone levels following a 50 mg oral dose of naltrexone at steady state during treatment with 50 mg/day naltrexone[100][101]
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[102][103][104][105]

The absorption of naltrexone with oral administration is rapid and nearly complete (96%).[1] The bioavailability of naltrexone with oral administration is 5 to 60% due to extensive first-pass metabolism.[4][5] Peak concentrations of naltrexone are 19 to 44 μg/L after a single 100 mg oral dose and time to peak concentrations of naltrexone and 6β-naltrexol (metabolite) is within 1 hour.[4][5][1] Linear increases in circulating naltrexone and 6β-naltrexol concentrations occur over an oral dose range of 50 to 200 mg.[4] 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.[4]

The plasma protein binding of naltrexone is about 20% over a naltrexone concentration range of 0.1 to 500 μg/L.[4][1] 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.[4]

Naltrexone is metabolized in the liver mainly by dihydrodiol dehydrogenases into 6β-naltrexol (6β-hydroxynaltrexone).[4][5] Levels of 6β-naltrexol are 10- to 30-fold higher than those of naltrexone with oral administration due to extensive first-pass metabolism.[106] Conversely, 6β-naltrexol exposure is only about 2-fold higher than that of naltrexone with intramuscular injection of naltrexone in microspheres (brand name Vivitrol).[102] 6β-Naltrexol is an opioid receptor antagonist similarly to naltrexone and shows a comparable binding profile to the opioid receptors.[107] However, 6β-naltrexol is peripherally selective and crosses into the brain much less readily than does naltrexone.[107] In any case, 6β-naltrexol does still show some central activity and may contribute significantly to the central actions of oral naltrexone.[107][4] Other metabolites of naltrexone include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxynaltrexone.[4] Following their formation, the metabolites of naltrexone are further metabolized by conjugation with glucuronic acid to form glucuronides.[4] Naltrexone is not metabolized by the cytochrome P450 system and has low potential for drug interactions.[9]

The elimination of naltrexone is biexponential and rapid over the first 24 hours followed by a third extremely slow decline after 24 hours.[4] The fast elimination half-lives of naltrexone and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively.[1] In Contrave oral tablets, which also contain bupropion and are described as extended-release, the half-life of naltrexone is 5 hours.[2] The slow terminal-phase elimination half-life of naltrexone is approximately 96 hours.[8] As microspheres of naltrexone by intramuscular injection (Vivitrol), the elimination half-lives of naltrexone and 6β-naltrexol are both 5 to 10 days.[3] Whereas oral naltrexone is administered daily, naltrexone in microspheres by intramuscular injection is suitable for administration once every 4 weeks or once per month.[3]

Naltrexone and its metabolites are excreted in urine.[1]

Pharmacogenetics

Tentative evidence suggests that family history and presence of the Asn40Asp polymorphism predicts naltrexone being effective.[108][22]

Chemistry

Naltrexone, also known as N-cyclopropylmethylnoroxymorphone, is a derivative of oxymorphone (14-hydroxydihydromorphinone). It is specifically the derivative of oxymorphone in which the tertiary amine methyl substituent is replaced with methylcyclopropane.

Analogues

The closely related medication, methylnaltrexone (N-methylnaltrexone), is used to treat opioid-induced constipation, but does not treat addiction as it does not cross the blood–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 with naloxone (N-allylnoroxymorphone), which is used in emergency cases of opioid overdose. Other opioid antagonists related to naltrexone include 6β-naltrexol (6β-hydroxynaltrexone), samidorphan (3-carboxamido-4-hydroxynaltrexone), β-funaltrexamine (naltrexone fumarate methyl ester), nalodeine (N-allylnorcodeine), nalorphine (N-allylnormorphine), and nalbuphine (N-cyclobutylmethyl-14-hydroxydihydronormorphine).

History

Naltrexone was first synthesized in 1963 by Metossian at Endo Laboratories, a small pharmaceutical company in New York City .[109] 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.[109][110][111][12] 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.[12] It was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by DuPont in 1969.[112][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.[112] 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.[112][40] 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.[41][40]

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.[113][114][115][116]

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.[113][114][115][116] It is also marketed in combination with bupropion (naltrexone/bupropion) as Contrave,[117] and was marketed with morphine (morphine/naltrexone) as Embeda.[116][118] A combination of naltrexone with buprenorphine (buprenorphine/naltrexone) has been developed, but has not been marketed.[119]

Controversies

The FDA authorized use of injectable naltrexone (Vivitrol) for opioid addiction using a single study[120] that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia,[121] 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 .[122] 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.[123] Nearly 30% of patients in the US trial did not complete induction.[31] 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.[28]

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.[124] 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."[125][126] The company's marketing techiques have led to a Congressional investigation,[127] and warning from the FDA about failure to adequately state risks of fatal overdose to patients receiving the medicine.[128]

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.[124] 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".[129] 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"[124] 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."[129]

