View source for Chemistry:Methylnaltrexone

{{Short description|Medication in the treatment for Opioid-Induced Constipation}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 459588162
| image = Methylnaltrexone.svg
| width = 200

<!--Clinical data-->
| tradename =  Relistor
| Drugs.com = {{drugs.com|monograph|methylnaltrexone-bromide}}
| MedlinePlus = a608052
| licence_EU = yes
| DailyMedID = Methylnaltrexone
| licence_US = Methylnaltrexone
| pregnancy_AU = B1
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Methylnaltrexone (Relistor) Use During Pregnancy | website=Drugs.com | date=9 July 2020 | url=https://www.drugs.com/pregnancy/methylnaltrexone.html | access-date=21 September 2020}}</ref>
| pregnancy_category =  
| routes_of_administration = Oral, intravenous, subcutaneous

| legal_AU = S4
| legal_BR = C1
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Relistor Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=79388 | access-date=6 September 2022}}</ref><ref>{{cite web | title=Relistor Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=84164 | access-date=6 September 2022}}</ref><ref>{{cite web | title=Relistor Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=84165 | access-date=6 September 2022}}</ref>
| legal_UK = POM
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_status =  

<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound = 11–15.3%
| metabolism = [[Biology:Liver|Liver]]
| elimination_half-life = 8 hours
| excretion = Urine (50%), faeces (50%)

<!--Identifiers-->
| IUPHAR_ligand = 7563
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 916055-93-1
| ATC_prefix = A06
| ATC_suffix = AH01
| PubChem = 5361918
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank =DB06800  
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4514884
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 0RK7M7IABE
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1186579

<!--Chemical data-->
| IUPAC_name = (5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-one
| C=21 | H=26 | N=1 | O=4 
| smiles = O=C6[C@@H]3Oc1c2c(ccc1O)C[C@@H]4[C@@](O)([C@@]23CC[N+]4(C)CC5CC5)CC6
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H25NO4/c1-22(11-12-2-3-12)9-8-20-17-13-4-5-14(23)18(17)26-19(20)15(24)6-7-21(20,25)16(22)10-13/h4-5,12,16,19,25H,2-3,6-11H2,1H3/p+1/t16-,19+,20+,21-,22?/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JVLBPIPGETUEET-GAAHOAFPSA-O
| synonyms = MNTX, naltrexone-methyl-bromide
}}

'''Methylnaltrexone''' ('''MNTX''', brand name '''Relistor'''), used in form of '''methylnaltrexone bromide''' (INN, USAN, [[Chemistry:British Approved Name|BAN]]), is a medication that acts as a [[Medicine:Peripherally acting μ-opioid receptor antagonist|peripherally acting μ-opioid receptor antagonist]] that acts to reverse some of the side effects of [[Chemistry:Opioid|opioid]] drugs such as [[Medicine:Constipation|constipation]] without significantly affecting pain relief or precipitating [[Medicine:Drug withdrawal|withdrawal]]s. Because MNTX is a [[Chemistry:Quaternary ammonium cation|quaternary ammonium cation]], it cannot cross the [[Biology:Blood–brain barrier|blood–brain barrier]], and so has antagonist effects throughout the body, counteracting effects such as itching and constipation, but without affecting opioid effects in the brain such as pain relief.<ref name="npsradar">{{cite web |url=http://www.nps.org.au/health_professionals/publications/nps_radar/2010/march_2010/methylnaltrexone |title=Methylnaltrexone injections (Relistor) for opioid-induced constipation in palliative care |author=National Prescribing Service |date=1 March 2010 |access-date=12 March 2010 |archive-url=https://web.archive.org/web/20100601105141/http://www.nps.org.au/health_professionals/publications/nps_radar/2010/march_2010/methylnaltrexone |archive-date=2010-06-01 |url-status=dead }}</ref> However, since a significant fraction (up to 60%) of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain,<ref name="Stein C, Lang LJ (2009)">{{cite journal | vauthors = Stein C | title = Peripheral mechanisms of opioid analgesia | journal = Anesthesia and Analgesia | volume = 76 | issue = 1 | pages = 182–91 | date = January 1993 | pmid = 8380316 | doi = 10.1213/00000539-199301000-00031 | s2cid = 10113604 | doi-access = free }}</ref> MNTX may increase pain under such circumstances.

