Antianxiety Drugs
Julia Jackson
BENZODIAZEPINES
Benzodiazepines, introduced into clinical practice in the early 1960s, were the most frequently prescribed drugs in the United States between 1968 and 1980. In 1978 alone, 68 million prescriptions for benzodiazepines were written for approximately 10 million individuals; more than half of these were for diazepam (Ayd, 1980). Greenblatt et al. (1983) noted that by 1980, however, the trend toward increasing use of benzodiazepines reversed, perhaps due to negative publicity regarding the potential for abuse and dependency with these medications. In 1989, in response to these concerns, New York State mandated that all benzodiazepine prescriptions be written on triplicate forms, as was required for other controlled drugs. Many experts at the time, however, felt the dangers of benzodiazepines were “greatly exaggerated” (Simeon and Ferguson, 1985). In a summary statement, the American Psychiatric Association (APA) Task Force opined that “benzodiazepines, when prescribed appropriately, are therapeutic drugs with relatively mild toxic profiles and low tendency for abuse” (Salzman, 1990, p. 62). An exception to this occurs among substance abusers, however. Benzodiazepine abuse is very frequent among alcoholics, cocaine, narcotic, and methadone abusers, who use benzodiazepines to “augment the euphoria (narcotics and methadone users), decrease anxiety and withdrawal symptoms (alcoholics), or to ease the ‘crash’ from cocaine-induced euphoria” (Salzman, 1990, p. 62).
Little was known at the time about the efficacy of benzodiazepine medications for child and adolescent psychiatric disorders. In a 1974 monograph, after reviewing the use of benzodiazepines in youth, Greenblatt and Shader stated, “At present it is doubtful that the benzodiazepines have a role in the pharmacotherapy of psychoses or in the treatment of emotional disorders in children” (p. 88). Werry concluded that if pharmacotherapy is necessary for certain childhood sleep disturbances, including insomnia, night waking, night terrors, and somnambulism, benzodiazepines are “probably” indicated, and for some kinds of anxiety they are “possibly” indicated (Rapoport et al., 1978b).
In 1983, Coffey et al. reported that benzodiazepines appeared to be prescribed to both older adolescents and adults for relief of anxiety and tension,
muscle relaxation, sleep disorders, and seizures. In children, however, they were used primarily for treatment of sleep and seizure disorders and were used much less commonly for their anxiolytic and muscle-relaxant qualities.
muscle relaxation, sleep disorders, and seizures. In children, however, they were used primarily for treatment of sleep and seizure disorders and were used much less commonly for their anxiolytic and muscle-relaxant qualities.
The literature concerning benzodiazepine use in children was reviewed by both Campbell et al. (1985) and Simeon and Ferguson (1985). Most published reports appeared in the 1960s, involved open studies composed of diagnostically heterogeneous subjects and resulted in discrepant findings. The most common drugs studied were diazepam and chlordiazepoxide.
At present, the childhood psychiatric conditions that have the most convincing rationale for the use of a benzodiazepine as the drug of choice are sleep terror disorder (pavor nocturnus) and sleepwalking disorder (somnambulism). These conditions are not usually treated with pharmacotherapy, however, unless they are unusually frequent or severe. Both sleep terror disorder and sleepwalking disorder typically occur “during the first third of the major sleep period (the interval of nonrapid eye movement [NREM] sleep that typically contains EEG delta activity, sleep stages 3 and 4)” (APA, 1987, pp. 310-311). Because benzodiazepines decrease stage 4 sleep, they are thought to be of value in these conditions. Reite et al. (1990) suggested that either 2 mg of diazepam or 0.125 mg of triazolam at bedtime may decrease the frequency of night terrors or somnambulism in children with severe cases. Conversely, benzodiazepines were hypothesized to be contraindicated in treating sleep disturbance associated with psychosocial dwarfism (psychosocially determined short stature) due to concern that they may further compromise nocturnal secretion of growth hormone, which occurs maximally during sleep stages 3 and 4, slow-wave sleep (Green, 1986).