Film

One Little Pill was a 2014 documentary film about use of naltrexone to treat alcohol use disorder.[130]

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.[131][132] Some studies suggest it might help.[133] Other small, preliminary studies have also shown benefit.[131][132] Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization.[131][132] Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than typically used seem to be necessary.[131][132]

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.[134] Evidence for recommending low-dose naltrexone is lacking.[135][136] This treatment has received attention on the Internet.[137] In 2022, four studies (in a few hundred patients) were conducted on naltrexone for long COVID.[138]

Self-injury

One study suggests that self-injurious behaviors present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.[139] 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.[140] 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.[141][142][143] A 2008 case study reported successful use of naltrexone in suppressing and treating an internet pornography addiction.[144]

Interferon alpha

Naltrexone is effective in suppressing the cytokine-mediated adverse neuropsychiatric effects of interferon alpha therapy.[145][146]

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.[147] Studies have suggested the use of naltrexone in drug courts or healthcare rehabs is a form of "post-social control,"[148] or "post-disciplinary control,"[149] 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.[150][151]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 "Revia (naltrexone hydrochloride tablets USP50 mgOpioid Antagonist". 24 April 2015. https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=172953. 
  2. ↑ 2.0 2.1 2.2 "Contrave Extended-Release – naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". 4 November 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b. 
  3. ↑ 3.0 3.1 3.2 3.3 "Vivitrol- naltrexone kit". 10 March 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd11c435-b0f0-4bb9-ae78-60f101f3703f. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 "Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence". Drugs 35 (3): 192–213. March 1988. doi:10.2165/00003495-198835030-00002. PMID 2836152. 
  5. ↑ 5.0 5.1 5.2 5.3 "Naltrexone for the treatment of obesity: review and update". Expert Opinion on Pharmacotherapy 10 (11): 1841–1845. August 2009. doi:10.1517/14656560903048959. PMID 19537999. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 "Naltrexone Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/naltrexone.html. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "Opioids Neuroimaging". Biological Research on Addiction. Comprehensive Addictive Behaviors and Disorders. 2. Elsevier. 2013. pp. 675–687. doi:10.1016/B978-0-12-398335-0.00066-2. ISBN 9780123983350. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 "Duration of occupancy of opiate receptors by naltrexone". Journal of Nuclear Medicine 29 (7): 1207–1211. July 1988. PMID 2839637. https://jnm.snmjournals.org/content/29/7/1207.long. Retrieved 29 October 2021. 
  9. ↑ 9.0 9.1 9.2 "Naltrexone for Initiation and Maintenance of Opiate Abstinence". Opiate Receptors and Antagonists. Humana Press. 2009. pp. 227–245. doi:10.1007/978-1-59745-197-0_12. ISBN 978-1-58829-881-2. 
  10. ↑ 10.0 10.1 10.2 "Naltrexone: A Pan-Addiction Treatment?". CNS Drugs 30 (8): 719–733. August 2016. doi:10.1007/s40263-016-0373-0. PMID 27401883. 
  11. ↑ "Methadone, Buprenorphine, and Naltrexone for the Treatment of Opioid Use Disorder in Pregnant Women". Pharmacotherapy 37 (7): 824–839. July 2017. doi:10.1002/phar.1958. PMID 28543191. 
  12. ↑ 12.0 12.1 12.2 (in en) Kaplan & Sadock's Pocket Handbook of Psychiatric Drug Treatment. Lippincott Williams & Wilkins. 2012. p. 265. ISBN 978-1451154467. https://books.google.com/books?id=qp-H3UruKvIC&pg=PT265. 
  13. ↑ "Naltrexone/bupropion for obesity". Drug and Therapeutics Bulletin 55 (11): 126–129. November 2017. doi:10.1136/dtb.2017.11.0550. PMID 29117992. 
  14. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list. Geneva: WHO. 2023. WHO/MHP/HPS/EML/2023.02. 
  15. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  16. ↑ "Naltrexone - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Naltrexone. 
