View source for Naltrexone

{{Short description|Medication}}
{{Distinguish|Naloxone|Nalmexone}}
{{Redirect|Revia|the cantillation mark|Revia (Hebrew cantillation mark)}}
{{Use dmy dates|date=November 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 464372546
| image = Naltrexone_skeletal.svg
| image_class = skin-invert-image
| width = 200
| alt = 
| image2 = Naltrexone-from-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| width2 = 250
| alt2 = 
| caption = <!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|n|æ|l|ˈ|t|r|ɛ|k|s|oʊ|n}}
| tradename = Revia, Vivitrol, Depade, others
| Drugs.com = {{drugs.com|monograph|naltrexone}}
| MedlinePlus = a685041
| DailyMedID = Naltrexone
| pregnancy_AU = B3
| pregnancy_AU_comment = 
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection|intramuscular]], [[subcutaneous implant]]
| class = 
| ATC_prefix = N07
| ATC_suffix = BB04
| ATC_supplemental = <!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>
| legal_BR = C1
| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="ReviaLabel" /><ref name="ContraveLabel" /><ref name="VivitrolLabel" />
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = Rx-only

<!-- Pharmacokinetic data -->| bioavailability = 5–60%<ref name="pmid2836152" /><ref name="pmid19537999" />
| protein_bound = 20%<ref name="pmid2836152" /><ref name="ReviaLabel" />
| metabolism = [[Liver]] (non-[[cytochrome P450|CYP450]])<ref name="SevarinoKosten2009">{{cite book | veditors = Dean RL, Bilsky EJ, Negus SS | title = Opiate Receptors and Antagonists | vauthors = Sevarino KA, Kosten TR | chapter = Naltrexone for Initiation and Maintenance of Opiate Abstinence | date = 2009 | pages = 227–245 | publisher = Humana Press | doi = 10.1007/978-1-59745-197-0_12 | isbn = 978-1-58829-881-2| url = }}</ref>
| metabolites = [[6β-Naltrexol]], others<ref name="pmid2836152" />
| onset = 30 minutes<ref name=AHFS2017/>
| elimination_half-life = Oral (Revia):<ref name="ReviaLabel">{{cite web | title=Revia (naltrexone hydrochloride tablets USP50 mgOpioid Antagonist | website=DailyMed | date=24 April 2015 | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=172953 | access-date=13 June 2022 | archive-date=14 June 2022 | archive-url=https://web.archive.org/web/20220614045520/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=172953 | url-status=live }}</ref><br />• Naltrexone: 4 hours<br />• [[6β-Naltrexol]]: 13 hours<br />Oral (Contrave):<ref name="ContraveLabel">{{cite web | title=Contrave Extended-Release – naltrexone hydrochloride and bupropion hydrochloride tablet, extended release | website=DailyMed | date=4 November 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b | access-date=13 June 2022 | archive-date=4 June 2020 | archive-url=https://web.archive.org/web/20200604190921/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b | url-status=live }}</ref><br />• Naltrexone: 5 hours<br />{{Abbrlink|IM|Intramuscular injection}} (Vivitrol):<ref name="VivitrolLabel">{{cite web | title=Vivitrol- naltrexone kit | website=DailyMed | date=10 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd11c435-b0f0-4bb9-ae78-60f101f3703f | access-date=13 June 2022 | archive-date=30 May 2022 | archive-url=https://web.archive.org/web/20220530151413/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd11c435-b0f0-4bb9-ae78-60f101f3703f | url-status=live }}</ref><br />• Naltrexone: 5–10 days<br />• 6β-Naltrexol: 5–10 days
| duration_of_action = >72 hours<ref name="pmid2836152" /><ref name="ColasantiLingford-HughesNutt2013" /><ref name="pmid2839637" />
| excretion = [[Urine]]<ref name="ReviaLabel" />

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 16590-41-3
| CAS_supplemental = 
| PubChem = 5360515
| IUPHAR_ligand = 1639
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00704
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4514524
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 5S6W795CQM
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D05113
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7465
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 19019
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = EN-1639A; UM-792; ALKS-6428; ''N''-cyclopropylmethylnoroxymorphone; ''N''-cyclopropylmethyl-14-hydroxydihydromorphinone; 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one

<!-- Chemical and physical data -->| IUPAC_name = (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1''H''-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one
| C = 20
| H = 23
| N = 1
| O = 4
| SMILES = O=C4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)CC6CC6
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19+,20-/m1/s1
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DQCKKXVULJGBQN-XFWGSAIBSA-N
| density = 
| density_notes = 
| melting_point = 169
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}
<!-- Definition and medical uses -->

'''Naltrexone''', sold under the brand name '''Revia''' among others, is a [[medication]] primarily used to manage [[alcohol use disorder|alcohol use]] or [[opioid use disorder]] by reducing [[craving (withdrawal)|cravings]] and feelings of [[euphoria]] associated with [[substance use disorder]].<ref name="AHFS2017" /> It has also been found effective in the treatment of other [[Addiction|addictions]] and may be used for them [[off-label use|off-label]].<ref name="pmid27401883" /> An opioid-dependent person should not receive naltrexone before [[drug detoxification|detoxification]].<ref name="AHFS2017" /> It is taken [[Oral administration|orally]] or by [[intramuscular|injection into a muscle]].<ref name="AHFS2017" /> Effects begin within 30 minutes,<ref name="AHFS2017" /> though a decreased desire for opioids may take a few weeks to occur.<ref name="AHFS2017" />

<!-- Side effects and mechanism -->
Side effects may include [[trouble sleeping]], [[anxiety]], [[nausea]], and [[headache]]s.<ref name=AHFS2017/> In those still on opioids, [[opioid withdrawal]] may occur.<ref name=AHFS2017/> Use is not recommended in people with [[liver failure]].<ref name=AHFS2017/> It is unclear if use is safe during [[pregnancy]].<ref name=AHFS2017/><ref>{{cite journal | vauthors = Tran TH, Griffin BL, Stone RH, Vest KM, Todd TJ | title = Methadone, Buprenorphine, and Naltrexone for the Treatment of Opioid Use Disorder in Pregnant Women | journal = Pharmacotherapy | volume = 37 | issue = 7 | pages = 824–839 | date = July 2017 | pmid = 28543191 | doi = 10.1002/phar.1958 | s2cid = 13772333 }}</ref> Naltrexone is an [[opioid antagonist]] and works by blocking the effects of [[opioid]]s, including both opioid drugs as well as [[endorphins|opioids naturally produced in the brain]].<ref name=AHFS2017>{{cite web|title=Naltrexone Monograph for Professionals |url=https://www.drugs.com/monograph/naltrexone.html|website=Drugs.com|publisher=American Society of Health-System Pharmacists|access-date=9 November 2017|url-status=live|archive-url=https://web.archive.org/web/20171109134845/https://www.drugs.com/monograph/naltrexone.html|archive-date=9 November 2017}}</ref>

<!-- History and culture -->
Naltrexone was first made in 1965 and was approved for medical use in the United States in 1984.<ref name=AHFS2017/><ref name=Sad2012>{{cite book| vauthors = Sadock BJ, Sadock VA, Sussman N |title=Kaplan & Sadock's Pocket Handbook of Psychiatric Drug Treatment|date=2012|publisher=Lippincott Williams & Wilkins|isbn=978-1451154467|page=265|url=https://books.google.com/books?id=qp-H3UruKvIC&pg=PT265|language=en|url-status=live|archive-url=https://web.archive.org/web/20171205042100/https://books.google.ca/books?id=qp-H3UruKvIC&pg=PT265|archive-date=5 December 2017}}</ref> Naltrexone, as [[naltrexone/bupropion]] (brand name Contrave), is also used to treat [[obesity]].<ref>{{cite journal | vauthors = <!-- No authors listed --> | title = Naltrexone/bupropion for obesity | journal = Drug and Therapeutics Bulletin | volume = 55 | issue = 11 | pages = 126–129 | date = November 2017 | pmid = 29117992 | doi = 10.1136/dtb.2017.11.0550 | s2cid = 547660 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list  | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = WHO | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2021, it was the 254th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Naltrexone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Naltrexone | access-date = 14 January 2024}}</ref>
{{TOC limit}}

==Medical uses==

===Alcohol use disorder===
Naltrexone has been best studied as a treatment for [[alcoholism]].<ref name="pmid27401883">{{cite journal | vauthors = Aboujaoude E, Salame WO | title = Naltrexone: A Pan-Addiction Treatment? | journal = CNS Drugs | volume = 30 | issue = 8 | pages = 719–733 | date = August 2016 | pmid = 27401883 | doi = 10.1007/s40263-016-0373-0 | s2cid = 6372144 }}</ref> Naltrexone has been shown to decrease the quantity and frequency of [[ethanol]] consumption by reducing the dopamine release from the brain after consuming alcohol.<ref name = "Spencer_2023">{{cite journal | vauthors = Spencer CN, Elton A, Dove S, Faulkner ML, Robinson DL, Boettiger CA |date= September 2023 |title=Naltrexone engages a brain reward network in the presence of reward-predictive distractor stimuli in males |journal=Addiction Neuroscience |language=en |volume=7 |pages=100085 |doi=10.1016/j.addicn.2023.100085 |pmid= 37424633 |pmc= 10328541 |s2cid= 257919116 |issn=2772-3925 }}</ref><ref>{{cite journal | vauthors = Spanagel R, Weiss F | title = The dopamine hypothesis of reward: past and current status | journal = Trends in Neurosciences | volume = 22 | issue = 11 | pages = 521–527 | date = November 1999 | pmid = 10529820 | doi = 10.1016/s0166-2236(99)01447-2 | s2cid = 35758115 }}</ref><ref name=Ros2010>{{cite journal | vauthors = Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M | title = Opioid antagonists for alcohol dependence | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD001867 | date = December 2010 | pmid = 21154349 | doi = 10.1002/14651858.CD001867.pub2 | veditors = Srisurapanont M }}</ref> It does not appear to change the percentage of people drinking.<ref>{{cite journal | vauthors = Donoghue K, Elzerbi C, Saunders R, Whittington C, Pilling S, Drummond C | title = The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis | journal = Addiction | volume = 110 | issue = 6 | pages = 920–930 | date = June 2015 | pmid = 25664494 | doi = 10.1111/add.12875 | url = http://findings.org.uk/PHP/dl.php?file=Donoghue_K_1.txt&s=eb | access-date = 15 April 2019 | url-status = live | archive-url = https://web.archive.org/web/20190415034450/https://findings.org.uk/PHP/dl.php?file=Donoghue_K_1.txt&s=eb | archive-date = 15 April 2019 | url-access = subscription }}</ref> Its overall benefit has been described as "modest".<ref>{{cite journal | vauthors = Garbutt JC | title = Efficacy and tolerability of naltrexone in the management of alcohol dependence | journal = Current Pharmaceutical Design | volume = 16 | issue = 19 | pages = 2091–2097 | year = 2010 | pmid = 20482515 | doi = 10.2174/138161210791516459 }}</ref><ref name = "Spencer_2023" /><ref name="Clinical and biological moderators">{{cite journal | vauthors = Garbutt JC, Greenblatt AM, West SL, Morgan LC, Kampov-Polevoy A, Jordan HS, Bobashev GV | title = Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence | journal = Addiction | volume = 109 | issue = 8 | pages = 1274–1284 | date = August 2014 | pmid = 24661324 | doi = 10.1111/add.12557 }}</ref><ref name="pmid20201811"/>

[[Acamprosate]] may work better than naltrexone for eliminating alcohol abuse, while naltrexone may decrease the desire for [[alcohol (drug)|alcohol]] to a greater extent.<ref name=Mai2013>{{cite journal | vauthors = Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW | title = Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? | journal = Addiction | volume = 108 | issue = 2 | pages = 275–293 | date = February 2013 | pmid = 23075288 | pmc = 3970823 | doi = 10.1111/j.1360-0443.2012.04054.x }}</ref>