It is well known that if a benzodiazepine is used as a hypnotic, consideration of the serum half-life of the drug is important. Flurazepam (Dalmane), temazepam (Restoril), and triazolam (Halcion) can all be used for treating sleep disorders. Flurazepam is a long-acting benzodiazepine with a half-life (for it and its metabolites) of 47 to 100 hours. The manufacturer notes that this pharmacokinetic profile may explain the clinical observation that flurazepam is increasingly effective on the second or third night of use and that after discontinuing the drug, both sleep latency and total wake time may still be decreased. Because of flurazepam’s long half-life, it appears to be most useful in persons with both insomnia and significant daytime anxiety. Temazepam and triazolam, by contrast, are short-acting benzodiazepines, with a relatively rapid onset of action and half-lives of only 9.5 to 12.4 hours (temazepam) and 1.5 to 5.5 hours (triazolam). Triazolam’s notably short half-life renders it a drug of choice for sleep-onset insomnia and for times when daytime sedation is of concern.
Triazolam’s manufacturer warns that all benzodiazepines used to induce sleep can cause an anterior-grade amnesia, in which the person may not recall events occurring for several hours after taking the drug. Triazolam is more likely than the other benzodiazepines to cause such amnesia, particularly if a person is awakened before the drug is metabolized or excreted sufficiently to eliminate the effect. This phenomenon is referred to as “traveler’s amnesia,” as many travelers, especially on long flights, take medication to induce sleep and are subsequently awakened before the effects of the drug wear off. Triazolam should not be used in such situations. Because of triazolam’s short half-life, patients should also be warned of the increased likelihood of experiencing a withdrawal effect, which may entail increased wakefulness during the last third of the night, and/or increased daytime anxiety or nervousness.
Wysowski and Barash (1991) compared postmarketing adverse behavioral reactions of triazolam and temazepam reported through the FDA’s spontaneous reporting system. Triazolam was associated with significantly more frequent reports of confusion than did temazepam (133 vs. 2), of amnesia (109 vs. 3), of
bizarre behavior (59 vs. 2), of agitation (58 vs. 4), and of hallucinations (40 vs. 1). The incidence of adverse events was quite low, however, because during the period of comparison, 13.5 million prescriptions were written for triazolam and 19.1 million prescriptions were written for temazepam. The authors noted that adverse reactions to triazolam tended to occur at higher doses (0.25 mg and higher) and in the elderly.
bizarre behavior (59 vs. 2), of agitation (58 vs. 4), and of hallucinations (40 vs. 1). The incidence of adverse events was quite low, however, because during the period of comparison, 13.5 million prescriptions were written for triazolam and 19.1 million prescriptions were written for temazepam. The authors noted that adverse reactions to triazolam tended to occur at higher doses (0.25 mg and higher) and in the elderly.
Klein et al. (1980) suggested that a low dose of a benzodiazepine (e.g., diazepam 5 mg) might be useful in treating residual anticipatory anxiety in schoolphobic youngsters whose separation anxiety had been alleviated by treatment with imipramine. Simeon and Ferguson (1985) reported that some overly inhibited children may show lasting behavioral improvement following brief (not exceeding 4 to 6 weeks) treatment with a benzodiazepine. They attributed the improvement to an interaction between disinhibition facilitated by the medication and social learning. Consistent with this finding, they noted that children and adolescents with impulsivity and aggression, who were under significant environmental stress, should not be treated with benzodiazepines because the disinhibition could result in a worsening of behavior (Simeon and Ferguson, 1985).
Most of the literature suggests that benzodiazepines worsen symptoms in psychotic children and provide little benefit for hyperactive youth. In studies comparing dextroamphetamine, placebo, and chlordiazepoxide or diazepam in treating hyperactive children, chlordiazepoxide and diazepam were both less effective than dextroamphetamine, and placebo was rated better than diazepam (Zrull et al., 1963, 1964).
Contraindications and Cautions for Benzodiazepine Administration
Known hypersensitivity to benzodiazepines and acute narrow-angle glaucoma are usually considered absolute contraindications.
Persons predisposed to substance abuse or alcoholism should not be prescribed benzodiazepines unless the benefits clearly outweigh the increased risk for physical and psychological dependence in this patient population. Benzodiazepines should not be abruptly discontinued after extended therapy, as this may result in withdrawal symptoms.
