Editing Naloxone (section)

==Medical uses==

===Opioid overdose===
[[File:NaloxoneKit.jpg|thumb|A naloxone kit as distributed in British Columbia, Canada]]

Naloxone is useful in treating both acute [[opioid overdose]] and respiratory or mental depression due to opioids.<ref name="AHFS2015"/> Whether it is useful in those in [[cardiac arrest]] due to an opioid overdose is unclear.<ref name="special circum 2015">{{cite journal | vauthors = Lavonas EJ, Drennan IR, Gabrielli A, Heffner AC, Hoyte CO, Orkin AM, Sawyer KN, Donnino MW | title = Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care | journal = Circulation | volume = 132 | issue = 18 Suppl 2 | pages = S501–S518 | date = November 2015 | pmid = 26472998 | doi = 10.1161/cir.0000000000000264 | doi-access = free | title-link = doi }}</ref>

It is included as a part of emergency overdose response kits distributed to [[heroin]], [[fentanyl]], and other opioid drug users, and to emergency responders. This has been shown to reduce rates of deaths due to overdose.<ref name="pmid16956873">{{cite journal | vauthors = Maxwell S, Bigg D, Stanczykiewicz K, Carlberg-Racich S | title = Prescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deaths | journal = Journal of Addictive Diseases | volume = 25 | issue = 3 | pages = 89–96 | year = 2006 | pmid = 16956873 | doi = 10.1300/J069v25n03_11 | s2cid = 17246459 }}</ref> A prescription for naloxone is recommended if a person is on a high dose of opioid (>100{{nbsp}}mg of [[morphine]] equivalence/day), is prescribed any dose of opioid accompanied by a [[benzodiazepine]], or is suspected or known to use opioids nonmedically.<ref>{{cite web |title=Project Lazarus, Wilkes County, North Carolina |work=Policy Briefing Document Prepared for the North Carolina Medical Board in Advance of the Public Hearing Regarding Prescription Naloxone |year=2007 |location=Raleigh, NC |url=http://intranasal.net/Peer%20Reviewed%20literature/Project%20Lazarus,%20North%20Carolina%20IN%20Naloxone%202007.pdf |access-date=20 March 2022 |archive-date=26 May 2022 |archive-url=https://web.archive.org/web/20220526182242/http://intranasal.net/Peer%20Reviewed%20literature/Project%20Lazarus,%20North%20Carolina%20IN%20Naloxone%202007.pdf |url-status=live }}{{page needed|date=February 2014}}{{verify source|date=February 2014}}</ref> Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling emergency services.<ref name="pmid23664112">{{cite journal | vauthors = Bowman S, Eiserman J, Beletsky L, Stancliff S, Bruce RD | title = Reducing the health consequences of opioid addiction in primary care | journal = The American Journal of Medicine | volume = 126 | issue = 7 | pages = 565–571 | date = July 2013 | pmid = 23664112 | doi = 10.1016/j.amjmed.2012.11.031 }}</ref>

Distribution of naloxone to individuals likely to encounter people who overdose is one aspect of [[harm reduction]] strategies.<ref>{{cite book | veditors = Marlatt GA, Larimer ME, Witkiewitz K | date = 2011 | title = Harm reduction: Pragmatic strategies for managing high-risk behaviors. | edition = 2nd | location = New York | publisher = Guilford Press | isbn = 978-1-4625-0256-1 }}</ref>

However, with opioids that have longer half-lives, respiratory depression returns after naloxone has worn off; therefore, adequate dosing and continuous monitoring may be necessary.<ref>{{cite journal | vauthors = van Dorp E, Yassen A, Dahan A | title = Naloxone treatment in opioid addiction: the risks and benefits | journal = Expert Opinion on Drug Safety | volume = 6 | issue = 2 | pages = 125–132 | date = March 2007 | pmid = 17367258 | doi = 10.1517/14740338.6.2.125 | s2cid = 11650530 }}</ref>

