Levorphanol: Difference between revisions

{{Short description|Opioid analgesic drug}}

{{cs1 config|name-list-style=vanc}}

{{Use mdy dates|date=March 2024}}

| verifiedrevid = 458437606

| IUPAC_name = (1''R'',9''R'',10''R'')-17-Methyl-17-azatetracyclo[7.5.3.0¹,¹⁰.0²,⁷]heptadeca-2(7),3,5-trien-4-ol

| image = Levorphanol2DCSD2.svg

| width = 190px

| alt = Structural formula

| image2 = Levorphanol molecule ball.png

| width2 = 200px

| alt2 = Ball-and-stick model

| pronounce =

| tradename = Levo-Dromoran

| pregnancy_US = C

| legal_BR = A1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=March 31, 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=August 3, 2023 |access-date=August 16, 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=April 4, 2023}}</ref>

| legal_UK= Class A

| legal_DE = Anlage II

| routes_of_administration = Oral, intravenous, subcutaneous, intramuscular

| elimination_half-life = 11–16 hours

| IUPHAR_ligand = 7595

| ATC_suffix =

| ATC_supplemental =

| ChEMBL = 592

<!--Chemical data-->

| C=17 | H=23 | N=1 | O=1

| smiles = CN1CC[C@]23CCCC[C@H]2[C@H]1Cc4c3cc(O)cc4

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| synonyms = Ro 1-5431<ref name="Elks2014" />

'''Levorphanol''' (brand name '''Levo-Dromoran''') is an [[opioid]] medication used to treat moderate to severe [[pain]].<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=PA656|date=November 14, 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=656–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA606|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=606–}}</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=PA165 |date=December 6, 2012 |publisher=Springer Science & Business Media|isbn=978-94-011-4439-1 |pages=165– }}</ref> It is the [[levorotatory]] [[enantiomer]] of the compound [[racemorphan]]. Its [[dextrorotatory]] counterpart is [[dextrorphan]].

<!-- Society and culture -->

It was first described in [[Germany]] in 1946.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title= Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=527 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA527 |language=en}}</ref> The drug has been in medical use in the [[United States]] since 1953.<ref name="GudinFudin2015">{{cite journal | vauthors = Gudin J, Fudin J, Nalamachu S | title = Levorphanol Use: Past, Present and Future | journal = Postgraduate Medicine | volume = 128 | issue = 1 | pages = 46–53 | date = January 2016 | pmid = 26635068 | doi = 10.1080/00325481.2016.1128308 | s2cid = 3912175 }}</ref>

==Pharmacology==

Levorphanol acts predominantly as an [[agonist]] of the [[mu-opioid receptor|μ-opioid receptor]] (MOR), but is also an agonist of the [[δ-opioid receptor]] (DOR), [[κ-opioid receptor]] (KOR), and the [[nociceptin receptor]] (NOP), as well as an [[NMDA receptor antagonist]] and a [[serotonin-norepinephrine reuptake inhibitor]] (SNRI).<ref name="GudinFudin2015" /> Levorphanol, similarly to certain other opioids, also acts as a [[glycine receptor antagonist]] and [[GABA receptor antagonist]] at very high concentrations.<ref name="Osborne2013">{{cite book| first = Neville N. | last = Osborne |title=Selected Topics from Neurochemistry |url= https://books.google.com/books?id=ldnWAgAAQBAJ&pg=PA244 |date=October 22, 2013 |publisher=Elsevier Science |isbn=978-1-4832-8635-8 |pages=244– }}</ref> As per the World Health Organization, levorphanol is a step 3 opioid and is considered eight times more potent than morphine at the MOR (2&nbsp;mg levorphanol is equivalent to 15&nbsp;mg morphine).{{Citation needed|date=March 2017}}

Relative to morphine, levorphanol lacks complete [[cross-tolerance]]<ref name="OUP09">{{Cite book | isbn = 978-0-19-157532-7 | title = Opioids in Cancer Pain | vauthors = Davis MP, Glare PA, Hardy J | edition = 2nd | year = 2009 | orig-year = 2005 | publisher = Oxford University Press | location = Oxford, UK }}</ref> and possesses greater [[intrinsic activity]] at the MOR.<ref name = OUP09/> The [[duration of action]] is generally long compared to other comparable analgesics and varies from 4 hours to as much as 15 hours. For this reason levorphanol is useful in palliation of chronic pain and similar conditions. Levorphanol has an oral to parenteral effectiveness ratio of 2:1, one of the most favorable of the strong narcotics. Its antagonism of the NMDA receptor, similar to those of the [[phenylheptylamine]] open-chain opioids such as [[methadone]] or the [[phenylpiperidine]] [[ketobemidone]], make levorphanol useful for types of pain that other analgesics may not be as effective against, such as [[neuropathic pain]].<ref>{{cite journal | vauthors = Prommer E | title = Levorphanol: the forgotten opioid | journal = Supportive Care in Cancer | volume = 15 | issue = 3 | pages = 259–64 | date = March 2007 | pmid = 17039381 | doi = 10.1007/s00520-006-0146-2 | s2cid = 10916508 }}</ref> Levorphanol's exceptionally high analgesic efficacy in the treatment of neuropathic pain is also conferred by its action on [[serotonin transporter|serotonin]] and [[norepinephrine transporter]]s, similar to the opioids [[tramadol]] and [[tapentadol]], and mutually complements the analgesic effect of its NMDA receptor antagonism.<ref>{{cite journal | vauthors = Nalamachu S, Gudin J | date = April 2016 | title = Levorphanol, another choice in opioid rotation | doi = 10.1016/j.jpain.2016.01.056 | journal = J Pain | volume = 17 | issue = 4 | page = S14 | doi-access = free }}</ref>

