Levorphanol

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Levorphanol
Levorphanol2DCSD2.svg
Levorphanol molecule ball.png
Clinical data
Trade names Levo-Dromoran
Other namesRo 1-5431 [1]
AHFS/Drugs.com Monograph
MedlinePlus a682020
Routes of
administration 		Oral, intravenous, subcutaneous, intramuscular
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Bioavailability 70% (oral); 100% (IV)
Protein binding 40%
Metabolism Hepatic
Elimination half-life 11–16 hours
Identifiers
  • (1R,9R,10R)-17-Methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.912 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H23NO
Molar mass 257.377 g·mol−1
3D model (JSmol)
  • CN1CC[C@]23CCCC[C@H]2[C@H]1Cc4c3cc(O)cc4
  • 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 Yes check.svgY
  • Key:JAQUASYNZVUNQP-USXIJHARSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.

Contents

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. Levorphanol and dextrorphan.png
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]

See also

Related Research Articles

<span class="mw-page-title-main">Recreational use of dextromethorphan</span> Cough suppressant drug susceptible to misuse.

Dextromethorphan, or DXM, a common active ingredient found in many over-the-counter cough suppressant cold medicines, is used as a recreational drug and entheogen for its dissociative effects. Street names include Brownies, Dextro, Drix, Gel, Groove, Lean, Mega-perls, Poor man's ecstasy, Poor man's PCP, Red devils, Robo, Rojo, Rome, Skittles, Sizzurp, Triple Cs, Sky and Velvet.

<span class="mw-page-title-main">Morphine</span> Pain medication of the opiate family

Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: orally; administered under the tongue; via inhalation; injection into a vein, injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via administered into the rectal canal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are sold under the brand names MS Contin and Kadian, among others. Generic long-acting formulations are also available.

<span class="mw-page-title-main">Dextrorphan</span> Psychoactive cough suppressant medication

Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and in high doses a dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6. Dextrorphan is an NMDA antagonist and contributes to the psychoactive effects of dextromethorphan.

<span class="mw-page-title-main">Dextromethorphan</span> Cough suppressant, antidepressant, and dissociative drug

Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropion to serve as a rapid-acting antidepressant in people with major depressive disorder.

<span class="mw-page-title-main">Nalbuphine</span> Opioid analgesic

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

<span class="mw-page-title-main">Butorphanol</span> Opioid analgesic

Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.

<span class="mw-page-title-main">Morphinan</span> Parent compound of opiates/opioids

Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Typical examples include compounds such as morphine, codeine, and dextromethorphan (DXM). Despite related molecular structures, the pharmacological profiles and mechanisms of action between the various types of morphinan substances can vary substantially. They tend to function either as μ-opioid receptor agonists (analgesics), or NMDA receptor antagonists (dissociatives).

<span class="mw-page-title-main">Levomethorphan</span> Opioid analgesic

Levomethorphan (LVM) (INN, BAN) is an opioid analgesic of the morphinan family that has never been marketed. It is the L-stereoisomer of racemethorphan (methorphan). The effects of the two isomers of racemethorphan are quite different, with dextromethorphan (DXM) being an antitussive at low doses and a dissociative hallucinogen at much higher doses. Levomethorphan is about five times stronger than morphine.

<span class="mw-page-title-main">Methorphan</span> Group of stereoisomers

Methorphan comes in two isomeric forms, each with differing pharmacology and effects:

<span class="mw-page-title-main">Dimemorfan</span> Cough suppressant

Dimemorfan (INN), or dimemorfan phosphate (JAN), also known as 3,17-dimethylmorphinan, is an antitussive of the morphinan family that is widely used in Japan and is also marketed in Spain and Italy. It was developed by Yamanouchi Pharmaceutical and introduced in Japan in 1975. It was later introduced in Spain in 1981 and Japan in 1985.

<span class="mw-page-title-main">Tapentadol</span> Opioid analgesic of benzenoid class

Tapentadol, sold under the brand names Nucynta and Palexia among others, is a synthetic opioid analgesic of the benzenoid class with a dual mode of action as a highly selective full agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Tapentadol is used medically for the treatment of moderate to severe pain. It is addictive, a commonly abused drug, and poses a high risk of physical and/or mental dependence.

