Dextromethorphan
Systematic (IUPAC) name
(4bS,8aR,9S)-3-Methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene
Clinical data
Trade names Robitussin, Delsym, DM, DexAlone, Duract
AHFS/Drugs.com
MedlinePlus
Pregnancy cat.
Legal status
Low
Routes Oral
Pharmacokinetic data
Bioavailability 11%[1]
Metabolism Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Half-life 2-4 hours (extensive metabolisers); 24 hours (poor metabolisers)[2]
Excretion Renal
Identifiers
CAS number  YesY
ATC code R05
PubChem
DrugBank
ChemSpider  YesY
UNII  YesY
KEGG  YesY
ChEBI  N
ChEMBL  YesY
Chemical data
Formula C18H25NO 
Mol. mass 271.40 g/mol
Physical data
Melt. point 111 °C (232 °F)
 N   

Dextromethorphan (DXM or DM) is an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, including generic labels and store brands, Benylin DM, Mucinex DM, Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, and others. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder.[3]

DXM is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen. Its mechanism of action is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor[4] and a sigma-1 receptor agonist.[5][6] DXM and its major metabolite, dextrorphan, also acts as an NMDA receptor antagonist at high doses, which produces effects similar to, yet distinct from, the dissociative states created by other dissociative anaesthetics such as ketamine and phencyclidine. As well, the metabolite 3-methoxymorphinan of dextrorphan (thus a second-level metabolite of DXM) produces local anesthetic effects in rats with potency above dextrorphan, but below that of DXM.[7]

Medical use

Generic Dextromethorphan syrup.

The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants.[8]

A 2011 Cochrane systematic review of randomized controlled trials comparing dextromethorphan, diphenhydramine, and honey for treating cough symptoms in children found that dextromethorphan and honey were similarly effective at reducing cough frequency.[9]

A combination of dextromethorphan and quinidine, a CYP2D6 inhibitor, has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis.[10] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.[11] In 2010, the FDA approved the combination product dextromethorphan/quinidine (Nuedexta) for the treatment of pseudobulbar affect (PBA).

Dextromethorphan has been shown to be effective in treating opioid withdrawal. At doses of 2 mg/kg in rats all signs of opioid withdrawal were eliminated.[12]

Recreational use

Dextromethorphan gel capsules

Over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug.[13] At doses much higher than medically recommended, DXM and its major metabolite, dextrorphan, acts as an NMDA receptor antagonist, which produces effects similar to, yet distinct from, the dissociative hallucinogenic states created by other dissociative anaesthetics such as ketamine and phencyclidine.[14] It may produce distortions of the visual field - feelings of dissociation, distorted bodily perception, and excitement, as well as a loss of sense of time. Some users report stimulant-like euphoria, particularly in response to music. Dextromethorphan usually provides its recreational effects in a non-linear fashion, so that they are experienced in significantly varied stages. These stages are commonly referred to as "plateaus".[15]

Adverse effects

Side effects of dextromethorphan use can include:[2][8][16]

At normal doses:

Rare side effects include respiratory depression.[8] It is considered less addictive than the other common weak opioid cough suppressant, codeine.[2]

At doses three to 10 times the recommended therapeutic dose:[17]

  • Increased energy
  • Increased confidence
  • Mild nausea
  • Restlessness
  • Insomnia
  • "Speeding"/talking fast
  • Feelings of increased strength
  • Enlargened pupils/glazed eyes (but not red)

At dosages 15 to 75 times the recommended therapeutic dose:[17]

Dextromethorphan can also cause other gastrointestinal disturbances. It had been thought to cause WHO Committee on Drug Dependence.[20]

Contraindications

Because dextromethorphan can trigger a histamine release (allergic reaction), atopic children, who are especially susceptible to allergic reactions, should be administered dextromethorphan only if absolutely necessary, and only under the strict supervision of a healthcare professional.[16]

Drug interactions

Dextromethorphan should not be taken with monoamine oxidase inhibitors[16] due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body. Dextromethorphan can also cause serotonin syndrome when used with SSRI medicines, an interaction which has been documented in clinical cases where dextromethorphan is taken at recreational doses. The link between therapeutic dosages of dextromethorphan and serotonin syndrome has been suggested to be less conclusive.[4]

Food interactions

Caution should be exercised when taking dextromethorphan when drinking [21]) generally are recommended to be avoided while using dextromethorphan and numerous other medications.

Laboratory testing

Testing for this drug is done either by blood or by urine. Blood can be either serum or plasma. Urine requires only 2 ml minimum.