A method pioneered by scientist John David Sinclair (dubbed commercially the “Sinclair Method”) advocates for “pharmacological extinction” of problem drinking behavior by administering naltrexone alongside controlled alcohol consumption. In effect, he argues 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 them
found any significant benefit of naltrexone over placebo when combined with support for abstinence."<ref name="Sin2001">{{cite journal |vauthors=Sinclair JD |year=2001 |title=Evidence about the use of naltrexone and for different ways of using it in the treatment of alcoholism |journal=Alcohol and Alcoholism |volume=36 |issue=1 |pages=2–10 |doi=10.1093/alcalc/36.1.2 |pmid=11139409 |doi-access=free}}</ref>

===Opioid use disorder===
Long-acting injectable naltrexone (under the brand name '''Vivitrol''') is an [[opioid antagonist]], blocking the effects of [[heroin]] and other [[Opioid|opioids]], and decreases heroin use compared to a placebo.<ref name=Shar2017>{{cite journal | vauthors = Sharma A, Kelly SM, Mitchell SG, Gryczynski J, O'Grady KE, Schwartz RP | title = Update on Barriers to Pharmacotherapy for Opioid Use Disorders | journal = Current Psychiatry Reports | volume = 19 | issue = 6 | pages = 35 | date = June 2017 | pmid = 28526967 | pmc = 7075636 | doi = 10.1007/s11920-017-0783-9 }}</ref> Unlike [[methadone]] and [[buprenorphine]], it is not a controlled medication.<ref name=Shar2017/> 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.<ref name=AHFS2017/><ref>{{cite journal | vauthors = Sharma B, Bruner A, Barnett G, Fishman M | title = Opioid Use Disorders | journal = Child and Adolescent Psychiatric Clinics of North America | volume = 25 | issue = 3 | pages = 473–487 | date = July 2016 | pmid = 27338968 | pmc = 4920977 | doi = 10.1016/j.chc.2016.03.002 }}</ref><ref name="Wakeman_2020" /> It is given once per month and has better [[Compliance (medicine)|compliance]] and effect for opioid use than the oral formulation.<ref name="ComerSullivan2006">{{cite journal | vauthors = Comer SD, Sullivan MA, Yu E, Rothenberg JL, Kleber HD, Kampman K, Dackis C, O'Brien CP | title = Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial | journal = Archives of General Psychiatry | volume = 63 | issue = 2 | pages = 210–218 | date = February 2006 | pmid = 16461865 | pmc = 4200530 | doi = 10.1001/archpsyc.63.2.210 }}</ref>

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.<ref name="pmid31062259">{{cite journal | vauthors = Shulman M, Wai JM, Nunes EV | title = Buprenorphine Treatment for Opioid Use Disorder: An Overview | journal = CNS Drugs | volume = 33 | issue = 6 | pages = 567–580 | date = June 2019 | pmid = 31062259 | pmc = 6585403 | doi = 10.1007/s40263-019-00637-z }}</ref> Among patients able to successfully initiate injectable naltrexone, long-term remission rates were similar to those seen in clinical buprenorphine/naloxone administration.<ref name="Comparative effectiveness of extend">{{cite journal | vauthors = Lee JD, Nunes EV, Novo P, Bachrach K, Bailey GL, Bhatt S, Farkas S, Fishman M, Gauthier P, Hodgkins CC, King J, Lindblad R, Liu D, Matthews AG, May J, Peavy KM, Ross S, Salazar D, Schkolnik P, Shmueli-Blumberg D, Stablein D, Subramaniam G, Rotrosen J | title = Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial | journal = Lancet | volume = 391 | issue = 10118 | pages = 309–318 | date = January 2018 | pmid = 29150198 | pmc = 5806119 | doi = 10.1016/S0140-6736(17)32812-X }}</ref> 

The consequence of relapse when weighing the best course of treatment for opiate use disorder remains a concern. Methadone and buprenorphine administration maintain greater [[drug tolerance]] while naltrexone allows tolerance to fade, leading to higher instances of an overdose in people who relapse and thus higher [[Mortality rate|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.<ref>{{cite book |title=Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence |date=2009 |publisher=World Health Organization |isbn=978-92-4-154754-3 |url=https://www.who.int/publications/i/item/9789241547543 |access-date=28 September 2022 |archive-date=28 September 2022 |archive-url=https://web.archive.org/web/20220928174406/https://www.who.int/publications/i/item/9789241547543 |url-status=live }}{{page needed|date=September 2022}}</ref>

A 2011 review found insufficient evidence to determine the effect of naltrexone taken orally on opioid dependence.<ref>{{cite journal | vauthors = Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A | title = Oral naltrexone maintenance treatment for opioid dependence | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 4 | pages = CD001333 | date = April 2011 | pmid = 21491383 | pmc = 7045778 | doi = 10.1002/14651858.CD001333.pub4 | veditors = Minozzi S }}</ref> 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 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 additional [[contingency management]] support, naltrexone may be effective in a broader population.<ref>{{cite journal | vauthors = Johansson BA, Berglund M, Lindgren A | title = Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review | journal = Addiction | volume = 101 | issue = 4 | pages = 491–503 | date = April 2006 | pmid = 16548929 | doi = 10.1111/j.1360-0443.2006.01369.x }}</ref>

===Others===
Unlike [[varenicline]] (brand name Chantix), naltrexone is not useful for [[smoking cessation|quitting smoking]].<ref>{{cite journal | vauthors = David SP, Lancaster T, Stead LF, Evins AE, Prochaska JJ | title = Opioid antagonists for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 6 | issue = 6 | pages = CD003086 | date = June 2013 | pmid = 23744347 | pmc = 4038652 | doi = 10.1002/14651858.CD003086.pub3 }}</ref> Naltrexone has also been under investigation for reducing [[Behavioral addiction|behavioral addictions]] such as gambling, [[Self-harm|NSSID]] (non-suicidal self-injury disorder), and [[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.<ref>{{cite journal | vauthors = Mouaffak F, Leite C, Hamzaoui S, Benyamina A, Laqueille X, Kebir O | title = Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials | journal = European Addiction Research | volume = 23 | issue = 4 | pages = 204–210 | date = 2017 | pmid = 28877518 | doi = 10.1159/000480539 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ryback RS | title = Naltrexone in the treatment of adolescent sexual offenders | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 7 | pages = 982–986 | date = July 2004 | pmid = 15291688 | doi = 10.4088/jcp.v65n0715 }}</ref>

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 [[Chronic fatigue syndrome|ME/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.<ref name="Low dose naltrexone - MEpedia">{{cite web | url=https://me-pedia.org/wiki/Low_dose_naltrexone | title=Low dose naltrexone | publisher=MEpedia | access-date=24 September 2022 | archive-date=24 September 2022 | archive-url=https://web.archive.org/web/20220924165641/https://me-pedia.org/wiki/Low_dose_naltrexone | url-status=live }}</ref>  LDN is also being considered as a potential treatment for [[long COVID]].<ref name="Safety and efficacy of low dose nal">{{cite journal | vauthors = O'Kelly B, Vidal L, McHugh T, Woo J, Avramovic G, Lambert JS | title = Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study | journal = Brain, Behavior, & Immunity – Health | volume = 24 | pages = 100485 | date = October 2022 | pmid = 35814187 | pmc = 9250701 | doi = 10.1016/j.bbih.2022.100485 }}</ref>

===Available forms===
{{See also|Bupropion/naltrexone|Morphine/naltrexone|Buprenorphine/naltrexone}}

Naltrexone is available and most commonly used in the form of an [[oral administration|oral]] [[tablet (pharmacy)|tablet]] (50&nbsp;mg).<ref name="Milhorn2017" /> Vivitrol, a naltrexone formulation for [[depot injection]] containing 380&nbsp;mg of the medication per vial, is also available.<ref name="Milhorn2017" /><ref name="MedicalNewsToday2006">"{{cite web | url = http://www.medicalnewstoday.com/articles/41707.php | title = Alcoholism Once A Month Injectable Drug, Vivitrol, Approved By FDA | archive-url = https://web.archive.org/web/20090105124047/http://www.medicalnewstoday.com/articles/41707.php | archive-date= 5 January 2009 | work = Medical News Today | date = 16 April 2006 }}</ref> Additionally, naltrexone [[subcutaneous implant]]s that are surgically implanted are available.<ref name=TGA>{{cite web | url = https://www.ebs.tga.gov.au/ebs/ANZTPAR/PublicWeb.nsf/cuMedicines?OpenView | title = Australian Register of Therapeutic Goods Medicines | access-date = 22 March 2009 | author = Therapeutic Goods Administration | format = Online database of approved medicines | url-status = live | archive-url = https://web.archive.org/web/20090514095145/https://www.ebs.tga.gov.au/ebs/ANZTPAR/PublicWeb.nsf/cuMedicines?OpenView | archive-date = 14 May 2009 }}</ref> While these are manufactured in Australia, they are not authorized for use within Australia, but only for export.<ref>{{cite web | url = https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs%2FPublicHTML%2FpdfStore.nsf&docid=12AA89E8C8E53B46CA257FA7004211EE&agid=(PrintDetailsPublic)&actionid=1 | title = Australian Register of Therapeutic Goods Medicines | access-date = 27 April 2017 | author = Therapeutic Goods Administration | format = Online database of approved medicines, specific entry for "O'Neil Long Acting Naltrexone Implant" }} {{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> By 2009, naltrexone implants showed superior efficacy in the treatment of heroin dependence when compared to the oral form.<ref>{{cite journal | vauthors = Hulse GK, Morris N, Arnold-Reed D, Tait RJ | title = Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone | journal = Archives of General Psychiatry | volume = 66 | issue = 10 | pages = 1108–1115 | date = October 2009 | pmid = 19805701 | doi = 10.1001/archgenpsychiatry.2009.130 | doi-access = free }}</ref>

==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]].<ref name="ReviaLabel" /> 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:<ref name="ReviaLabel" />

* Greater than 10%: [[difficulty sleeping]], [[anxiety]], [[wikt:nervousness|nervousness]], [[abdominal pain]]/[[abdominal cramp|cramp]]s, [[nausea]] and/or [[vomiting]], [[low energy]], [[joint pain|joint]]/[[muscle pain]], and [[headache]].<ref name="ReviaLabel" />
* Less than 10%: [[loss of appetite]], [[diarrhea]], [[constipation]], [[thirst]]iness, increased energy, [[low mood|feeling down]], [[irritability]], [[dizziness]], [[skin rash]], [[delayed ejaculation]], [[erectile dysfunction]], and [[chills]].<ref name="ReviaLabel" />
* A variety of other adverse events have also been reported with less than 1% incidence.<ref name="ReviaLabel" />

===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.<ref name="galanter">{{cite book | veditors = Galanter M, Kleber HD |title=The American Psychiatric Publishing Textbook of Substance Abuse Treatment |date=2008 |publisher=American Psychiatric |isbn=978-1-58562-276-4 }}{{page needed|date=January 2017}}</ref>

