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Meprobamate: A Decade of Experience
Meprobamate: A Decade of Experience FRANK J. AYD, JR., M.D.
• The history of meprobamate is a narrative of a creation, of a struggle against prejudice and resistance to acceptance, and of progress in the pharmacological mastery of the most pervasive of psychiatric symptomsanxiety and tension. In 1945, Berger fortuitously observed that a glycol derivative paralyzed mice without affecting vital functions. Almost seven years later, after careful observations and systematic experimentation and investigation in the laboratory, meprobamate was a reality and ready for clinical trials. At that time no one could have foretold the role this dmg would play in the chemical conquest of psychic disorders. Yet, within a decade, meprobamate became and continues to be the most frequently prescribed psychopharmaceutical. An estimated 80 million patients have been given this tranquilizer and thousands of scientific articles have been written about it. This sum of experience has provided the medical profession with an abundance of data to assess the clinical utility and safety of meprobamate. When meprobamate was introduced for general use in 1955, the attention of the medical world had just become focused on the treatment of mental illnesses with the tranquilizers, chlorpromazine and reserpine. The chemical revolution in psychiatry was causing a change in the clinical course and outlook for psychotics, especially for manics and schizophrenics with severe anxiety, tension, agitation, and psychomotor excitement. Therapeutic optimism was replacing nihilism in mental hospitals throughout the world. However, there remained a need for a drug to treat the troublesome emotional prohlems of the vast number of neurotics and mild psychotics whom physicians encountered daily. Ideally, this compound would be free of most or all of the undesirable effects of the major tranquilizers and would represent a significant advance over the barbiturates. The initial 82
reports of Selling, I Borrus," and others suggested that meprobamate was such a drug. Two years after becoming clinically available, meprobamate was being administered extensively for every conceivable psychiatric condition. Much of its early use was predicated on hopefulness and enthusiasm. As a result, some premature uncritical and unscientific reports appeared. Critics and skeptics, among whom were eminent and influential psychiatrists and pharmacologists, attacked these along with the claims for an tranquilizers. Accompanying these animadversions were reports of side effects, including some of serious nature. These, in turn, were joined with announcements of treatment failures and of controlled trials which indicated that meprobamate was no better than a placebo or barbiturate. Meanwhile, other major and minor tranquilizers were introduced to compete with meprobamate. Nevertheless, physicians continued to prescribe this compound and, as time passed, the evidence showed that meprobamate is a valuable and safe drug. EFFICACY
Anxiety and Tension.-Meprobamate alone is most likely to be beneficial when anxiety and tension are the predominant symptoms, especially in neurotics. When prescribed in adequate doses for properly selected patients, the expectation of prompt amelioration of these target symptoms and associated secondary effects is high. This is particularly true when these specific symptoms occur in previously stable individuals. The more chronic the neurosis and the more immature and labile the basic personality of the patient, the less favorable is the outcome of meprobamate therapy. It is unrealistic to expect meprobamate or any medicine to materially help any individual who since childhood has been unable to cope with even the minor vicissitudes of life without developing anxiety. Likewise, Volume V
MEPROBAMATE: A DECADE OF EXPERIENCE-AYD
although lifelong inadequate personalities may manifest anxiety symptoms, extreme caution should be observed in prescribing meprobamate for such persons. These are the patients who most frequently abuse sedative dmgs, and the risk of habituation in them is high. Such persons can be detected through history as well as behavior in the office, and treatment with meprobamate then can he avoided.
IJepressioll.-Although definitely not a specific antidepressant, meprobamate has heen found of value in depressive states associated with symptoms of anxiety. In such patients, the drug decreases or abolishes the anxiety without enhancing the depression. It may also be useful in reactive depressions and, according to Hollister and his associates," in selected cases of all types of depression. Tucker· reported that 20 of 27 patients with reactive or involutional depression improved when meprobamate was given. Four of these patients exhihited a marked positive change in their status. In contrast, previous sedatives and tranquilizers had not been able to effect a pronounced change in any of these same individuals, and only some improvement was achieved in 12 patients. Psychoses.-Meprobomate is palliative, not curative. The evidence accumulated during the past years clearly shows that this compound is devoid of antipsychotic properties and not suited as the primary dmg for treatment of hospitalized psychotics. Its value in the management of psychoses is limited to patients who have anxiety symptoms independent of or in addition to the basic illness. Usually, these individuals are not hospitalized, have fairly well-preserved personalities, and seldom are recognized as psychotic. They may he beset with acute or chronic anxiety for which meprobamate may be preferable over the phenothiazines or other antipsychotic pharmaceuticals. Aside from this indication, psychotics usually are hest treated with other dmgs, although a combination of meprobamate and an antipsychotic agent is at times quite efficacious. Neurological Disorders.-Earlyexperimental studies in animals showed that meprohamate March-April, 1964
exerted a strong anticonvulsive action. This finding led naturally to an evaluation of its use in epilepsy and other motor disturbances. It was found to be of considerable value in petit mal and related minor epilepsies, where it has heen shown to at least significantly lengthen the intervals hetween attacks." Favorable results also have been achieved in patients with cerebral palsy, spinal-cord injuries, and other conditions. The drug is not indicated for grand mal epilepsy. It may, indeed, precipitate grand mal attacks in patients suffering from hoth petit mal and grand mal epilepsy, hy suppressing petit mal attacks and so permitting the appearance of grand mal seizures.
