Contemporary Drugs in the Management of Anxiety

Current Therapeutic Concepts

Contemporary Drugs in the Management of Anxiety Martin Jinks

This paper discusses therapeutic liberalism vs. therapeutic nihilism in the pharmaco- . therapy of anxiety and the use of benzodiazepines in the treatment of this condition. Although they offer several advantages over other drug groups, the benzodiazepines may cause physical dependence after prolonged use, and their misuse may lead to acute intoxication and death. Benzodiazepines also may produce congenital anomalies; although

the teratogenic potential is low, their use should be minimized in women of childbearing age. Therapy with benzodiazepines is best reserved as an adjunct to psychotherapy in patients with true pathological anxiety and a clear degree of disability or discomfort. If possible, therapy should be episodic and intermittent and dosage should be individualized to prod!Jce relief with minimum impair-

ment of mental alertness. Since most benzodiazepines have long plasma half-lives, the major portion of the daytime dosage often may be given at bedtime. No one drug group is superior to another in the treatment of anxiety, and all antianxiety agents produce similar side effects. The choice involves a consideration of expected length of therapy, drug safety, drug interactions and drug cost.

The pharmacist, in planning or evaluating rational drug therapy of any disease state, looks for paradigms of logic in the drug-use decision-making process. To those who deal with applied therapeutics, logic consists of first assigning prerequisite conditions that are objective and measurable and clearly define the indications for therapy. Secondly, once indications for therapy are identified, the purist then insists on defined therapeutic goals which are measurable and which indicate a successful response. Ultimately, the desired outcome is to render a "cure" and achieve for the patient a drug-free state. In the treatment of medical complaints to which one cannot apply rational drug-use logic, one would exercise responsibility and minimize therapy whenever possible. In the pharmacological management of anxiety, the use of paradigms of logic is often impossible or ignored. The definition of "pathological anxiety" remains subjective and unquantifiable. Yet antianxiety agents seem to be prescribed almost on demand, where often the prescriber subsumes a patient request or expectation for these drugs to be a legitimate indication. In the chemotherapy of anxiety, philosophical bent replaces measurable indication, and little agreement exists on which therapeutic endpOints determine a successful course. Unlike with hypertension or diabetes, no laboratory value will divulge adequate drug response to anxiety, and thus anxiolytic therapy is apt to be more art than science.

normal reaction and does not require drug management. A pathological anxiety state exists when, subjectively, no cause is apparent and when the anxiety is intense, associated with phobias, sleep disorders, aggravation of somatic functional disorders or inability to sustain work activities. Pathological anxiety produces a catalogue of obscure and inconsistent psychosomatic symptoms. Bodily signs range from quivering hyperventilation to irritable colon, peptic ulcer and eczema. Behavioral symptoms are common. Extreme apprehension-a feeling that something terrible is going to happen, yet not knowing what it will be or when it will happen-is characteristic. The truly anxious patient is easily upset, distracted or disinterested in work, and often insomniac. He or she often turns to excessive drinking, alcohol being a "self-administered" antianxiety agent. More severe behavorial disturbances, such as schizophrenia or depression, can complicate pathological anxiety. When anxiety is complicated by underlying disease,

specific therapy aimed at the underlying disorder may obviate the need for antianxiety agents. In uncomplicated anxiety reactions which are severe enough to produce dysfunction or discomfort, temporary use of an antianxiety agent is often indicated. What exactly constitutes dysfunction or discomfort depends on the combined and negotiated perceptions of both the patient and physician. In cases where environmental stresses or other conflicts can be identified, psychotherapy may be superior to drugs; however, the optimal choice between pharmacological management and psychotherapy is not "either / or," but" both." In actual practice, psychiatrists and / or psychologists almost never enter the picture, as indicated by the fact that about 70 percent of all antianxiety agent prescription orders are written by general practitioners. 1

Pathological Anxiety

In threatening situations, anxiety is a

Martin Jinks, PharmD, is Health Services Consultant, Professional Health Research, Inc., Burlingame, California , and Associate Clinical Professor of Pharmacy, University of California at San Francisco, San Francisco, California 94143.

Vol. NS 17, No.5, May 1977

The purpose of Current Therapeutic Concepts is to present to the practicing pharmacist up-to-date information on the treatment of commonly encountered disease states. Some background on the pathology, etiology and diagnosis of these diseases is also presented so that therapeutic concepts discussed can be placed into a clinical perspective. These articles are not intended to be reviews of current literature but rather a source of continuing education for the pharmacist. The series was originally initiated and is currently coordinated by Eric T. Herfindal, PharmO, Associate Clinical Professor of Pharmacy, and Joseph L. Hirschman, PharmO: Assistant Clinical Professor of Pharmacy at the University of California School of Pharmacy at San Francisco.