===Clonidine overdose===
Naloxone can also be used as an antidote in an overdose of [[clonidine]], a medication that lowers blood pressure.<ref>{{cite journal | vauthors = Niemann JT, Getzug T, Murphy W | title = Reversal of clonidine toxicity by naloxone | journal = Annals of Emergency Medicine | volume = 15 | issue = 10 | pages = 1229–1231 | date = October 1986 | pmid = 3752658 | doi = 10.1016/s0196-0644(86)80874-5 }}</ref> Clonidine overdoses are of special relevance for children, in whom even small doses can cause significant harm.<ref name="Ahmad et al 2015 Review">{{cite journal | vauthors = Ahmad SA, Scolnik D, Snehal V, Glatstein M | title = Use of naloxone for clonidine intoxication in the pediatric age group: case report and review of the literature | journal = American Journal of Therapeutics | volume = 22 | issue = 1 | pages = e14–e16 | date = 2015 | pmid = 23782760 | doi = 10.1097/MJT.0b013e318293b0e8 }}</ref> However, there is controversy regarding naloxone's efficacy in treating the symptoms of clonidine overdose, namely [[bradycardia|slow heart rate]], [[hypotension|low blood pressure]], and [[altered mental status|confusion/somnolence]].<ref name="Ahmad et al 2015 Review"/> Case reports that used doses of 0.1{{nbsp}}mg/kg (maximum of 2{{nbsp}}mg/dose) repeated every 1–2 minutes (10{{nbsp}}mg total dose) have shown inconsistent benefit.<ref name="Ahmad et al 2015 Review"/> As the doses used throughout the literature vary, it is difficult to form a conclusion regarding the benefit of naloxone in this setting.<ref name="Seger DL Review">{{cite journal | vauthors = Seger DL | title = Clonidine toxicity revisited | journal = Journal of Toxicology. Clinical Toxicology | volume = 40 | issue = 2 | pages = 145–155 | date = 2002 | pmid = 12126186 | doi = 10.1081/CLT-120004402 | s2cid = 2730597 }}</ref> The mechanism for naloxone's proposed benefit in clonidine overdose is unclear. Still, it has been suggested that endogenous opioid receptors mediate the [[sympathetic nervous system]] in the brain and elsewhere in the body.<ref name="Seger DL Review"/>

===Preventing recreational opioid use===
Naloxone is poorly absorbed when taken orally or sublingually, so it is often combined with several oral or sublingual opioid preparations, including [[Buprenorphine/naloxone|buprenorphine]] and [[pentazocine]], so that when swallowed or taken sublingually, only the non-naloxone opioid has an effect.<ref name="AHFS2015"/><ref name="Orman2009">{{cite journal | vauthors = Orman JS, Keating GM | title = Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence | journal = Drugs | volume = 69 | issue = 5 | pages = 577–607 | date = 2009 | pmid = 19368419 | doi = 10.2165/00003495-200969050-00006 | s2cid = 209147406 }}</ref> However, if the combination is injected (such as by dissolving a pill or sublingual strip in water), the naloxone is believed to block the effect of the other opioid.<ref name="AHFS2015"/><ref name="Orman2009"/> This combination is used to prevent non-medical use.<ref name="Orman2009"/>

However, [[SAMHSA]]'s clinical guidelines state that if the combination of buprenorphine and naloxone is injected by a regular user of buprenorphine or buprenorphine/naloxone, then the buprenorphine would still produce an agonist effect but the naloxone would fail to produce an antagonist effect. This is because the amount of naloxone that would be required to block the buprenorphine after injection is much larger than the amount that is contained in buprenorphine/naloxone (Suboxone) pills and strips.<ref name="Guidelines SAMHSA"/> If someone who is not physically dependent on opioids were to inject the buprenorphine/naloxone combination, then the effects of the buprenorphine may at most be slightly lessened, but the individual would still be expected to experience euphoric effects.<ref name="Guidelines SAMHSA">{{cite book | vauthors=((Center for Substance Abuse Treatment)) | title=Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction | series=SAMHSA/CSAT Treatment Improvement Protocols | page=23| publisher=U.S. [[Substance Abuse and Mental Health Services Administration]] (SAMHSA) | date=2004 | url=https://www.ncbi.nlm.nih.gov/books/NBK64245/ | pmid=22514846 }}</ref>