Adolescents who are likely to become pregnant or who are known to be pregnant should not be prescribed benzodiazepines, as there is a risk of congenital malformations particularly during the first trimester of pregnancy. Maternal abuse of benzodiazepines may cause a withdrawal syndrome in the newborn (Rall, 1990). Simeon and Ferguson (1985) concluded that benzodiazepines are relatively contraindicated in children and adolescents with significant impulsivity, aggressiveness, and environmental stress, as negative disinhibiting drug effects may occur.
Interactions of Benzodiazepines with Other Drugs
Additive effects, when combined with other sedative or hypnotic drugs, including alcohol (ethanol), are clinically important drug interactions to consider when prescribing benzodiazepine medication. Phenothiazines, narcotics, barbiturates, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and cimetidine (Tagamet) may potentiate benzodiazepines. The rate of absorption of benzodiazepines, and the resulting central nervous system depression, are both increased by ethanol (Rall, 1990). CYP3A inhibitors, such as oral antifungals, may increase benzodiazepine levels. Benzodiazepines are relatively safe drugs, and even large overdoses are infrequently fatal unless taken in combination with other drugs (Rall, 1990).
Flumazenil (Romazicon) is a benzodiazepine receptor antagonist that reverses the sedative effects of benzodiazepines. Flumazenil does not reverse hypoventilation or
respiratory suppression caused by benzodiazepines, however. In pediatric patients, flumazenil is indicated for the reversal of benzodiazepine-induced conscious sedation (ages 1 to 17 years). It is also indicated for the management of benzodiazepine overdose in adults. In cases of benzodiazepine overdose in adults, flumazenil is administered intravenously in doses of 0.2 mg (2 mL) over a 30-second period. A second dose of 0.3 mg may be administered over 30 seconds, and additional doses of 0.5 mg over 30 seconds, at 1-minute intervals to a maximum of 3 mg, may be given until the desired level of consciousness is obtained. Only rarely do patients benefit from higher doses. Due to its relatively short half-life, resedation may occur. In such cases, additional flumazenil may be given at 20-minute intervals (max of 1 mg/dose and 3 mg/hour).
respiratory suppression caused by benzodiazepines, however. In pediatric patients, flumazenil is indicated for the reversal of benzodiazepine-induced conscious sedation (ages 1 to 17 years). It is also indicated for the management of benzodiazepine overdose in adults. In cases of benzodiazepine overdose in adults, flumazenil is administered intravenously in doses of 0.2 mg (2 mL) over a 30-second period. A second dose of 0.3 mg may be administered over 30 seconds, and additional doses of 0.5 mg over 30 seconds, at 1-minute intervals to a maximum of 3 mg, may be given until the desired level of consciousness is obtained. Only rarely do patients benefit from higher doses. Due to its relatively short half-life, resedation may occur. In such cases, additional flumazenil may be given at 20-minute intervals (max of 1 mg/dose and 3 mg/hour).
Untoward Effects of Benzodiazepines
Given that benzodiazepines are central nervous system depressants, the most common untoward effects are oversedation, fatigue, drowsiness, and ataxia. Confusion progressing to coma may occur at high doses. When targeting daytime symptoms such as anxiety, benzodiazepines should be administered in divided doses to minimize sedation.
“Paradoxical reactions,” or episodes of marked dyscontrol and disinhibition, have been reported in children and adolescents. Symptoms have included acute excitation, increased anxiety, increased aggression and hostility, rage reactions, loss of all control, hallucinations, insomnia, and nightmares.
Psychiatric and behavioral disturbances, including suicidality, have also been attributed to clonazepam use. For example, Kandemir et al. (2008) reported that a 9-year-old boy with no personal or family psychiatric history, experienced excessive anger, irritability, and suicidal thinking and behavior after being prescribed clonazepam 1.5 mg/day by his neurologist to treat blepharospasm. On the fourth day of treatment with clonazepam, he developed suicidal thoughts and admitted to cutting his arms and chest with a razor in response to these thoughts. His parents reported he had no history of like behavior prior to treatment with clonazepam and stated he was taking no other medication. They described him as a “calm, well adjusted, and happy” child at baseline. A complete medical work-up, including head imaging, was negative. After clonazepam was decreased and stopped over a 3-day period, his psychiatric symptoms resolved entirely. At follow-up 6 months later, he had no recurrence of symptoms (Kandemir et al., 2008).