===Adverse effects===
Whether naltrexone causes [[dysphoria]], [[depression (mood)|depression]], [[anhedonia]], or other aversive effects has been studied and reviewed.<ref name="pmid12028745">{{cite journal | vauthors = Miotto K, McCann M, Basch J, Rawson R, Ling W | title = Naltrexone and dysphoria: fact or myth? | journal = The American Journal on Addictions | volume = 11 | issue = 2 | pages = 151–160 | date = 2002 | pmid = 12028745 | doi = 10.1080/10550490290087929 }}</ref><ref name="StrainStitzer2006">{{cite book| vauthors = Strain EC, Stitzer ML |title=The Treatment of Opioid Dependence|url=https://books.google.com/books?id=timYFx278CUC&pg=PA296|year=2006|publisher=JHU Press|isbn=978-0-8018-8219-7|pages=296–|access-date=2 June 2021|archive-date=2 June 2021|archive-url=https://web.archive.org/web/20210602233938/https://books.google.com/books?id=timYFx278CUC&pg=PA296|url-status=live}}</ref><ref name="pmid21951371">{{cite journal | vauthors = Nathan PJ, O'Neill BV, Napolitano A, Bullmore ET | title = Neuropsychiatric adverse effects of centrally acting antiobesity drugs | journal = CNS Neuroscience & Therapeutics | volume = 17 | issue = 5 | pages = 490–505 | date = October 2011 | pmid = 21951371 | pmc = 6493804 | doi = 10.1111/j.1755-5949.2010.00172.x }}</ref><ref name="pmid27436632">{{cite journal | vauthors = Krupitsky E, Zvartau E, Blokhina E, Verbitskaya E, Wahlgren V, Tsoy-Podosenin M, Bushara N, Burakov A, Masalov D, Romanova T, Tyurina A, Palatkin V, Yaroslavtseva T, Pecoraro A, Woody G | title = Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant | journal = The American Journal of Drug and Alcohol Abuse | volume = 42 | issue = 5 | pages = 614–620 | date = September 2016 | pmid = 27436632 | pmc = 5156574 | doi = 10.1080/00952990.2016.1197231 }}</ref> 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 (medical)|fatigue]], loss of energy, [[sleepiness]], mild [[dysphoria]], [[depression (mood)|depression]], [[lightheadedness]], [[faintness]], [[confusion]], [[nausea]], [[gastrointestinal disturbance]]s, [[sweating]], and occasional [[derealization]].<ref name="pmid21951371" /><ref name="pmid219434">{{cite journal | vauthors = Mendelson JH, Ellingboe J, Keuhnle JC, Mello NK | title = Effects of naltrexone on mood and neuroendocrine function in normal adult males | journal = Psychoneuroendocrinology | volume = 3 | issue = 3–4 | pages = 231–236 | date = October 1978 | pmid = 219434 | doi = 10.1016/0306-4530(78)90013-6 | s2cid = 7712730 }}</ref><ref name="pmid7297411">{{cite journal | vauthors = Hollister LE, Johnson K, Boukhabza D, Gillespie HK | title = Aversive effects of naltrexone in subjects not dependent on opiates | journal = Drug and Alcohol Dependence | volume = 8 | issue = 1 | pages = 37–41 | date = August 1981 | pmid = 7297411 | doi = 10.1016/0376-8716(81)90084-3 }}</ref><ref name="pmid2992300">{{cite journal | vauthors = Crowley TJ, Wagner JE, Zerbe G, Macdonald M | title = Naltrexone-induced dysphoria in former opioid addicts | journal = The American Journal of Psychiatry | volume = 142 | issue = 9 | pages = 1081–1084 | date = September 1985 | pmid = 2992300 | doi = 10.1176/ajp.142.9.1081 }}</ref><ref name="pmid3593812">{{cite journal | vauthors = Malcolm R, O'Neil PM, Von JM, Dickerson PC | title = Naltrexone and dysphoria: a double-blind placebo controlled trial | journal = Biological Psychiatry | volume = 22 | issue = 6 | pages = 710–716 | date = June 1987 | pmid = 3593812 | doi = 10.1016/0006-3223(87)90202-2 | s2cid = 39628172 }}</ref> However, these studies were small, often uncontrolled, and used subjective means of assessing side effects.<ref name="pmid3593812" /><ref name="pmid12028745" /> 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.<ref name="pmid21951371"/><ref name="pmid17110818">{{cite journal | vauthors = Pettinati HM, O'Brien CP, Rabinowitz AR, Wortman SP, Oslin DW, Kampman KM, Dackis CA | title = The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 6 | pages = 610–625 | date = December 2006 | pmid = 17110818 | doi = 10.1097/01.jcp.0000245566.52401.20 | s2cid = 35171287 }}</ref><ref name="pmid3593812" /> According to one source:<ref name="StrainStitzer2006" />

: 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.<ref name="pmid12028745" /><ref name="StrainStitzer2006" /><ref name="pmid21951371" /><ref name="pmid27436632" /> 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.<ref name="pmid21951371" /><ref name="pmid12028745" /> For example, marked [[receptor upregulation|upregulation]] of opioid receptors and hyper-sensitivity to opioids have been observed with naltrexone in [[preclinical research|preclinical studies]].<ref name="pmid2836152">{{cite journal | vauthors = Gonzalez JP, Brogden RN | title = Naltrexone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence | journal = Drugs | volume = 35 | issue = 3 | pages = 192–213 | date = March 1988 | pmid = 2836152 | doi = 10.2165/00003495-198835030-00002 | s2cid = 195697174 }}</ref><ref name="pmid12028745" /><ref name="pmid21768981" /> 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 [[psychological stress|stress]].<ref name="pmid21768981" /> 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.<ref name="pmid12028745" /><ref name="pmid21768981" /> It is notable in this regard that most studies of naltrexone have been in people with substance dependence.<ref name="pmid12028745" />

Naltrexone may also initially produce [[opioid withdrawal]]-like symptoms in a small subset of people not dependent on opioids:<ref name="pmid8742771">{{cite journal | vauthors = Rounsaville BJ | title = Can psychotherapy rescue naltrexone treatment of opioid addiction? | journal = NIDA Research Monograph | volume = 150 | issue =  | pages = 37–52 | date = 1995 | pmid = 8742771 | doi =  | url = https://archives.drugabuse.gov/sites/default/files/monograph150.pdf#page=43 | access-date = 31 October 2021 | url-status = live | archive-url = https://web.archive.org/web/20220119134913/https://archives.drugabuse.gov/sites/default/files/monograph150.pdf#page=43 | archive-date = 19 January 2022 }}</ref>

: 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 [[drug discontinuation|drop out]] of treatment.<ref name="pmid30300800">{{cite journal | vauthors = Carroll KM, Nich C, Frankforter TL, Yip SW, Kiluk BD, DeVito EE, Sofuoglu M | title = Accounting for the uncounted: Physical and affective distress in individuals dropping out of oral naltrexone treatment for opioid use disorder | journal = Drug and Alcohol Dependence | volume = 192 | issue =  | pages = 264–270 | date = November 2018 | pmid = 30300800 | pmc = 6203294 | doi = 10.1016/j.drugalcdep.2018.08.019 }}</ref><ref name="pmid12028745" /><ref name="pmid8742771" />

Naltrexone has been reported to reduce feelings of [[social connection]].<ref name="pmid31414860">{{cite journal | vauthors = Inagaki TK, Hazlett LI, Andreescu C | title = Opioids and social bonding: Effect of naltrexone on feelings of social connection and ventral striatum activity to close others | journal = Journal of Experimental Psychology. General | volume = 149 | issue = 4 | pages = 732–745 | date = April 2020 | pmid = 31414860 | pmc = 7021584 | doi = 10.1037/xge0000674 }}</ref><ref name="pmid30976797">{{cite journal | vauthors = Inagaki TK, Hazlett LI, Andreescu C | title = Naltrexone alters responses to social and physical warmth: implications for social bonding | journal = Social Cognitive and Affective Neuroscience | volume = 14 | issue = 5 | pages = 471–479 | date = May 2019 | pmid = 30976797 | pmc = 6545530 | doi = 10.1093/scan/nsz026 }}</ref><ref name="pmid26796966">{{cite journal | vauthors = Inagaki TK, Ray LA, Irwin MR, Way BM, Eisenberger NI | title = Opioids and social bonding: naltrexone reduces feelings of social connection | journal = Social Cognitive and Affective Neuroscience | volume = 11 | issue = 5 | pages = 728–735 | date = May 2016 | pmid = 26796966 | pmc = 4847702 | doi = 10.1093/scan/nsw006 }}</ref><ref name="pmid27588701">{{cite journal | vauthors = Meier IM, Bos PA, Hamilton K, Stein DJ, van Honk J, Malcolm-Smith S | title = Naltrexone increases negatively-valenced facial responses to happy faces in female participants | journal = Psychoneuroendocrinology | volume = 74 | issue =  | pages = 65–68 | date = December 2016 | pmid = 27588701 | doi = 10.1016/j.psyneuen.2016.08.022 | hdl = 1874/339404 | s2cid = 40097592 | hdl-access = free }}</ref> The μ-opioid receptor has been found to play a major role in social reward in animals and the μ-opioid receptor [[knockout mouse]] is an [[animal model]] of [[autism]].<ref name="OddiCrusioD'Amato2013">{{cite journal | vauthors = Oddi D, Crusio WE, D'Amato FR, Pietropaolo S | title = Monogenic mouse models of social dysfunction: implications for autism | journal = Behav Brain Res | volume = 251 | issue = | pages = 75–84 | date = August 2013 | pmid = 23327738 | doi = 10.1016/j.bbr.2013.01.002 | url = }}</ref> Studies on whether naltrexone can decrease the [[pleasure|pleasurable]] effects of listening to [[music]] are conflicting.<ref name="pmid21314752">{{cite journal | vauthors = O'Brien CP, Gastfriend DR, Forman RF, Schweizer E, Pettinati HM | title = Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone | journal = The American Journal on Addictions | volume = 20 | issue = 2 | pages = 106–112 | date = 2011 | pmid = 21314752 | pmc = 3895092 | doi = 10.1111/j.1521-0391.2010.00107.x }}</ref><ref name="pmid28176798">{{cite journal | vauthors = Mallik A, Chanda ML, Levitin DJ | title = Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone | journal = Scientific Reports | volume = 7 | issue =  1| pages = 41952 | date = February 2017 | pmid = 28176798 | pmc = 5296903 | doi = 10.1038/srep41952 | bibcode = 2017NatSR...741952M }}</ref><ref name="pmid33711654">{{cite journal | vauthors = Laeng B, Garvija L, Løseth G, Eikemo M, Ernst G, Leknes S | title = 'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure | journal = Consciousness and Cognition | volume = 90 | issue =  | pages = 103105 | date = April 2021 | pmid = 33711654 | doi = 10.1016/j.concog.2021.103105 | s2cid = 232163311 }}</ref> Besides humans, naltrexone has been found to produce aversive effects in rodents as assessed by [[conditioned place aversion]].<ref name="pmid12028745" />

===Liver damage===
Naltrexone has been reported to cause [[liver damage]] when given at doses higher than recommended.<ref name="pmid20201811" /> It carries an FDA boxed warning for this rare side effect. 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&nbsp;mg of naltrexone.<ref>{{cite journal | vauthors = Pfohl DN, Allen JI, Atkinson RL, Knopman DS, Malcolm RJ, Mitchell JE, Morley JE | title = Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage | journal = NIDA Research Monograph | volume = 67 | pages = 66–72 | year = 1986 | pmid = 3092099 | url = https://archives.drugabuse.gov/pdf/monographs/download67.html | url-status = dead | access-date = 23 January 2017 | archive-url = https://web.archive.org/web/20170121150620/https://archives.drugabuse.gov/pdf/monographs/download67.html | archive-date = 21 January 2017 }}</ref> Subsequent studies have suggested limited or no toxicity in other patient populations and at typical recommended doses such as 50 to 100&nbsp;mg/day.<ref name="pmid20201811" /><ref name="pmid27401883" />

==Overdose==
No [[toxicity|toxic]] effects have been observed with naltrexone in doses of up to 800&nbsp;mg/day in clinical studies.<ref name="pmid2836152" /><ref name="ReviaLabel" /> The largest reported [[overdose]] of naltrexone, which was 1,500&nbsp;mg in a female patient and was equivalent to an entire bottle of medication (30 × 50&nbsp;mg tablets), was uneventful.<ref name="pmid22778191">{{cite journal | vauthors = Reece AS | title = Clinical safety of 1500 mg oral naltrexone overdose | journal = BMJ Case Reports | volume = 2010 | issue =  sep06 1| pages = bcr0420102871 | date = September 2010 | pmid = 22778191 | pmc = 3028212 | doi = 10.1136/bcr.04.2010.2871 }}</ref> No deaths are known to have occurred with naltrexone overdose.<ref name="PettinatiDundonCasares López2013">{{cite book | veditors = Miller PM | title = Interventions for Addiction | vauthors = Pettinati HM, Dundon WD, Casares López MJ | chapter = Naltrexone and Opioid Antagonists for Alcohol Dependence | date = 2013 | pages = 375–384 | publisher = Elsevier | doi = 10.1016/B978-0-12-398338-1.00039-7 | isbn = 978-0-12-398338-1 }}</ref>