===Other uses===

A 2003 meta-analysis of existing research showed naloxone to improve blood flow in patients with [[circulatory shock|shock]], including [[septic shock|septic]], cardiogenic, hemorrhagic, or spinal shock, but could not determine if this reduced patient deaths.<ref>{{cite journal | vauthors = Boeuf B, Poirier V, Gauvin F, Guerguerian AM, Roy C, Farrell CA, Lacroix J | title = Naloxone for shock | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD004443 | date = 2003 | volume = 2010 | pmid = 14584016 | doi = 10.1002/14651858.CD004443 | pmc = 9036847 }}</ref>

Oral naloxone has been used for [[opioid-induced constipation]] (OIC). A 2018 meta-analysis cites 5 studies that tests it for this purpose. It found that medical treatment for OIC can be more efficacious than placebo, but did not look into the effect of individual treatments such as naloxone. As a result, no conclusion can be drawn from the study on naloxone's effectiveness for OIC.<ref>{{cite journal | vauthors = Nusrat S, Syed T, Saleem R, Clifton S, Bielefeldt K | title = Pharmacological Treatment of Opioid-Induced Constipation Is Effective but Choice of Endpoints Affects the Therapeutic Gain | journal = Digestive Diseases and Sciences | volume = 64 | issue = 1 | pages = 39–49 | date = January 2019 | pmid = 30284134 | doi = 10.1007/s10620-018-5308-9 }}</ref>

===Special populations===

====Pregnancy and breastfeeding====

Whether naloxone is excreted in [[breast milk]] is unknown, however, it is not [[Bioavailability|orally bioavailable]] and therefore is unlikely to affect a [[breastfeeding]] infant.<ref>{{cite news|url=https://www.drugs.com/breastfeeding/naloxone.html|title=Naloxone use while Breastfeeding|work=Drugs.com|access-date=15 August 2018|archive-date=2 November 2020|archive-url=https://web.archive.org/web/20201102082637/https://www.drugs.com/breastfeeding/naloxone.html|url-status=live}}</ref>

====Children====
Naloxone can be used on infants who were exposed to intrauterine opiates administered to mothers during delivery. However, there is insufficient evidence for the use of naloxone to lower cardiorespiratory and neurological depression in these infants.<ref name="Naloxone for opioid-exposed newborn">{{cite journal | vauthors = Moe-Byrne T, Brown JV, McGuire W | title = Naloxone for opioid-exposed newborn infants | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 10 | pages = CD003483 | date = October 2018 | pmid = 30311212 | pmc = 6517169 | doi = 10.1002/14651858.CD003483.pub3 }}</ref> Infants exposed to high concentrations of opiates during pregnancy may have CNS damage in the setting of [[perinatal asphyxia]]. Naloxone has been studied to improve outcomes in this population, however the evidence is currently weak.<ref>{{cite journal | vauthors = McGuire W, Fowlie PW, Evans DJ | title = Naloxone for preventing morbidity and mortality in newborn infants of greater than 34 weeks gestation with suspected perinatal asphyxia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003955 | date = 26 January 2004 | volume = 2010 | pmid = 14974047 | pmc = 6485479 | doi = 10.1002/14651858.CD003955.pub2 | publisher = John Wiley & Sons, Ltd }}</ref><ref name="Naloxone for opioid-exposed newborn"/>

Intravenous, intramuscular, or subcutaneous administration of naloxone can be given to children and neonates to reverse opiate effects. The [[American Academy of Pediatrics]] recommends only intravenous administration as the other two forms can cause unpredictable absorption. After a dose is given, the child should be monitored for at least 24 hours. For children with low blood pressure due to [[septic shock]], naloxone safety and effectiveness are not established.<ref>{{cite web|url=https://www.rxlist.com/narcan-drug.htm|title=Narcan (Naloxone Hydrochloride Injection): Side Effects, Interactions, Warning, Dosage & Uses|website=RxList|access-date=24 October 2019|archive-date=11 November 2020|archive-url=https://web.archive.org/web/20201111191403/https://www.rxlist.com/narcan-drug.htm|url-status=live}}</ref>