Behavior Disorders.-Meprohamate ean exert a favorable relaxant effect upon disturhed children with such symptoms as anxiety, sleeplessness, hyperactivity, and uncooperative attitude. The use of the drug makes such children more manageable and permits them to perform effectively in school and general activities. Children with behavior prohlems, such as enuresis, stuttering, and hostility, hecome much more amenable to psychotherapy after meprobamate treatment is initiated. Frank psychoses have heen generally unresponsive. 6 SAFETY
Physicians currently have a justifiable and healthy concern for the side effects and potential dangers of medicines. This should not interfere with providing patients with the possible benefits of drugs with safety established through administration to a multitude of persons, and for periods of time sufficient to reasonably assume that any deleterious effects should have been detected. Meprobamate belongs in this latter category. The low toxicity of this compound becomes more apparent as each year goes on. Most of its side effects are minor and usually occur in the first few days of treatment. Autonomic-blocking, endocrine, or extrapyramidal reactions have not been associated with meprobamate administration. Sedation or drowsiness is the most common side effect. The occurrence and intensity of the effect is contingent upon the sensitivity of the individual patient as well as upon the starting 83
PSYCHOSOMATICS
dosage. Excessive drowsiness usually means unusual personal sensitivity to meprobamate. Most patients experience little or no sedation from therapeutic doses of this dmg. Where necessary, drowsiness can be relieved promptly by a temporary reduction in dosage or by temporary addition of a central stimulant, such as methylphenidate. Usually, these measures are unnecessary, for as treatment with meprobamate continues there is a metamorphosis in the action of this compound. After ahout two weeks of uninterrupted treatment, meprobamate seldom causes drowsiness, even when the dosage is increased. In this respect the dmg resembles the sedatiw phenothiazines, such as chlorpromazine.
Hepatitis.- That meprohamate is free from hepatotoxicity is incontrovertihle, for neither jaundice nor any type of hepatic dysfunction assoeiated with the sole administration of this drug has ever heen reported. Zweifler' obserwd hepatitis along with agranuloeytosis or granuloeytopenia in three patients receiving a comhination of meprobamate and promazine. He concluded that "it seems reasonable to assume that the offending agent in these eases was promazine ..." Blood Dyscrasias.-According to the latest report of the Study Group on Blood Dyserasias' of the Couneil on Drugs, American Medical Association, aplastie anemia has never heen reported to occur when meprohamate was the sole drug administered. It has heen reported to the Group in 13 patients all of whom reecived other dmgs together with meprobamate. In no ease was meprobamate the sole agent used during the six months prior to the onset of the dyserasia. In six of these cases it was administered with dmgs whieh have heen shown hy direct or circumstantial evidence to he associated with the development of this dyscrasia. In contrast, the published literature contains only one "-nown reference to aplastic anemia associated with meprohamate therapy. In this case, as in the foregoing citations, other drugs known to cause this dyscrasia were also administered. Thrombocytopenia has been reported to the Study Group in 13 instances, five of which occurred with meprohamate alone. In four 84
cases the patients received, in addition, one or more other dmgs which are not known to cause thrombocytopenia. In the last four cases, the patients received meprobamate along with other dmgs known to cause this dyscrasia. Leukopenia or agranulocytosis has been reported 14 times to the Study Group, but only in one case was meprobamate reported as the only dmg given; seven cases involved other dmgs known to cause this reaction. There are no reports in the literature of agranulocytosis in patients treated with meprobamate alone. Finally, there has been a report to the Study Group of erythrohypoplasia without pancytopenia in one patient who received meprobamate as well as other dmgs. According to the Study Group's guide to interpretation of their tabulation, there is only a chance association of meprobamate with any of these blood disorders. Although it is impossible to obtain precise data which would supply the ratio of number of hlood dyscrasias reported against total number of patients treated with meprobamate, it may be reasonably concluded that the incidence of hematopoietic toxicity of this dmg is extremely low. Certainly there is reason to believe that thrombocytopenia, which is the principal dyscrasia reported with meprobamate alone, has occurred less than once in every 5 million patients treated.
