Carisoprodol

Carisoprodol

Systematic (IUPAC) name
2-{[(aminocarbonyl)oxy]methyl}-2-methylpentyl isopropylcarbamate
Clinical data
Trade names	Soma
AHFS/Drugs.com	monograph
MedlinePlus	a682578
Pregnancy cat.	C
Legal status	℞-only (US) , CIV in some states.
Routes	Oral
Pharmacokinetic data
Protein binding	60%
Metabolism	Hepatic (CYP2C19-mediated)
Half-life	2 hours
Excretion	Renal
Identifiers
CAS number	78-44-4 Y
ATC code	M03BA02
PubChem	CID 2576
DrugBank	APRD00417
ChemSpider	2478 Y
UNII	21925K482H Y
KEGG	D00768 Y
ChEBI	CHEBI:3419 Y
ChEMBL	CHEMBL1233 Y
Chemical data
Formula	C12H24N2O4
Mol. mass	260.33 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H24N2O4/c1-5-6-12(4,7-17-10(13)15)8-18-11(16)14-9(2)3/h9H,5-8H2,1-4H3,(H2,13,15)(H,14,16) Y Key:OFZCIYFFPZCNJE-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Carisoprodol is a centrally-acting skeletal muscle relaxant. Carisoprodol is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals.^[1] under the brand name Soma, and in the United Kingdom and other countries under the brand names Sanoma and Carisoma. The drug is available by itself or mixed with aspirin and in one preparation (Soma Compound With Codeine) along with codeine and caffeine as well.

History

On June 1, 1959 several American pharmacologists convened at Wayne State University in Detroit, Michigan to discuss a new drug. The drug, originally thought to have antiseptic properties, was found to have central muscle relaxing properties.^[2] It had been developed by Frank M. Berger at Wallace Laboratories and was named carisoprodol.

Carisoprodol made on the basis of meprobamate, in the hope that it would have better muscle relaxing properties, less potential for abuse, and less risk of overdose than meprobamate.^[3] The substitution of one hydrogen atom with an isopropyl group on one of the carbamyl nitrogens was intended to yield a molecule with new pharmacological properties.

The brand name Soma is shared with the Soma/Haoma of ancient India, a drug mentioned in ancient Sanskrit writings. Various classical and modern researchers have theorised that Soma/Haoma could be anything from ephedra or opium to mushrooms of the genus Amanita with hallucinogenic effects, or other anti-cholinergic-drug containing plant—or a still unknown hallucinogen, stimulant and/or narcotic of unknown chemical class and origin.

Soma is also the name of the fictional drug featured in Aldous Huxley's Brave New World.^[4]

Usage and legal status

Reports from Norway have shown that carisoprodol has abuse potential^[5] as a prodrug of meprobamate and/or potentiator of hydrocodone, dihydrocodeine, codeine and similar drugs. But it continues to be prescribed in North America, alongside orphenadrine and cyclobenzaprine. In Europe, doctors favor the safer alternative, cyclobenzaprine. In the United Kingdom, benzodiazepines are preferred instead. All of the above plus chlorzoxazone are used in Canada.

As of November 2007, carisoprodol (Somadril, Somadril comp.) has been taken off the market in Sweden due to problems with dependence and side effects. The agency overseeing pharmaceuticals considered other drugs used with the same indications as carisoprodol to have the same or better effects without the risks of the drug.^[6] In May 2008 it was taken off the market in Norway as well.^[7]

In the EU, the European Medicines Agency issued a release recommending that member states suspend marketing authorization for this product in the treatment of acute (not chronic) back pain.^[8]

In the United States, carisoprodol was not a federally controlled substance, as of February 2010. However it is classified as a schedule IV controlled substance by the states of Alabama, Arizona, Arkansas, Florida, Georgia, Hawaii, Illinois, Indiana, Kentucky, Louisiana, Massachusetts, Minnesota, Mississippi, New Mexico, Nevada, Oklahoma, Oregon and Texas (scheduled using the state's new controlled substance program which requires physicians to obtain, and include, a state "DPS" number as well as a DEA number on all controlled substances prescriptions), Utah,^[9] and Washington. It is a Schedule IV controlled substance in West Virginia.^[10] The rest of the United States, excluding the above named states, falls under the DEA scheduling for the medication, which considers carisoprodol a non-scheduled chemical, meaning that carisoprodol is considered a general prescription medication by the federal government of the United States, with oversight provided solely by the U.S. Food and Drug Administration (FDA).^[11]

Misuse

On March 26, 2010 the DEA issued a Notice of Hearing on proposed rule making in respect to the placement of carisoprodol in schedule IV of the Controlled Substances Act. [2]

Recreational users of carisoprodol usually seek its potentially heavy sedating, relaxant, and anxiolytic effects.^[12] Also, because of its potentiating effects on narcotics, it is often abused in conjunction with many opioid drugs.

