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| Clinical data | |
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| Trade names | Miltown,Equanil,Meprospan,Amepromat,Quivet,Zirponand, and many others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682077 |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Eliminationhalf-life | 10 hours |
| Excretion | Renal |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.306 |
| Chemical and physical data | |
| Formula | C9H18N2O4 |
| Molar mass | 218.253 g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.229 g/cm3 |
| Melting point | 105 to 106 °C (221 to 223 °F) |
| Boiling point | 200 °C (392 °F) to 210 °C (410 °F) |
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Meprobamate—marketed asMiltown byWallace Laboratories andEquanil byWyeth, among others—is acarbamate derivative used as ananxiolytic drug. It was the best-sellingminor tranquilizer for a time, but has largely been replaced by thebenzodiazepines due to their widertherapeutic index (lower risk of toxicity at therapeutically prescribed doses) and lower incidence of serious side effects.
Frank Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound calledmephenesin (or myanesin) calmed laboratory rodents without actually sedating them.[2] Berger subsequently referred to this “tranquilizing” effect in a now-historic article, published by theBritish Journal of Pharmacology in 1946.[3][4] However, three major drawbacks existed to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain (resulting in a very lowtherapeutic index), and a weak activity.[5]
In May 1950, after moving toCarter Products in New Jersey, Berger and a chemist, Bernard John Ludwig, synthesized a chemically related tranquilizing compound, meprobamate, that overcame these three drawbacks.[6] Wallace Laboratories, a subsidiary of Carter Products, bought the license and named their new product "Miltown" after the borough ofMilltown, New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining fame for its seemingly miraculous effects.[7] It has since been marketed under more than 100 trade names, from Amepromat through Quivet to Zirpon.[8]
A December 1955 study of 101 patients at theMississippi State Hospital inWhitfield, Rankin County, Mississippi, found meprobamate useful in the alleviation of "mental symptoms": 3% of patients made a complete recovery, 29% were greatly improved, 50% were somewhat better, while 18% realized little change. Self-destructive patients became cooperative and calmer, and experienced a resumption of logical thinking. In 50% of the cases, relaxation brought about more favorable sleep habits. Following the trial,hydrotherapy and all types ofshock treatment were subsequently halted.[9] Meprobamate was found to help in the treatment of alcoholics by 1956.[10] By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written.[11] Berger, clinical director of Wallace Laboratories, described it as a relaxant of thecentral nervous system, whereas othertranquilizers suppressed it. AUniversity of Michigan study found that meprobamate affected driving skills. Though patients reported being able to relax more easily, meprobamate did not completely alleviate their tense feelings. The disclosures came at a special scientific meeting at theBarbizon Plaza Hotel inNew York City, at whichAldous Huxley addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness", in the next few years.[12]
Meprobamate was one of the first drugs to be widely advertised to the general public, with userMilton Berle promoting the drug heavily on his television show, calling himself 'Uncle Miltown'.[13] Miltown soon became ubiquitous in 1950s American life, with 1 in 20 Americans having used it by late 1956,[14] and popular comedians making as many jokes about the drug as they did aboutElvis Presley.[15]
In January 1960, Carter Products, Inc. and American Home Products Corporation (which marketed meprobamate as Equanil) were charged with having conspired to monopolize the market in mild tranquilizers. It was revealed that the sale of meprobamate earned $40,000,000 for the defendants. Of this amount, American Home Products accounted for about two-thirds and Carter about one-third. The U.S. government sought an order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it.[16]
In April 1965, meprobamate was removed from the list of tranquilizers when experts ruled that the drug was asedative, instead. TheU.S. Pharmacopoeia published the ruling. At the same time, theMedical Letter disclosed that meprobamate could be addictive at doses not much above recommended.[17] In December 1967, meprobamate was placed under abuse control amendments to theFood, Drug and Cosmetic Act. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.[18]
Production continued throughout the 1960s, but by 1970, meprobamate was listed as a controlled substance after it was discovered to cause physical and psychological dependence.
On January 19, 2012, theEuropean Medicines Agency withdrew marketing authorization in theEuropean Union for all medicines containing meprobamate, "due to serious side effects seen with the medicine." The Agency's Committee for Medicinal Products for Human Use "concluded that the benefits of meprobamate do not outweigh its risks."[19] In October 2013, Canada also withdrew marketing authorization.[20]
Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers ofbarbiturates and acts at the barbiturate binding site (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties againstabsence seizures, but can exacerbate generalizedtonic-clonic seizures.
Meprobamate's mechanism of action is not completely known. It has been shown in animal studies to have effects at multiple sites in the central nervous system, including thethalamus andlimbic system. Meprobamate binds toGABAA receptors[21][22] which interruptsneuronal communication in thereticular formation andspinal cord, causing sedation and altered perception of pain. Meprobamate has the ability to activate currents even in the absence of GABA.[21] This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (includingalcohol). It is also a potentadenosine reuptake inhibitor.[23][24] Related drugs includecarisoprodol andtybamate (prodrugs of meprobamate),phenprobamate,felbamate,mebutamate, andmethocarbamol.
Meprobamate is licensed[where?] for the short-term relief of anxiety, although whether the purported antianxiety effects of meprobamate are separable from its sedative effects is not known. Its effectiveness as a selective agent for the treatment of anxiety has not been proven in humans,[25] and is not used as often as the benzodiazepines for this purpose.
Meprobamate is available in 200- and 400-mg tablets for oral administration. It is also a component of the combination drugEquagesic (discontinued in the UK in 2002), acting as amuscle relaxant.
Meprobamate, like barbiturates, possesses an analgesic/anesthetic potential. It is also found as a component of the combination analgesic Stopayne capsules [along withparacetamol (acetaminophen),caffeine andcodeine phosphate].
Symptoms of meprobamate overdose include drowsiness, headache, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock.[26] Death has been reported with ingestion of as little as 12 g of meprobamate and survival with as much as 40 g. In an overdose, meprobamate tablets may form a gastricbezoar, requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration ofactivated charcoal should be considered even after 4 or more hours or if levels are rising.[27]
Meprobamate is aSchedule IV drug (S5 in South Africa)[28] under theConvention on Psychotropic Substances. With protracted use, it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that ofbarbiturates andalcohol (delirium tremens). For this reason, discontinuation is often achieved through an extended regimen of slowly decreasing doses over a period of weeks or even months. Alternatively, the patient may be switched to a longer-actinggabaergic agent, such asdiazepam (in a manner similar to the use ofmethadone therapy for opiate addiction), before attempting tapering.
While an acutecerebral edema is widely believed to be the initial cause of actor and martial artistBruce Lee's death in 1973, another factor which may have compounded and thereby contributed to Lee's death, was his decision to take Equagesic (a brand which combined meprobamate and aspirin).[29]
"In the January 2008 issue of Drug Safety Update, a stop press article announced the recent European review ofcarisoprodol for which the Committee for Medicinal Products for Human Use concluded that the risks of treatment outweigh the benefits. This review was triggered by concerns from the Norwegian Medical Agency that carisoprodol (converted to meprobamate after administration) was associated with increased risk of abuse, addiction, intoxication, and psychomotor impairment." February 2008.[30]
The European Medicines Agency recommended suspension of marketing authorisations for meprobamate-containing medicines in the European Union in January 2012.
Meprobamate, 2-methyl-2-propyl-1,3-propanediol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules offormaldehyde and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate via successive reactions withphosgene andammonia.