====Geriatric use====
For patients 65 years and older, it is unclear if there is a difference in response. However, older people often have decreased liver and kidney function which may lead to an increased level of naloxone in their body.<ref name="Narcan FDA label"/>

=== Available forms ===

====Intravenous====
In hospital settings, naloxone is injected [[intravenously]], with an onset of 1–2 minutes and a duration of up to 45 minutes.<ref name="Lexicomp. 2013">{{cite book |title=Drug information handbook for advanced practice nursing: a comprehensive resource for nurse practitioners, nurse midwives, and clinical specialists, including selected disease management guidelines. |date=2013|publisher=Lexicomp|isbn=978-1591953234|oclc=827841946}}</ref>

====Intramuscular or subcutaneous====
Naloxone can also be administered via [[intramuscular]] or [[subcutaneous injection]]. The onset of naloxone provided through this route is 2 to 5 minutes with a duration of around 30–120min.<ref>{{cite web | title = Naloxone for Treatment of Opioid Overdose | date = October 2016 | url = https://www.fda.gov/media/100429/download | author = Advisory Committee | work = Insys Development Company, Inc. | publisher = U.S. Food and Drug Administration }}</ref> Naloxone administered intramuscularly are provided through pre-filled syringes, vials, and auto-injector. A hand-held auto-injector is pocket-sized and can be used in non-medical settings such as in the home.<ref name="special circum 2015"/> It is designed for use by laypersons, including family members and caregivers of opioid users at risk for an opioid emergency, such as an overdose.<ref name="FDA News Release">{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391465.htm|title=FDA approves new hand-held auto-injector to reverse opioid overdose |publisher = U.S. [[Food and Drug Administration]] (FDA) |archive-url= https://web.archive.org/web/20150716003000/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391465.htm|archive-date=16 July 2015|access-date=20 July 2015|url-status=dead}}</ref> According to the FDA's [[National Drug Code]] Directory, a generic version of the auto-injector began to be marketed at the end of 2019.<ref>{{cite web|url=https://ndclist.com/ndc/72853-051/package/72853-051-02|title=NDC 72853-051-02 Naloxone Hydrochloride Auto-injector|website=NDClist.com|access-date=21 March 2020|archive-date=21 March 2020|archive-url=https://web.archive.org/web/20200321212308/https://ndclist.com/ndc/72853-051/package/72853-051-02|url-status=dead}}</ref>

====Intranasal====
Narcan nasal spray was approved in the US in 2015 and is the first FDA-approved nasal spray for emergency treatment or suspected overdose.<ref name="FDA PR 20190419">{{cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-naloxone-nasal-spray-treat-opioid-overdose|title=FDA approves first generic naloxone nasal spray to treat opioid overdose|date=11 September 2019|publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=23 October 2019|archive-date=14 September 2019|archive-url=https://web.archive.org/web/20190914122901/https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-naloxone-nasal-spray-treat-opioid-overdose|url-status=live}}</ref><ref>{{cite web |title = FDA Approves Narcan Nasal Spray|url = http://www.jems.com/articles/2015/11/fda-approves-narcan-nasal-spray.html|website = www.jems.com|access-date = 21 November 2015|url-status = live|archive-url = https://web.archive.org/web/20151120184918/http://www.jems.com/articles/2015/11/fda-approves-narcan-nasal-spray.html|archive-date = 20 November 2015}}</ref> It was developed in a partnership between LightLake Therapeutics and the [[National Institute on Drug Abuse]].<ref>{{cite web |url=https://www.drugabuse.gov/about-nida/noras-blog/2015/11/narcan-nasal-spray-life-saving-science-nida|title=Narcan Nasal Spray: Life Saving Science at NIDA| vauthors = Volkow N |date=18 November 2015|website=[[National Institute on Drug Abuse]] (NIDA) |url-status=live|archive-url=https://web.archive.org/web/20170226133910/https://www.drugabuse.gov/about-nida/noras-blog/2015/11/narcan-nasal-spray-life-saving-science-nida|archive-date=26 February 2017}}</ref> The approval process was fast-tracked.<ref>{{cite news|url=https://www.washingtonpost.com/national/health-science/fda-approves-device-to-combat-opiod-drug-overdose/2014/04/03/35b69cac-bb3e-11e3-96ae-f2c36d2b1245_story.html|title=FDA approves device to combat opioid drug overdose| vauthors = Dennis B |date=3 April 2014|newspaper=[[The Washington Post]]|access-date=8 April 2014|url-status=live|archive-url=https://web.archive.org/web/20140407173215/http://www.washingtonpost.com/national/health-science/fda-approves-device-to-combat-opiod-drug-overdose/2014/04/03/35b69cac-bb3e-11e3-96ae-f2c36d2b1245_story.html|archive-date=7 April 2014}}</ref> A generic version of the nasal spray was approved in the United States in 2019, though did not come to market until 2021.<ref name="FDA PR 20190419" /><ref name="Teva Pharmaceuticals_2021" />

