International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.

Despite decades of relevant basic and clinical research, active debate continues about the appropriate extent and duration of benzodiazepine use in the treatment of anxiety and related disorders. The primary basis of the controversy seems to be concern among clinicians, regulators, and the public about the dependence potential and the abuse liability of benzodiazepines. This article reports systematically elicited judgments on these issues by a representative panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depressive disorders, a panel which was constituted by a multistage process of peer nomination. The criterion for inclusion at each stage was the nomination by at least two peers as one of the "professionally most respected physicians of the world with extensive experience and knowledge in the pharmacotherapy of anxiety and depressive disorders." Sixty-six respondents (90%) completed a comprehensive questionnaire covering a wide range of topics relevant to the therapeutic use of benzodiazepines and other medications that might be used for the same purposes. Overall, the expert panel judged that benzodiazepines pose a higher risk of dependence and abuse than most potential substitutes but a lower risk than older sedatives and recognized drugs of abuse. There was little consensus about the relative risk of dependence and abuse among the benzodiazepines. Differences between benzodiazepines with shorter and longer half-lives in inducing withdrawal symptoms are much less clear during tapered than during abrupt discontinuation. There was little agreement about the most important factors contributing to withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic properties of the medication may be the most important contributors to withdrawal symptoms. In contrast, the clinical characteristics of the patient may be the most important contributors to failure to discontinue medication. The experts' judgment seems to support the widespread use of benzodiazepines for the treatment of bona fide anxiety disorders, even over long periods. The experts generally viewed dependence and abuse liability as clinical issues amenable to appropriate management, as for other adverse events related to therapy. However, more definitive clinical research on the remaining controversial issues is urgently needed to promote optimal patient care.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997.

OBJECTIVE: To assemble expert clinical experience and judgment regarding the treatment of anxiety disorders in a systematic, quantitative manner, particularly with respect to changes during the preceding five years. METHOD: A panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options relevant to seven vignettes describing typical cases of different anxiety disorders. RESULTS: The preferred initial treatment strategy in 1992 was a combination of medication with a psychological therapy for all vignettes except simple phobia, where a psychological procedure alone was favored. There was little change in 1997, primarily some decrease in the choice of psychological therapy and some increase in the choice of medication for social phobia. Experts recommending a medication in 1992 most often chose as first-line treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA) for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's most frequent recommendation for agoraphobia, PD, and OCD changed to a specific serotonin reuptake inhibitor (SSRI); and they also recommended these compounds more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or TCAs. However, in 1997 many again chose a combination of medications, often a BZ plus a SSRI, so that, overall, there was only a small decline in recommendations for BZs. As second-line medications (1997 only), the experts recommended SSRIs most often for most vignettes, but a TCA for PD and GAD. Recommendations for a combination of medications rose substantially for most vignettes, usually a BZ plus an antidepressant. CONCLUSIONS: Combined cognitive-behavioral therapy plus medication was highly favored by the experts as the initial treatment strategy for anxiety disorders. During the preceding five years, SSRIs displaced older antidepressants as the experts' first-line choices for the pharmacotherapy of anxiety disorders. In case of an unsatisfactory response, the experts' second-line choices more often were an older antidepressant or a combination of an antidepressant plus a BZ. According to the experts' judgements, the BZs, especially combined with an antidepressant, remain mainstays of pharmacotherapy for anxiety disorders.

Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997.

A follow-up survey in 1997 to a 1992 study of the recommendations of an international expert panel on the use of benzodiazepines (BZDs) and other psychotherapeutic medications in the treatment of anxiety disorders suggests that the BZDs remain a mainstay of pharmacotherapy for most of these conditions. BZDs were mentioned more often than any other class of drugs as preferred first-line therapy for anxiety disorders, except obsessive compulsive disorder. The introduction of the selective serotonin reuptake inhibitors (SSRIs) did not significantly affect the experts' recommendations for the use of BZDs as first-line pharmacotherapy. Rather, the SSRIs displaced the tricyclic antidepressants. Some implications of the continuing recommendations for the use of BZDs in anxiety disorders are discussed.

