Chapter 31. The nonbarbiturate sedatives and the "minor" tranquilizers

As the barbiturates came under frequent attack following 1941, and as the market for them soared, efforts were naturally revived to find additional drugs that might compete for that flourishing market.

One result of this search was the introduction into medical practice of a variety of prescription sedatives and sleeping pills bearing such trade names as Doriden, Placidyl, and Noludar. Advertisements in the medical journals urged physicians to prescribe these drugs precisely because they were nonbarbiturates. In fact, however, these newer sedatives and hypnotics belong, pharmacologically if not chemically, to the same class of drugs as alcohol and the barbiturates. You can get drunk on them; you can become addicted to them; and you can suffer delirium tremens when they are withdrawn. The parallel can be seen in this excerpt from the Placidyl "product information" material prepared for physicians by the manufacturer, Abbott Laboratories:

Patients who are taking PLACIDYL or other [central nervous system]-acting drugs should be cautioned about the possible combined exaggerated effects with alcohol, barbiturates, tranquilizers or other central nervous system depressants [that] might result in blurring of vision, paralysis of accommodation and profound hypnosis.

Patients also should be cautioned concerning driving a motor vehicle, operating machinery, or other hazardous operations requiring alertness shortly after taking PLACIDYL.

PLACIDYL should be administered with caution [to] patients with suicidal tendencies and large quantities of the drug should not be prescribed.

Psychological and Physical Dependence: PLACIDYL, LIKE OTHER SEDATIVE-HYPNOTIC DRUGS, HAS THE POTENTIAL . . . FOR THE DEVELOPMENT OF PSYCHOLOGICAL AND PHYSICAL DEPENDENCE. INSTANCES OF SEVERE WITHDRAWAL SYMPTOMS, INCLUDING CONVULSIONS AND [DELIRIUM] CLINICALLY SIMILAR TO THOSE SEEN WITH BARBITURATES, HAVE BEEN REPORTED IN PATIENTS TAKING REGULAR DOSES AS LOW AS 1000 MG. PER DAY OVER A PERIOD OF TIME WHEN THE DRUG WAS SUDDENLY DISCONTINUED. [Capitals in original.]

In view of the potential of PLACIDYL (ethchlorvynol) for inducing dependence, prolonged administration of the drug is not recommended.

Patients, particularly those known to be addiction-prone, or those who are likely to increase dosage Of PLACIDYL on their own initiative, should be observed for evidence of signs or symptoms which may indicate possible early withdrawal or abstinence symptoms. Signs and symptoms associated with withdrawal and abstinence include unusual anxiety, tremor, ataxia [muscular incoordination], slurring of speech, memory loss, perceptual distortions, irritability, agitation and delirium. Other less well defined signs and symptoms, not necessarily due to withdrawal and abstinence [,] may include anorexia, nausea, or vomiting, weakness, dizziness, sweating, muscle twitching and weight loss. Abrupt discontinuance Of PLACIDYL following prolonged overdosage may result in convulsions and [delirium].

Treatment of a patient who manifests withdrawal symptoms from PLACIDYL abuse involves readministration of the drug to approximate the same level of chronic intoxication which existed before the abrupt discontinuance. . . . A gradual, stepwise reduction of dosage may then be made over a period of days or weeks. The patient must be hospitalized or closely observed and gives general supportive care as indicated.

PRECAUTIONS: . . . Patients who respond unpredictably to barbiturates or alcohol, or who exhibit excitement and release of inhibitions in association with such agents may also react in this way to PLACIDYL.

Rarely, patients may exhibit symptoms suggestive of an unusual susceptibility to the drug: prolonged hypnosis, profound muscular weakness, excitement, hysteria, or syncope [fainting] without marked hypotension.

In occasional patients the drug appears to be absorbed very rapidly and may produce transient giddiness or ataxia. Should this occur, a glass of milk or other food should be given with subsequent doses of the drug, or the drug discontinued.

