Levorphanol: Difference between revisions
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Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL', 'StdInChI'). |
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{{Short description|Opioid analgesic drug}} |
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{{cs1 config|name-list-style=vanc}} |
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{{Use mdy dates|date=March 2024}} |
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{{Drugbox |
{{Drugbox |
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| Verifiedfields = changed |
| Verifiedfields = changed |
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| Watchedfields = changed |
| Watchedfields = changed |
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| verifiedrevid = |
| verifiedrevid = 458437606 |
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| IUPAC_name = (1''R'',9''R'',10''R'')-17-Methyl-17-azatetracyclo[7.5.3.0<sup>1</sup>,<sup>10</sup>.0<sup>2</sup>,<sup>7</sup>]heptadeca-2(7),3,5-trien-4-ol |
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| IUPAC_name = 17-methylmorphinan-3-ol |
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| image = |
| image = Levorphanol2DCSD2.svg |
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| width = |
| width = 190px |
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| alt = Structural formula |
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| drug_name = Levorphanol |
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| image2 = Levorphanol molecule ball.png |
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| width2 = 200px |
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| alt2 = Ball-and-stick model |
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<!--Clinical data--> |
<!--Clinical data--> |
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| pronounce = |
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| tradename = Levo- |
| tradename = Levo-Dromoran |
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| Drugs.com = {{drugs.com|monograph|levo-dromoran}} |
| Drugs.com = {{drugs.com|monograph|levo-dromoran}} |
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| MedlinePlus = a682020 |
| MedlinePlus = a682020 |
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| |
| pregnancy_US = C |
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| legal_AU = S8 |
| legal_AU = S8 |
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| legal_BR = A1 |
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| 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> |
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| legal_CA = Schedule I |
| legal_CA = Schedule I |
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| legal_US = Schedule II |
| legal_US = Schedule II |
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| legal_UK= Class A |
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| legal_DE = Anlage II |
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| dependency_liability = High |
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| routes_of_administration = |
| routes_of_administration = Oral, intravenous, subcutaneous, intramuscular |
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<!--Pharmacokinetic data--> |
<!--Pharmacokinetic data--> |
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| bioavailability = 70% (oral); 100% (IV) |
| bioavailability = 70% (oral); 100% (IV) |
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| protein_bound = 40% |
| protein_bound = 40% |
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| metabolism = [[Hepatic]] |
| metabolism = [[Hepatic]] |
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| elimination_half-life = |
| elimination_half-life = 11–16 hours |
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<!--Identifiers--> |
<!--Identifiers--> |
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| IUPHAR_ligand = 7595 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 77-07-6 |
| CAS_number = 77-07-6 |
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| ATC_prefix = None |
| ATC_prefix = None |
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| ATC_suffix = |
| ATC_suffix = |
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| ATC_supplemental = |
| ATC_supplemental = |
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| PubChem = 5359272 |
| PubChem = 5359272 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| KEGG = D08123 |
| KEGG = D08123 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = |
| ChEMBL = 592 |
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<!--Chemical data--> |
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| C=17 | H=23 | N=1 | O=1 |
| C=17 | H=23 | N=1 | O=1 |
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| molecular_weight = 257.371 g/mol |
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| smiles = |
| smiles = CN1CC[C@]23CCCC[C@H]2[C@H]1Cc4c3cc(O)cc4 |
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⚫ | |||
| InChI = 1/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m0/s1 |
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| InChIKey = JAQUASYNZVUNQP-USXIJHARBM |
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⚫ | |||
| StdInChI = 1S/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m0/s1 |
| StdInChI = 1S/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = JAQUASYNZVUNQP-USXIJHARSA-N |
| StdInChIKey = JAQUASYNZVUNQP-USXIJHARSA-N |
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| synonyms = Ro 1-5431<ref name="Elks2014" /> |
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}} |
}} |
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'''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]]. |
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'''Levorphanol''' ('''Levo-Dromoran''') is an [[opioid]] medication used to treat severe pain. It is the levorotatory [[stereoisomer]] of the synthetic [[morphinan]] (Dromoran) and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic. Morphinan is the parent drug and prototype of a large series of opioid and/or NMDA antagonists and opioid agonists used in medicine including [[nalbuphine]], [[butorphanol]], [[dextromethorphan]], and others. |
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<!-- Society and culture --> |
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Levorphanol labeled with [[tritium]] was used in the research which led to the discovery of [[opioid receptors]] in the human nervous system, including the first study published in 1971.<ref>[[opioid receptors]]</ref> |