Pharmacotherapy of Anxiety

The therapist who Sincerely attempts to distinguish between normal stress and pathological anxiety will find the task vexatious. The majority of patients do not have clearcut pathological anxiety and could probably weather a storm of "uneasiness" without drugs. However, many patients are conditioned to expect a prescription, and many prescribers are conditioned to expect the patient to expect a pr~scription. Either way, the patient ends up with a tranquilizer whether or not he wants it. The fortitude of the prescriber to resist these real or imaginary pressures to prescribe "comfort medications" is determined by his attitude toward psychoactive drug use-a case of therapeutic liberalism versus therapeutic nihilism. The therapeutic Ii beral considers antianxiety agents safe and effective and prescribes these agents freely. He feels patients can't-and shouldn't have to-cope with

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Contemporary Drugs in the Management of Anxiety

problems causing or resulting in anxiety without chemical support. Drugs keep complaining patients happy, usually preempt expensive and often impractical psychotherapy, and prevent patients from becoming an "office fixture." On the other hand, the therapeutic nihilist believes the increasing reliance of large numbers of patients on antianxiety agents to treat symptoms usually related to common life experiences denies the patient the benefits and reduces risks of nonpharmacological solutions. What's more, cavalier prescribing of antianxiety agents reinforces the notion that the patient is indeed sick rather than confronted with normal stresses. The nihilist feels that, in most cases, anxiety is a normal prerequisite to coping with problems, and pharmacological intervention is rarely indicated. In the best interests of most patients, drugs are to be avoided whenever possible and reassurance and counseling substituted. The existence of these opposing philosophies makes health professionals uncomfortable. Antianxiety agents are phenomenally popular and most providers in the mainstream of health care delivery have either prescribed o{ dispensed them in significant quantities. Many providers use these agents themselves on occasion. A significant percentage of any random sample of adults also will react defensively when antianxiety agent use is questioned. Direct discussion with lay groups will disclose that 10-20 percent of the group will be currently taking antianxiety agents, and over one-fourth will have taken these drugs for anxiety sometime in the past. 1-3 Indeed, espousing therapeutic nihilism toward popular antianxiety agents in any public forum these days can be a very disconcerting experience, given the household familiarity of such drugs .. Depending on one's attitude toward antianxiety agent use, one of two conclusions is inevitable: 1. The rate of antianxiety agent use in our society is rational and appropriate; 2. The rate of antianxiety agent use in our society indicates overutilization. If the pattern of use of antianxiety agents within a society is a true reflection of that society's attitude, then the balance is clearly in favor of the therapeutic liberals. To reiterate, 10-20 percent of adults consume antianxiety agents at any given time. Chlordiazepoxide, diazepam, meprobamate and phenobarbital prescriptions constitute nearly 70 percent of all psychoactive drug

use in the U.S. Chlordiazepoxide and diazepam, both benzodiazepine derivatives, account for 50 percent of psychoactive drug use alone as a result of the 100 million prescription orders written for them annually. Surveys show that during any given threemonth period, 10 percent of the adult population is consuming the most popular of these drugs, diazepam. 2 ,3 Benzodiazepines in Anxiety

The benzodiazepine drug group (chlordiazepoxide, chlorazepate, diazepam, oxazepam) dominates antianxiety agent utilization statistics. Chlordiazepo~ide (Librium) and diazepam (Valium) are the most commercially successful prescription drugs ever marketed, having brought in over $2 billion in sales and contributing to making Roche Laboratories what Fortune magazine calls "one of the most profitable enterprises on earth." 4 In fact, in 1973, of ail prescription drugs marketed in the U.S., Valium and Librium occupied the first arid second spots, respectively. The most recent prescription drug survey shows Librium slipping to seventh on the list, but Valium retains a firm hold as the number one prescription drug in this country.5 The prodigious use of benzodiazepines, relative to other antianxiety agents, is attributable to several factors: (a) they produce less drowsiness at therapeutic doses; (b) they are relatively safe, even in overdoses; (c) they do not Significantly induce drug-metabolizing enzymes and thus are not subject to the drug interactions incurred by their therapeutic cousins; (d) tolerance deveiops more slowly and physical dependence is less likely to Qccur than with other antianxiety agents, and (e) their attributes, compared to competitors, have been successfully promoted. dn the basis of these factors, . the relative popularity of benzodiazepines over other aritianxiety agent groups is justifiable. Despite the favorable characteristics distinguishing benzodiazepines from other antianxiety agents, the broader and more basic issue of their high utilization rate in the total drug-use cosmos has only been meekly challenged in the recent past. Lonely soothsayers have been occasionally heard to caution the unbelieving medical community regarding the hazards of indiscriminate distribution of these agents. Largely unheeded at first, their strident voices finally began to penetrate the apathy so that a few authorities now embrace the basic concern