As with most psychoactive substances, tolerance can form very rapidly. This may cause the user to continually increase dosage to obtain desired effects. As with any drug, this can be dangerous for a multitude of reasons. For this reason, those with a background of addiction should not be prescribed carisoprodol. Because carisoprodol is not a controlled substance, people sometimes think that it will be easier to get a prescription for carisoprodol, compared to other potentially addicting medications (such as narcotics). However, most healthcare providers are quite familiar with the problems associated with carisoprodol. Most healthcare providers react to a request for carisoprodol just as they would react for a request for a controlled substance (usually with caution and sometimes suspicion). Soma® (carisoprodol) is a muscle relaxant that is available by prescription only. Because carisoprodol is not a controlled substance, many people assume that it has no potential for misuse. However, carisoprodol is actually a commonly misused medication. Many healthcare providers believe that carisoprodol should be reclassified to be a Schedule IV controlled substance, which would put it under the scrutiny of the Drug Enforcement Administration (DEA).^[13]

The metabolism of carisoprodol may affect the potential for misuse. Carisoprodol itself is probably not addicting. However, the liver metabolizes carisoprodol into meprobamate, a different medication. Meprobamate has significant anti-anxiety properties and is a controlled substance with the potential to be misused. Theoretically, it is possible that people whose livers are more efficient at metabolizing carisoprodol into meprobamate may be more likely to misuse carisoprodol.

Effects

• Analgesia
• Anxiolysis
• Muscle relaxation (and relief from hypertonia)
• Sedation
• Somnolence

Side effects

The usual dose of 350 mg is unlikely to engender prominent side effects other than somnolence, and possibly mild euphoria or dysphoria. The medication is well tolerated and without adverse effects in the majority of patients for which it is indicated. In some patients however, and/or early in therapy, carisoprodol can have the full spectrum of sedative side effects and can impair the patient's ability to operate a firearm, motorcycle, and other machinery of various types especially when taken with medications containing alcohol, in which case an alternative medication would be considered. The intensity of the side effects of carisoprodol tends to lessen as therapy continues, as is the case with many other drugs.

The interaction of carisoprodol with opioids, essentially all opioids and other centrally-acting analgesics, but especially those of the codeine-derived subgroup of the semi-synthetic class (codeine, ethylmorphine, dihydrocodeine, hydrocodone, oxycodone, nicocodeine, benzylmorphine, the various acetylated codeine derivatives including acetyldihydrocodeine, dihydroisocodeine, nicodicodeine and others) which allows the use of a smaller dose of the opioid to have a given effect, is useful in general and especially where injury and/or muscle spasm is a large part of the problem. The potentiation effect is also useful in other pain situations and is also especially useful with opioids of the open-chain class such as methadone, levomethadone, ketobemidone, phenadoxone and others. In recreational drug users, deaths have resulted from carelessly combining overdoses of hydrocodone and carisoprodol.

Meprobamate and other muscle relaxing drugs often were subjects of misuse in the 1950s and 1960s.^[14][15] Overdose cases were reported as early as 1957 and have been reported on several occasions since then.^{[16][17][18][19][20][21][22]}

Carisoprodol, meprobamate, and related drugs such as tybamate have the potential to produce physical dependence with prolonged use. Withdrawal of the drug after extensive use may require hospitalization in medically-compromised patients.

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf).

Pharmacokinetics

Carisoprodol has a rapid, 30 minute onset of action, with the aforementioned effects lasting for approximately 2–6 hours. It is metabolized in the liver via the cytochrome P450 oxidase isozyme CYP2C19, excreted by the kidneys and has an approximate 8 hour half-life. A considerable proportion of carisoprodol is metabolized to meprobamate, which is a known drug of abuse and dependence; this could account for the abuse potential of carisoprodol.

Chemistry

Carisoprodol is a carbamic acid ester. It is a racemic mixture of two stereoisomers.

Carisoprodol is synthesized by reacting 2-methyl-2-propylpropane-1,3-diol with 1 molar equivalent of phosgene, forming the chloroformate, from which carbamate is formed by reacting it with isopropylamine. Reacting this with either urethane or sodium cyanate gives carisoprodol.

• F.M. Berger, B.J. Ludwig, U.S. Patent 2,937,119 (1960).