Levorphanol shows a high rate of [[psychotomimetic]] [[side effect]]s such as [[hallucination]]s and [[delirium]], which have been attributed to its binding to and activation of the KOR.<ref name="BrueraPortenoy2009">{{cite book | vauthors = Bruera ED, Portenoy RK |title=Cancer Pain: Assessment and Management |url= https://books.google.com/books?id=2TJ-_oECXM4C&pg=PA215 |date=October 12, 2009 |publisher=Cambridge University Press | isbn=978-0-521-87927-9| pages=215– }}</ref> At the same time however, activation of this receptor as well as of the DOR have been determined to contribute to its analgesic effects.<ref name="BrueraPortenoy2009" />

==Chemistry==

[[File:Levorphanol and dextrorphan.png|thumb|left|Levorphanol and its stereoisomer dextrorphan, the enantiomers of the racemic mixture racemorphan.]]

Chemically, levorphanol belongs to the [[morphinan]] class and is (−)-3-hydroxy-''N''-methyl-morphinan.<ref name = OUP09/> It is the "left-handed" ([[levorotatory]]) [[stereoisomer]] of [[racemorphan]], the [[racemic mixture]] of the two stereoisomers with differing [[pharmacology]]. The "right-handed" (dextrorotatory) enantiomer of racemorphan is [[dextrorphan]] (DXO), an [[antitussive]], potent [[dissociative drug|dissociative]] [[hallucinogen]] ([[NMDA receptor antagonist]]), and weakly active opioid. DXO is an [[active metabolite]] of the [[pharmaceutical drug]] [[dextromethorphan]] (DXM), which, analogously to DXO, is an enantiomer of the racemic mixture [[racemethorphan]] along with [[levomethorphan]], the latter of which has similar properties to those of levorphanol.

==Society and culture==

===Name===

''Levorphanol'' is the [[International Nonproprietary Name|INN]], [[British Approved Name|BAN]], and [[Dénomination Commune Française|DCF]].<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /> As the medically used [[tartrate]] [[salt (chemistry)|salt]], the drug is also known as ''levorphanol tartrate'' ([[United States Adopted Name|USAN]], [[British Approved Name|BANM]]).<ref name="Elks2014" /><ref name="MortonHall2012" /> The former developmental code name of levorphanol at [[Hoffmann-La Roche|Roche]] was ''Ro 1-5431''.<ref name="Elks2014" /><ref name="MortonHall2012" />

===Availability===

As the tartrate salt, levorphanol is marketed by Hikma Pharmaceuticals USA Inc.<ref>{{cite web | title = LEVORPHANOL TARTRATE tablet | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b2ab70e4-ca0c-4a73-9c98-974bf94e890c | publisher = National Institutes of Health | work = National Library of Medicine}}</ref> and Virtus Pharmaceuticals in the U.S., and [[Canada]] under the brand name '''Levo-Dromoran'''.<ref name="IndexNominum2000" />

===Legality===

Levorphanol is listed under the [[Single Convention On Narcotic Drugs|Single Convention On Narcotic Drugs 1961]] and is regulated like morphine in most countries. In the U.S., it is a [[Controlled Substances Act#Schedule II controlled substances|Schedule II]] Narcotic [[controlled substance]] with a [[Drug Enforcement Administration|DEA]] [[Administrative Controlled Substances Code Number|ACSCN]] of 9220 and 2013 annual aggregate manufacturing quota of 4.5&nbsp;kilograms. The salts in use are the tartrate (free base conversion ratio 0.58) and [[hydrobromide]] (0.76).<ref>{{cite web | title = Conversion Factors for Controlled Substances | url = https://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html | publisher = U.S. Department of Justice • Drug Enforcement Administration | work = Diversion Control Division}}</ref>

* [[Cough syrup]]

* [[Racemorphan]]; [[Dextrorphan]];

* [[Noscapine]]

* [[Codeine]]; [[Pholcodine]]

* [[Dextromethorphan]]; [[Dimemorfan]]

* [[Butamirate]]

* [[Pentoxyverine]]

* [[Tipepidine]]

* [[Cloperastine]]; [[Levocloperastine]]

{{Neuropathic pain and fibromyalgia pharmacotherapies}}

{{Hallucinogens}}

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[[Category:Delta-opioid receptor agonists]]

[[Category:Dissociative drugs]]

[[Category:Enantiopure drugs]]

[[Category:Euphoriants]]

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[[Category:Glycine receptor antagonists]]

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[[Category:Synthetic opioids]]