==Medical uses==
Methylnaltrexone is approved for the treatment of opioid-induced constipation in chronic non cancer pain or when ordinary laxatives have failed.<ref name=":2">{{Cite web|title=Highlights of Prescribing Information - Metylnaltrexone bromide|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208271s000lbl.pdf}}</ref>

==Mechanism of action==
Methylnaltrexone is a peripheral acting mu-opioid receptor antagonist, and does not cross the blood brain barrier.<ref name=":0">{{cite journal | vauthors = Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, Stambler N, Kremer AB, Israel RJ | display-authors = 6 | title = Methylnaltrexone for opioid-induced constipation in advanced illness | journal = The New England Journal of Medicine | volume = 358 | issue = 22 | pages = 2332–2343 | date = May 2008 | pmid = 18509120 | doi = 10.1056/nejmoa0707377 | doi-access = free }}</ref> Methylnaltrexone has restricted access through the blood brain barrier because it is a quaternary amine, which carries a positive charge when in a solution and more has polarity with lower lipid solubility than a lot of the opioid agonists used for pain treatment.<ref name=":1">{{Cite journal| vauthors = Rotshteyn Y |date=11 January 2011|title=Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration| doi = 10.1517/17425255.2011.549824|journal=Expert Opinion on Drug Metabolism & Toxicology|volume=7|issue=2 |pages=227–235|pmid=21222554 |s2cid=24993500 }}</ref> The peripheral action of methylnaltrexone makes it effective for decreasing the constipating effects of opioids, without interfering with the analgesic effects (of opioids) on the central nervous system.<ref name=":1" /> This is the primary characteristic that makes methylnaltrexone behave differently than [[Chemistry:Naltrexone|naltrexone]].<ref name="FDALabel">{{cite web|title=Relistor Full Prescribing Information|url=http://www.wyeth.com/content/showlabeling.asp?id=499|access-date=2009-05-09}}{{dead link|date=January 2018|bot=InternetArchiveBot|fix-attempted=yes}}</ref> 

Furthermore, as methylnaltrexone cannot cross the blood–brain barrier, it does not reverse the pain-killing properties of opioid agonists or cause withdrawal symptoms, but since a small portion of analgesia comes from the peripheral opioid receptors, it can increase pain from inflammatory conditions such as [[Medicine:Osteoarthritis|arthritis]].{{Citation needed|date=December 2021}}

== Side effects ==
The most common side effects for methylnaltrexone include:<ref name=":2" /><ref name=":1" />

* Abdominal pain
*Dizziness
*Vomiting
*Nausea
*Diarrhea

== History ==
In 1978, a dying friend and colleague presented the late University of Chicago pharmacologist Leon Goldberg with a clinical challenge.<ref>{{Cite web|url=https://news.uchicago.edu/story/drug-developed-university-chicago-wins-fda-approval|title=Drug developed at the University of Chicago wins FDA approval|website=University of Chicago News|date=30 April 2008 |language=en|access-date=2019-08-15}}</ref> Struggling with the pain of prostatic cancer that had metastasized to his bones, the man was now declining the morphine he required for analgesia because of constipation. Research on opioids which would target only the sub-types of receptors associated with pain relief and not with side effects had seen little success outside of in-vitro models. Considering drugs such as [[Chemistry:Loperamide|loperamide]], which acted on the opioid receptors in the gut without acting on the central nervous system, Goldberg proposed a targeted opioid receptor antagonist.<ref>{{cite journal | vauthors = Moss J | title = Identifying and Treating Opioid Side Effects: The Development of Methylnaltrexone | journal = Anesthesiology | volume = 130 | issue = 1 | pages = 142–148 | date = January 2019 | pmid = 30277930 | doi = 10.1097/ALN.0000000000002428 | s2cid = 52908307 | url = https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2705906 | doi-access = free }}</ref>