==Pharmacology==

===Pharmacodynamics===

====Opioid receptor blockade====
{| class="wikitable floatright" style="text-align: center;"
|+ Naltrexone at human opioid receptors
|-
! colspan="3" | [[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratios || rowspan="2" | Refs
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! MOR:KOR:DOR
|-
| 1.0 nM || 3.9 nM || 149 nM || 1:4:149 || <ref name="pmid8114680">{{cite journal | vauthors = Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T | title = Pharmacological characterization of the cloned κ-, δ-, and μ-opioid receptors | journal = Molecular Pharmacology | volume = 45 | issue = 2 | pages = 330–334 | date = February 1994 | pmid = 8114680 | url = http://molpharm.aspetjournals.org/content/45/2/330.short | access-date = 22 June 2018 | url-status = live | citeseerx = 10.1.1.1076.4629 | id = {{INIST|3935705}} | archive-url = https://web.archive.org/web/20180622111441/http://molpharm.aspetjournals.org/content/45/2/330.short | archive-date = 22 June 2018 }}</ref>
|-
| 0.0825 nM || 0.509 nM || 8.02 nM || 1:6:97 || <ref name="pmid7562497">{{cite journal | vauthors = Codd EE, Shank RP, Schupsky JJ, Raffa RB | title = Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 274 | issue = 3 | pages = 1263–1270 | date = September 1995 | pmid = 7562497 | url = http://jpet.aspetjournals.org/content/274/3/1263.short | access-date = 23 January 2017 | url-status = live | archive-url = https://web.archive.org/web/20170202020241/http://jpet.aspetjournals.org/content/274/3/1263.short | archive-date = 2 February 2017 }}</ref>
|-
| 0.2 nM || 0.4 nM || 10.8 nM || 1:2:54 || <ref name="pmid9686407">{{cite journal | vauthors = Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS | title = Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications | journal = NIDA Research Monograph | volume = 178 | issue =  | pages = 440–466 | date = March 1998 | pmid = 9686407 | citeseerx = 10.1.1.475.3403 }}</ref><ref name="pmid31376930">{{cite journal | vauthors = Clark SD, Abi-Dargham A | title = The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence | journal = Biological Psychiatry | volume = 86 | issue = 7 | pages = 502–511 | date = October 2019 | pmid = 31376930 | doi = 10.1016/j.biopsych.2019.05.012 | s2cid = 162168648 | doi-access = free }}</ref>
|-
| 0.23 nM || 0.25 nM || 38 nM || 1:1.1:165 || <ref name="pmid17407276">{{cite journal | vauthors = Peng X, Knapp BI, Bidlack JM, Neumeyer JL | title = Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 9 | pages = 2254–2258 | date = May 2007 | pmid = 17407276 | pmc = 3357624 | doi = 10.1021/jm061327z }}</ref><ref name="pmid21768981">{{cite journal | vauthors = Unterwald EM | title = Naltrexone in the treatment of alcohol dependence | journal = Journal of Addiction Medicine | volume = 2 | issue = 3 | pages = 121–127 | date = September 2008 | pmid = 21768981 | doi = 10.1097/ADM.0b013e318182b20f | s2cid = 23603792 }}</ref>
|-
| 0.62 nM || 1.88 nM || 12.3 nM || 1:3:20 || <ref name="pmid23353688">{{cite journal | vauthors = Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin SF, Mitch C, Quimby S, Barth V, Rash K, Masters J, Navarro A, Seest E, Morris ED, Carson RE, Huang Y | title = Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging | journal = Journal of Nuclear Medicine | volume = 54 | issue = 3 | pages = 455–463 | date = March 2013 | pmid = 23353688 | pmc = 3775344 | doi = 10.2967/jnumed.112.109512 }}</ref><ref name="pmid31752279">{{cite journal | vauthors = Cumming P, Marton J, Lilius TO, Olberg DE, Rominger A | title = A Survey of Molecular Imaging of Opioid Receptors | journal = Molecules | volume = 24 | issue = 22 | page = 4190 | date = November 2019 | pmid = 31752279 | pmc = 6891617 | doi = 10.3390/molecules24224190 | doi-access = free }}</ref>
|-
| 0.11 nM || 0.19 nM || 60 nM || 1:1.7:545 || <ref name="pmid15808478">{{cite journal | vauthors = Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack JM | title = Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 8 | pages = 2107–2110 | date = April 2005 | pmid = 15808478 | doi = 10.1016/j.bmcl.2005.02.032 }}</ref><ref name="pmid19282177">{{cite journal | vauthors = Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM | title = Syntheses of novel high affinity ligands for opioid receptors | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 8 | pages = 2289–2294 | date = April 2009 | pmid = 19282177 | pmc = 2791460 | doi = 10.1016/j.bmcl.2009.02.078 }}</ref><ref name="Dwoskin2014">{{cite book | veditors = Dwoskin LP | date = 29 January 2014 | title = Emerging Targets and Therapeutics in the Treatment of Psychostimulant Abuse | publisher = Academic Press | pages = 398– | isbn = 978-0-12-420177-4 | oclc = 1235841274 | url = https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398 | access-date = 30 October 2021 | archive-date = 27 April 2021 | archive-url = https://web.archive.org/web/20210427142317/https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398 | url-status = live }}</ref>
|}

Naltrexone and its [[active metabolite]] [[6β-naltrexol]] are [[competitive antagonist]]s of the [[opioid receptor]]s.<ref name="pmid4600601" /><ref name="pmid17267582" /> 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).<ref name="pmid4600601">{{cite journal | vauthors = Niciu MJ, Arias AJ | title = Targeted opioid receptor antagonists in the treatment of alcohol use disorders | journal = CNS Drugs | volume = 27 | issue = 10 | pages = 777–787 | date = October 2013 | pmid = 23881605 | pmc = 4600601 | doi = 10.1007/s40263-013-0096-4 }}</ref> However, naltrexone is not actually a [[silent antagonist]] of these receptors but instead acts as a weak [[partial agonist]], with [[intrinsic activity|E<sub>max</sub>]] values of 14 to 29% at the MOR, 16 to 39% at the KOR, and 14 to 25% at the DOR in different studies.<ref name="pmid17267582">{{cite journal | vauthors = Wang D, Sun X, Sadee W | title = Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist pretreatment | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 321 | issue = 2 | pages = 544–552 | date = May 2007 | pmid = 17267582 | doi = 10.1124/jpet.106.118810 | s2cid = 28500012 }}</ref><ref name="pmid19282177" /><ref name="Dwoskin2014" /> 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.<ref name="pmid2836152" />

By itself, naltrexone acts as an antagonist or weak partial agonist of the opioid receptors.<ref name="pmid17267582" /> In combination with agonists of the MOR such as [[morphine]] however, naltrexone appears to become an [[inverse agonist]] of the MOR.<ref name="pmid17267582" /> Conversely, the naltrexone remains a neutral antagonist (or weak partial agonist) of the KOR and DOR.<ref name="pmid17267582" /> In contrast to naltrexone, 6β-naltrexol is purely a neutral antagonist of the opioid receptors.<ref name="pmid15680308" /> The MOR inverse agonism of naltrexone, when it is co-present with MOR agonists, may in part underlie its ability to precipitate [[opioid withdrawal|withdrawal]] in [[opioid dependence|opioid-dependent]] individuals.<ref name="pmid15680308">{{cite journal | vauthors = Sadée W, Wang D, Bilsky EJ | title = Basal opioid receptor activity, neutral antagonists, and therapeutic opportunities | journal = Life Sciences | volume = 76 | issue = 13 | pages = 1427–1437 | date = February 2005 | pmid = 15680308 | doi = 10.1016/j.lfs.2004.10.024 }}</ref><ref name="pmid17267582" /> This may be due to suppression of basal MOR signaling via inverse agonism.<ref name="pmid15680308" /><ref name="pmid17267582" />

[[Receptor occupancy|Occupancy]] of the opioid receptors in the brain by naltrexone has been studied using [[positron emission tomography]] (PET).<ref name="pmid20201811" /><ref name="pmid32541931" /> Naltrexone at a dose of 50&nbsp;mg/day has been found to occupy approximately 90 to 95% of brain MORs and 20 to 35% of brain DORs.<ref name="pmid20201811">{{cite journal | vauthors = Ray LA, Chin PF, Miotto K | title = Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics | journal = CNS & Neurological Disorders Drug Targets | volume = 9 | issue = 1 | pages = 13–22 | date = March 2010 | pmid = 20201811 | doi = 10.2174/187152710790966704 }}</ref> Naltrexone at a dose of 100&nbsp;mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies.<ref name="pmid34363128">{{cite book | vauthors = Placzek MS | title = The Kappa Opioid Receptor | chapter = Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography | volume = 271 | pages = 547–577 | date = August 2021 | pmid = 34363128 | doi = 10.1007/164_2021_498 | isbn = 978-3-030-89073-5 | series = Handbook of Experimental Pharmacology | publisher = Springer | location = Cham | s2cid = 236947969 }}</ref><ref name="pmid32541931">{{cite journal | vauthors = de Laat B, Nabulsi N, Huang Y, O'Malley SS, Froehlich JC, Morris ED, Krishnan-Sarin S | title = Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving | journal = Molecular Psychiatry | volume = 26 | issue = 9 | pages = 5053–5060 | date = September 2021 | pmid = 32541931 | doi = 10.1038/s41380-020-0811-8 | s2cid = 219692020 | pmc = 11815980 }}</ref><ref name="VijayMorrisGoldberg2017">{{cite journal | vauthors = Vijay A, Morris E, Goldberg A, Petrulli J, Liu H, Huang Y, Krishnan-Sarin S | title=Naltrexone occupancy at kappa opioid receptors investigated in alcoholics by PET occupancy at kappa opioid receptors investigated in alcoholics by PET | journal=Journal of Nuclear Medicine | volume=58 | issue=Supplement 1 | date=1 April 2017 | pages=1297 | url=https://jnm.snmjournals.org/content/58/supplement_1/1297 | access-date=29 October 2021 | archive-date=29 October 2021 | archive-url=https://web.archive.org/web/20211029050553/https://jnm.snmjournals.org/content/58/supplement_1/1297 | url-status=live }}</ref> Per simulation, a lower dose of naltrexone of 25&nbsp;mg/day might be expected to achieve around 60% brain occupancy of the KOR but still close to 90% occupancy of the MOR.<ref name="pmid32541931" /> In a study of the duration of MOR blockade with naltrexone, the drug with a single 50&nbsp;mg dose showed 91% blockade of brain [[carfentanil|[<sup>11</sup>C]carfentanil]] (a selective MOR ligand) binding at 48&nbsp;hours (2&nbsp;days), 80% blockade at 72&nbsp;hours (3&nbsp;days), 46% blockade at 120&nbsp;hours (5&nbsp;days), and 30% blockade at 168&nbsp;hours (7&nbsp;days).<ref name="ColasantiLingford-HughesNutt2013">{{cite book | veditors = Miller PM | title = Biological Research on Addiction | series = Comprehensive Addictive Behaviors and Disorders | volume = 2 | vauthors = Colasanti A, Lingford-Hughes A, Nutt D | chapter = Opioids Neuroimaging | date = 2013 | pages = 675–687 | publisher = Elsevier | doi = 10.1016/B978-0-12-398335-0.00066-2 | isbn = 9780123983350 | url = }}</ref><ref name="pmid2839637">{{cite journal | vauthors = Lee MC, Wagner HN, Tanada S, Frost JJ, Bice AN, Dannals RF | title = Duration of occupancy of opiate receptors by naltrexone | journal = Journal of Nuclear Medicine | volume = 29 | issue = 7 | pages = 1207–1211 | date = July 1988 | pmid = 2839637 | doi =  | url = https://jnm.snmjournals.org/content/29/7/1207.long | access-date = 29 October 2021 | url-status = live | archive-url = https://web.archive.org/web/20211029203041/https://jnm.snmjournals.org/content/29/7/1207.long | archive-date = 29 October 2021 }}</ref> The half-time of brain MOR blockade by naltrexone in this study was 72 to 108&nbsp;hours (3.0 to 4.5&nbsp;days).<ref name="ColasantiLingford-HughesNutt2013" /><ref name="pmid2839637" /> Based on these findings, doses of naltrexone of even less than 50&nbsp;mg/day would be expected to achieve virtually complete brain MOR occupancy.<ref name="ColasantiLingford-HughesNutt2013" /><ref name="pmid2839637" /> Blockade of brain MORs with naltrexone is much longer-lasting than with other [[opioid antagonist]]s like [[naloxone]] (half-time of ~1.7&nbsp;hours [[intranasal administration|intranasally]]) or [[nalmefene]] (half-time of ~29&nbsp;hours).<ref name="ColasantiLingford-HughesNutt2013" /><ref name="van WaardeAbsalomVisser2020">{{cite book | veditors = Dierckx RA, Otte A, de Vries EF, van Waarde A, Lammertsma AA | title = PET and SPECT of Neurobiological Systems | vauthors = Waarde AV, Absalom AR, Visser AK, Dierckx RA | chapter = Positron Emission Tomography (PET) Imaging of Opioid Receptors | date = 30 September 2020 | pages = 749–807 | publisher = Springer International Publishing | doi = 10.1007/978-3-030-53176-8_21 | isbn = 978-3-030-53175-1 | s2cid = 241535315 | url = https://pure.rug.nl/ws/files/349191745/978_3_030_53176_8.pdf | chapter-url = https://pure.rug.nl/ws/files/349191745/978_3_030_53176_8.pdf | access-date = 21 May 2023 | archive-date = 31 May 2023 | archive-url = https://web.archive.org/web/20230531054330/https://pure.rug.nl/ws/files/349191745/978_3_030_53176_8.pdf | url-status = live }}</ref><ref name="pmid20868291">{{cite journal | vauthors = Soyka M, Rösner S | title = Nalmefene for treatment of alcohol dependence | journal = Expert Opinion on Investigational Drugs | volume = 19 | issue = 11 | pages = 1451–1459 | date = November 2010 | pmid = 20868291 | doi = 10.1517/13543784.2010.522990 | s2cid = 9227860 }}</ref>

