Sedatives Hypnotics and Benzodiazepines

ROBERT L. DUPONT CAROLINE M. DUPONT

The sedatives and the hypnotics, especially the benzodiazepines, are widely used in medical practice in the treatment of anxiety, insomnia, epilepsy, and for several other indications (Baldessarini, 2001). The combination of abuse by alcoholics and drug addicts, and the withdrawal symptoms on discontinuation leads to the view that these are "addictive" drugs (DuPont, 2000; Juergens & Cowley, 2003). The pharmacology and the epidemiology of sedatives and hypnotics are reviewed in this chapter, which focuses on the needs of the clinician.

A sedative lowers excitement and calms the awake patient, whereas a hypnotic produces drowsiness and promotes sleep. The nonbenzodiazepine sedatives generally depress central nervous system (CNS) activity in a continuum, depending on the dose, beginning with calming and extending progressively to sleep, unconsciousness, coma, surgical aesthesia, and, ultimately, to fatal respiratory and cardiovascular depression. Sedatives share this spectrum of effects with many other compounds, including general anesthetic agents, a variety of aliphatic alcohols, and ethyl alcohol. At lower doses, sedatives can cause impaired cognitive and motor functioning (including staggering and slurred speech). Sedation is a side effect of many other medicines, including antihista-mines and neuroleptics.

The benzodiazepines resemble the other sedatives, except that they do not produce surgical anesthesia, coma, or death, even at high doses, except when coadministered with other agents that suppress respiration. The benzodiazepines can be antagonized by specific agents that do not block the effects of other sedatives. The benzodiazepine antagonists do not produce significant effects in the absence of the benzodiazepines. These properties distinguish the benzodiazepines from the other sedatives and produce a margin of safety that has led to the widespread use of benzodiazepines (Charney, Minie, & Harris, 2001).

The National Comorbidity Survey (NCS) found that 17.2% of the population had an anxiety disorder in the past 12 months, and 24.9% had a lifetime history of anxiety disorder (DuPont, Dupont, & Rice, 2002; Kessler et al., 1994). These studies establish that the anxiety disorders are the most prevalent class of mental disorders over a 12-month period of time (DuPont, 1995). Using the standard human capital approach to estimate the social costs of illnesses in 1994, the anxiety disorders produced a total social cost of $65 billion (DuPont et al., 2002). Of this total, the cost of all treatments was only $15 billion, whereas $50 billion was due to lost productivity as a result of the often seriously disabling nature of the anxiety disorders. For comparison, using the same methodology, the costs of all mental illnesses in 1994 was $204 billion, of which the mood disorders—including depression and bipolar disorders—totaled $42 billion and schizophrenia totaled $45 billion.

The benzodiazepines were introduced in 1960s as comparatively problemfree compared to the barbiturates, which they rapidly replaced. Their popularity reached unprecedented levels in the early 1970s. However, a powerful backlash, labeled the "social issues," emerged, which caused a drop in the use of benzodiazepines during the 1980s, even though there was a rise in the prevalence of the disorders for which they are used (DuPont, 1986, 1988).

As the benzodiazepines became more controversial, and as various regulatory approaches were employed to limit their use in medical practice, there was a danger that clinicians would revert to the older and generally more toxic sedatives and hypnotics, which, in the era of the benzodiazepines, had become unfamiliar (Juergens & Cowley, 2003). Thus, there is more than historical interest in looking at these earlier sedatives, because for some younger medical practitioners, they are new medicines. The use of sedatives and hypnotics for the treatment of anxiety and insomnia in patients with addiction to alcohol and other drugs entails additional risks, especially when benzodiazepines are used (Handelsman, 2002).

For more than three decades, the federal government has tracked the rates of self-reported, nonmedical use of a variety of drugs within the United States, primarily in two surveys—one of high school seniors (Monitoring the Future [MTF]), and the other of Americans 12 years of age and older (National Household Survey on Drug Abuse [NHSDA]) (U.S. Department of Health and Human Services, 2001, 2002). The NHSDA separately tracks the use of "tran-

quilizers" and "sedatives" while the MTF survey tracks "tranquilizers" and "barbiturates." Neither survey identifies "benzodiazepines" specifically. In general, the trends over this extended period of time show a steady rise in nonmedical use, peaking in the late 1970s, followed by a low point in the early 1990s. This was followed by a subsequent upturn in the levels of use that continued into 2001. In 2000, the NHSDA estimated the total number of use Americans, 12 years of age and older, who had used a tranquilizer nonmedically during the prior 30 days as 788,000, down from 950,000 the prior year (U.S. Department of Health and Human Services, 2001). Most of the people who had used a benzodiazepine nonmedically had done so only a few times in their lifetimes. Nonmedical benzodiazepine use, which is different from, and far less common than medical use of the benzodiazepines, is a small but significant part of the overall nonmedical drug problem in the nation.

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