Notes

References

1. ^ Meda Pharmaceuticals Inc. of Somerset, New Jersey is the U.S. subsidiary of Meda AB of Solna, Sweden "Meda Pharmaceuticals Inc.". http://www.medpointepharma.com/index.html/. Retrieved June 22, 2010 
2. ^ Miller JG, ed. The pharmacology and clinical usefulness of carisoprodol. Detroit:Wayne State University; 1959.
3. ^ Berger F, Kletzkin M, Ludwig B, Margolin S. The history, chemistry, and pharmacology of carisoprodol. Annals of the New York Academy of Sciences. 1959;86:90-107
4. ^ "Brave New Soma - TIME". Time. 1959-06-08. http://www.time.com/time/magazine/article/0,9171,892617,00.html. Retrieved 2007-08-20. 
5. ^ Bramness JG, Furu K, Engeland A, . (2007). "Carisoprodol use and abuse in Norway. A pharmacoepidemiological study". Br J Clin Pharmacol 64 (2): 210–218. doi:10.1111/j.1365-2125.2007.02847.x. PMC 2000626. PMID 17298482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2000626. 
6. ^ "Marknadsföringen av Somadril och Somadril comp rekommenderas upphöra tillfälligt". 16 NOV 2007. http://www.lakemedelsverket.se/Tpl/NewsPage____6712.aspx. Retrieved 9 MAY 2009. 
7. ^ "Somadril trekkes fra markedet". 20 April 2008. http://www.legemiddelverket.no/templates/InterPage____71544.aspx. Retrieved 12 March 2010. 
8. ^ "Carisprodol press release" (PDF). EMEA. http://www.emea.europa.eu/pdfs/human/press/pr/Pressrelease_Carisoprodol_52046307en.pdf. Retrieved 2008-05-12. 
9. ^ [1]
10. ^ Respective state Boards of Pharmacy and controlled substance authorities.
11. ^ "Florida Senate House Bill 351" (PDF). http://www.flsenate.gov/data/session/2002/House/bills/analysis/pdf/2002h0351z.cpcs.pdf. 
12. ^ "DEA Drugs & Chemicals of Concern "Carisoprodol"". http://www.deadiversion.usdoj.gov/drugs_concern/carisoprodol.htm. Retrieved 29 April 2011. 
13. ^ Fass JA.. Ann Pharmacother. 2010 Dec;44(12):1962-7. Epub 2010 Nov 9.. http://www.ncbi.nlm.nih.gov/pubmed/21062909. 
14. ^ Kamin I, Shaskan D. (1959). "Death due to massive overdose of meprobamate". Am J Psychiatry 115 (12): 1123–1124. PMID 13649976. 
15. ^ Hollister LE (1983). "The pre-benzodiazepine era". J Psychoactive Drugs 15 (1-2): 9–13. PMID 6350551. 
16. ^ Gaillard Y, Billault F, Pepin G (1997). "Meprobamate overdosage: a continuing problem. Sensitive GC-MS quantitation after solid phase extraction in 19 fatal cases". Forensic Sci.Int 86 (3): 173–180. doi:10.1016/S0379-0738(97)02128-2. PMID 9180026. 
17. ^ Allen MD, Greenblatt DJ, Noel BJ (1977). "Meprobamate overdosage: a continuing problem". Clin Toxicol 11 (5): 501–515. doi:10.3109/15563657708988216. PMID 608316. 
18. ^ Kintz P, Tracqui A, Mangin P, Lugnier AA (1988). "Fatal meprobamate self-poisoning". Am J Forensic Med Pathol 9 (2): 139–140. doi:10.1097/00000433-198806000-00009. PMID 3381792. 
19. ^ Eeckhout E, Huyghens L, Loef B, Maes V, Sennesael J (1988). "Meprobamate poisoning, hypotension and the Swan-Ganz catheter". Intensive Care Med 14 (4): 437–438. doi:10.1007/BF00262904. PMID 3403779. 
20. ^ Lhoste F, Lemaire F, Rapin M (1977). "Treatment of hypotension in meprobamate poisoning". N Engl J Med 296 (17): 1004. doi:10.1056/NEJM197704282961717. PMID 846530. 
21. ^ Bedson H (1959). "Coma due to meprobamate intoxication. Report of a case confirmed by chemical analysis". Lancet 273 (1): 288–290. doi:10.1016/S0140-6736(59)90209-0. PMID 13632000. 
22. ^ Blumberg A, Rosett H, Dobrow A (1959). "Severe hypotension reactions following meprobamate overdosage". Ann Intern Med 51: 607–612. PMID 13801701. 

External links

• Drug information
• Drug information for Patients, Drug information for Professionals
• "SOMA 250 mg (carisoprodol) for Painful Musculoskeletal Conditions". Meda Pharmaceuticals Inc.. http://www.soma250.com/. Retrieved June 22, 2010.