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]].<ref name="ColasantiLingford-HughesNutt2013" /><ref name="pmid21731898">{{cite journal | vauthors = Mannelli P, Peindl KS, Wu LT | title = Pharmacological enhancement of naltrexone treatment for opioid dependence: a review | journal = Substance Abuse and Rehabilitation | volume = 2011 | issue = 2 | pages = 113–123 | date = June 2011 | pmid = 21731898 | pmc = 3128868 | doi = 10.2147/SAR.S15853 | doi-access = free }}</ref><ref name="pmid2839637" /><ref name="pmid10463317">{{cite journal | vauthors = Schuh KJ, Walsh SL, Stitzer ML | title = Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans | journal = Psychopharmacology | volume = 145 | issue = 2 | pages = 162–174 | date = July 1999 | pmid = 10463317 | doi = 10.1007/s002130051045 | s2cid = 5930936 }}</ref> A single 50&nbsp;mg oral dose of naltrexone has been found to block brain MORs and opioid effects for at least 48 to 72&nbsp;hours.<ref name="pmid21731898" /><ref name="pmid2839637" /><ref name="DHHS1981">{{cite book|title=Narcotic Antagonists: Naltrexone Pharmacochemistry and Sustained-release Preparations|url=https://books.google.com/books?id=HyVsAAAAMAAJ&pg=PA148|year=1981|publisher=Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, Division of Research|pages=148–|access-date=2 June 2021|archive-date=2 June 2021|archive-url=https://web.archive.org/web/20210602234451/https://books.google.com/books?id=HyVsAAAAMAAJ&pg=PA148|url-status=live}}</ref> The half-time of brain MOR blockade by naltrexone (72–108&nbsp;hours) is much longer than the fast plasma clearance component of naltrexone and 6β-naltrexol (~4–12&nbsp;hours) but was reported to correspond well to the longer terminal phase of plasma naltrexone clearance (96&nbsp;hours).<ref name="ColasantiLingford-HughesNutt2013" /><ref name="pmid2839637" /><ref name="pmid12028745" /> 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 (pharmacology)|affinity]] (<1.0&nbsp;nM).<ref name="pmid20868291" /><ref name="pmid15956985">{{cite journal | vauthors = Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H | title = Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2245–2253 | date = December 2005 | pmid = 15956985 | doi = 10.1038/sj.npp.1300790 | s2cid = 2453226 | doi-access = free }}</ref>

Naltrexone [[opioid antagonist|blocks the effects]] of MOR agonists like [[morphine]], [[heroin]], and [[hydromorphone]] in humans via its MOR antagonism.<ref name="pmid2836152" /><ref name="SevarinoKosten2009" /> Following a single 100&nbsp;mg dose of naltrexone, the subjective and objective effects of heroin were blocked by 90% at 24&nbsp;hours, with blockade then decreasing up to 72&nbsp;hours.<ref name="pmid2836152" /> Similarly, 20 to 200&nbsp;mg naltrexone dose-dependently antagonized the effects of heroin for up to 72&nbsp;hours.<ref name="pmid2836152" /> Naltrexone also [[trip killer|blocks the effects]] of KOR agonists like [[salvinorin A]], [[pentazocine]], and [[butorphanol]] in humans via its KOR antagonism.<ref name="pmid26874330">{{cite journal | vauthors = Maqueda AE, Valle M, Addy PH, Antonijoan RM, Puntes M, Coimbra J, Ballester MR, Garrido M, González M, Claramunt J, Barker S, Lomnicka I, Waguespack M, Johnson MW, Griffiths RR, Riba J | title = Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans | journal = The International Journal of Neuropsychopharmacology | volume = 19 | issue = 7 | pages = pyw016 | date = July 2016 | pmid = 26874330 | pmc = 4966277 | doi = 10.1093/ijnp/pyw016 }}</ref><ref name="pmid17909753">{{cite journal | vauthors = Walsh SL, Chausmer AE, Strain EC, Bigelow GE | title = Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade | journal = Psychopharmacology | volume = 196 | issue = 1 | pages = 143–155 | date = January 2008 | pmid = 17909753 | pmc = 2766188 | doi = 10.1007/s00213-007-0948-z }}</ref><ref name="pmid7679737">{{cite journal | vauthors = Preston KL, Bigelow GE | title = Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 264 | issue = 2 | pages = 813–823 | date = February 1993 | pmid = 7679737 | url = https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7679737 | access-date = 28 September 2022 | archive-date = 28 November 2023 | archive-url = https://web.archive.org/web/20231128061014/https://jpet.aspetjournals.org/content/264/2/813.long | url-status = live }}</ref><ref name="pmid31376930" /> In addition to opioids, naltrexone has been found to block or reduce the rewarding and other effects of other [[euphoriant]] drugs including [[alcohol (drug)|alcohol]],<ref name="pmid21768981" /> [[nicotine]],<ref name="pmid12233982">{{cite journal | vauthors = Modesto-Lowe V, Van Kirk J | title = Clinical uses of naltrexone: a review of the evidence | journal = Experimental and Clinical Psychopharmacology | volume = 10 | issue = 3 | pages = 213–227 | date = August 2002 | pmid = 12233982 | doi = 10.1037/1064-1297.10.3.213 }}</ref> and [[substituted amphetamine|amphetamine]]s.<ref name="pmid30451013">{{cite journal | vauthors = Lam L, Anand S, Li X, Tse ML, Zhao JX, Chan EW | title = Efficacy and safety of naltrexone for amfetamine and methamfetamine use disorder: a systematic review of randomized controlled trials | journal = Clinical Toxicology | volume = 57 | issue = 4 | pages = 225–233 | date = April 2019 | pmid = 30451013 | doi = 10.1080/15563650.2018.1529317 | s2cid = 53951406 }}</ref>

The opioid receptors are involved in [[neuroendocrine]] regulation.<ref name="pmid2836152" /> MOR agonists produce increases in levels of [[prolactin]] and decreases in levels of [[luteinizing hormone]] (LH) and [[testosterone]].<ref name="pmid2836152" /> Doses of naltrexone of 25 to 150&nbsp;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).<ref name="pmid2836152" /> Naltrexone influences the [[hypothalamic–pituitary–adrenal axis]] (HPA axis) probably through interference with opioid receptor signaling by [[endorphin]]s.<ref name="pmid2836152" />

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.<ref name="pmid26845589">{{cite journal | vauthors = Soyka M, Friede M, Schnitker J | title = Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-Analysis | journal = Pharmacopsychiatry | volume = 49 | issue = 2 | pages = 66–75 | date = March 2016 | pmid = 26845589 | doi = 10.1055/s-0035-1565184 | s2cid = 11540631 }}</ref><ref name="pmid27475769">{{cite journal | vauthors = Koob GF, Volkow ND | title = Neurobiology of addiction: a neurocircuitry analysis | journal = The Lancet. Psychiatry | volume = 3 | issue = 8 | pages = 760–773 | date = August 2016 | pmid = 27475769 | pmc = 6135092 | doi = 10.1016/S2215-0366(16)00104-8 }}</ref>

====Other activities====
In addition to the [[opioid receptor]]s, naltrexone binds to and acts as an [[receptor antagonist|antagonist]] of the [[opioid growth factor receptor]] (OGFR) and [[toll-like receptor 4]] (TLR4) and interacts with high- and low-[[affinity (pharmacology)|affinity]] [[binding site]]s in [[FLNA|filamin A]] (FLNA).<ref name="pmid30248938">{{cite journal | vauthors = Toljan K, Vrooman B | title = Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization | journal = Medical Sciences | volume = 6 | issue = 4 | page = 82 | date = September 2018 | pmid = 30248938 | pmc = 6313374 | doi = 10.3390/medsci6040082 | doi-access = free }}</ref><ref name="pmid26022268">{{cite journal | vauthors = Bachtell R, Hutchinson MR, Wang X, Rice KC, Maier SF, Watkins LR | title = Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4 | journal = CNS & Neurological Disorders Drug Targets | volume = 14 | issue = 6 | pages = 692–699 | date = 2015 | pmid = 26022268 | pmc = 5548122 | doi = 10.2174/1871527314666150529132503 }}</ref><ref name="pmid30582992">{{cite journal | vauthors = Lee B, Elston DM | title = The uses of naltrexone in dermatologic conditions | journal = Journal of the American Academy of Dermatology | volume = 80 | issue = 6 | pages = 1746–1752 | date = June 2019 | pmid = 30582992 | doi = 10.1016/j.jaad.2018.12.031 | s2cid = 58595160 }}</ref><ref name="pmid11890982">{{cite journal | vauthors = Zagon IS, Verderame MF, McLaughlin PJ | title = The biology of the opioid growth factor receptor (OGFr) | journal = Brain Research. Brain Research Reviews | volume = 38 | issue = 3 | pages = 351–376 | date = February 2002 | pmid = 11890982 | doi = 10.1016/s0165-0173(01)00160-6 | s2cid = 37812525 }}</ref> It is said that very low doses of naltrexone (<0.001–1&nbsp;mg/day) interact with FLNA, low doses (1 to 5&nbsp;mg/day) produce TLR4 antagonism, and standard clinical doses (50 to 100&nbsp;mg/day) exert opioid receptor and OGFR antagonism.<ref name="pmid30248938" /><ref name="pmid30582992" /> The interactions of naltrexone with FLNA and TLR4 are claimed to be involved in the therapeutic effects of [[low-dose naltrexone]].<ref name="pmid30248938" />