  17. ↑ 17.0 17.1 "Naltrexone engages a brain reward network in the presence of reward-predictive distractor stimuli in males" (in en). Addiction Neuroscience 7: 100085. September 2023. doi:10.1016/j.addicn.2023.100085. ISSN 2772-3925. PMID 37424633. 
  18. ↑ "The dopamine hypothesis of reward: past and current status". Trends in Neurosciences 22 (11): 521–527. November 1999. doi:10.1016/s0166-2236(99)01447-2. PMID 10529820. 
  19. ↑ "Opioid antagonists for alcohol dependence". The Cochrane Database of Systematic Reviews (12): CD001867. December 2010. doi:10.1002/14651858.CD001867.pub2. PMID 21154349. 
  20. ↑ "The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis". Addiction 110 (6): 920–930. June 2015. doi:10.1111/add.12875. PMID 25664494. http://findings.org.uk/PHP/dl.php?file=Donoghue_K_1.txt&s=eb. Retrieved 15 April 2019. 
  21. ↑ "Efficacy and tolerability of naltrexone in the management of alcohol dependence". Current Pharmaceutical Design 16 (19): 2091–2097. 2010. doi:10.2174/138161210791516459. PMID 20482515. 
  22. ↑ 22.0 22.1 "Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence". Addiction 109 (8): 1274–1284. August 2014. doi:10.1111/add.12557. PMID 24661324. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics". CNS & Neurological Disorders Drug Targets 9 (1): 13–22. March 2010. doi:10.2174/187152710790966704. PMID 20201811. 
  24. ↑ "Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful?". Addiction 108 (2): 275–293. February 2013. doi:10.1111/j.1360-0443.2012.04054.x. PMID 23075288. 
  25. ↑ "Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism". Alcohol and Alcoholism 36 (1): 2–10. 2001. doi:10.1093/alcalc/36.1.2. PMID 11139409. 
  26. ↑ 26.0 26.1 "Update on Barriers to Pharmacotherapy for Opioid Use Disorders". Current Psychiatry Reports 19 (6): 35. June 2017. doi:10.1007/s11920-017-0783-9. PMID 28526967. 
  27. ↑ "Opioid Use Disorders". Child and Adolescent Psychiatric Clinics of North America 25 (3): 473–487. July 2016. doi:10.1016/j.chc.2016.03.002. PMID 27338968. 
  28. ↑ 28.0 28.1 "Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder". JAMA Network Open 3 (2): e1920622. February 2020. doi:10.1001/jamanetworkopen.2019.20622. PMID 32022884. 
  29. ↑ "Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial". Archives of General Psychiatry 63 (2): 210–218. February 2006. doi:10.1001/archpsyc.63.2.210. PMID 16461865. 
  30. ↑ "Buprenorphine Treatment for Opioid Use Disorder: An Overview". CNS Drugs 33 (6): 567–580. June 2019. doi:10.1007/s40263-019-00637-z. PMID 31062259. 
  31. ↑ 31.0 31.1 "Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial". Lancet 391 (10118): 309–318. January 2018. doi:10.1016/S0140-6736(17)32812-X. PMID 29150198. 
  32. ↑ Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. World Health Organization. 2009. ISBN 978-92-4-154754-3. https://www.who.int/publications/i/item/9789241547543. Retrieved 28 September 2022. [page needed]
  33. ↑ "Oral naltrexone maintenance treatment for opioid dependence". The Cochrane Database of Systematic Reviews 2011 (4): CD001333. April 2011. doi:10.1002/14651858.CD001333.pub4. PMID 21491383. 
  34. ↑ "Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review". Addiction 101 (4): 491–503. April 2006. doi:10.1111/j.1360-0443.2006.01369.x. PMID 16548929. 
  35. ↑ "Opioid antagonists for smoking cessation". The Cochrane Database of Systematic Reviews 6 (6): CD003086. June 2013. doi:10.1002/14651858.CD003086.pub3. PMID 23744347. 
  36. ↑ "Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials". European Addiction Research 23 (4): 204–210. 2017. doi:10.1159/000480539. PMID 28877518. 
  37. ↑ "Naltrexone in the treatment of adolescent sexual offenders". The Journal of Clinical Psychiatry 65 (7): 982–986. July 2004. doi:10.4088/jcp.v65n0715. PMID 15291688. 
  38. ↑ "Low dose naltrexone". MEpedia. https://me-pedia.org/wiki/Low_dose_naltrexone. 
  39. ↑ "Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study". Brain, Behavior, & Immunity – Health 24: 100485. October 2022. doi:10.1016/j.bbih.2022.100485. PMID 35814187. 
  40. ↑ 40.0 40.1 40.2 40.3 Substance Use Disorders: A Guide for the Primary Care Provider. Springer International Publishing. 17 October 2017. pp. 88–. ISBN 978-3-319-63040-3. https://books.google.com/books?id=wH86DwAAQBAJ&pg=PA88. Retrieved 4 December 2017. 
  41. ↑ 41.0 41.1 ""Alcoholism Once A Month Injectable Drug, Vivitrol, Approved By FDA". Medical News Today. 16 April 2006. http://www.medicalnewstoday.com/articles/41707.php. 