Allergic Reactions.-The most frequent manifestations of allergy to meprobamate are erythematous, pmritic rashes or urticarial or maculopapular reactions, which may be generalized or confined to the arms, inframammary areas, tmnk, groin, and thighs. Concomitantly, there may be pyrexia up to 104°F ( 40°C), nausea, vomiting, hypotension, and pain or swelling of the joints, along with leukocytosis and eosinophilia. A few cases have heen accompanied by a nonthromhocytopenic purpura. Such hypersensitivity reactions usually appear within a few hours after the ingestion of the first to fourth tablets. In all but one of the cases reported, the symptoms have remitted in one to seven days, either without therapy or following treatinent with antihistamines or adrenocortical steroids. Subsequent voluntary or accidental ingestion of Volume V
\IEPROBAMATE: A DECADE OF EXPERIENCE-AYD
meprobamate may be responsible for the reappearance of the same symptoms. An unusual and isolated case of bullous dermatitis was described by Adlin and his associates.!! Autopsy findings in this patient were "suggestive of a toxic reaction to a drug or other exogenous substance." While meprobamate may have contributed to this reaction, the patient also received large doses of corticosteroids. Some of the autopsy findings, for example, pancreatitis, purpura, moniliasis, and bronchopneumonia have been reported with steroid overdosageY)
Overdosage.-Deliberate or accidental overdosage with tranquilizers is apparently increasing-but although ingestion of large doses of meprobamate causes central nervous system ( CNS) depression, it is usually of a degree less extensive than that of several other tranquilizers. I I In 1960, the National Clearinghouse for Poison Control Centers in the United States analyzed 93 reports of meprobamate overdosage during a two-year period. There were no deaths. 12 The 1963 report from the same source analyzed 276 meprobamate overdosages in a 17-month period. n There were no deaths, although there were 166 suicidal attempts, a significantly greater number than reported for any other drug in the study and representing 60 per cent of all cases tabulated. Of 276 cases of overdosage attributed to meprobamate, 72 patients had no symptoms, 31 were drowsy, 64 stuporous, and 40 comatose. Three patients convulsed and two had hypotension. Suicidal attempts with meprobamate are increasing. To some extent this reflects the widespread use of this drug. In England, for example, there were about 870,000 prescriptions for meprobamate in 1961." Fortunately, as seen from the reports cited above, suicidal attempts with this drug are seldom successful. Thus far, the literature contains only eight suicidal deaths in which meprobamate, or a combination product containing meprobamate, was believed to have been the responsible agent. Death from accidental overdosage has not been reported. Unlike the barbiturates, meprobamate does not produce the confusional states during which accidental suicides appear to occur. ~arch-April,
1964
Long-Term Therapy.-Since meprobamate acts upon symptoms rather than the basic illness, it may have to be administered for prolonged periods. This poses the question of the safety of long-term treatment. There are at least 200,000 patients who have taken fixed or progressively lower doses of this drug for one or more years. To date there have been no validated reports of toxic effects from prolonged meprobamate therapy. On the contrary, the absence of toxicity has been implied or specifically stated in the literature. Habitllation.-Although meprobamate treatment is sufficiently safe to justify its longterm use, there have been some reports of habituation, usually in psychopathic personalities with histories of abuse of alcohol or drugs, especially barbiturates and morphine. Its incidence of misuse is so very low that it can be positively stated that for the vast majority of patients the risk of habituation to meprobamate is not very serious. This is particularly pertinent for n('urotic patients with anxiety. Such patients will often take less rather than more of the prescribed dose of sedative medicine, because of their phobias of addiction. Withdrawal.-Abrupt withdrawal of any CNS depressant may result in confused states or convulsions-reactions most likely to occur in patients taking the drug for a long time and in high doses. Only under such circumstances have withdrawal symptoms been reported with meprobamate. The first and only case of death following withdrawal of this drug was reported recently by Swanson and Okada. 1,. This case illustrates the possibility of danger in the suddent withdrawal of meprobamate. On the other hand, gradual discontinuation of this compound has no apparent harmful effects. COMlI-lENT
Meprobamate and the barbiturates often have been compared and their similarities emphasized. Both are CNS depressants with risks of habituation and withdrawal symptoms, both counteract insomnia, and both can be used to relieve anxiety and tension. For these reasons it has been asserted that one can readily be substituted for the other and that 85
PSYCHOSOMATICS