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that we are an "overmedicated society." Still, total antianxiety agent use has continued to increase unchecked, and the increase is linked to the widespread use of benzodiazepines. Despite a growing sensitivity and concern toward the high rate of benzodiazepine use, about the only thing providers presently agree upon is that their colleagues (but not themselves) are overprescribing and overdispensing these agents. Hazards of Indiscriminate Use

Therapy with benzodiazepines is most rational when adjusted to the episodic nature of anxiety. During severe periods of anxiety, drug dosage is reduced or the drug is eliminated. Sustained "pathological anxiety" is very rare, and thus, indefinite drug use is inappropriate. A conservative approach is supported by controlied studies demonstrating that benzodiazepines can be benefiqial during short-term use, but become ineffective or unnecessary when given continuously for months at a time. 6,7 Most of the hazards associated with benzodiazepines occur when these agents are prescribed in high doses for prolonged periods. Physical Dependence. Physical dependence to benzodiazepines develops more slowly than with other drug groups, but after prolonged use, tolerance is well documented. 8 In therapeutic doses, sudden withdrawal after long-term use produces most of the withdrawal symptoms associated with chronic ethanol or barbiturate use. 9 In iarge doses (more than 300 mg diazepam equivalent! day) withdrawal seizures can occur. 10- 12 Other reports of seizures and inexplicable behavior suggesting withdrawal psychosis have appeared in the literature. 13- 15 A recent report presents a strong indictment of benzodiazepines in the production of psychotic withdrawal syndromes in three patients. 16 The prerequisite conditions for physical dependence on benzodiazepines are prolonged use leading to tolerance and increasing doses. The more severe benzodiazepine withdrawal syndromes are characterized by this type of drug-use pattern. These case reports, though infrequent, stress the importance of intermittent therapy with benzodiazepines. Acute Intoxication. It has been said about the safety of benzodiazepines that "the only way to kill an animal . . . is to smother it under a mound of tablets." 17 The attitude that these agents are "suicideproof" has been nourished and perpetuated

Journal of the American Pharmaceutical Association

in the literature so that most pharmacists and physicians accept the idea as fact. This perception, perhaps more than anything else, has catapulted benzodiazepines to the pinnacle of success. Undoubtedly, benzodiazepines are the safest of all currently available antianxiety drug groups and other depressant agents. However, their remarkable popularity and high utilization rate have resulted in an insidious upward trend in benzodiazepine misuse statistics. As reported in the Jour- · nal of the American Medical Association, 18 the federally supported Drug Abuse Warning Network (DAWN) , which monitors visits to emergency rooms and drug crisis centers, has found in its latest statistics that diazepam is now the most frequently abused drug in the U.S. In the DAWN report, diazepam was mentioned in over 27,000 (14 percent) of acute drug intoxication episodes-more than any other drug. Forty-four percent of these episodes involved diazepam alone, and 51 percent were suicide attempts. A very disturbing finding was that more than 100 of the 11,000 drug-related deaths involved diazepam as the single, exclusive agent. Perhaps many of those patients successfully committing suicide had some predisposing condition , such as pulmonary or cardiovascular disease, but regardless of this possibility, the belief that benzodiazepines ~re "suicide-proof" is a myth. The DAWN report can be analyzed ir many ways, but there is no denying the striking incidence of diazepam abuse. The report corroborates earlier findings in Canada that diazepam is the single, most common cause of adult poisoning in our northern neighbors, 19 and concludes that diazepam " is the number one drug of abuse in the U.S.A.". Interestingly, 60 percent of patients monitored in these episodes obtain~d diazepam legally by prescription. In a similar report from the National Council on Drug Abuse, Dr. Jordan Scher provides more alarming statistics. The Council estimates that 25 million Americans currently take diazepam, a'nd that in 1974, more than 500 deaths were caused by benzodiazepine overdose in combination with alcohol and other drugs. His data indicate that 80 percent of the pati~nts in these episodes obtained the drug by prescription. 2o These statistics illustrate how overprescribing has turned a relatively safe drug such as diazepam into a highly abused and potentially dangerous one. Although fatal