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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> |
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==Pharmacology== |
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Levorphanol has the same properties as [[morphine]] with respect to the potential for [[habituation]], [[Drug tolerance|tolerance]], [[physical dependence]] and [[withdrawal]] syndrome. It is 4 to 8 times as potent as morphine and has a longer half-life. Approximately 30 mg of oral morphine is roughly [[equianalgesic]] to 4 mg of oral levorphanol.<ref>[http://www.globalrph.com/narcoticonv.htm www.globalrph.com/narcoticonv.htm]</ref> The laevo isomer is the source of the narcotic properties of the racemic drug Dromoran, but the dextro isomers are also useful in medicine: in addition to acting on [[Sigma-1_receptor|sigma receptors]], the O-methyl derivative of its dextrorotary isomer, [[dextromethorphan]], is a common [[NMDA receptor]] antagonist and pro-drug to [[dextrorphan]].<ref> Brookoff D. ''Hospital Practice''. 2000;35:45-59.</ref> Oral doses of levorphanol come in 2 mg and 4 mg strengths or [[subcutaneous]] injection every 6 to 8 hours. |
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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 mg levorphanol is equivalent to 15 mg morphine).{{Citation needed|date=March 2017}} |
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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> |
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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" /> |
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==Chemistry== |
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[[File:Levorphanol and dextrorphan.png|thumb|left|Levorphanol and its stereoisomer dextrorphan, the enantiomers of the racemic mixture racemorphan.]] |
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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. |
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==Society and culture== |
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===Name=== |
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''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" /> |
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===Availability=== |
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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" /> |
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===Legality=== |
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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 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> |
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== See also == |
== See also == |
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* [[ |
* [[Cough syrup]] |
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* [[Racemorphan]]; [[Dextrorphan]]; |
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* [[Levomethorphan]] |
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* [[Noscapine]] |
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* [[Codeine]]; [[Pholcodine]] |
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* [[Dextromethorphan]]; [[Dimemorfan]] |
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* [[Butamirate]] |
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* [[Pentoxyverine]] |
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* [[Tipepidine]] |
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* [[Cloperastine]]; [[Levocloperastine]] |
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== References == |
== References == |
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{{Reflist|2}} |
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{{Analgesics}} |
{{Analgesics}} |
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{{Neuropathic pain and fibromyalgia pharmacotherapies}} |
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{{Adrenergics}} |
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{{ |
{{Hallucinogens}} |
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{{Serotonergics}} |
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| title = [[Pharmacodynamics]] |
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{{GABA receptor modulators}} |
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{{Glycine receptor modulators}} |
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{{Ionotropic glutamate receptor modulators}} |
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{{Opioid receptor modulators}} |
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[[Category: |
[[Category:Delta-opioid receptor agonists]] |
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[[Category:Dissociative drugs]] |
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[[Category:Enantiopure drugs]] |
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[[Category:Euphoriants]] |
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[[Category:GABA receptor antagonists]] |
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[[Category:German inventions]] |
[[Category:German inventions]] |
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[[Category:Glycine receptor antagonists]] |
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[[Category:Kappa-opioid receptor agonists]] |
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[[Category:Morphinans]] |
[[Category:Morphinans]] |
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[[Category:Mu-opioid receptor agonists]] |
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[[Category:NMDA receptor antagonists]] |
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[[Category:Nociceptin receptor agonists]] |
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[[Category:Phenols]] |
[[Category:Phenols]] |
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[[Category:Serotonin–norepinephrine reuptake inhibitors]] |
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[[Category:Synthetic opioids]] |
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{{analgesic-stub}} |
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[[pl:Leworfanol]] |
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[[ru:Леворфанол]] |
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[[fi:Levorfanoli]] |
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[[sv:Levorfanol]] |