Levorphanol

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 458437606

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

| image = Levorphanol2DCSD2.svg

| image_class = skin-invert-image

| width = 190px

| alt = Structural formula

| image2 = Levorphanol molecule ball.png

| width2 = 200px

| alt2 = Ball-and-stick model

| pronounce =

| tradename = Levo-Dromoran

| Drugs.com = {{drugs.com|monograph|levo-dromoran}}

| MedlinePlus = a682020

| pregnancy_US = C

| legal_AU = S8

| legal_BR = A1

| legal_BR_comment = {{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}}

| legal_CA = Schedule I

| legal_US = Schedule II

| legal_UK= Class A

| legal_DE = Anlage II

| routes_of_administration = Oral, intravenous, subcutaneous, intramuscular

| bioavailability = 70% (oral); 100% (IV)

| protein_bound = 40%

| metabolism = Hepatic

| elimination_half-life = 11–16 hours

| IUPHAR_ligand = 7595

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 77-07-6

| ATC_prefix = None

| ATC_suffix =

| ATC_supplemental =

| PubChem = 5359272

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00854

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 16736212

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 27618J1N2X

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08123

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 592

| 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}}

| 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = JAQUASYNZVUNQP-USXIJHARSA-N

| synonyms = Ro 1-5431

}}

Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain.{{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–}}{{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–}}{{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– }} It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.

It was first described in Germany in 1946.{{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}} The drug has been in medical use in the United States since 1953.{{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 }}

Pharmacology

Levorphanol acts predominantly as an agonist of the 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). Levorphanol, similarly to certain other opioids, also acts as a glycine receptor antagonist and GABA receptor antagonist at very high concentrations.{{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– }} 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}}

Relative to morphine, levorphanol lacks complete cross-tolerance{{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 }} and possesses greater intrinsic activity at the MOR. 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.{{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 }} Levorphanol's exceptionally high analgesic efficacy in the treatment of neuropathic pain is also conferred by its action on serotonin and norepinephrine transporters, similar to the opioids tramadol and tapentadol, and mutually complements the analgesic effect of its NMDA receptor antagonism.{{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 }}

Levorphanol shows a high rate of psychotomimetic side effects such as hallucinations and delirium, which have been attributed to its binding to and activation of the KOR.{{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– }} At the same time however, activation of this receptor as well as of the DOR have been determined to contribute to its analgesic effects.

Chemistry

File:Levorphanol and dextrorphan.png

Chemically, levorphanol belongs to the morphinan class and is (−)-3-hydroxy-N-methyl-morphinan. 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 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 INN, BAN, and DCF. As the medically used tartrate salt, the drug is also known as levorphanol tartrate (USAN, BANM). The former developmental code name of levorphanol at Roche was Ro 1-5431.

=Availability=

As the tartrate salt, levorphanol is marketed by Hikma Pharmaceuticals USA Inc.{{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}} and Virtus Pharmaceuticals in the U.S., and Canada under the brand name Levo-Dromoran.

=Legality=

Levorphanol is listed under the Single Convention On Narcotic Drugs 1961 and is regulated like morphine in most countries. In the U.S., it is a Schedule II Narcotic controlled substance with a DEA 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).{{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}}