International Study of Expert Judgement on Therapeutic Use of Benzodiazepines and Other Psychotherapeutic Medications: V. Treatment strategies in panic disorder, 1992-1997.

The objective of this study was to assemble expert clinical experience and judgment regarding the treatment of panic disorder in a systematic, quantitative manner, particularly with respect to changes during the past 5 years. A panel of 73 internationally recognized experts in the field of pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six experts completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options as they relate to a vignette describing a typical case of panic disorder. The preferred initial treatment strategy in 1992 (59%) and in 1997 (55%) was a combination of medication with cognitive behavioral therapy. The vast majority of the expert panel included a medication in their recommendations--91% in 1992 and 90% in 1997. Experts recommending a medication for panic in 1992 chose as first-line treatment a benzodiazepine (35%), a selective serotonin reuptake inhibitor (SSRI, 7%), an older antidepressant (33%), or a combination of medications (25%), principally a benzodiazepine plus an older antidepressant (19%). In 1997, fewer chose a benzodiazepine (15%) or an older antidepressant (11%) alone, whereas 33% chose an SSRI alone. More experts chose a combination of medications in 1997 (39%), and the increase was attributable mainly to the choice of a benzodiazepine plus an SSRI (17%). Overall, there was only a small decline in recommendations for benzodiazepines, whereas the increased choice of SSRIs came largely at the expense of the older antidepressants. As second-line medications for panic should their first-line choice fail, the experts in 1997 recommended a benzodiazepine (7%), an SSRI (15%), an older antidepressant (28%), or a combination of medications (50%), most often a benzodiazepine plus an older antidepressant (21%) or a benzodiazepine plus an SSRI (17%). (Experts were not asked to recommend second-line treatment in 1992). Thus, in case of unsatisfactory response, the experts' choices shifted from benzodiazepines and SSRIs alone toward the older antidepressants alone or combinations of an antidepressant plus a benzodiazepine. This report concluded that combined cognitive behavioral therapy plus medication was highly favored by the experts as the initial treatment strategy for panic disorder. Over the past 5 years, SSRIs displaced older antidepressants as the experts' choice for first-line pharmacotherapy of panic disorder. In case of an unsatisfactory response, the experts more often recommended an older antidepressant or a combination of an antidepressant plus a benzodiazepine. According to the experts' judgments, the benzodiazepines, especially combined with an antidepressant, remain mainstays of pharmacotherapy for panic disorder.

International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications: II. Pharmacotherapy of anxiety disorders.

OBJECTIVE: To assemble expert clinical experience and judgement in the treatment of anxiety and related disorders in a systematic, quantitative manner. METHODS: A panel of internationally recognized Experts in treating anxiety and depression was constituted by multistage peer nomination. 90% completed a questionnaire. This report focuses on case vignettes of 7 anxiety disorders followed by questions about relevant therapeutic options. RESULTS: Panelists usually recommended both psychological and pharmacological interventions. Most favored antidepressants, usually tricyclic, for agoraphobia, panic and OCD; beta-blockers for specific social phobia; and benzodiazepines for GAD and adjustment disorder. Some Experts favored polypharmacy, usually an antidepressant and a benzodiazepine. The majority usually advocated pharmacotherapy for 6 months or more. They recommended the same duration of treatment with benzodiazepines and other medications, except for GAD. CONCLUSIONS: The responses of the Expert Panel imply that; (1) most anxiety disorders are serious and merit vigorous, prolonged pharmacotherapy; and (2) antidepressants and benzodiazepines are effective and safe for long-term treatment of these conditions. This outcome contrasts with the widespread apprehension about long-term pharmacotherapy, especially with benzodiazepines, and some regulatory views.

International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: III. Clinical features affecting experts' therapeutic recommendations in anxiety disorders.