In 2021, the FDA approved Kloxxado, an 8{{nbsp}}mg dose of intranasal naloxone developed by [[Hikma Pharmaceuticals]].<ref>{{cite press release |date=11 May 2021 |title=FDA Approves Higher Dosage of Naloxone Nasal Spray to Treat Opioid Overdose |url=https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose |access-date=21 September 2022 |publisher=U.S. [[Food and Drug Administration]] (FDA) |archive-date=1 September 2022 |archive-url=https://web.archive.org/web/20220901084121/https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose |url-status=live }}</ref> Citing the frequent need for multiple 4{{nbsp}}mg doses of Narcan to successfully reverse overdose, packs of Kloxxado Nasal Spray contain two pre-packaged nasal spray devices, each containing 8{{nbsp}}mg of naloxone.<ref>{{cite journal | vauthors = Abdelal R, Raja Banerjee A, Carlberg-Racich S, Darwaza N, Ito D, Shoaff J, Epstein J | title = Real-world study of multiple naloxone administration for opioid overdose reversal among bystanders | journal = Harm Reduction Journal | volume = 19 | issue = 1 | pages = 49 | date = May 2022 | pmid = 35596213 | pmc = 9122081 | doi = 10.1186/s12954-022-00627-3 | doi-access = free }}</ref><ref name="Kloxxado FDA label">{{cite web | title=Kloxxado- naloxone hcl spray | website=DailyMed | date=10 May 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf0f833-c1c0-487c-8f29-01fa8c61b6cb | access-date=7 January 2023 | archive-date=7 January 2023 | archive-url=https://web.archive.org/web/20230107044215/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf0f833-c1c0-487c-8f29-01fa8c61b6cb | url-status=live }}</ref>

However, a wedge device (nasal atomizer) can also be attached to a syringe that may also be used to create a mist to deliver the drug to the nasal{{nbsp}}[[mucosa]].<ref name="pmid15039670">{{cite journal | vauthors = Wolfe TR, Bernstone T | title = Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases | journal = Journal of Emergency Nursing | volume = 30 | issue = 2 | pages = 141–147 | date = April 2004 | pmid = 15039670 | doi = 10.1016/j.jen.2004.01.006 }}</ref> This is useful near facilities where many overdoses occur that already stock injectors.<ref>{{cite web| vauthors = Fiore K |title=On-Label Nasal Naloxone in the Works|url=http://www.medpagetoday.com/PublicHealthPolicy/PublicHealth/52118|website=MedPage Today|access-date=20 July 2015|url-status=live|archive-url=https://web.archive.org/web/20150801184056/http://www.medpagetoday.com/PublicHealthPolicy/PublicHealth/52118|archive-date=1 August 2015|date=13 June 2015}}</ref>
[[File:NARCAN teardown.jpg|thumb|Internal components of a naloxone nasal spray. ]]