Thousands of opioid-like molecules had been synthesized by pharmaceutical companies looking for the better analgesic - and many of those with no pain-relieving properties had been shelved. Screening these compounds led to the examination of putative antagonists which when modified had properties that suggested they might not readily cross the blood–brain barrier based on their size and charge. One of these compounds, N-methyl-naltrexone (MNTX), was amongst a group of compounds synthesized by Boehringer Ingelheim.<ref>{{cite patent|country=US|number=3101339|status=patent|title=Quaternary salts of normorphine and its acylated derivatives|gdate=1963-08-20|fdate=1959-10-26|pridate=1958-10-30|inventor=Karl Zeile and Kurt Freter|invent1=Zeile, Karl|invent2=Freter, Kurt|assign1=C. H. Boehringer Sohn. About Karl Zeile: born 1905. ''Untersuchungen über häminhaltige Fermente'', habilitation treatise, Technische Hochschule, Munich 1933; In 1933 also SS-Member; 1937 NSDAP-Member; ao. (i.e. extra-ordinary) Professor in Göttingen; 1938 Delegate of NS-Dozentenbund; 1942 Prof. Organic Chemistry and [[Biology:Biochemistry|biochemistry]] at Reichsuniversität Straßburg, and military research; after WW II deputy of Science-Dptm at Chemische Fabrik C. H. Boehringer Ingelheim}}</ref> The compound looked promising and passed initial screening in which rodents were given opioids along with charcoal meals to track GI transit, and were tested for analgesia.<ref>{{cite patent|country=US|number=4176186|status=patent|title=Quaternary derivatives of noroxymorphone which relieve intestinal immobility|gdate=1979-11-27|fdate=1978-07-28|inventor= Goldberg L, Merz H, Stockhaus K |assign1=Boehringer Ingelheim}}</ref> In a 1982 paper by Russell et al., it was first reported that the GI effects of the opioids could be prevented without affecting centrally mediated analgesia in this model.<ref>{{cite journal | vauthors = Russell J, Bass P, Goldberg LI, Schuster CR, Merz H | title = Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists | journal = European Journal of Pharmacology | volume = 78 | issue = 3 | pages = 255–61 | date = March 1982 | pmid = 7200037 | doi = 10.1016/0014-2999(82)90026-7 }}</ref> Subsequent preclinical studies also demonstrated this separation of central and peripherally mediated opioid effects for other smooth muscles of the GI tract and the cough reflex.<ref>{{cite journal | vauthors = Yuan CS, Foss JF, Moss J | title = Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine | journal = European Journal of Pharmacology | volume = 276 | issue = 1–2 | pages = 107–11 | date = March 1995 | pmid = 7781680 | doi = 10.1016/0014-2999(95)00018-G }}</ref><ref>{{cite journal | vauthors = Foss JF, Orelind E, Goldberg LI | title = Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs | journal = Life Sciences | volume = 59 | issue = 15 | pages = PL235-8 | year = 1996 | pmid = 8845013 | doi = 10.1016/0024-3205(96)00451-1 }}</ref> Interest also developed in the potential for MNTX to act at the chemoreceptor trigger zone and block the emetic effect of opioids. This blockade of opioid-induced emesis was demonstrated in a canine model.<ref>{{cite journal | vauthors = Foss JF, Bass AS, Goldberg LI | title = Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs | journal = Journal of Clinical Pharmacology | volume = 33 | issue = 8 | pages = 747–51 | date = August 1993 | pmid = 8408737 | doi = 10.1002/j.1552-4604.1993.tb05618.x | s2cid = 217261 }}</ref><ref>{{ cite patent |country=US |number=4719215|status=patent|title=Quaternary derivatives of noroxymorphone which relieve nausea and emesis|gdate=1988-01-12|fdate=1986-03-07| inventor = Goldberg LI |assign1=University of Chicago}}</ref> Goldberg died before he could see the core of this idea come into clinical practice.

Research on methylnaltrexone continued in the Department of Anesthesiology and Critical Care at the University of Chicago through the 1990s. More recent investigations, however, discovered opioid receptors on peripheral sensory neurons.<ref name="Stein_2003">{{cite journal | vauthors = Stein C, Schäfer M, Machelska H | title = Attacking pain at its source: new perspectives on opioids | journal = Nature Medicine | volume = 9 | issue = 8 | pages = 1003–8 | date = August 2003 | pmid = 12894165 | doi = 10.1038/nm908 | s2cid = 25453057 | url = }}</ref> 

In December 2005, [[Company:Wyeth|Wyeth]] and Progenics entered into an exclusive, worldwide agreement for the joint development and commercialization of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and post-operative [[Medicine:Ileus|ileus]] (POI), a prolonged dysfunction of the gastrointestinal tract following surgery. Under the terms of the agreement, the companies are collaborating on worldwide development. Wyeth received worldwide rights to commercialize methylnaltrexone, and Progenics retained an option to co-promote the product in the United States. Wyeth will pay Progenics royalties on worldwide sales and co-promotion fees within the United States.

Methylnaltrexone is being developed in subcutaneous and oral forms to treat opioid induced constipation (OIC).