===Pharmacokinetics===
[[File:Naltrexone levels with a 50 mg oral dose of naltrexone at steady state.png|class=skin-invert-image|thumb|right|400px|Naltrexone levels following a 50&nbsp;mg oral dose of naltrexone at [[steady state (pharmacokinetics)|steady state]] during treatment with 50&nbsp;mg/day naltrexone<ref name="pmid15569605">{{cite journal | vauthors = Dean RL | title = The preclinical development of Medisorb Naltrexone, a once a month long acting injection, for the treatment of alcohol dependence | journal = Frontiers in Bioscience | volume = 10 | issue = 1–3 | pages = 643–655 | date = January 2005 | pmid = 15569605 | doi = 10.2741/1559 | doi-access = free }}</ref><ref name="pmid24704710">{{cite journal | vauthors = Goonoo N, Bhaw-Luximon A, Ujoodha R, Jhugroo A, Hulse GK, Jhurry D | title = Naltrexone: a review of existing sustained drug delivery systems and emerging nano-based systems | journal = Journal of Controlled Release | volume = 183 | issue =  | pages = 154–166 | date = June 2014 | pmid = 24704710 | doi = 10.1016/j.jconrel.2014.03.046 }}</ref>]]

[[File:Naltrexone levels following an intramuscular injection of 380 mg naltrexone in microspheres.png|class=skin-invert-image|thumb|right|400px|Naltrexone levels following a 380&nbsp;mg dose of naltrexone in microspheres (Vivitrol) by intramuscular injection at steady state during monthly treatment with 380&nbsp;mg naltrexone in microspheres<ref name="pmid16499489">{{cite journal | vauthors = Dunbar JL, Turncliff RZ, Dong Q, Silverman BL, Ehrich EW, Lasseter KC | title = Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone | journal = Alcoholism: Clinical and Experimental Research | volume = 30 | issue = 3 | pages = 480–490 | date = March 2006 | pmid = 16499489 | doi = 10.1111/j.1530-0277.2006.00052.x }}</ref><ref name="pmid16978037">{{cite journal | vauthors = Swainston Harrison T, Plosker GL, Keam SJ | title = Extended-release intramuscular naltrexone | journal = Drugs | volume = 66 | issue = 13 | pages = 1741–1751 | date = 2006 | pmid = 16978037 | doi = 10.2165/00003495-200666130-00006 | s2cid = 21309382 }}</ref><ref name="pmid17939765">{{cite journal | vauthors = Mannelli P, Peindl K, Masand PS, Patkar AA | title = Long-acting injectable naltrexone for the treatment of alcohol dependence | journal = Expert Review of Neurotherapeutics | volume = 7 | issue = 10 | pages = 1265–1277 | date = October 2007 | pmid = 17939765 | doi = 10.1586/14737175.7.10.1265 | s2cid = 36453900 }}</ref><ref name="Vivitrol2018">{{cite web | title=Vivitrol (naltrexone for extended-release injectable suspension) | website=ALK-VIV | date=28 November 2018 | url=https://www.vivitrolhcp.com/dosing-and-administration | archive-url=https://web.archive.org/web/20211031233914/https://www.vivitrolhcp.com/dosing-and-administration | access-date=31 October 2021| archive-date=31 October 2021 }}</ref>]]

====Absorption====
The [[absorption (pharmacokinetics)|absorption]] of naltrexone with [[oral administration]] is rapid and nearly complete (96%).<ref name="ReviaLabel" /> The [[bioavailability]] of naltrexone with oral administration is 5 to 60% due to extensive [[first-pass metabolism]].<ref name="pmid2836152" /><ref name="pmid19537999">{{cite journal | vauthors = Lee MW, Fujioka K | title = Naltrexone for the treatment of obesity: review and update | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 11 | pages = 1841–1845 | date = August 2009 | pmid = 19537999 | doi = 10.1517/14656560903048959 | s2cid = 207477935 | citeseerx = 10.1.1.496.9477 }}</ref> [[Cmax (pharmacology)|Peak concentrations]] of naltrexone are 19 to 44&nbsp;μg/L after a single 100&nbsp;mg oral dose and [[Tmax (pharmacology)|time to peak concentrations]] of naltrexone and [[6β-naltrexol]] ([[metabolite]]) is within 1&nbsp;hour.<ref name="pmid2836152" /><ref name="pmid19537999" /><ref name="ReviaLabel" /> Linear increases in circulating naltrexone and 6β-naltrexol concentrations occur over an oral dose range of 50 to 200&nbsp;mg.<ref name="pmid2836152" /> 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.<ref name="pmid2836152" />

====Distribution====
The [[plasma protein binding]] of naltrexone is about 20% over a naltrexone concentration range of 0.1 to 500&nbsp;μg/L.<ref name="pmid2836152" /><ref name="ReviaLabel" /> Its apparent [[volume of distribution]] at 100&nbsp;mg orally is 16.1&nbsp;L/kg after a single dose and 14.2&nbsp;L/kg with repeated doses.<ref name="pmid2836152" />

====Metabolism====
Naltrexone is [[metabolism|metabolized]] in the liver mainly by [[dihydrodiol dehydrogenase]]s into [[6β-naltrexol]] (6β-hydroxynaltrexone).<ref name="pmid2836152" /><ref name="pmid19537999" /> Levels of 6β-naltrexol are 10- to 30-fold higher than those of naltrexone with oral administration due to extensive [[first-pass metabolism]].<ref name="DavisGlare2009">{{cite book|vauthors=Davis MP, Glare PA, Hardy J|title=Opioids in Cancer Pain|url=https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA41|date=28 May 2009|publisher=Oxford University Press|isbn=978-0-19-923664-0|pages=41–|access-date=31 October 2021|archive-date=31 October 2021|archive-url=https://web.archive.org/web/20211031063640/https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA41|url-status=live}}</ref> Conversely, 6β-naltrexol exposure is only about 2-fold higher than that of naltrexone with [[intramuscular injection]] of naltrexone in [[microsphere]]s (brand name Vivitrol).<ref name="pmid16499489" /> 6β-Naltrexol is an opioid receptor antagonist similarly to naltrexone and shows a comparable binding profile to the opioid receptors.<ref name="HipkinDolle2010">{{cite book |doi=10.1016/S0065-7743(10)45009-5 |title=Opioid Receptor Antagonists for Gastrointestinal Dysfunction |series=Annual Reports in Medicinal Chemistry |year=2010 | vauthors = Hipkin RW, Dolle RE |volume=45 |pages=142–155 |publisher=Elsevier |isbn=978-0-12-380902-5 }}</ref> However, 6β-naltrexol is [[peripherally selective drug|peripherally selective]] and crosses into the brain much less readily than does naltrexone.<ref name="HipkinDolle2010" /> In any case, 6β-naltrexol does still show some central activity and may contribute significantly to the central actions of oral naltrexone.<ref name="HipkinDolle2010" /><ref name="pmid2836152"/> Other [[metabolite]]s of naltrexone include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxynaltrexone.<ref name="pmid2836152" /> Following their formation, the metabolites of naltrexone are further metabolized by [[conjugation (biochemistry)|conjugation]] with [[glucuronic acid]] to form [[glucuronide]]s.<ref name="pmid2836152" /> Naltrexone is not metabolized by the [[cytochrome P450]] system and has low potential for [[drug interaction]]s.<ref name="SevarinoKosten2009" />

====Elimination====
The [[elimination (pharmacology)|elimination]] of naltrexone is [[exponential decay|biexponential]] and rapid over the first 24&nbsp;hours followed by a third extremely slow decline after 24&nbsp;hours.<ref name="pmid2836152" /> The fast [[elimination half-life|elimination half-lives]] of naltrexone and its metabolite 6β-naltrexol are about 4&nbsp;hours and 13&nbsp;hours, respectively.<ref name="ReviaLabel" /> In Contrave oral tablets, which also contain [[bupropion]] and are described as [[extended-release]], the half-life of naltrexone is 5&nbsp;hours.<ref name="ContraveLabel" /> The slow terminal-phase elimination half-life of naltrexone is approximately 96&nbsp;hours.<ref name="pmid2839637" /> As microspheres of naltrexone by intramuscular injection (Vivitrol), the elimination half-lives of naltrexone and 6β-naltrexol are both 5 to 10&nbsp;days.<ref name="VivitrolLabel" /> Whereas oral naltrexone is administered daily, naltrexone in microspheres by intramuscular injection is suitable for administration once every 4&nbsp;weeks or once per month.<ref name="VivitrolLabel" />

Naltrexone and its metabolites are [[excretion|excreted]] in [[urine]].<ref name="ReviaLabel" />

===Pharmacogenetics===
Tentative evidence suggests that family history and presence of the Asn40Asp polymorphism predict naltrexone being effective.<ref>{{cite journal | vauthors = Ray LA, Barr CS, Blendy JA, Oslin D, Goldman D, Anton RF | title = The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: a critical review | journal = Alcoholism: Clinical and Experimental Research | volume = 36 | issue = 3 | pages = 385–394 | date = March 2012 | pmid = 21895723 | pmc = 3249007 | doi = 10.1111/j.1530-0277.2011.01633.x }}</ref><ref name="Clinical and biological moderators"/>

==Chemistry==
Naltrexone, also known as ''N''-cyclopropylmethylnoroxymorphone, is a [[chemical derivative|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 [[chemical synthesis|synthesized]] in 1963 by Metossian at Endo Laboratories, a small [[pharmaceutical company]] in [[New York City]].<ref name="Dependence1974">{{cite book|author=National Research Council (U.S.). Committee on Problems of Drug Dependence|title=Report of the Thirty-sixth Annual Scientific Meeting: Committee on Problems of Drug Dependence, Mexico City, March 10-14, 1974|url=https://books.google.com/books?id=pEYrAAAAYAAJ&pg=PA265|year=1974|publisher=National Academies|pages=265–|id=NAP:13963|isbn=9780309022446|access-date=4 December 2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427150422/https://books.google.com/books?id=pEYrAAAAYAAJ&pg=PA265|url-status=live}}</ref> It was characterized by Blumberg, Dayton, and Wolf in 1965 and was found to be an [[oral administration|orally active]], long-acting, and very [[potency (pharmacology)|potent]] opioid antagonist.<ref name="Dependence1974" /><ref name="PadwaCunningham2010">{{cite book| vauthors = Padwa HM, Cunningham J |title=Addiction: A Reference Encyclopedia|url=https://archive.org/details/addictionreferen0000padw| url-access = registration |year=2010|publisher=ABC-CLIO|isbn=978-1-59884-229-6|pages=[https://archive.org/details/addictionreferen0000padw/page/207 207]–}}</ref><ref name="Bennett2004">{{cite book| vauthors = Bennett G |title=Treating Drug Abusers|url=https://books.google.com/books?id=ft6IAgAAQBAJ&pg=PT112|date=14 January 2004|publisher=Routledge|isbn=978-1-134-93173-6|pages=112–|access-date=4 December 2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427160708/https://books.google.com/books?id=ft6IAgAAQBAJ&pg=PT112|url-status=live}}</ref><ref name=Sad2012 /> 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.<ref name=Sad2012 /> It was [[patent]]ed by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by [[DuPont]] in 1969.<ref name="Wouk2009">{{cite book| vauthors = Wouk J |title=Google Ldn !|url=https://books.google.com/books?id=9hOBAgAAQBAJ&pg=RA1-PA78|date=1 March 2009|publisher=Lulu.com|isbn=978-0-578-00439-6|pages=78–88|access-date=4 December 2017|archive-date=28 April 2021|archive-url=https://web.archive.org/web/20210428040328/https://books.google.com/books?id=9hOBAgAAQBAJ&pg=RA1-PA78|url-status=live}}</ref>{{self-published inline|date=February 2020}} [[Clinical trial]]s 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.<ref name="Wouk2009" /> 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.<ref name="Wouk2009" /><ref name="Milhorn2017">{{cite book| vauthors = Milhorn HT |title=Substance Use Disorders: A Guide for the Primary Care Provider|url=https://books.google.com/books?id=wH86DwAAQBAJ&pg=PA88|date=17 October 2017|publisher=Springer International Publishing|isbn=978-3-319-63040-3|pages=88–|access-date=4 December 2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427131539/https://books.google.com/books?id=wH86DwAAQBAJ&pg=PA88|url-status=live}}</ref> 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.<ref name="MedicalNewsToday2006" /><ref name="Milhorn2017"/>