Vol. NS 17, No.5, May 1977

misuse is rare in proportion to overqll use, toxic ingestion of benzodiazepines produoes significant morbidity (Le., illness requiring hospital admissions) . Obviously, the problem could be much worse if a less safe drug like phenobarbital were prescri bed for the s~me numbers of patients in the same quantities for the same durations. The essential point, however, is that overprescribing, nqt the specific drug involved, is the crux Qf the misuse problem. Overprescribing fpr the often dubitable syndrome "anxiety," with its consistently amorphous therapeutic endpOints, has transformed "safe" drugs such as diazepam and other benzodiazepines into errant culprits evoking a significant public health problem. Use in Women of Childbearing Age. Three recent studies were summarized which report an association between the ingestion of benzodiazepines during pregnancy and an increased risk of congenital anomalies. 21 This is a significant finding because the majority of users of these agents are women . To recognize the delicate problem this presents, one must recognize that women have been a main target for antianxiety agent promotion. Many readers will remember the journal advertisements of the 1960s and early 1970s depicting women not only as the weaker sex but also qS the sicker sex. The "Flown-the-Coop Syndrome," in which the middle-aged mother / housewife languishes in her large, empty house after her children have left for college, and the "Educated Woman Syndrom~," in which the woman with a college degree is unhappily relegated to the role of P.T.A. mother, were

promotional scenarios importuning the physician to intervene with mind-altering chemicals-a chemical frontal lobotomy, if you will-to dispel women's less than ecstatic attitude. Critics in recent years, particularly those in the women's movement, have challenged the attempts (and apparent success) of drug companies to create "domestic unhappiness" as an indication for antianxiety agents. Such promotion, they contend, transforms normal trials of female existence into a pathological state requiring chemical suppression, and they resent the implication that it is both psychiatrically sound and medically ethical to treat women with antianxiety agents so that they will accept the responsibilities (e.g., domestic surrogate, fawning mother, etc.) assigned to them by society. 19 Fortunately, this type of promotion to providers of health care services has all but disappeared, but the attitudes reflected and fostered by it linger on. Women continue to greatly outnumber men in their rate of antianxiety drug use. Given this context, the potential teratogenicity of benzodiazepines is particularly sobering. It means that the patient group with the highest rate of benzodiazepine use is most susceptible to this potential adverse reaction. The teratogenic potential, although low, is strong motivation to avoid or minimize benzodiazepine use in women of childbearing age unless birth control measures are assured. Finally, transplacental exposure to benzodiazepines can cause withdrawal symptoms in the newborn. In a case report, a woman who consumed chlordiazepoxide, 20 mg daily from the twelfth week of pregnancy, gave birth to female twins who exhibited severe signs of chlordiazepoxide withdrawal. 22 Benzodiazepines: Whom, When, How to Treat

Whom-One of the most difficult decisions facing the conscientious clinician is whom to treat with penzodiazepines. In a world filled with anxiety, t~e decision is as much a philosophical matter as it is a medical one. The prescriber's attitude and values regarding psychogenic disease and psychotropic drugs (Le., therapeutic liberal v~rsus therapeutic nihilist) are frequently the determining factors. Generally, the patient with true pathological anxiety, causing clearcut dysfunction and discomfort, will benefit from pharmacological intervention as'

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Contemporary Drugs in the Management of Anxiety

well as psychotherapy. This initial step of critically evaluating patients and determining appropriate candidates to receive antianxiety agents is crucial for preventing trivial prescribing and curtailing the alarming benzo-diazepine misuse statistics. When-Anxiety is characterized as an episodic affliction, waxing and waning, dependent on ongoing life experiences. Psychotherapy and alteration of stresses in the environment may be the most specific therapy, but benzodiazepines can provide important symptomatic relief. Therapy should be episodic, concentrating the use of medication in times of disabling symptoms and withholding drugs during less stressful periods. How-Hollister7 recommends treatment for a week or less if possible, pointing out that if anxiety is relieved, it might remain so without drugs thereafter. Just the knowledge that relief is available might sustain the patient over subsequent episodes. Treatment in this manner not only follows the natural course of the symptom, but also avoids two problems associated with chronic benzodiazepine use: (a) tolerance with loss of efficacy leading to increasing doses and (b) physical and psychological dependence. Some patients appear to have "trait" or chronic anxiety and do hot do well unless antianxiety agents are maintained indefinitely. Again, philosophical conflicts arise regarding the actual benefits of therapy in such patients as opposed to the pharmacological risks or the time and difficulty involved in managing such patients without drugs. What generally happens is that the patient is supplied drugs continuously to "keep him/her happy" and to avoid straining the delicate patient-physician relationship. Drug companies have capitalized on this sensitivity by promoting antianxiety agents for aggressive patients' 'to keep those constant complainers from becoming an office fixture." 19 Used this way, antianxiety agents tend to allay the prescriber's nervousness, as well as that of the patient. The use of benzodiazepines in this manner is extremely common, potentially harmful and hardly optimal. If the decision is made to treat patients chronically, the doses should be kept small' to minimize the development of tolerance and some degree of psychological drug dependence should be expected. In all patients, doses should be titrated to obtain relief with a minimum impairment of mental alertness. Traditional TID or OlD di-