ADVERSE REACTIONS: Hypotension [low blood pressure], nausea or vomiting, gastric upset, aftertaste, blurring of vision, dizziness, facial numbness, and allergic reaction typified by urticaria [hives] have been reported following PLACIDYL (ethchlorvynol) administration. Mild "hangover" and symptoms of mild excitation have occurred in some patients ....

In addition to these nonbarbiturate sedatives, a second new class of drugs has been introduced in an effort to capture some of the vast barbiturate market. These drugs are the minor tranquilizers, * of which meprobamate (marketed as Miltown and as Equanil) was the first and remains the best known. Other well-known minor tranquilizers are chlordiazepoxide (Librium) and diazepam (Valium).

* The "minor tranquilizers" are so called to distinguish them from the drugs used in the treatment of schizophrenia and other psychoses–– the "major tranquilizers" such as chlorpromazine. The major tranquilizers are not used nonmedically, and are therefore not considered in this Report.

These tranquilizers have effects so similar to those of the barbiturates that for a number of years experienced clinicians refused to recognize any real difference; and even today the distinction is difficult to establish. Thus Dr. Murray E. Jarvik states in Goodman and Gilman's textbook (1970):

The pharmacological effects of meprobamate are very similar to those of the barbiturates. Indeed, in clinical usage it is difficult, if not impossible, to differentiate between the two drugs. Only by careful pharmacological analysis can certain distinctions be discerned.

The major difference is that a dose of a minor tranquilizer sufficient to calm anxiety seems to produce a little less sleepiness and interference with motor activities than does a dose of a barbiturate equally effective against anxiety. In other respects, the differences are hardly noteworthy. "The withdrawal syndrome following abrupt discontinuance of high doses of meprobamate resembles that following barbiturate withdrawal," Dr. Jarvik notes.

According to  The Medical Letter (1969), "Librium and Valium are effective sedatives, but, except in potentially suicidal patients, it is still not clear that they have any important advantage over the barbiturates." In 1971,  The Medical Letter added, "When anxiety is severe or interferes with everyday pursuits and relationships, a sedative drug such as a barbiturate, chlordiazepoxide [Librium], diazepam. [Valium], or meprobamate is a useful adjunct to psychotherapy. . . ."

The hazards of Valium are set forth in the "product information" supplied to physicians by the manufacturer, Roche Laboratories, reading in part as follows:

WARNINGS: . . . As is true of most preparations containing central nervous system-acting drugs, patients receiving . . . Valium (diazepam) should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle....

Since Valium (diazepam) has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other central nervous system depressant drugs....

Physical and Psychological Dependence: Withdrawal symptoms (similar in character to those noted with barbiturates and alcohol) have occurred following abrupt discontinuance of diazepam (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating). These were usually limited to those patients who had received excessive doses over an extended period of time. Particularly addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam....

ADVERSE REACTIONS: ... Side effects most commonly reported were drowsiness, fatigue and ataxia. Infrequently encountered were confusion, constipation, depression, diplopia [double vision], dysarthria [stammering], headache, hypotension, incontinence, jaundice, changes in libido, nausea . . . slurred speech, tremor ... vertigo [dizziness] and blurred vision ....

–– in short, much the same side effects as those produced by alcohol, the barbiturates, and the nonbarbiturate depressants.

The risks associated with Placidyl and Valium are cited here only as examples; virtually all prescription drugs carry lists of "contraindications," "precautions," "warnings," and "adverse reactions." Those hazards of prescription drugs should be borne in mind when the hazards of black-market drugs such as LSD (Part VII) and marijuana (Part VIII) are evaluated. Consideration might also be given to requiring comparable warnings on packages of and in advertisements for alcoholic beverages and tobacco products.

To round out the picture, let us return for just a moment to the prebarbiturate sedatives, chloral hydrate and paraldehyde. These, too, it has now been established, can produce drunkenness, addiction, and delirium tremens hardly distinguishable from those produced by alcohol, the barbiturates, the nonbarbiturate sedatives, and the minor tranquilizers.

Thus the wheel comes full circle.

Footnotes
Chapter 31