Levorphanol (brand name Levo-Dromoran) is an

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

medication used to treat moderate to severe

pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...

. It is the

levorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

of the compound

racemorphan Racemorphan, or morphanol, is the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol, each with differing pharmacology and effects: * Dextrorphan - an antitussive and dissociative hallucinogen ( NMDA receptor antagonist) * L ...

. Its

dextrorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

counterpart is

dextrorphan Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. D ...

. It was first described in

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...

in 1946. The drug has been in medical use in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

since 1953.

Pharmacology

Levorphanol acts predominantly as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

(MOR), but is also an agonist of the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...

(DOR),

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

(KOR), and the

nociceptin receptor The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the ''OPRL1'' (opioid receptor-like 1) gene. The nociceptin receptor ...

(NOP), as well as an

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

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. Levorphanol is 6 to 8 times as potent as morphine at the MOR. Relative to morphine, levorphanol lacks complete

cross-tolerance Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor o ...

and possesses greater

intrinsic activity Intrinsic activity (IA) and efficacy refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its mol ...

at the MOR. The

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ( ...

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 Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin ...

or the

phenylpiperidine Phenylpiperidines are chemical compounds with a phenyl moiety directly attached to piperidine. There are a variety of pharmacological effects associated with phenylpiperidines including morphine-like activity or other central nervous system effects ...

ketobemidone Ketobemidone, sold under the brand name Ketogan among others, is a powerful synthetic opioid painkiller. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted, in part, by its m ...

, make levorphanol useful for types of pain that other analgesics may not be as effective against, such as

neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...

. Levorphanol's exceptionally high analgesic efficacy in the treatment of neuropathic pain is also conferred by its action on

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

and

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium- ...

s, similar to the opioids

tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...

and

tapentadol Tapentadol, brand names Nucynta among others, is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Analgesia occurs wit ...

, and mutually complements the analgesic effect of its NMDA receptor antagonism. Levorphanol shows a high rate of

psychotomimetic A drug with psychotomimetic (also known as psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms following the administrati ...

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s such as

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

s and

delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...

, which have been attributed to its binding to and activation of the KOR. 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

Chemically, levorphanol belongs to the

morphinan 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. Structure Morphinan has a phenanthrene core stru ...

class and is (−)-3-hydroxy-''N''-methyl-morphinan. It is the "left-handed" (

)

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

, the

racemic mixture In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

of the two stereoisomers with differing

pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...

. The "right-handed" (dextrorotatory) enantiomer of racemorphan is

(DXO), an

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

, potent

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

hallucinogen Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorized ...

(

), and weakly active opioid. DXO is an

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

of the

pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

(DXM), which, analogously to DXO, is an enantiomer of the racemic mixture

racemethorphan Methorphan comes in two isomeric forms, each with differing pharmacology and effects: * Dextromethorphan - An over-the-counter cough suppressant, as well as dissociative hallucinogen. * Levomethorphan - A potent opioid analgesic that was never ...

along with

levomethorphan 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 the racemethorphan are quite different, with ...

, the latter of which has similar properties to those of levorphanol.

Society and culture

Name

''Levorphanol'' is the

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, BAN, and DCF. As the medically used

tartrate A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−. The main forms of tartrates used commercially are pure crystalline ta ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

, the drug is also known as ''levorphanol tartrate'' (

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

, BANM). The former developmental code name of levorphanol at

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

was ''Ro 1-5431''.

Availability

As the tartrate salt, levorphanol is marketed by Sentynl Therapeutics and Virtus Pharmaceuticals in the U.S., and

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

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 A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...

with a

DEA The Drug Enforcement Administration (DEA; ) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within the U.S. It is the lead agency for domestic en ...

ACSCN Administrative Controlled Substances Code Number (ACSCN) is a number assigned to drugs listed on the schedules created by the US Controlled Substances Act (CSA). The ACSCN is defined in 21 CFR § 1308.03(a). Each chemical/drug on one of the schedu ...

of 9220 and 2013 annual aggregate manufacturing quota of 4.5 kilos. The salts in use are the tartrate (free base conversion ratio 0.58) and

hydrobromide In chemistry, a hydrobromide is an acid salt resulting, or regarded as resulting, from the reaction of hydrobromic acid with an organic base (e.g. an amine). The compounds are similar to hydrochlorides. Some drugs are formulated as hydrobromides, ...

(0.76).

References

{{Navboxes , title =

Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

, titlestyle = background:#ccccff , list1 = {{GABA receptor modulators {{Glycine receptor modulators {{Ionotropic glutamate receptor modulators {{Monoamine reuptake inhibitors {{Opioid receptor modulators Delta-opioid receptor agonists Dissociative drugs Enantiopure drugs Euphoriants GABA receptor antagonists German inventions Glycine receptor antagonists Kappa-opioid receptor agonists Morphinans Mu-opioid receptor agonists NMDA receptor antagonists Nociceptin receptor agonists Phenols Serotonin–norepinephrine reuptake inhibitors Synthetic opioids