The use of methylnaltrexone (Relistor) for more than 4 months has not been studied.<ref>{{cite web |url=http://www.wyeth.com/hcp/relistor/information-14 |title=Relistor Dosage and Administration |publisher=Wyeth |access-date=2010-08-12 |url-status=dead |archive-url=https://web.archive.org/web/20100804001647/http://www.wyeth.com/hcp/relistor/information-14 |archive-date=2010-08-04 }}</ref>

==Society and culture==

===Approval===
On April 1, 2008, Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid-induced constipation.<ref>{{cite web |url=http://www.wyeth.com/news?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/1207054025120.html |title=Wyeth press release - Wyeth and Progenics Announce Relistor Receives Canadian Marketing Approval |access-date=2008-04-01 |url-status=dead |archive-url=https://web.archive.org/web/20080411131434/http://www.wyeth.com/news?nav=display&navTo=%2Fwyeth_html%2Fhome%2Fnews%2Fpressreleases%2F2008%2F1207054025120.html |archive-date=2008-04-11 }}</ref>
It was later approved by the US FDA on April 24, 2008.<ref>{{cite web |url=http://www.wyeth.com/news?nav=display&navTo=/wyeth_html/home/news/pressreleases/2008/1209080590441.html |title=Wyeth press release - Progenics and Wyeth Announce FDA has Approved Relistor |access-date=2008-04-27 |url-status=dead |archive-url=https://web.archive.org/web/20080502232344/http://www.wyeth.com/news?nav=display&navTo=%2Fwyeth_html%2Fhome%2Fnews%2Fpressreleases%2F2008%2F1209080590441.html |archive-date=2008-05-02 }}</ref><ref>{{cite web |url=https://www.fda.gov/bbs/topics/NEWS/2008/NEW01826.html |title=FDA Approves Relistor for Opioid-Induced Constipation |website=[[Organization:Food and Drug Administration|Food and Drug Administration]] |access-date=2009-05-09 }}</ref>

===Forms===
As of 2010, methylnaltrexone is supplied as an injection in trays containing seven one-dose vials containing 0.6 mL of solution. Each tray also contains seven {{convert|12|mm|in|adj=on|abbr=on}} 1 mL 27 gauge needles with retractable tips, and alcohol wipes for home use. A single vial can treat someone who weighs as much as {{convert|115|kg|lb}}.<ref name="FDALabel" />  For hospital use, vials are available separately.

== See also ==
* [[Chemistry:Loperamide|Loperamide]] - an [[Biology:Μ-opioid receptor|μ-opioid receptor]] ''agonist'' that doesn't cross the BBB in significant amounts, and treats diarrhea (in contrast to methynaltrexone, a Mu-opioid receptor ''antagonist'' that doesn't cross the BBB, avoiding opiate withdrawal effects in patients, while treating constipation)
* [[Chemistry:Naloxegol|Naloxegol]] (trade names Movantik and Moventig) - another peripherally selective opioid antagonist used to treat opioid-induced constipation
* [[Chemistry:(+)-Naloxone|(+)-Naloxone]] - a non-opioid drug which also reduces some side effects of opioids without significantly affecting analgesia when used in small oral doses
* [[Chemistry:6β-Naltrexol|6β-Naltrexol]] (6α-hydroxynaltrexone) - another naltrexone derivative that is also a peripherally selective opioid antagonist

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Holzer P | title = Treatment of opioid-induced gut dysfunction | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 2 | pages = 181–94 | date = February 2007 | pmid = 17243938 | doi = 10.1517/13543784.16.2.181 | s2cid = 9838569 }}
* {{cite journal | vauthors = Yuan CS, Foss JF | title = Oral methylnaltrexone for opioid-induced constipation | journal = JAMA | volume = 284 | issue = 11 | pages = 1383–4 | date = September 2000 | pmid = 10989399 | doi = 10.1001/jama.284.11.1383 }}
{{refend}}

{{Laxatives}}
{{Opioidergics}}

[[Category:Cyclopropanes]]
[[Category:4,5-Epoxymorphinans]]
[[Category:Kappa-opioid receptor antagonists]]
[[Category:Ketones]]
[[Category:Peripherally selective drugs]]
[[Category:Phenols]]
[[Category:Quaternary ammonium compounds]]
[[Category:Semisynthetic opioids]]
[[Category:Tertiary alcohols]]

{{Sourceattribution|Methylnaltrexone}}