Levorphanol

Levorphanol
Clinical data
Trade names	Levo-Dromoran
Other names	Ro 1-5431
AHFS/Drugs.com	Monograph
MedlinePlus	a682020
Routes of; administration	Oral, intravenous, subcutaneous, intramuscular
ATC code	None;
Legal status
Legal status	AU: S8 (Controlled drug); BR: Class A1 (Narcotic drugs); CA: Schedule I; DE: Anlage II (Authorized trade only, not prescriptible); UK: Class A; US: Schedule II;
Pharmacokinetic data
Bioavailability	70% (oral); 100% (IV)
Protein binding	40%
Metabolism	Hepatic
Elimination half-life	11–16 hours
Identifiers
	IUPAC name (1R,9R,10R)-17-Methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-ol;
CAS Number	77-07-6 ;
PubChem CID	5359272;
IUPHAR/BPS	7595;
DrugBank	DB00854 ;
ChemSpider	16736212 ;
UNII	27618J1N2X;
KEGG	D08123 ;
ChEMBL	ChEMBL592 ;
CompTox Dashboard (EPA)	DTXSID3023213 ;
ECHA InfoCard	100.000.912
Chemical and physical data
Formula	C17H23NO
Molar mass	257.377 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN1CC[C@]23CCCC[C@H]2[C@H]1Cc4c3cc(O)cc4;
	InChI InChI=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 ; Key:JAQUASYNZVUNQP-USXIJHARSA-N ;
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Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain.^[1]^[3]^[4] It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.

It was first described in Germany in 1946.^[5] The drug has been in medical use in the United States since 1953.^[6]

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).^[6] Levorphanol, similarly to certain other opioids, also acts as a glycine receptor antagonist and GABA receptor antagonist at very high concentrations.^[7] 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]}

Relative to morphine, levorphanol lacks complete cross-tolerance^[8] and possesses greater intrinsic activity at the MOR.^[8] 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.^[9] 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.^[10]

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.^[11] At the same time however, activation of this receptor as well as of the DOR have been determined to contribute to its analgesic effects.^[11]

Chemistry

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.^[8] 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.^[1]^[3]^[4] As the medically used tartrate salt, the drug is also known as levorphanol tartrate (USAN, BANM).^[1]^[4] The former developmental code name of levorphanol at Roche was Ro 1-5431.^[1]^[4]

Availability

As the tartrate salt, levorphanol is marketed by Hikma Pharmaceuticals USA Inc.^[12] and Virtus Pharmaceuticals in the U.S., and Canada under the brand name Levo-Dromoran.^[3]

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).^[13]

References

^ ^a ^b ^c ^d ^e Elks J (November 14, 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 656–. ISBN 978-1-4757-2085-3.
^ Anvisa (March 31, 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published April 4, 2023). Archived from the original on August 3, 2023. Retrieved August 16, 2023.
^ ^a ^b ^c Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 606–. ISBN 978-3-88763-075-1.
^ ^a ^b ^c ^d Morton IK, Hall JM (December 6, 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 165–. ISBN 978-94-011-4439-1.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 527. ISBN 978-3-527-60749-5.
^ ^a ^b Gudin J, Fudin J, Nalamachu S (January 2016). "Levorphanol Use: Past, Present and Future". Postgraduate Medicine. 128 (1): 46–53. doi:10.1080/00325481.2016.1128308. PMID 26635068. S2CID 3912175.
^ Osborne NN (October 22, 2013). Selected Topics from Neurochemistry. Elsevier Science. pp. 244–. ISBN 978-1-4832-8635-8.
^ ^a ^b ^c Davis MP, Glare PA, Hardy J (2009) [2005]. Opioids in Cancer Pain (2nd ed.). Oxford, UK: Oxford University Press. ISBN 978-0-19-157532-7.
^ Prommer E (March 2007). "Levorphanol: the forgotten opioid". Supportive Care in Cancer. 15 (3): 259–64. doi:10.1007/s00520-006-0146-2. PMID 17039381. S2CID 10916508.
^ Nalamachu S, Gudin J (April 2016). "Levorphanol, another choice in opioid rotation". J Pain. 17 (4): S14. doi:10.1016/j.jpain.2016.01.056.
^ ^a ^b Bruera ED, Portenoy RK (October 12, 2009). Cancer Pain: Assessment and Management. Cambridge University Press. pp. 215–. ISBN 978-0-521-87927-9.
^ "LEVORPHANOL TARTRATE tablet". National Library of Medicine. National Institutes of Health.
^ "Conversion Factors for Controlled Substances". Diversion Control Division. U.S. Department of Justice • Drug Enforcement Administration.