Our objective was to assemble expert clinical experience and judgment in the treatment of anxiety and related disorders in a systematic, quantitative manner. This article reports on some clinical features apart from diagnosis that may affect choice of strategy in the pharmacotherapy of anxiety disorders. A panel of internationally recognized experts in treating anxiety and depression was constituted by multistage peer nomination. Ninety percent (66 of 73) completed an extensive questionnaire. This report focuses on the expert panel's responses to questions on therapeutic options, based on multi-part case vignettes of several anxiety disorders presenting clinical variations within the same diagnosis. In the presence of higher levels of functional impairment, the experts more often recommended formal psychosocial procedures for adjustment disorder; medication for agoraphobia, social phobia, obsessive-compulsive disorder, and adjustment disorder; and polypharmacy for agoraphobia. Their therapeutic recommendations were not materially affected by chronicity in the case of panic disorder. Under the condition of heavy use of alcohol in the case of generalized anxiety disorder, the experts avoided benzodiazepines in favor of various other medications. In the presence of a serious cardiac conduction defect in the case of obsessive-compulsive disorder, they less often recommended medication. Those who did recommend medication changed their preference from tricyclic antidepressants (clomipramine) to selective serotonin reuptake inhibitors. Under the condition of a more severe precipitating event in the case of adjustment disorder, the experts were more likely to recommend both formal psychosocial intervention and medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical variables in pharmacoepidemiology.

Pharmacoepidemiology traditionally concerns itself with the rates at which drugs are prescribed and used in the general population. Interpretations of these data frequently assume that the rates--for psychotropic drugs--reflect primarily the reinforcing properties of the drugs. This paper, in contrast, focuses on the influence of certain clinical characteristics of consumers on patterns of psychotherapeutic drug use. The data are from a nationwide (US) probability sample of 3,161 persons aged 18-79 years surveyed in 1979. One-year prevalence rates of use and the longest period of regular daily use serve as indices of drug consumption. Scores on a 43-item checklist of psychological symptoms were used to compute two clinical descriptors of the respondents--a quantitative index of the level of psychic distress and a qualitative syndromal classification including depression, agoraphobia/panic, other phobias, and generalized anxiety. The data showed that, although anxiolytics and antidepressants have characteristic patterns of prevalence and duration of use, the clinical characteristics of users (severity and pattern of symptoms) strongly influence these patterns. Prevalence and duration of drug use alone do not suffice to illuminate the social functions and significance of psychotherapeutic agents, to provide a basis for value judgments about the use of such compounds, and to guide medical decision-making. Since clinical variables play such a major role in the consumption of these agents, it is crucial to include information about these variables in the analysis and interpretation of patterns of psychotherapeutic drug use.

New epidemiologic findings about insomnia and its treatment.

This paper examines several clinical concerns about the shorter half-life benzodiazepine hypnotics from an epidemiologic perspective. It draws on data from (1) 1979 and 1990 comprehensive probability-based U.S. national household surveys of the medical use of psychotherapeutic medications; (2) a 1990 four-city community-based volunteer call-in survey of the beneficial and adverse effects of hypnotics; and (3) an analogous random-digit dialing telephone survey in the general population. The issues addressed are abuse liability, rebound, depersonalization/derealization, paranoid feelings, accidents/injuries, and the unexamined consequences of the target illness in assessments of benefit-risk. In populations representative of everyday outpatient practice, we found that (1) the abuse liability of benzodiazepine hypnotics with shorter and longer elimination half-lives was generally low and comparable; (2) prevalence rates for rebound were low and not differential for flurazepam, temazepam, triazolam, and OTC sleeping pills; (3) reports of a single or an occasional experience involving depersonalization/derealization or paranoid feelings were fairly frequent in normals, in insomnia patients prior to treatment, and in persons with untreated insomnia; (4) treatment-emergent rates of occurrence for these same symptoms were low and not drug-specific; (5) past-year prevalence rates for serious accidents/injuries were much higher for chronic untreated insomnia than for normal controls and most groups treated with psychotherapeutic medications. A high proportion of past-year users of hypnotics were satisfied with their medication and would take it again.

The beneficial and adverse effects of hypnotics.