==Society and culture==

===Generic names===
Naltrexone is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|DCIT|Denominazione Comune Italiana}}, while naltrexone hydrochloride is its {{abbrlink|USP|United States Pharmacopeia}} and {{abbrlink|BANM|British Approved Name}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com" />

===Brand names===
Naltrexone is or has been sold under a variety of brand names, including Adepend, Antaxone, Celupan, Depade, Destoxican, Nalorex, Narcoral, Nemexin, Nodict, Revia, Trexan, Vivitrex, and Vivitrol.<ref name="Elks2014">{{cite book|vauthors=Elks J|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA851|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=851–|access-date=4 December 2017|archive-date=6 August 2020|archive-url=https://web.archive.org/web/20200806230945/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA851|url-status=live}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA715|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=715–|access-date=4 December 2017|archive-date=6 August 2020|archive-url=https://web.archive.org/web/20200806165935/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA715|url-status=live}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA189|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=189–}}</ref><ref name="Drugs.com">{{cite web |url=https://www.drugs.com/international/naltrexone.html |title=Naltrexone |access-date=4 December 2017 |url-status=live |archive-url=https://web.archive.org/web/20171204114601/https://www.drugs.com/international/naltrexone.html |archive-date=4 December 2017 }}</ref> It is also marketed in combination with [[bupropion]] ([[naltrexone/bupropion]]) as Contrave,<ref>{{cite web | title=Bupropion and naltrexone Uses, Side Effects & Warnings | website=Drugs.com | date=8 June 2020 | url=https://www.drugs.com/mtm/bupropion-and-naltrexone.html | access-date=16 September 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026105451/https://www.drugs.com/mtm/bupropion-and-naltrexone.html | url-status=live }}</ref> and was marketed with [[morphine]] ([[morphine/naltrexone]]) as Embeda.<ref name="Drugs.com" /><ref>{{cite web | title=Morphine and naltrexone Uses, Side Effects & Warnings | website=Drugs.com | date=14 October 2019 | url=https://www.drugs.com/mtm/morphine-and-naltrexone.html | access-date=16 September 2020 | archive-date=25 October 2020 | archive-url=https://web.archive.org/web/20201025230724/https://www.drugs.com/mtm/morphine-and-naltrexone.html | url-status=live }}</ref> A combination of naltrexone with [[buprenorphine]] ([[buprenorphine/naltrexone]]) has been developed, but has not been marketed.<ref name="pmid18212797">{{cite journal | vauthors = McCann DJ | title = Potential of buprenorphine/naltrexone in treating polydrug addiction and co-occurring psychiatric disorders | journal = Clinical Pharmacology and Therapeutics | volume = 83 | issue = 4 | pages = 627–630 | date = April 2008 | pmid = 18212797 | doi = 10.1038/sj.clpt.6100503 | s2cid = 21165673 }}</ref>

===Controversies===
The FDA authorized use of injectable naltrexone (Vivitrol) for opioid addiction using a single study<ref>{{cite web|url=https://psmag.com/social-justice/vivitrol-help-control-addictions-57261|title=A Shot in the Dark: Can Vivitrol Help Us Control Our Addictions?| vauthors = Armstrong W |date=7 May 2013|website=Pacific Standard|url-status=live|archive-url=https://web.archive.org/web/20170913135050/https://psmag.com/social-justice/vivitrol-help-control-addictions-57261|archive-date=13 September 2017}}</ref> that was led by Evgeny Krupitsky at Bekhterev Research Psychoneurological Institute, St Petersburg State Pavlov Medical University, St Petersburg, Russia,<ref name="Lancet_Krupitsky_2011_naltrexone">{{cite journal | vauthors = Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL | title = Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial | journal = Lancet | volume = 377 | issue = 9776 | pages = 1506–1513 | date = April 2011 | pmid = 21529928 | doi = 10.1016/s0140-6736(11)60358-9 | s2cid = 16690413 }}</ref> 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 (company)|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 .<ref>{{cite journal |doi=10.1016/S0140-6736(11)61333-0 |title=Injectable extended-release naltrexone for opioid dependence – Authors' reply |journal=The Lancet |volume=378 |issue=9792 |pages=666 |year=2011 | vauthors = Wolfe D, Carrieri MP, Dasgupta N, Bruce D, Wodak A |s2cid=205963967 |doi-access=free }}</ref> 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.<ref>{{cite journal | vauthors = Tanum L, Solli KK, Latif ZE, Benth JŠ, Opheim A, Sharma-Haase K, Krajci P, Kunøe N | title = Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial | journal = JAMA Psychiatry | volume = 74 | issue = 12 | pages = 1197–1205 | date = December 2017 | pmid = 29049469 | pmc = 6583381 | doi = 10.1001/jamapsychiatry.2017.3206 }}</ref> Nearly 30% of patients in the US trial did not complete induction.<ref name="Comparative effectiveness of extend"/> 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.<ref name="Wakeman_2020">{{cite journal | vauthors = Wakeman SE, Larochelle MR, Ameli O, Chaisson CE, McPheeters JT, Crown WH, Azocar F, Sanghavi DM | title = Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder | journal = JAMA Network Open | volume = 3 | issue = 2 | pages = e1920622 | date = February 2020 | pmid = 32022884 | doi = 10.1001/jamanetworkopen.2019.20622 | s2cid = 211035316 | doi-access = free | pmc = 11143463 }}</ref>

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.<ref name="NYT_2017_Vivitrol" /> 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."<ref>{{cite web| vauthors = MacGillis A |title=The Last Shot|url=https://www.propublica.org/article/vivitrol-opiate-crisis-and-criminal-justice|access-date=29 December 2021|website=ProPublica|language=en|archive-date=28 December 2021|archive-url=https://web.archive.org/web/20211228162438/https://www.propublica.org/article/vivitrol-opiate-crisis-and-criminal-justice|url-status=live}}</ref><ref>{{cite journal | vauthors = Wolfe D, Saucier R | title = Biotechnologies and the future of opioid addiction treatments | journal = The International Journal on Drug Policy | volume = 88 | pages = 103041 | date = February 2021 | pmid = 33246267 | doi = 10.1016/j.drugpo.2020.103041 | s2cid = 227191111 }}</ref> The company's marketing techniques have led to a Congressional investigation,<ref>{{cite web| vauthors = Harper J |date=7 November 2017|title=Kamala Harris Investigating Addiction Drug Manufacturer Alkermes|url=https://www.wfyi.org/news/articles/kamala-harris-investigating-addiction-drug-manufacturer-alkermes|access-date=29 December 2021|website=WFYI Public Media|language=en-us|archive-date=14 June 2022|archive-url=https://web.archive.org/web/20220614045521/https://www.wfyi.org/news/articles/kamala-harris-investigating-addiction-drug-manufacturer-alkermes|url-status=live}}</ref> and warning from the FDA about failure to adequately state risks of fatal overdose to patients receiving the medicine.<ref>{{cite web| author = Office of the FDA Commissioner|date=24 March 2020|title=FDA issues warning letter for not including the most serious risks in advertisement for medication-assisted treatment drug|url=https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letter-not-including-most-serious-risks-advertisement-medication-assisted|url-status=dead|access-date=29 December 2021|website=Food and Drug Administration|language=en|archive-date=29 December 2021|archive-url=https://web.archive.org/web/20211229153437/https://www.fda.gov/news-events/press-announcements/fda-issues-warning-letter-not-including-most-serious-risks-advertisement-medication-assisted}}</ref>

In May 2017, [[United States Secretary of Health and Human Services]] [[Tom Price (American politician)|Tom Price]] praised [Vivitrol] as the future of opioid addiction treatment after visiting the company's plant in Ohio.<ref name="NYT_2017_Vivitrol" /> 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".<ref name="Tom-Price-Letter-Re-MAT_2017">{{cite web |url=https://www.documentcloud.org/documents/3723472-Tom-Price-Letter-Re-MAT.html |title=Letter to Tom Price |date=May 2017 |access-date=11 June 2017 |url-status=live |archive-url=https://web.archive.org/web/20170625103407/http://www.documentcloud.org/documents/3723472-Tom-Price-Letter-Re-MAT.html |archive-date=25 June 2017 }}</ref> 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"<ref name="NYT_2017_Vivitrol">{{cite news |url=https://www.nytimes.com/2017/06/11/health/vivitrol-drug-opioid-addiction.html |newspaper=[[The New York Times]] |date=11 June 2017 |access-date=11 June 2017 |title=Seizing on Opioid Crisis, a Drug Maker Lobbies Hard for Its Product |quote=Advertising for Vivitrol on a subway car in Brooklyn last month. Marketing for the drug has shifted into high gear. | vauthors = Goodnough A, Zernike K |url-status=live |archive-url=https://web.archive.org/web/20170611133547/https://www.nytimes.com/2017/06/11/health/vivitrol-drug-opioid-addiction.html |archive-date=11 June 2017 }}</ref> 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."<ref name="Tom-Price-Letter-Re-MAT_2017" />

===Film===
[[One Little Pill (2014 film)|''One Little Pill'']] was a 2014 documentary film about the use of naltrexone to treat alcohol use disorder.<ref name="IMDB">{{IMDb title|qid=Q18171043|title=One Little Pill (2014)}}</ref>

''[[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 [[dissociation (psychology)|dissociative]] symptoms such as [[depersonalization]] and [[derealization]].<ref name="SimeonAbugel2008">{{cite book| vauthors = Simeon D, Abugel J |title=Feeling Unreal: Depersonalization Disorder and the Loss of the Self|url=https://books.google.com/books?id=ONLyq-mVLuIC&pg=PA166|date=10 October 2008|publisher=Oxford University Press|isbn=978-0-19-976635-2|pages=166–|access-date=4 October 2016|archive-date=15 February 2017|archive-url=https://web.archive.org/web/20170215043741/https://books.google.com/books?id=ONLyq-mVLuIC&pg=PA166|url-status=live}}</ref><ref name="PhDPhD2014">{{cite book | vauthors = Lanius UF, Paulsen SL, Corrigan FM | title = Neurobiology and Treatment of Traumatic Dissociation: Towards an Embodied Self | url = https://books.google.com/books?id=0i-FAwAAQBAJ&pg=PA489 | date = 13 May 2014 | publisher = Springer Publishing Company | isbn = 978-0-8261-0632-2 | pages = 489– | access-date = 4 October 2016 | archive-date = 15 February 2017 | archive-url = https://web.archive.org/web/20170215044041/https://books.google.com/books?id=0i-FAwAAQBAJ&pg=PA489 | url-status = live }}</ref> Some studies suggest it might help.<ref>{{cite journal | vauthors = Sierra M | title = Depersonalization disorder: pharmacological approaches | journal = Expert Review of Neurotherapeutics | volume = 8 | issue = 1 | pages = 19–26 | date = January 2008 | pmid = 18088198 | doi = 10.1586/14737175.8.1.19 | s2cid = 22180718 }}</ref> Other small, preliminary studies have also shown benefit.<ref name="SimeonAbugel2008" /><ref name="PhDPhD2014" /> Blockade of the KOR by naltrexone and naloxone is thought to be responsible for their effectiveness in ameliorating depersonalization and derealization.<ref name="SimeonAbugel2008" /><ref name="PhDPhD2014" /> Since these drugs are less efficacious in blocking the KOR relative to the MOR, higher doses than typically used seem to be necessary.<ref name="SimeonAbugel2008" /><ref name="PhDPhD2014" />