  42. ↑ Therapeutic Goods Administration. "Australian Register of Therapeutic Goods Medicines" (Online database of approved medicines). https://www.ebs.tga.gov.au/ebs/ANZTPAR/PublicWeb.nsf/cuMedicines?OpenView. 
  43. ↑ Therapeutic Goods Administration. "Australian Register of Therapeutic Goods Medicines" (Online database of approved medicines, specific entry for "O'Neil Long Acting Naltrexone Implant"). https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs%2FPublicHTML%2FpdfStore.nsf&docid=12AA89E8C8E53B46CA257FA7004211EE&agid=(PrintDetailsPublic)&actionid=1.  [yes|permanent dead link|dead link}}]
  44. ↑ "Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone". Archives of General Psychiatry 66 (10): 1108–1115. October 2009. doi:10.1001/archgenpsychiatry.2009.130. PMID 19805701. 
  45. ↑ The American Psychiatric Publishing Textbook of Substance Abuse Treatment. American Psychiatric. 2008. ISBN 978-1-58562-276-4. [page needed]
  46. ↑ 46.0 46.1 46.2 46.3 46.4 46.5 46.6 46.7 46.8 46.9 "Naltrexone and dysphoria: fact or myth?". The American Journal on Addictions 11 (2): 151–160. 2002. doi:10.1080/10550490290087929. PMID 12028745. 
  47. ↑ 47.0 47.1 47.2 The Treatment of Opioid Dependence. JHU Press. 2006. pp. 296–. ISBN 978-0-8018-8219-7. https://books.google.com/books?id=timYFx278CUC&pg=PA296. Retrieved 2 June 2021. 
  48. ↑ 48.0 48.1 48.2 48.3 48.4 "Neuropsychiatric adverse effects of centrally acting antiobesity drugs". CNS Neuroscience & Therapeutics 17 (5): 490–505. October 2011. doi:10.1111/j.1755-5949.2010.00172.x. PMID 21951371. 
  49. ↑ 49.0 49.1 "Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant". The American Journal of Drug and Alcohol Abuse 42 (5): 614–620. September 2016. doi:10.1080/00952990.2016.1197231. PMID 27436632. 
  50. ↑ "Effects of naltrexone on mood and neuroendocrine function in normal adult males". Psychoneuroendocrinology 3 (3–4): 231–236. October 1978. doi:10.1016/0306-4530(78)90013-6. PMID 219434. 
  51. ↑ "Aversive effects of naltrexone in subjects not dependent on opiates". Drug and Alcohol Dependence 8 (1): 37–41. August 1981. doi:10.1016/0376-8716(81)90084-3. PMID 7297411. 
  52. ↑ "Naltrexone-induced dysphoria in former opioid addicts". The American Journal of Psychiatry 142 (9): 1081–1084. September 1985. doi:10.1176/ajp.142.9.1081. PMID 2992300. 
  53. ↑ 53.0 53.1 53.2 "Naltrexone and dysphoria: a double-blind placebo controlled trial". Biological Psychiatry 22 (6): 710–716. June 1987. doi:10.1016/0006-3223(87)90202-2. PMID 3593812. 
  54. ↑ "The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking". Journal of Clinical Psychopharmacology 26 (6): 610–625. December 2006. doi:10.1097/01.jcp.0000245566.52401.20. PMID 17110818. 
  55. ↑ 55.0 55.1 55.2 55.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid21768981
  56. ↑ 56.0 56.1 "Can psychotherapy rescue naltrexone treatment of opioid addiction?". NIDA Research Monograph 150: 37–52. 1995. PMID 8742771. https://archives.drugabuse.gov/sites/default/files/monograph150.pdf#page=43. Retrieved 31 October 2021. 
  57. ↑ "Accounting for the uncounted: Physical and affective distress in individuals dropping out of oral naltrexone treatment for opioid use disorder". Drug and Alcohol Dependence 192: 264–270. November 2018. doi:10.1016/j.drugalcdep.2018.08.019. PMID 30300800. 
  58. ↑ "Opioids and social bonding: Effect of naltrexone on feelings of social connection and ventral striatum activity to close others". Journal of Experimental Psychology. General 149 (4): 732–745. April 2020. doi:10.1037/xge0000674. PMID 31414860. 
  59. ↑ "Naltrexone alters responses to social and physical warmth: implications for social bonding". Social Cognitive and Affective Neuroscience 14 (5): 471–479. May 2019. doi:10.1093/scan/nsz026. PMID 30976797. 
  60. ↑ "Opioids and social bonding: naltrexone reduces feelings of social connection". Social Cognitive and Affective Neuroscience 11 (5): 728–735. May 2016. doi:10.1093/scan/nsw006. PMID 26796966. 
  61. ↑ "Naltrexone increases negatively-valenced facial responses to happy faces in female participants". Psychoneuroendocrinology 74: 65–68. December 2016. doi:10.1016/j.psyneuen.2016.08.022. PMID 27588701. 
  62. ↑ "Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone". The American Journal on Addictions 20 (2): 106–112. 2011. doi:10.1111/j.1521-0391.2010.00107.x. PMID 21314752. 