Chemistry

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As the pure free base, dextromethorphan occurs as an odorless, white to slightly yellow crystalline powder. It is freely soluble in chloroform and insoluble in water. Dextromethorphan is commonly available as the monohydrated hydrobromide salt, however some newer extended-release formulations contain dextromethorphan bound to an ion exchange resin based on polystyrene sulfonic acid. Dextromethorphan's specific rotation in water is +27.6° (20 °C, Sodium D-line).

Pharmacology

Pharmacodynamics

Dextromethorphan has been shown to possess the following properties, mainly in binding assays to various receptors of animal tissues. Low Ki values mean strong binding or high affinity; high Ki values mean weak binding to the target or low affinity:

Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptors and opioid receptors, even at high recreational doses. Instead of acting as a direct antagonist of the NMDA receptor itself, dextromethorphan likely functions as a prodrug to its nearly 10-fold more potent metabolite dextrorphan, and this is the true mediator of its dissociative effects.[31] What role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects is not entirely clear.[32]

Pharmacokinetics

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood–brain barrier.

At therapeutic doses, dextromethorphan acts centrally (meaning that it acts on the brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the active metabolite dextrorphan in the liver by the cytochrome P450 enzyme CYP2D6. The average dose necessary for effective antitussive therapy is between 10 and 45 mg, depending on the individual. The International Society for the Study of Cough recommends "an adequate first dose of medication is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."[33]

The duration of action after oral administration is about three to eight hours for dextromethorphan-hydrobromide, and 10 to 12 hours for dextromethorphan-polistirex. Around one in 10 of the Caucasian population has little or no CYP2D6 enzyme activity, leading to long-lived high drug levels.[34]

Metabolism

The first pass through the hepatic portal vein results in some of the drug's being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan (DXO). DXO is the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM),[35] and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine.[16]

A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. O-demethylation of DXM to DXO contributes to at least 80% of the DXO formed during DXM metabolism.[35] As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers.[36] In one study on 252 Americans, 84.3% were found to be "fast" (extensive) metabolizers, 6.8% to be "intermediate" metabolizers, and 8.8% were "slow" metabolizers of DXM.[37] A number of alleles for CYP2D6 are known, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups.

A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRIs and tricyclic antidepressants, some antipsychotics, and the commonly available antihistamine diphenhydramine. Therefore, the potential of interactions exists between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers. DXM is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of DXM.[35]

A number of other CYP enzymes are implicated as minor pathways of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 at N-demethylation of DXM, but, since the average individual has a much lower CYP2B6 content in his/her liver relative to CYP3A4, most N-demethylation of DXM is catalyzed by CYP3A4.[35]

History

The racemic parent compound racemorphan was first described in a Swiss and US patent application from Hoffmann-La Roche in 1946 and 1947, respectively; a patent was granted in 1950.[38] A resolution of the two isomers of racemorphan with tartaric acid was published in 1952,[38] and DXM was successfully tested in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine.[39] DXM was approved by the FDA in 1958 as an over-the-counter antitussive.[38] As had been initially hoped, DXM was a solution for some of the problems associated with the use of codeine phosphate as a cough suppressant, such as sedation and opiate dependence, but like the dissociative anesthetics phencyclidine and ketamine, DXM later became associated with nonmedical use.[38][13]

During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves after a burst in sales because of frequent misuse, and was replaced by cough syrup in an attempt to cut down on abuse.[13] The advent of widespread internet access in the 1990s allowed users to rapidly disseminate information about DXM, and online discussion groups formed around use and acquisition of the drug.[38] As early as 1996, DXM HBr powder could be purchased in bulk from online retailers, allowing users to avoid consuming DXM in syrup preparations.[38] As of January 1, 2012, dextromethorphan is prohibited for sale to minors in the state of California, except with a doctor's prescription.[40]

See also

References

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  3. ^ "Reference Tables: Description and Solubility - D". Retrieved 2011-05-06. 
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  5. ^ Shin EJ, Nah SY, Chae JS, Bing G, Shin SW, Yen TP, Baek IH, Kim WK, Maurice T, Nabeshima T, Kim HC (May 2007). "Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats". Neurochemistry International 50 (6): 791–9.  
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  40. ^ "Senate Bill No. 514". An act to add Sections 11110 and 11111 to the Health and Safety Code, relating to nonprescription drugs. State of California, Legislative Counsel. 

External links

  • U.S. National Library of Medicine: Drug Information Portal - Dextromethorphan
  • Nuedexta (dextromethorphan hydrobromide and quinidine sulfate): Prescribing Information (Original Approval Date FDA: October 29, 2010)