Findings from a four-city study of the beneficial and adverse effects of hypnotics are reported. The study employed a new volunteer call-in method for monitoring drug effects outside of the clinical setting. Respondents were recruited through newspaper advertisements. They were invited to complete a short telephone interview if, during the past 12 months, they (1) had significant trouble with insomnia or (2) had taken a medication to induce sleep. Comparison groups were flurazepam, temazepam, triazolam, and over-the-counter (OTC) sleep medications. An untreated insomnia group also was included. Results indicate that most users of prescription hypnotics attributed positive effects to their sleep medications and that adverse effects were infrequent. OTC hypnotics were less effective and more likely to produce negative effects. The untreated insomnia group was more symptomatic than any of the medication groups.

Risks and benefits of long-term benzodiazepine use.

Despite a sharp decline in the prescription of benzodiazepines during the past decade, reservations about their use have continued to escalate. This article presents converging data from three diverse sources: national survey data from consumers, laboratory data on the drug preferences of normal subjects, and a controlled clinical study of long-term diazepam treatment and withdrawal. These data suggest that (1) the risks of overuse, dependence, and addiction with benzodiazepines are low in relation to the massive exposure in our society; (2) benzodiazepine addiction can occur when doses within the clinical range are taken regularly over about 6 months; (3) many patients continue to derive benefit from long-term treatment with benzodiazepines; and (4) attitudes strongly against the use of these drugs may be depriving many anxious patients of appropriate treatment.

Survey method for post-marketing drug surveillance: a demonstration.

Distinguishing characteristics of a community survey method for post-marketing drug monitoring are described, as are results of a pilot study of the method. Representative samples of outpatients treated with tricyclic antidepressants or benzodiazepine anxiolytics were identified in a clinic or pharmacy and interviewed at baseline and specified intervals thereafter in the home or by telephone. Data were collected by lay interviewers trained to use a detailed interview schedule designed with input from experts in pharmacology, relevant clinical disciplines, and survey research. The critical validity question was the degree to which predicted outcomes for the two well-studied drug classes matched observed outcomes. The analytic design involved two contrast groups, three measurement periods, and six key symptom measures. The latter were specific to the disorder (anxiety and depression), to the medications, or to neither the disorders nor the medication (neutral symptoms). Predictions took account of degree and direction of change, as well as differences in profile levels over time. Results conformed precisely to expectations. As one component of a comprehensive system, the method provides an opportunity to examine efficacy as well as safety under conditions that are typically absent or excluded in clinical trials. Data on patterns of prescribing by physicians and use by patients are valuable by-products that are immediately relevant for professional education and product liability. Advantages and limitations of the method are discussed.

Changes in popular attitudes and beliefs about tranquilizers. 1970-1979.

In nationwide surveys of the extent and nature of psychotherapeutic drug use conducted in 1970 and 1979, respondents were also questioned about their knowledge of tranquilizers and attitudes toward the use of these medications in general and in specific situations. In both 1970 and 1979, most Americans believed that tranquilizers were effective; by 1979, however, we found a sharp increase in the proportion of respondents who believed that these medications were overprescribed. Reservations about the effects of tranquilizers on health, mood, and behavior had also become more widespread by 1979. In both 1970 and 1979, however, respondents were generally more accepting of tranquilizer use when presented with practical situations pitting benefit against risk. A majority condoned the use of tranquilizers in situations involving pronounced impairment.

Insomnia and its treatment. Prevalence and correlates.

Data for this report come from a nationally representative probability sample survey of noninstitutionalized adults, aged 18 to 79 years. The survey, conducted in 1979, found that insomnia afflicts 35% of all adults during the course of a year; about half of these persons experience the problem as serious. Those with serious insomnia tend to be women and older, and they are more likely than others to display high levels of psychic distress and somatic anxiety, symptoms resembling major depression, and multiple health problems. During the year prior to the survey, 2.6% of adults had used a medically prescribed hypnotic. Typically, use occurred on brief occasions, one or two days at a time, or for short durations of regular use lasting less than two weeks. The survey also found a small group of hypnotic users (11% of all users; 0.3% of all adults) who reported using the medication regularly for a year or longer. If we include anxiolytics and antidepressants, 4.3% of adults had used a medically prescribed psychotherapeutic drug that was prescribed for sleep; 3.1% had used an over-the-counter sleeping pill. The majority of serious insomniacs (85%) were untreated by either prescribed or over-the-counter medications.