  63. ↑ "Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone". Scientific Reports 7 (1): 41952. February 2017. doi:10.1038/srep41952. PMID 28176798. Bibcode: 2017NatSR...741952M. 
  64. ↑ "'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure". Consciousness and Cognition 90: 103105. April 2021. doi:10.1016/j.concog.2021.103105. PMID 33711654. 
  65. ↑ "Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage". NIDA Research Monograph 67: 66–72. 1986. PMID 3092099. https://archives.drugabuse.gov/pdf/monographs/download67.html. Retrieved 23 January 2017. 
  66. ↑ "Clinical safety of 1500 mg oral naltrexone overdose". BMJ Case Reports 2010 (sep06 1): bcr0420102871. September 2010. doi:10.1136/bcr.04.2010.2871. PMID 22778191. 
  67. ↑ "Naltrexone and Opioid Antagonists for Alcohol Dependence". Interventions for Addiction. Elsevier. 2013. pp. 375–384. doi:10.1016/B978-0-12-398338-1.00039-7. ISBN 978-0-12-398338-1. 
  68. ↑ "Pharmacological characterization of the cloned κ-, δ-, and μ-opioid receptors". Molecular Pharmacology 45 (2): 330–334. February 1994. INIST:3935705. PMID 8114680. http://molpharm.aspetjournals.org/content/45/2/330.short. Retrieved 22 June 2018. 
  69. ↑ "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". The Journal of Pharmacology and Experimental Therapeutics 274 (3): 1263–1270. September 1995. PMID 7562497. http://jpet.aspetjournals.org/content/274/3/1263.short. Retrieved 23 January 2017. 
  70. ↑ "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Research Monograph 178: 440–466. March 1998. PMID 9686407. 
  71. ↑ 71.0 71.1 "The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence". Biological Psychiatry 86 (7): 502–511. October 2019. doi:10.1016/j.biopsych.2019.05.012. PMID 31376930. 
  72. ↑ "Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging". Journal of Nuclear Medicine 54 (3): 455–463. March 2013. doi:10.2967/jnumed.112.109512. PMID 23353688. 
  73. ↑ "A Survey of Molecular Imaging of Opioid Receptors". Molecules 24 (22): 4190. November 2019. doi:10.3390/molecules24224190. PMID 31752279. 
  74. ↑ "Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone". Bioorganic & Medicinal Chemistry Letters 15 (8): 2107–2110. April 2005. doi:10.1016/j.bmcl.2005.02.032. PMID 15808478. 
  75. ↑ 75.0 75.1 "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters 19 (8): 2289–2294. April 2009. doi:10.1016/j.bmcl.2009.02.078. PMID 19282177. 
  76. ↑ 76.0 76.1 Emerging Targets and Therapeutics in the Treatment of Psychostimulant Abuse. Academic Press. 29 January 2014. pp. 398–. ISBN 978-0-12-420177-4. OCLC 1235841274. https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398. Retrieved 30 October 2021. 
  77. ↑ 77.0 77.1 "Targeted opioid receptor antagonists in the treatment of alcohol use disorders". CNS Drugs 27 (10): 777–787. October 2013. doi:10.1007/s40263-013-0096-4. PMID 23881605. 
  78. ↑ 78.0 78.1 78.2 78.3 78.4 78.5 78.6 "Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist pretreatment". The Journal of Pharmacology and Experimental Therapeutics 321 (2): 544–552. May 2007. doi:10.1124/jpet.106.118810. PMID 17267582. 
  79. ↑ 79.0 79.1 79.2 "Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities". Life Sciences 76 (13): 1427–1437. February 2005. doi:10.1016/j.lfs.2004.10.024. PMID 15680308. 
  80. ↑ 80.0 80.1 80.2 "Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving". Molecular Psychiatry 26 (9): 5053–5060. September 2021. doi:10.1038/s41380-020-0811-8. PMID 32541931. 
  81. ↑ "Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography". The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. 271. Cham: Springer. August 2021. pp. 547–577. doi:10.1007/164_2021_498. ISBN 978-3-030-89073-5. 
  82. ↑ "Naltrexone occupancy at kappa opioid receptors investigated in alcoholics by PET occupancy at kappa opioid receptors investigated in alcoholics by PET". Journal of Nuclear Medicine 58 (Supplement 1): 1297. 1 April 2017. https://jnm.snmjournals.org/content/58/supplement_1/1297. Retrieved 29 October 2021. 
  83. ↑ "Positron Emission Tomography (PET) Imaging of Opioid Receptors". PET and SPECT of Neurobiological Systems. Springer International Publishing. 30 September 2020. pp. 749–807. doi:10.1007/978-3-030-53176-8_21. ISBN 978-3-030-53175-1. https://pure.rug.nl/ws/files/349191745/978_3_030_53176_8.pdf. Retrieved 21 May 2023. 