Use of Benzodiazepines in Child and Adolescent Psychiatry
In general psychiatry, benzodiazepines are indicated for the management of anxiety disorders, or for short-term relief of anxiety and/or sleep disorders. They are also used to treat acute symptoms of alcohol withdrawal. The effectiveness of benzodiazepines for chronic treatment (lasting >4 months) has not been assessed in systematic clinical studies.
At present, randomized controlled trials do not suggest efficacy of benzodiazepine medication for the treatment of childhood anxiety disorders. In clinical practice, benzodiazepines are used at times in youth, however, to acutely reduce severe anxiety until more effective medications, such as selective serotonin reuptake inhibitors (SSRIs), achieve therapeutic effect. If used, manufacturers’ clinical recommendations for children should not be exceeded. Table 9.1 gives usual daily dosages for some representative benzodiazepines, an estimate of the serum half-life of the parent compound and/or its significant active metabolites, the youngest age for which the FDA has approved their use for any purpose, and when applicable, suggested dosages for their use in child and adolescent psychiatric disorders.
The need for benzodiazepines should be reassessed frequently, and long-term, chronic use should be avoided.
TABLE 9.1 ≫ Some Representative Benzodiazepines | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
As previously mentioned, there is a relative paucity of studies examining the use of benzodiazepines in youth. The few studies done are reviewed below, although many entail older, uncontrolled studies or case reports.
Chlordiazepoxide (Librium)
Reports of Interest
Chlordiazepoxide in the Treatment of Behaviorally Disordered Children and Adolescents of Various Diagnoses
Krakowski (1963) treated 51 emotionally disturbed children and adolescents 4 to 16 years of age with chlordiazepoxide. Criteria for inclusion were the presence of anxiety (especially with coexisting hyperactivity), irritability, hostility, impulsivity, and insomnia. Nine children had concurrent individual therapy, and seven received other medications, mainly antiepileptics. Chlordiazepoxide was administered initially in divided doses totaling 15 mg and individually titrated. Maintenance dosage for periods of up to 10 months ranged from 15 to 40 mg/day (mean, 26 mg/day). Twelve patients (23.5%) showed complete remission of psychiatric symptoms, and 22 (43.1%) improved moderately. Children with adjustment disorders were particularly likely to improve; specifically, 11 of 18 with conduct disorders, 2 of 3 with habit disturbances, and all 4 with neurotic traits showed marked or moderate remission of symptoms. Of 12 developmentally delayed patients, 3 improved moderately and 3 improved markedly. Untoward effects were relatively infrequent and included drowsiness, fatigue, muscular weakness, ataxia, anxiety, and depression. These effects were alleviated to a satisfactory degree by dosage reduction in all but one case.
Kraft et al. (1965) prescribed chlordiazepoxide to 130 patients (99 males, 31 females) who ranged in age from 2 to 17 years (112 were between 7 and 14 years of age). The most common diagnoses were primary behavior disorder (50), school phobia (18), adjustment reaction of adolescence (17), and chronic brain damage (14). Most subjects had marked hyperactivity and neurotic traits. Doses ranged from 20 to 130 mg/day and were administered in divided doses; 94 subjects (72%) received 40 mg or more daily. Moderate or marked improvement occurred in 53 subjects (40.8%). Forty subjects (30.8%) had either no or insignificant improvement, and 37 (28.5%) worsened. The diagnostic group showing the greatest improvement was school phobia (77%). Only 38% of the primary behavior disorder subjects and 41.2% of the adolescent adjustment disorder subjects improved to a moderate or marked degree. Of those with organic brain damage, 50% worsened, 28.6% showed minimal or no benefit, and none had an excellent response. Across diagnoses, symptoms of hyperactivity, fear, night terrors, enuresis, reading and speech problems, truancy, and disturbed or bizarre behavior were moderately or markedly improved in 40.8% of the 130 subjects. The authors concluded that chlordiazepoxide was effective in decreasing anxiety and “emotional overload” (Kraft et al., 1965). The authors also reported that 22 of the 130 had untoward effects of sufficient severity to interfere with treatment results and that 14 other subjects had milder untoward effects that were transient or responded to a lowering of the dose.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