<span class="mw-page-title-main">Oxilorphan</span> Chemical compound

Oxilorphan is an opioid antagonist of the morphinan family that was never marketed. It acts as a μ-opioid receptor (MOR) antagonist but a κ-opioid receptor (KOR) partial agonist, and has similar effects to naloxone and around the same potency as an MOR antagonist. Oxilorphan has some weak partial agonist actions at the MOR and can produce hallucinogenic/dissociative effects at sufficient doses, indicative of KOR activation. It was trialed for the treatment of opioid addiction, but was not developed commercially. The KOR agonist effects of oxilorphan are associated with dysphoria, which combined with its hallucinogenic effects, serve to limit its clinical usefulness; indeed, many patients who experienced these side effects refused to take additional doses in clinical trials.

<span class="mw-page-title-main">Levallorphan</span> Opioid medication

Levallorphan, also known as levallorphan tartrate (USAN), is an opioid modulator of the morphinan family used as an opioid analgesic and opioid antagonist/antidote. It acts as an antagonist of the μ-opioid receptor (MOR) and as an agonist of the κ-opioid receptor (KOR), and as a result, blocks the effects of stronger agents with greater intrinsic activity such as morphine whilst simultaneously producing analgesia.

<span class="mw-page-title-main">Alazocine</span> Synthetic opioid analgesic

Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.

<span class="mw-page-title-main">Racemorphan</span> Racemic mixture

Racemorphan, or morphanol, is the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol, each with differing pharmacology and effects:

<span class="mw-page-title-main">Cyclorphan</span> Opioid analgesic

Cyclorphan is an opioid analgesic of the morphinan family that was never marketed. It acts as a μ-opioid receptor (MOR) weak partial agonist or antagonist, κ-opioid receptor (KOR) full agonist, and, to a much lesser extent, δ-opioid receptor (DOR) agonist. The drug was first synthesized in 1964 by scientists at Research Corporation. In clinical trials, it had relatively long duration, good absorption, and provided strong pain relief but produced psychotomimetic effects via KOR activation, so its development was not continued.

<span class="mw-page-title-main">Dextrallorphan</span> Chemical compound

Dextrallorphan (DXA) is a chemical of the morphinan class that is used in scientific research. It acts as a σ1 receptor agonist and NMDA receptor antagonist. It has no significant affinity for the σ2, μ-opioid, or δ-opioid receptor, or for the serotonin or norepinephrine transporter. As an NMDA receptor antagonist, in vivo, it is approximately twice as potent as dextromethorphan, and five-fold less potent than dextrorphan.

<span class="mw-page-title-main">(+)-Naloxone</span> Drug

(+)-Naloxone (dextro-naloxone) is a drug which is the opposite enantiomer of the opioid antagonist drug (−)-naloxone. Unlike (−)-naloxone, (+)-naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4. This receptor is involved in immune system responses, and activation of TLR4 induces glial activation and release of inflammatory mediators such as TNF-α and Interleukin-1.

<span class="mw-page-title-main">3-Hydroxymorphinan</span> Chemical compound

3-Hydroxymorphinan (3-HM), or morphinan-3-ol, is a psychoactive drug of the morphinan family. It is the racemic counterpart to norlevorphanol.

<span class="mw-page-title-main">Levomethadone</span> Synthetic opioid

Levomethadone, sold under the brand name L-Polamidon among others, is a synthetic opioid analgesic and antitussive which is marketed in Europe and is used for pain management and in opioid maintenance therapy. In addition to being used as a pharmaceutical drug itself, levomethadone is the main therapeutic component of methadone.

References

  1. 1 2 3 4 5 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.
  3. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 606–. ISBN   978-3-88763-075-1.
  4. 1 2 3 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.
  5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 527. ISBN   978-3-527-60749-5.
  6. 1 2 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.
  7. ↑ Osborne NN (October 22, 2013). Selected Topics from Neurochemistry. Elsevier Science. pp. 244–. ISBN   978-1-4832-8635-8.
  8. 1 2 3 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 .
  11. 1 2 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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