  84. ↑ 84.0 84.1 "Nalmefene for treatment of alcohol dependence". Expert Opinion on Investigational Drugs 19 (11): 1451–1459. November 2010. doi:10.1517/13543784.2010.522990. PMID 20868291. 
  85. ↑ 85.0 85.1 "Pharmacological enhancement of naltrexone treatment for opioid dependence: a review". Substance Abuse and Rehabilitation 2011 (2): 113–123. June 2011. doi:10.2147/SAR.S15853. PMID 21731898. 
  86. ↑ "Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans". Psychopharmacology 145 (2): 162–174. July 1999. doi:10.1007/s002130051045. PMID 10463317. 
  87. ↑ Narcotic Antagonists: Naltrexone Pharmacochemistry and Sustained-release Preparations. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, Division of Research. 1981. pp. 148–. https://books.google.com/books?id=HyVsAAAAMAAJ&pg=PA148. Retrieved 2 June 2021. 
  88. ↑ "Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing". Neuropsychopharmacology 30 (12): 2245–2253. December 2005. doi:10.1038/sj.npp.1300790. PMID 15956985. 
  89. ↑ "Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans". The International Journal of Neuropsychopharmacology 19 (7): pyw016. July 2016. doi:10.1093/ijnp/pyw016. PMID 26874330. 
  90. ↑ "Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade". Psychopharmacology 196 (1): 143–155. January 2008. doi:10.1007/s00213-007-0948-z. PMID 17909753. 
  91. ↑ "Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers". The Journal of Pharmacology and Experimental Therapeutics 264 (2): 813–823. February 1993. PMID 7679737. https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7679737. Retrieved 28 September 2022. 
  92. ↑ "Clinical uses of naltrexone: a review of the evidence". Experimental and Clinical Psychopharmacology 10 (3): 213–227. August 2002. doi:10.1037/1064-1297.10.3.213. PMID 12233982. 
  93. ↑ "Efficacy and safety of naltrexone for amfetamine and methamfetamine use disorder: a systematic review of randomized controlled trials". Clinical Toxicology 57 (4): 225–233. April 2019. doi:10.1080/15563650.2018.1529317. PMID 30451013. 
  94. ↑ "Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-Analysis". Pharmacopsychiatry 49 (2): 66–75. March 2016. doi:10.1055/s-0035-1565184. PMID 26845589. 
  95. ↑ "Neurobiology of addiction: a neurocircuitry analysis". The Lancet. Psychiatry 3 (8): 760–773. August 2016. doi:10.1016/S2215-0366(16)00104-8. PMID 27475769. 
  96. ↑ 96.0 96.1 96.2 "Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization". Medical Sciences 6 (4): 82. September 2018. doi:10.3390/medsci6040082. PMID 30248938. 
  97. ↑ "Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4". CNS & Neurological Disorders Drug Targets 14 (6): 692–699. 2015. doi:10.2174/1871527314666150529132503. PMID 26022268. 
  98. ↑ 98.0 98.1 "The uses of naltrexone in dermatologic conditions". Journal of the American Academy of Dermatology 80 (6): 1746–1752. June 2019. doi:10.1016/j.jaad.2018.12.031. PMID 30582992. 
  99. ↑ "The biology of the opioid growth factor receptor (OGFr)". Brain Research. Brain Research Reviews 38 (3): 351–376. February 2002. doi:10.1016/s0165-0173(01)00160-6. PMID 11890982. 
  100. ↑ "The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence". Frontiers in Bioscience 10 (1–3): 643–655. January 2005. doi:10.2741/1559. PMID 15569605. 
  101. ↑ "Naltrexone: a review of existing sustained drug delivery systems and emerging nano-based systems". Journal of Controlled Release 183: 154–166. June 2014. doi:10.1016/j.jconrel.2014.03.046. PMID 24704710. 
  102. ↑ 102.0 102.1 "Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone". Alcoholism: Clinical and Experimental Research 30 (3): 480–490. March 2006. doi:10.1111/j.1530-0277.2006.00052.x. PMID 16499489. 
  103. ↑ "Extended-release intramuscular naltrexone". Drugs 66 (13): 1741–1751. 2006. doi:10.2165/00003495-200666130-00006. PMID 16978037. 
  104. ↑ "Long-acting injectable naltrexone for the treatment of alcohol dependence". Expert Review of Neurotherapeutics 7 (10): 1265–1277. October 2007. doi:10.1586/14737175.7.10.1265. PMID 17939765. 
  105. ↑ "Vivitrol (naltrexone for extended-release injectable suspension)". 28 November 2018. https://www.vivitrolhcp.com/dosing-and-administration. 
  106. ↑ Opioids in Cancer Pain. Oxford University Press. 28 May 2009. pp. 41–. ISBN 978-0-19-923664-0. https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA41. Retrieved 31 October 2021. 