vided doses often can be changed to less frequent intervals once the daily requirement has been determined. Moreover, starting doses of benzodiazepines, which have long biological half-lives, should be conservative since the drug will accumulate in the body. The full therapeutic or toxic effect of the drugs may not occur until after several days of repeated administration. The long half-life of most benzodiazepines and their tendency to accumulate suggest that dosage to attain a therapeutic goal should not be adjusted more often than once weekly. 1,3 If a shortacting benzodiazepine is desired, oxazepam (TY2 3-21 hours) can be used. Since most of these drugs have long plasma half-lives (in the 1-3 day range) , and since most anxious patients are troubled by insomnia, the major portion of the daytime dosage can be given at bedtime.7 This takes advantage of the hypnotic effects of these agents at higher doses, while a desirable sedation persists throughout the following day. Small supplemental daytime doses can be employed "if needed." This single daily dose regimen should be used with caution in the elderly, in patients with respiratory disease and in others who might be susceptible to hypnotic doses of these agents. Chlorazepate (Tranxene) and chlordiazepoxide (Librium) exhibit delayed absorption half-times when administered with therapeutic doses of antacids. 23 ,24 For optimal absorption of these benzodiazepines, it would appear that the concurrent administration of antacids is best avoided.

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ethanol were nearly doubled, indicating ethanol-enhanced absorption of diazepam in addition to additive pharmacological effects.26 The choice of a benzodiazepine involves considerations of safety, drug costs and patient preferences. Short-term, episodic treatment in an otherwise stable patient can be reliably obtained from any of the antianxiety agents, and cost factors alone may be the best rationale for drug selection. The same basis for selection may hold in the patient who needs protracted therapy, who requ ires only small doses and who is clearly not a risk to misuse antianxiety drugs. On the other hand, the patient who requires chronic therapy and / or is at risk for misuse would benefit from one of the more expensive but safer benzodiazepine agents. Obviously, previous adverse reactions to a drug, or patient preference as determined by response, can aid the clinician in making a rational selection. Conclusion

No one drug group used for anxiety demonstrates any superiority over another in relieving anxiety. In fact , a number of large-scale studies designed to evaluate antianxiety agents fail to show any clear differences between these drugs and placebo. 25 This may stem from the fact that anxious patients tend to respond positively to any attention, including placebo therapy. Thus, the enthusiasm of the prescribing . physicia'n for therapeutic success, the receptiveness and expectations of the patient, and the treatment setting all influence treatment outcome. All antianxiety agents produce similar side effects such as drowsiness and impairment of intellectual and manual skills. Combined with alcohol , the sedative effects may be enhanced profoundly. According to one study, the maximum mean plasma levels of diazepam after combined ingestion with

Anxiety is a ubiquitous symptom which , under certain circumstances, can become intolerable and require treatment. The following points should be kept in mind when initiating and monitoring benzodiazepine therapy: 1. The decision to treat anxiety should be based on a clear degree of disability or discomfort. The trivial use of benzodiazepines is to be condemned. 2. Drug therapy is symptomatic and adjunctive to psychotherapy; the use of drugs should not preempt psychotherapy when the latter is appropriate and feasible. 3. If possible, therapy should be episodic and intermittent. 4. The use of benzodiazepines should be minimized in women of childbearing age. 5. Dosage should be individualized for each patient. Initial doses should be small, and an adequate time period should be allowed for response before dosage is adjusted. 6. Dosage schedules should be flexible to allow the clinician to exploit all characteristics of benzodiazepine pharmacology. 7. The choice of a benzodiazepine is largely empirical and should be based on careful weighing of patient characteristics, expected length of therapy, drug safety, drug interactions and drug costs. •

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Choosing an Antianxiety Agent

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