[Elks2014-1] Elks J (November 14, 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 656–. ISBN 978-1-4757-2085-3.

[2] Anvisa (March 31, 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published April 4, 2023). Archived from the original on August 3, 2023. Retrieved August 16, 2023.

[IndexNominum2000-3] Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 606–. ISBN 978-3-88763-075-1.

[MortonHall2012-4] Morton IK, Hall JM (December 6, 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 165–. ISBN 978-94-011-4439-1.

[Fis2006-5] Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 527. ISBN 978-3-527-60749-5.

[GudinFudin2015-6] Gudin J, Fudin J, Nalamachu S (January 2016). "Levorphanol Use: Past, Present and Future". Postgraduate Medicine. 128 (1): 46–53. doi:10.1080/00325481.2016.1128308. PMID 26635068. S2CID 3912175.

[Osborne2013-7] Osborne NN (October 22, 2013). Selected Topics from Neurochemistry. Elsevier Science. pp. 244–. ISBN 978-1-4832-8635-8.

[OUP09-8] Davis MP, Glare PA, Hardy J (2009) [2005]. Opioids in Cancer Pain (2nd ed.). Oxford, UK: Oxford University Press. ISBN 978-0-19-157532-7.

[9] Prommer E (March 2007). "Levorphanol: the forgotten opioid". Supportive Care in Cancer. 15 (3): 259–64. doi:10.1007/s00520-006-0146-2. PMID 17039381. S2CID 10916508.

[10] Nalamachu S, Gudin J (April 2016). "Levorphanol, another choice in opioid rotation". J Pain. 17 (4): S14. doi:10.1016/j.jpain.2016.01.056.

[BrueraPortenoy2009-11] Bruera ED, Portenoy RK (October 12, 2009). Cancer Pain: Assessment and Management. Cambridge University Press. pp. 215–. ISBN 978-0-521-87927-9.

[12] "LEVORPHANOL TARTRATE tablet". National Library of Medicine. National Institutes of Health.

[13] "Conversion Factors for Controlled Substances". Diversion Control Division. U.S. Department of Justice • Drug Enforcement Administration.

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v t e Neuropathic pain and fibromyalgia pharmacotherapies
Monoaminergics	SNRIsTooltip Serotonin–norepinephrine reuptake inhibitor (e.g., duloxetine, milnacipran) TCAsTooltip Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, dosulepin) Opioid MRIsTooltip monoamine reuptake inhibitors (e.g., tapentadol, tramadol)
Ion channel blockers	Anticonvulsants (e.g., gabapentin, pregabalin, mirogabalin, carbamazepine, oxcarbazepine, lacosamide, lamotrigine) Local anesthetics (e.g., lidocaine) Mexiletine TCAsTooltip Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) Ziconotide
Others	Alpha lipoic acid Benfotiamine Botulinum toxin A Bupropion Cannabinoids (e.g., cannabis, dronabinol, nabilone) NMDA receptor antagonists (e.g., ketamine, dextromethorphan, methadone) Opioids (e.g., hydrocodone, morphine, oxycodone, methadone, buprenorphine, tramadol, tapentadol) Sodium oxybate (GHB)