  107. ↑ 107.0 107.1 107.2 Opioid Receptor Antagonists for Gastrointestinal Dysfunction. Annual Reports in Medicinal Chemistry. 45. Elsevier. 2010. pp. 142–155. doi:10.1016/S0065-7743(10)45009-5. ISBN 978-0-12-380902-5. 
  108. ↑ "The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: a critical review". Alcoholism: Clinical and Experimental Research 36 (3): 385–394. March 2012. doi:10.1111/j.1530-0277.2011.01633.x. PMID 21895723. 
  109. ↑ 109.0 109.1 National Research Council (U.S.). Committee on Problems of Drug Dependence (1974). Report of the Thirty-sixth Annual Scientific Meeting: Committee on Problems of Drug Dependence, Mexico City, March 10-14, 1974. National Academies. pp. 265–. NAP:13963. ISBN 9780309022446. https://books.google.com/books?id=pEYrAAAAYAAJ&pg=PA265. Retrieved 4 December 2017. 
  110. ↑ Addiction: A Reference Encyclopedia. ABC-CLIO. 2010. pp. 207–. ISBN 978-1-59884-229-6. https://archive.org/details/addictionreferen0000padw. 
  111. ↑ Treating Drug Abusers. Routledge. 14 January 2004. pp. 112–. ISBN 978-1-134-93173-6. https://books.google.com/books?id=ft6IAgAAQBAJ&pg=PT112. Retrieved 4 December 2017. 
  112. ↑ 112.0 112.1 112.2 Google Ldn !. Lulu.com. 1 March 2009. pp. 78–88. ISBN 978-0-578-00439-6. https://books.google.com/books?id=9hOBAgAAQBAJ&pg=RA1-PA78. Retrieved 4 December 2017. 
  113. ↑ 113.0 113.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 851–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA851. Retrieved 4 December 2017. 
  114. ↑ 114.0 114.1 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 715–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA715. Retrieved 4 December 2017. 
  115. ↑ 115.0 115.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 189–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA189. 
  116. ↑ 116.0 116.1 116.2 "Naltrexone". https://www.drugs.com/international/naltrexone.html. 
  117. ↑ "Bupropion and naltrexone Uses, Side Effects & Warnings". 8 June 2020. https://www.drugs.com/mtm/bupropion-and-naltrexone.html. 
  118. ↑ "Morphine and naltrexone Uses, Side Effects & Warnings". 14 October 2019. https://www.drugs.com/mtm/morphine-and-naltrexone.html. 
  119. ↑ "Potential of buprenorphine/naltrexone in treating polydrug addiction and co-occurring psychiatric disorders". Clinical Pharmacology and Therapeutics 83 (4): 627–630. April 2008. doi:10.1038/sj.clpt.6100503. PMID 18212797. 
  120. ↑ "A Shot in the Dark: Can Vivitrol Help Us Control Our Addictions?". 7 May 2013. https://psmag.com/social-justice/vivitrol-help-control-addictions-57261. 
  121. ↑ "Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial". Lancet 377 (9776): 1506–1513. April 2011. doi:10.1016/s0140-6736(11)60358-9. PMID 21529928. 
  122. ↑ "Injectable extended-release naltrexone for opioid dependence – Authors' reply". The Lancet 378 (9792): 666. 2011. doi:10.1016/S0140-6736(11)61333-0. 
  123. ↑ "Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial". JAMA Psychiatry 74 (12): 1197–1205. December 2017. doi:10.1001/jamapsychiatry.2017.3206. PMID 29049469. 
  124. ↑ 124.0 124.1 124.2 "Seizing on Opioid Crisis, a Drug Maker Lobbies Hard for Its Product". The New York Times. 11 June 2017. https://www.nytimes.com/2017/06/11/health/vivitrol-drug-opioid-addiction.html. "Advertising for Vivitrol on a subway car in Brooklyn last month. Marketing for the drug has shifted into high gear." 
  125. ↑ "The Last Shot" (in en). https://www.propublica.org/article/vivitrol-opiate-crisis-and-criminal-justice. 
  126. ↑ "Biotechnologies and the future of opioid addiction treatments". The International Journal on Drug Policy 88: 103041. February 2021. doi:10.1016/j.drugpo.2020.103041. PMID 33246267. 
  127. ↑ "Kamala Harris Investigating Addiction Drug Manufacturer Alkermes" (in en-us). 7 November 2017. https://www.wfyi.org/news/articles/kamala-harris-investigating-addiction-drug-manufacturer-alkermes. 
  128. ↑ Office of the FDA Commissioner (24 March 2020). "FDA issues warning letter for not including the most serious risks in advertisement for medication-assisted treatment drug" (in en). https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letter-not-including-most-serious-risks-advertisement-medication-assisted. 
  129. ↑ 129.0 129.1 "Letter to Tom Price". May 2017. https://www.documentcloud.org/documents/3723472-Tom-Price-Letter-Re-MAT.html. 
  130. ↑ One Little Pill (2014) on IMDb