meprobamate may not be any more effective than phenobarbital. But a close scrutiny of the pharmacology and clinical actions of each discloses that the resemblance is superficial and that, in fact, there are marked differences between them. These have been reviewed thoroughly by Berger.'" He showed major differences in site and mode of action, effects on conditioned responses and other animal behavior, primary indications for use in humans, and effects on normal human behavior. He also showed that the barbiturates are lIseful primarily as hypnotics which, in clinical doses, produce motor and intellectual impairment, whereas meprobamate is a specific anti-anxiety agent, which in clinical doses produces no signi6cant behavioral impairment. Critics of psychopharmaceuticals repeatedly cite those double-blind studies which showed that the drug at issue was no better than a placeho; hut they fail to mention other controlled trials which demonstrated that the reverse was true. Meprobamate has not escaped this type of appraisal. In fact, however, 65 double-blind studies comparing meprobamate with other tranquilizers or placebos have been published. The majority of these show that meprobamate produces desirable effects not manifested by a placebo or barbiturate. Though properly designed and conducted controlled trials are important and necessary, they nevertheless have limitations and do not provide the final answer to the true value of a remedy. The most reliable test of the efficacy and safety of a drug is time and its administration to many persons. Nevertheless, the successes of every valuable psychopharmaceutical agent have been attributed at one time or another to placebo effects, or personality of the therapist, or an atmosphere of enthusiasm and optimism. The validity of these postulations is doubtful. Such reasoning does not explain, for instance, why clinicians everywhere use a major tranquilizer such as chlorpromazine for schizophrenia and other psychoses and seldom or not at all for neuroses; why physicians all over the world prescribe meprobamate for neuroses and rarely for psychoses; or why physicians soon learned that the antidepressants are far more effective for endogenous depressions than for reactive 86
depressions. That there are placebo effects at times is an incontrovertible fact, but it seems that they have been overemphasized. If psychiatric patients are so suggestible, what accounts for our failure to help so many of them with the numerous psychotherapeutic and physical methods of treatment at our disposal? To aver that affective drugs such as meprobamate are helpful primarily because of placebo effects is not consonant with the facts. As with other compounds which have passed the test of time, meprobamate should be prescribed rationally and with a healthy respect for its limitations and possible untoward effects. Of the vast quantities of this drug which have been prescribed, not all have been dispensed prudently or for good clinical indications. Such misuse is indicative of physicians who unwisely accede to the demands of patients or who supplant clinical judgment for expediency. This is careless medical practice which warrants condemnation. However, ten years and the worldwide clinical experience of physicians in treating an estimated 80 million patients with meprobamate have demonstrated that this is a valuable and safe drug with a wide range of clinical applications. BIBLIOGRAPHY
1. Selling, L. S.: Clinical study of a new tranquilizing drug: Use of Miltown (2-methyl-2-n-propyl1,3-propanediol dicarbamate). lAMA, 157:1594 (Apr. 30) 1955.
2. Borrus, J. C.: Study of eHed of Miltown (2methyl-2-n-propyl-l,3-propanediol dicarbamate) on psychiatric states. lAMA, 157: 1596 (Apr. 30) 1955. 3. Hollister, L. E., Elkins, H., Hiler, E. G., and St. Pierre, R.: Meprobamate in chronic psychiatric patients. Ann. Neu; York Acad. Sc., 67:789 (May 9) 1957. 4. Tucker, W. I.: The place of Miltown in general practice. South. Med. l., 50:1111 (Sept.) 1957. 5. Ayd, F. J., Jr.: Meprobamate therapy for convulsive disorders of children. Bull. School Med. Univ. Maryland, 42:2 (Jan.) 1957. 6. Ayd, F. J., Jr.: Emotional problems in childrenThe uses of drugs in therapeutic management. Calif. Med., 87:75 (Aug.) 1957. 7. ZweiHer, A. J.: Agranulocytosis and jaundice during therapy with meprobamate and promazine. New Engl. l. Med., 262:1229 (June 16) 1960. 8. Best, W. R.: Drug-associated blood dyscrasias. lAMA, 185:286 (July 27) 1963. Volume V
MEPROBAMATE: A DECADE OF EXPERIENCE-AYD 9. Adlin, E. V., Sher, P. B., and Berk, N. G.: Fatal reaction following the ingestion of meprobamate. AMA Arch. Int. Med., 102:484 (Sept.) 1958. 10. Carone, F. A., and Liebow, A. A.: Acute P~Il creatic lesions in patients treated with AcrH and adrenal corticoids. New Engl. l. Med., 257: 690 (Oct. 10) 1957. 11. Domino, E. G.: Human pharmacology of tranquilizing drugs. CUn. Pha1'f1UlCol. Ther., 3:599 (Sept.) 1962. 12. Cann, H. M., and Verhulst, H. L.: Accidental ingestio.n and overdosage involving psychopharmacolOgiC drugs. New Engl.}. Med., 263:719 (Oct. 13) 1960. 13. McKown, C. H., Verhulst, H. L., and Crotty,
J. J.:
Overdosage effects and danger from tranquilizing drugs. lAMA, 185:425 (Aug. 10) 1963. 14. Anon.: Meprobamate prescriptions, (Editorial). Brit. Med. ]., 5316: 1411, 1962. 15. Swanson, L. A., and Okada, T.: Death after withdrawal of meprobamate. lAMA, 184:780 (June 8) 1963. 16. Berger, F. M.: The similarities and differences between meprobamate and barbiturates. Clin. Pharm. Ther., 4:209, 1963. V ilia Madonna Via Lorenzo Val14 17 Rome, Italy
One of the basic facts of life in regard to a psychiatrist in a general hospital is the simple and pragmatic one as to whether he is of any value to the other members of the staff. The surgeon or internist is not interested, except in an academic way, as to what the diagnostic label or in what to him very frequently is an esoteric evaluation of psychodynamic factors. . . . He is interested in a colleague's help to understand and be of practical assistance in the total evaluation and furtherance of treatment of any given patient. He does not sell a psychiatric point of view if he disguises himself with a false face and pretends to erudition that is essentially superficial. -M. R. KAUFMAN, M.D. Quoted by Norman Q. Brill, M.D., Psychiatry in Medicine, University of California Press, 1962.