===Low-dose naltrexone===
Naltrexone has been used [[Off-label use|off-label]] at low doses for diseases not related to chemical dependency or intoxication, such as [[multiple sclerosis]].<ref name="Novella">{{cite web| vauthors = Novella S |date=5 May 2010|title=Low Dose Naltrexone – Bogus or Cutting Edge Science?|url=http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/|url-status=live|archive-url=https://web.archive.org/web/20110708043917/http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/|archive-date=8 July 2011|access-date=5 July 2011|work=Science-Based Medicine}}</ref> Evidence for recommending [[low-dose naltrexone]] is lacking.<ref>{{cite web|title=Low-Dose Naltrexone|url=http://www.nationalmssociety.org/Treating-MS/Complementary-Alternative-Medicines/Low-Dose-Naltrexone|access-date=12 May 2014|publisher=National MS Society|archive-date=13 May 2014|archive-url=https://web.archive.org/web/20140513044442/http://www.nationalmssociety.org/Treating-MS/Complementary-Alternative-Medicines/Low-Dose-Naltrexone|url-status=live}}</ref><ref name="Novella2010">{{cite web| vauthors = Novella S |author-link=Steven Novella|date=5 May 2010|title=Low Dose Naltrexone – Bogus or Cutting Edge Science?|url=http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/|access-date=5 July 2011|archive-date=8 July 2011|archive-url=https://web.archive.org/web/20110708043917/http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/|url-status=live}}</ref> This treatment has received attention on the [[Internet]].<ref name="NMSS">{{cite web| vauthors = Bowling AC |title=Low-dose naltrexone (LDN) The "411" on LDN |url= http://www.nationalmssociety.org/multimedia-library/momentum-magazine/back-issues/momentum-spring-09/download.aspx?id=5587 |url-status=dead |archive-url=https://web.archive.org/web/20090929054506/http://www.nationalmssociety.org/multimedia-library/momentum-magazine/back-issues/momentum-spring-09/download.aspx?id=5587|archive-date=29 September 2009|access-date=6 July 2011|publisher=National Multiple Sclerosis Society }}</ref> In 2022, four studies (in a few hundred patients) were conducted on naltrexone for [[long COVID]].<ref>{{cite news | url=https://www.reuters.com/business/healthcare-pharmaceuticals/addiction-drug-shows-promise-lifting-long-covid-brain-fog-fatigue-2022-10-18/ | title=Addiction drug shows promise lifting long COVID brain fog, fatigue | newspaper=Reuters | date=18 October 2022 | vauthors=Steenhuysen J | access-date=19 October 2022 | archive-date=19 October 2022 | archive-url=https://web.archive.org/web/20221019171516/https://www.reuters.com/business/healthcare-pharmaceuticals/addiction-drug-shows-promise-lifting-long-covid-brain-fog-fatigue-2022-10-18/ | url-status=live }}</ref>

===Self-injury===
One study suggests that [[self-harm|self-injurious behaviors]] present in persons with developmental disabilities (including autism) can sometimes be remedied with naltrexone.<ref>{{cite journal |doi=10.1007/BF02684958 |title=Effects of naltrexone on self-injury, stereotypy, and social behavior of adults with developmental disabilities |journal=Journal of Developmental and Physical Disabilities |volume=7 |issue=2 |pages=137–46 |year=1995 | vauthors = Smith SG, Gupta KK, Smith SH |s2cid=144215400 }}</ref>
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.<ref>{{cite news | publisher=The Reporter | vauthors = Manley C | date=20 March 1998 | url=http://www.mc.vanderbilt.edu/reporter/index.html?ID=461 | title=Self-injuries may have biochemical base: study | url-status=live | archive-url=https://web.archive.org/web/20090105011250/http://www.mc.vanderbilt.edu/reporter/index.html?ID=461 | archive-date=5 January 2009 }}</ref> 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.<ref>{{cite journal | vauthors = Grant JE, Kim SW, Odlaug BL | title = A double-blind, placebo-controlled study of the opiate antagonist, naltrexone, in the treatment of kleptomania | journal = Biological Psychiatry | volume = 65 | issue = 7 | pages = 600–606 | date = April 2009 | pmid = 19217077 | doi = 10.1016/j.biopsych.2008.11.022 | s2cid = 22992128 }}
*{{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2009/04/090401101900.htm|title = Drug Suppresses The Compulsion To Steal, Study Shows|date = 3 April 2009 |website = Science Daily}}</ref><ref name=gambling>{{ClinicalTrialsGov|NCT00326807|A Randomized, Double-Blind, Placebo-Controlled Trial of Naltrexone in the Treatment of Concurrent Alcohol Dependence and Pathological Gambling}}</ref><ref>{{cite journal | vauthors = Kim SW, Grant JE, Adson DE, Shin YC | title = Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling | journal = Biological Psychiatry | volume = 49 | issue = 11 | pages = 914–921 | date = June 2001 | pmid = 11377409 | doi = 10.1016/S0006-3223(01)01079-4 | s2cid = 22134798 }}</ref> A 2008 case study reported successful use of naltrexone in suppressing and treating an internet [[pornography addiction]].<ref>{{cite journal | vauthors = Bostwick JM, Bucci JA | title = Internet sex addiction treated with naltrexone | journal = Mayo Clinic Proceedings | volume = 83 | issue = 2 | pages = 226–230 | date = February 2008 | pmid = 18241634 | doi = 10.4065/83.2.226 | doi-access = free }}</ref>

===Interferon alpha===
Naltrexone is effective in suppressing the [[cytokine]]-mediated adverse neuropsychiatric effects of [[interferon alpha]] therapy.<ref name="pmid16142050">{{cite journal | vauthors = Vignau J, Karila L, Costisella O, Canva V | title = [Hepatitis C, interferon a and depression: main physiopathologic hypothesis] | language = fr | journal = L'Encéphale | volume = 31 | issue = 3 | pages = 349–357 | year = 2005 | pmid = 16142050 | doi = 10.1016/s0013-7006(05)82400-5 | trans-title = Hepatitis C, interferon a and depression: main physiopathologic hypothesis | id = {{INIST|16920336}} }}</ref><ref name="pmid17068950">{{cite journal | vauthors = Małyszczak K, Inglot M, Pawłowski T, Czarnecki M, Rymer W, Kiejna A | title = [Neuropsychiatric symptoms related to interferon alpha] | language = pl | journal = Psychiatria Polska | volume = 40 | issue = 4 | pages = 787–797 | year = 2006 | pmid = 17068950 | url = http://www.psychiatriapsychoterapia.pl/?a=articles_show&id=459 | url-status = live | trans-title = Neuropsychiatric symptoms related to interferon alpha | archive-url = https://web.archive.org/web/20170202010519/http://www.psychiatriapsychoterapia.pl/?a=articles_show&id=459 | archive-date = 2 February 2017 }}</ref>

===Critical addiction studies===
Some historians and sociologists have suggested that the meanings and uses attributed to anti-craving medicine, such as naltrexone, are context-dependent.<ref>{{cite book | vauthors = Campbell ND |date=28 March 2013 |title="Why Can't They Stop?" A Highly Public Misunderstanding of Science |pages=238–262 |publisher=Duke University Press |url=https://read.dukeupress.edu/books/book/1700/chapter/180902/Why-Can-t-They-Stop-A-Highly-Public |doi=10.1215/9780822395874-010 |isbn=978-0-8223-5350-8 |access-date=20 December 2020 |archive-date=14 June 2022 |archive-url=https://web.archive.org/web/20220614045524/https://read.dukeupress.edu/books/book/1700/chapter-abstract/180902/Why-Can-t-They-Stop-A-Highly-Public?redirectedFrom=fulltext |url-status=live }}</ref> Studies have suggested the use of naltrexone in drug courts or healthcare rehabs is a form of "post-social control,"<ref>{{cite journal| vauthors = Vrecko S |date=1 June 2009|title=Therapeutic Justice in Drug Courts: Crime, Punishment and Societies of Control |journal=Science as Culture|volume=18|issue=2|pages=217–232 |doi= 10.1080/09505430902885623 |s2cid=144197523 }}</ref> or "post-disciplinary control,"<ref>{{cite journal| vauthors = Aleksanyan J |date=9 May 2020|title=Governing beyond the closet: Remaking stigma, identity, and sexual behavior in a post-disciplinary rehab |journal=Ethnography|volume=23 |issue=4 |language=en|pages=516–538 |doi=10.1177/1466138120923702 |s2cid=218936388 }}</ref> 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.<ref>{{cite journal | vauthors = Malandain L, Blanc JV, Ferreri F, Thibaut F | title = Pharmacotherapy of Sexual Addiction | journal = Current Psychiatry Reports | volume = 22 | issue = 6 | pages = 30 | date = May 2020 | pmid = 32377953 | doi = 10.1007/s11920-020-01153-4 | s2cid = 218527367 | url = https://hal.sorbonne-universite.fr/hal-02880933/file/Pharmacotherapy%20of%20Sexual%20Addiction.pdf | access-date = 6 January 2023 | archive-date = 6 January 2023 | archive-url = https://web.archive.org/web/20230106174837/https://hal.sorbonne-universite.fr/hal-02880933/file/Pharmacotherapy%20of%20Sexual%20Addiction.pdf | url-status = live }}</ref><ref>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|date=September 2022}}</ref>
==Veterinary use==
Naltrexone is used in wild and zoo animals to reverse the effects of [[carfentanil]] and [[etorphine]]. Naltrexone has a longer duration of action than [[naloxone]] 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.<ref name="lamont">{{cite book | vauthors = Simon BT, Lizarraga I | chapter = Opioids | title = Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | pages = 384 | isbn = 978-1-119-83027-6 | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C | publisher = Wiley Blackwell }}</ref>

A [[quaternary ammonium compound]], methlynaltrexone is still being investigated for use in veterinary medicine. Naltrexone antagonises the [[μ-opioid receptor|μ-]], [[κ-opioid receptor|κ-]], and [[δ-opioid receptor|δ-]], 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 the [[blood-brain barrier]], which allows methlynaltrexone to treat peripheral effects of opioids such as [[gastrointestinal ileus]] whilst maintaining analgesia.<ref name="lamont"/> However, methlynaltrexone may not treat the side effects of [[buprenorphine]].<ref>{{cite journal | vauthors = Martin-Flores M, Singh B, Walsh CA, Brooks EP, Taylor L, Mitchell LM | title = Effects of Buprenorphine, Methylnaltrexone, and Their Combination on Gastrointestinal Transit in Healthy New Zealand White Rabbits | journal = Journal of the American Association for Laboratory Animal Science | volume = 56 | issue = 2 | pages = 155–159 | date = March 2017 | pmid = 28315644 }}</ref><ref name="lamont"/>

== References ==
{{Reflist}}

{{Dependence treatment}}
{{Antidotes}}
{{Opioid receptor modulators}}
{{Portal bar | Medicine}}
{{Authority control}}

[[Category:Alcohol and health]]
[[Category:Cyclopropyl compounds]]
[[Category:Delta-opioid receptor antagonists]]
[[Category:4,5-Epoxymorphinans]]
[[Category:Ethers]]
[[Category:GABAA receptor negative allosteric modulators]]
[[Category:Hallucinogen antidotes]]
[[Category:Hepatotoxins]]
[[Category:Kappa-opioid receptor agonists]]
[[Category:Kappa-opioid receptor antagonists]]
[[Category:Cyclic ketones]]
[[Category:Mu-opioid receptor antagonists]]
[[Category:Hydroxyarenes]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:World Health Organization essential medicines]]
[[Category:Diols]]
[[Category:Tertiary alcohols]]