  131. ↑ 131.0 131.1 131.2 131.3 Feeling Unreal: Depersonalization Disorder and the Loss of the Self. Oxford University Press. 10 October 2008. pp. 166–. ISBN 978-0-19-976635-2. https://books.google.com/books?id=ONLyq-mVLuIC&pg=PA166. Retrieved 4 October 2016. 
  132. ↑ 132.0 132.1 132.2 132.3 Neurobiology and Treatment of Traumatic Dissociation: Towards an Embodied Self. Springer Publishing Company. 13 May 2014. pp. 489–. ISBN 978-0-8261-0632-2. https://books.google.com/books?id=0i-FAwAAQBAJ&pg=PA489. Retrieved 4 October 2016. 
  133. ↑ "Depersonalization disorder: pharmacological approaches". Expert Review of Neurotherapeutics 8 (1): 19–26. January 2008. doi:10.1586/14737175.8.1.19. PMID 18088198. 
  134. ↑ "Low Dose Naltrexone – Bogus or Cutting Edge Science?". Science-Based Medicine. 5 May 2010. http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/. 
  135. ↑ "Low-Dose Naltrexone". National MS Society. http://www.nationalmssociety.org/Treating-MS/Complementary-Alternative-Medicines/Low-Dose-Naltrexone. 
  136. ↑ "Low Dose Naltrexone – Bogus or Cutting Edge Science?". 5 May 2010. http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/. 
  137. ↑ "Low-dose naltrexone (LDN) The "411" on LDN". National Multiple Sclerosis Society. http://www.nationalmssociety.org/multimedia-library/momentum-magazine/back-issues/momentum-spring-09/download.aspx?id=5587. 
  138. ↑ "Addiction drug shows promise lifting long COVID brain fog, fatigue". Reuters. 18 October 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/addiction-drug-shows-promise-lifting-long-covid-brain-fog-fatigue-2022-10-18/. 
  139. ↑ "Effects of naltrexone on self-injury, stereotypy, and social behavior of adults with developmental disabilities". Journal of Developmental and Physical Disabilities 7 (2): 137–46. 1995. doi:10.1007/BF02684958. 
  140. ↑ "Self-injuries may have biochemical base: study". The Reporter. 20 March 1998. http://www.mc.vanderbilt.edu/reporter/index.html?ID=461. 
  141. ↑ "A double-blind, placebo-controlled study of the opiate antagonist, naltrexone, in the treatment of kleptomania". Biological Psychiatry 65 (7): 600–606. April 2009. doi:10.1016/j.biopsych.2008.11.022. PMID 19217077. 
    • Lay summary in: "Drug Suppresses The Compulsion To Steal, Study Shows". Science Daily (Press release). 3 April 2009.
  142. ↑ Clinical trial number NCT00326807 for "A Randomized, Double-Blind, Placebo-Controlled Trial of Naltrexone in the Treatment of Concurrent Alcohol Dependence and Pathological Gambling" at ClinicalTrials.gov
  143. ↑ "Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling". Biological Psychiatry 49 (11): 914–921. June 2001. doi:10.1016/S0006-3223(01)01079-4. PMID 11377409. 
  144. ↑ "Internet sex addiction treated with naltrexone". Mayo Clinic Proceedings 83 (2): 226–230. February 2008. doi:10.4065/83.2.226. PMID 18241634. 
  145. ↑ "[Hepatitis C, interferon a and depression: main physiopathologic hypothesis]" (in fr). L'Encéphale 31 (3): 349–357. 2005. doi:10.1016/s0013-7006(05)82400-5. INIST:16920336. PMID 16142050. 
  146. ↑ "[Neuropsychiatric symptoms related to interferon alpha"] (in pl). Psychiatria Polska 40 (4): 787–797. 2006. PMID 17068950. http://www.psychiatriapsychoterapia.pl/?a=articles_show&id=459. 
  147. ↑ "Why Can't They Stop?" A Highly Public Misunderstanding of Science. Duke University Press. 28 March 2013. pp. 238–262. doi:10.1215/9780822395874-010. ISBN 978-0-8223-5350-8. https://read.dukeupress.edu/books/book/1700/chapter/180902/Why-Can-t-They-Stop-A-Highly-Public. Retrieved 20 December 2020. 
  148. ↑ "Therapeutic Justice in Drug Courts: Crime, Punishment and Societies of Control". Science as Culture 18 (2): 217–232. 1 June 2009. doi:10.1080/09505430902885623. 
  149. ↑ "Governing beyond the closet: Remaking stigma, identity, and sexual behavior in a post-disciplinary rehab" (in en). Ethnography 23 (4): 516–538. 9 May 2020. doi:10.1177/1466138120923702. 
  150. ↑ "Pharmacotherapy of Sexual Addiction". Current Psychiatry Reports 22 (6): 30. May 2020. doi:10.1007/s11920-020-01153-4. PMID 32377953. https://hal.sorbonne-universite.fr/hal-02880933/file/Pharmacotherapy%20of%20Sexual%20Addiction.pdf. Retrieved 6 January 2023. 
  151. ↑ Herron, Abigail J., Brennan, Tim K. eds. ASAM Essentials of Addiction Medicine, The. 3rd Edition. Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103 USA:Lippincott Williams & Wilkins; 2020.[page needed]



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