March-April, 1964
87
• The history of meprobamate is a narrative of a creation, of a struggle against prejudice and resistance to acceptance, and of progress in the pharmacological mastery of the most pervasive of psychiatric symptomsanxiety and tension. In 1945, Berger fortuitously observed that a glycol derivative paralyzed mice without affecting vital functions. Almost seven years later, after careful observations and systematic experimentation and investigation in the laboratory, meprobamate was a reality and ready for clinical trials. At that time no one could have foretold the role this dmg would play in the chemical conquest of psychic disorders. Yet, within a decade, meprobamate became and continues to be the most frequently prescribed psychopharmaceutical. An estimated 80 million patients have been given this tranquilizer and thousands of scientific articles have been written about it. This sum of experience has provided the medical profession with an abundance of data to assess the clinical utility and safety of meprobamate. When meprobamate was introduced for general use in 1955, the attention of the medical world had just become focused on the treatment of mental illnesses with the tranquilizers, chlorpromazine and reserpine. The chemical revolution in psychiatry was causing a change in the clinical course and outlook for psychotics, especially for manics and schizophrenics with severe anxiety, tension, agitation, and psychomotor excitement. Therapeutic optimism was replacing nihilism in mental hospitals throughout the world. However, there remained a need for a drug to treat the troublesome emotional prohlems of the vast number of neurotics and mild psychotics whom physicians encountered daily. Ideally, this compound would be free of most or all of the undesirable effects of the major tranquilizers and would represent a significant advance over the barbiturates. The initial 82
reports of Selling, I Borrus," and others suggested that meprobamate was such a drug. Two years after becoming clinically available, meprobamate was being administered extensively for every conceivable psychiatric condition. Much of its early use was predicated on hopefulness and enthusiasm. As a result, some premature uncritical and unscientific reports appeared. Critics and skeptics, among whom were eminent and influential psychiatrists and pharmacologists, attacked these along with the claims for an tranquilizers. Accompanying these animadversions were reports of side effects, including some of serious nature. These, in turn, were joined with announcements of treatment failures and of controlled trials which indicated that meprobamate was no better than a placebo or barbiturate. Meanwhile, other major and minor tranquilizers were introduced to compete with meprobamate. Nevertheless, physicians continued to prescribe this compound and, as time passed, the evidence showed that meprobamate is a valuable and safe drug. EFFICACY
Anxiety and Tension.-Meprobamate alone is most likely to be beneficial when anxiety and tension are the predominant symptoms, especially in neurotics. When prescribed in adequate doses for properly selected patients, the expectation of prompt amelioration of these target symptoms and associated secondary effects is high. This is particularly true when these specific symptoms occur in previously stable individuals. The more chronic the neurosis and the more immature and labile the basic personality of the patient, the less favorable is the outcome of meprobamate therapy. It is unrealistic to expect meprobamate or any medicine to materially help any individual who since childhood has been unable to cope with even the minor vicissitudes of life without developing anxiety. Likewise, Volume V
MEPROBAMATE: A DECADE OF EXPERIENCE-AYD
although lifelong inadequate personalities may manifest anxiety symptoms, extreme caution should be observed in prescribing meprobamate for such persons. These are the patients who most frequently abuse sedative dmgs, and the risk of habituation in them is high. Such persons can be detected through history as well as behavior in the office, and treatment with meprobamate then can he avoided.
IJepressioll.-Although definitely not a specific antidepressant, meprobamate has heen found of value in depressive states associated with symptoms of anxiety. In such patients, the drug decreases or abolishes the anxiety without enhancing the depression. It may also be useful in reactive depressions and, according to Hollister and his associates," in selected cases of all types of depression. Tucker· reported that 20 of 27 patients with reactive or involutional depression improved when meprobamate was given. Four of these patients exhihited a marked positive change in their status. In contrast, previous sedatives and tranquilizers had not been able to effect a pronounced change in any of these same individuals, and only some improvement was achieved in 12 patients. Psychoses.-Meprobomate is palliative, not curative. The evidence accumulated during the past years clearly shows that this compound is devoid of antipsychotic properties and not suited as the primary dmg for treatment of hospitalized psychotics. Its value in the management of psychoses is limited to patients who have anxiety symptoms independent of or in addition to the basic illness. Usually, these individuals are not hospitalized, have fairly well-preserved personalities, and seldom are recognized as psychotic. They may he beset with acute or chronic anxiety for which meprobamate may be preferable over the phenothiazines or other antipsychotic pharmaceuticals. Aside from this indication, psychotics usually are hest treated with other dmgs, although a combination of meprobamate and an antipsychotic agent is at times quite efficacious. Neurological Disorders.-Earlyexperimental studies in animals showed that meprohamate March-April, 1964
exerted a strong anticonvulsive action. This finding led naturally to an evaluation of its use in epilepsy and other motor disturbances. It was found to be of considerable value in petit mal and related minor epilepsies, where it has heen shown to at least significantly lengthen the intervals hetween attacks." Favorable results also have been achieved in patients with cerebral palsy, spinal-cord injuries, and other conditions. The drug is not indicated for grand mal epilepsy. It may, indeed, precipitate grand mal attacks in patients suffering from hoth petit mal and grand mal epilepsy, hy suppressing petit mal attacks and so permitting the appearance of grand mal seizures.