Anti-anxiety agents: duration of use and characteristics of users in the U.S.A.

A national survey of psychotherapeutic drug use was carried out in the U.S.A. in 1979. Data were obtained from a probability sample (n = 3161) of adults in the general population, using a clinically-oriented interview lasting an average of 90 minutes. The data provide estimates of the prevalence of using anxiolytic and other psychotherapeutic medications. Among users they also provide detailed descriptions of patterns of use and characteristics associated with various patterns of use. The study found that 11% of American adults used an anxiolytic during the 12 months prior to the survey. Benzodiazepines accounted for 84% of the anxiolytics mentioned. The analyses compared (i) users of anxiolytics with non-users and (ii) three groups of anxiolytic users classified according to pattern (frequency and regularity) of use. The results were generally consistent with an illness treatment model of psychotherapeutic drug use, and they raise interesting questions about short-term single-occasion use.

Anxiety disorders: prevalence and treatment.

A method is reported for classifying survey respondents according to syndromes resembling some of the anxiety disorders as defined by DSM III, using responses to a standard clinical symptom checklist administered on a large scale in the U.S.A. by trained survey interviewers in the 1979 National Survey of Psychotherapeutic Drug Use. These syndromes ('agoraphobia/panic', 'other phobia', and 'generalized anxiety') have several characteristics consistent with their DSM III diagnostic counterparts. They show 1-year prevalence rates of 1.2%, 2.3%, and 6.4%, respectively, roughly in accord with the limited relevant epidemiological data available. The prevalence of these anxiety syndromes is lower than clinical lore suggests. The very low prevalence of use of antidepressants (8%) and the much higher rate of use of anti-anxiety agents (55%) among agoraphobics are surprising. The infrequent use of anti-anxiety agents among respondents with generalized anxiety (27%) also is noteworthy. These findings suggest that the majority of persons with serious anxiety disorders still do not receive treatment or the most appropriate treatment, although other possible interpretations of the data also are considered.

A cross-national comparison of anti-anxiety/sedative drug use.

Findings are reported from a 1981 cross-national survey of the use of anti-anxiety/sedative medications by adults in the general population of the United States and 10 Western European countries. Representative national samples in the 11 countries were asked a standard set of questions about their use of these medications during the preceding 12 months. Data were obtained by personal interview in the course of a household visit. The number of persons interviewed ranged from 1486 to 2018. The data provide comparable estimates of past-year prevalence of use-the proportion of the population who took these medications one or more times, and duration of use-and the proportion of the population who took these medications daily for various lengths of time. Rates for past-year prevalence of use varied from 17.6% in Belgium to 7.4% in the Netherlands. The United States at 12.9% was in the middle of the distribution. There was wide variation among countries in the prevalence of long-term and short-term use, but regular daily use for 3 months or less was the predominant pattern in 10 of the 11 countries surveyed. Past-year prevalence rates were much higher for women than for men in every country surveyed. At the national level, the data show that simple past-year prevalence rates and durational parameters of use are relatively independent.

Prevalence and correlates of the long-term regular use of anxiolytics.

Long-term use of anxiolytics has been a cause for concern because of the possibility of dependency and other adverse consequences. In a nationally representative probability survey of adults conducted in 1979, we found that long-term use (defined as regular daily use for a year or longer) was relatively rare, occurring among 15% of all anxiolytic users--a rate of 1.6% of all adults between the ages of 18 and 79 years in the general population. The data indicate that long-term regular users tend to be older persons with high levels of emotional distress and chronic somatic health problems. They are preponderantly women, and many are sufficiently distressed to seek out other sources of help (mental health professionals and other psychotherapeutic medications) as well. The sizable majority of long-term users is being monitored by their physicians at reasonably frequent intervals. The data give little support to current stereotypes of long-term users and suggest, instead, that such use is associated with bona fide health problems that are being treated within the broader context of the health system.