Behavior Disorders.-Meprohamate ean exert a favorable relaxant effect upon disturhed children with such symptoms as anxiety, sleeplessness, hyperactivity, and uncooperative attitude. The use of the drug makes such children more manageable and permits them to perform effectively in school and general activities. Children with behavior prohlems, such as enuresis, stuttering, and hostility, hecome much more amenable to psychotherapy after meprobamate treatment is initiated. Frank psychoses have heen generally unresponsive. 6 SAFETY
Physicians currently have a justifiable and healthy concern for the side effects and potential dangers of medicines. This should not interfere with providing patients with the possible benefits of drugs with safety established through administration to a multitude of persons, and for periods of time sufficient to reasonably assume that any deleterious effects should have been detected. Meprobamate belongs in this latter category. The low toxicity of this compound becomes more apparent as each year goes on. Most of its side effects are minor and usually occur in the first few days of treatment. Autonomic-blocking, endocrine, or extrapyramidal reactions have not been associated with meprobamate administration. Sedation or drowsiness is the most common side effect. The occurrence and intensity of the effect is contingent upon the sensitivity of the individual patient as well as upon the starting 83
PSYCHOSOMATICS
dosage. Excessive drowsiness usually means unusual personal sensitivity to meprobamate. Most patients experience little or no sedation from therapeutic doses of this dmg. Where necessary, drowsiness can be relieved promptly by a temporary reduction in dosage or by temporary addition of a central stimulant, such as methylphenidate. Usually, these measures are unnecessary, for as treatment with meprobamate continues there is a metamorphosis in the action of this compound. After ahout two weeks of uninterrupted treatment, meprobamate seldom causes drowsiness, even when the dosage is increased. In this respect the dmg resembles the sedatiw phenothiazines, such as chlorpromazine.
Hepatitis.- That meprohamate is free from hepatotoxicity is incontrovertihle, for neither jaundice nor any type of hepatic dysfunction assoeiated with the sole administration of this drug has ever heen reported. Zweifler' obserwd hepatitis along with agranuloeytosis or granuloeytopenia in three patients receiving a comhination of meprobamate and promazine. He concluded that "it seems reasonable to assume that the offending agent in these eases was promazine ..." Blood Dyscrasias.-According to the latest report of the Study Group on Blood Dyserasias' of the Couneil on Drugs, American Medical Association, aplastie anemia has never heen reported to occur when meprohamate was the sole drug administered. It has heen reported to the Group in 13 patients all of whom reecived other dmgs together with meprobamate. In no ease was meprobamate the sole agent used during the six months prior to the onset of the dyserasia. In six of these cases it was administered with dmgs whieh have heen shown hy direct or circumstantial evidence to he associated with the development of this dyscrasia. In contrast, the published literature contains only one "-nown reference to aplastic anemia associated with meprohamate therapy. In this case, as in the foregoing citations, other drugs known to cause this dyscrasia were also administered. Thrombocytopenia has been reported to the Study Group in 13 instances, five of which occurred with meprohamate alone. In four 84
cases the patients received, in addition, one or more other dmgs which are not known to cause thrombocytopenia. In the last four cases, the patients received meprobamate along with other dmgs known to cause this dyscrasia. Leukopenia or agranulocytosis has been reported 14 times to the Study Group, but only in one case was meprobamate reported as the only dmg given; seven cases involved other dmgs known to cause this reaction. There are no reports in the literature of agranulocytosis in patients treated with meprobamate alone. Finally, there has been a report to the Study Group of erythrohypoplasia without pancytopenia in one patient who received meprobamate as well as other dmgs. According to the Study Group's guide to interpretation of their tabulation, there is only a chance association of meprobamate with any of these blood disorders. Although it is impossible to obtain precise data which would supply the ratio of number of hlood dyscrasias reported against total number of patients treated with meprobamate, it may be reasonably concluded that the incidence of hematopoietic toxicity of this dmg is extremely low. Certainly there is reason to believe that thrombocytopenia, which is the principal dyscrasia reported with meprobamate alone, has occurred less than once in every 5 million patients treated.
Allergic Reactions.-The most frequent manifestations of allergy to meprobamate are erythematous, pmritic rashes or urticarial or maculopapular reactions, which may be generalized or confined to the arms, inframammary areas, tmnk, groin, and thighs. Concomitantly, there may be pyrexia up to 104°F ( 40°C), nausea, vomiting, hypotension, and pain or swelling of the joints, along with leukocytosis and eosinophilia. A few cases have heen accompanied by a nonthromhocytopenic purpura. Such hypersensitivity reactions usually appear within a few hours after the ingestion of the first to fourth tablets. In all but one of the cases reported, the symptoms have remitted in one to seven days, either without therapy or following treatinent with antihistamines or adrenocortical steroids. Subsequent voluntary or accidental ingestion of Volume V
\IEPROBAMATE: A DECADE OF EXPERIENCE-AYD
meprobamate may be responsible for the reappearance of the same symptoms. An unusual and isolated case of bullous dermatitis was described by Adlin and his associates.!! Autopsy findings in this patient were "suggestive of a toxic reaction to a drug or other exogenous substance." While meprobamate may have contributed to this reaction, the patient also received large doses of corticosteroids. Some of the autopsy findings, for example, pancreatitis, purpura, moniliasis, and bronchopneumonia have been reported with steroid overdosageY)
Overdosage.-Deliberate or accidental overdosage with tranquilizers is apparently increasing-but although ingestion of large doses of meprobamate causes central nervous system ( CNS) depression, it is usually of a degree less extensive than that of several other tranquilizers. I I In 1960, the National Clearinghouse for Poison Control Centers in the United States analyzed 93 reports of meprobamate overdosage during a two-year period. There were no deaths. 12 The 1963 report from the same source analyzed 276 meprobamate overdosages in a 17-month period. n There were no deaths, although there were 166 suicidal attempts, a significantly greater number than reported for any other drug in the study and representing 60 per cent of all cases tabulated. Of 276 cases of overdosage attributed to meprobamate, 72 patients had no symptoms, 31 were drowsy, 64 stuporous, and 40 comatose. Three patients convulsed and two had hypotension. Suicidal attempts with meprobamate are increasing. To some extent this reflects the widespread use of this drug. In England, for example, there were about 870,000 prescriptions for meprobamate in 1961." Fortunately, as seen from the reports cited above, suicidal attempts with this drug are seldom successful. Thus far, the literature contains only eight suicidal deaths in which meprobamate, or a combination product containing meprobamate, was believed to have been the responsible agent. Death from accidental overdosage has not been reported. Unlike the barbiturates, meprobamate does not produce the confusional states during which accidental suicides appear to occur. ~arch-April,
1964
Long-Term Therapy.-Since meprobamate acts upon symptoms rather than the basic illness, it may have to be administered for prolonged periods. This poses the question of the safety of long-term treatment. There are at least 200,000 patients who have taken fixed or progressively lower doses of this drug for one or more years. To date there have been no validated reports of toxic effects from prolonged meprobamate therapy. On the contrary, the absence of toxicity has been implied or specifically stated in the literature. Habitllation.-Although meprobamate treatment is sufficiently safe to justify its longterm use, there have been some reports of habituation, usually in psychopathic personalities with histories of abuse of alcohol or drugs, especially barbiturates and morphine. Its incidence of misuse is so very low that it can be positively stated that for the vast majority of patients the risk of habituation to meprobamate is not very serious. This is particularly pertinent for n('urotic patients with anxiety. Such patients will often take less rather than more of the prescribed dose of sedative medicine, because of their phobias of addiction. Withdrawal.-Abrupt withdrawal of any CNS depressant may result in confused states or convulsions-reactions most likely to occur in patients taking the drug for a long time and in high doses. Only under such circumstances have withdrawal symptoms been reported with meprobamate. The first and only case of death following withdrawal of this drug was reported recently by Swanson and Okada. 1,. This case illustrates the possibility of danger in the suddent withdrawal of meprobamate. On the other hand, gradual discontinuation of this compound has no apparent harmful effects. COMlI-lENT
Meprobamate and the barbiturates often have been compared and their similarities emphasized. Both are CNS depressants with risks of habituation and withdrawal symptoms, both counteract insomnia, and both can be used to relieve anxiety and tension. For these reasons it has been asserted that one can readily be substituted for the other and that 85
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meprobamate may not be any more effective than phenobarbital. But a close scrutiny of the pharmacology and clinical actions of each discloses that the resemblance is superficial and that, in fact, there are marked differences between them. These have been reviewed thoroughly by Berger.'" He showed major differences in site and mode of action, effects on conditioned responses and other animal behavior, primary indications for use in humans, and effects on normal human behavior. He also showed that the barbiturates are lIseful primarily as hypnotics which, in clinical doses, produce motor and intellectual impairment, whereas meprobamate is a specific anti-anxiety agent, which in clinical doses produces no signi6cant behavioral impairment. Critics of psychopharmaceuticals repeatedly cite those double-blind studies which showed that the drug at issue was no better than a placeho; hut they fail to mention other controlled trials which demonstrated that the reverse was true. Meprobamate has not escaped this type of appraisal. In fact, however, 65 double-blind studies comparing meprobamate with other tranquilizers or placebos have been published. The majority of these show that meprobamate produces desirable effects not manifested by a placebo or barbiturate. Though properly designed and conducted controlled trials are important and necessary, they nevertheless have limitations and do not provide the final answer to the true value of a remedy. The most reliable test of the efficacy and safety of a drug is time and its administration to many persons. Nevertheless, the successes of every valuable psychopharmaceutical agent have been attributed at one time or another to placebo effects, or personality of the therapist, or an atmosphere of enthusiasm and optimism. The validity of these postulations is doubtful. Such reasoning does not explain, for instance, why clinicians everywhere use a major tranquilizer such as chlorpromazine for schizophrenia and other psychoses and seldom or not at all for neuroses; why physicians all over the world prescribe meprobamate for neuroses and rarely for psychoses; or why physicians soon learned that the antidepressants are far more effective for endogenous depressions than for reactive 86
depressions. That there are placebo effects at times is an incontrovertible fact, but it seems that they have been overemphasized. If psychiatric patients are so suggestible, what accounts for our failure to help so many of them with the numerous psychotherapeutic and physical methods of treatment at our disposal? To aver that affective drugs such as meprobamate are helpful primarily because of placebo effects is not consonant with the facts. As with other compounds which have passed the test of time, meprobamate should be prescribed rationally and with a healthy respect for its limitations and possible untoward effects. Of the vast quantities of this drug which have been prescribed, not all have been dispensed prudently or for good clinical indications. Such misuse is indicative of physicians who unwisely accede to the demands of patients or who supplant clinical judgment for expediency. This is careless medical practice which warrants condemnation. However, ten years and the worldwide clinical experience of physicians in treating an estimated 80 million patients with meprobamate have demonstrated that this is a valuable and safe drug with a wide range of clinical applications. BIBLIOGRAPHY
1. Selling, L. S.: Clinical study of a new tranquilizing drug: Use of Miltown (2-methyl-2-n-propyl1,3-propanediol dicarbamate). lAMA, 157:1594 (Apr. 30) 1955.
2. Borrus, J. C.: Study of eHed of Miltown (2methyl-2-n-propyl-l,3-propanediol dicarbamate) on psychiatric states. lAMA, 157: 1596 (Apr. 30) 1955. 3. Hollister, L. E., Elkins, H., Hiler, E. G., and St. Pierre, R.: Meprobamate in chronic psychiatric patients. Ann. Neu; York Acad. Sc., 67:789 (May 9) 1957. 4. Tucker, W. I.: The place of Miltown in general practice. South. Med. l., 50:1111 (Sept.) 1957. 5. Ayd, F. J., Jr.: Meprobamate therapy for convulsive disorders of children. Bull. School Med. Univ. Maryland, 42:2 (Jan.) 1957. 6. Ayd, F. J., Jr.: Emotional problems in childrenThe uses of drugs in therapeutic management. Calif. Med., 87:75 (Aug.) 1957. 7. ZweiHer, A. J.: Agranulocytosis and jaundice during therapy with meprobamate and promazine. New Engl. l. Med., 262:1229 (June 16) 1960. 8. Best, W. R.: Drug-associated blood dyscrasias. lAMA, 185:286 (July 27) 1963. Volume V
MEPROBAMATE: A DECADE OF EXPERIENCE-AYD 9. Adlin, E. V., Sher, P. B., and Berk, N. G.: Fatal reaction following the ingestion of meprobamate. AMA Arch. Int. Med., 102:484 (Sept.) 1958. 10. Carone, F. A., and Liebow, A. A.: Acute P~Il creatic lesions in patients treated with AcrH and adrenal corticoids. New Engl. l. Med., 257: 690 (Oct. 10) 1957. 11. Domino, E. G.: Human pharmacology of tranquilizing drugs. CUn. Pha1'f1UlCol. Ther., 3:599 (Sept.) 1962. 12. Cann, H. M., and Verhulst, H. L.: Accidental ingestio.n and overdosage involving psychopharmacolOgiC drugs. New Engl.}. Med., 263:719 (Oct. 13) 1960. 13. McKown, C. H., Verhulst, H. L., and Crotty,
J. J.:
Overdosage effects and danger from tranquilizing drugs. lAMA, 185:425 (Aug. 10) 1963. 14. Anon.: Meprobamate prescriptions, (Editorial). Brit. Med. ]., 5316: 1411, 1962. 15. Swanson, L. A., and Okada, T.: Death after withdrawal of meprobamate. lAMA, 184:780 (June 8) 1963. 16. Berger, F. M.: The similarities and differences between meprobamate and barbiturates. Clin. Pharm. Ther., 4:209, 1963. V ilia Madonna Via Lorenzo Val14 17 Rome, Italy
One of the basic facts of life in regard to a psychiatrist in a general hospital is the simple and pragmatic one as to whether he is of any value to the other members of the staff. The surgeon or internist is not interested, except in an academic way, as to what the diagnostic label or in what to him very frequently is an esoteric evaluation of psychodynamic factors. . . . He is interested in a colleague's help to understand and be of practical assistance in the total evaluation and furtherance of treatment of any given patient. He does not sell a psychiatric point of view if he disguises himself with a false face and pretends to erudition that is essentially superficial. -M. R. KAUFMAN, M.D. Quoted by Norman Q. Brill, M.D., Psychiatry in Medicine, University of California Press, 1962.
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