Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports.

BACKGROUND: Constipation is an exceedingly common side effect of treatment with clozapine. In rare cases, this side effect has resulted in fatal complications. OBJECTIVE: The authors review the literature on fatal complications of clozapine-related constipation and bowel obstruction. METHOD: The authors provide two new case reports of patients who died of similar causes. RESULTS: There were seven reports of deaths from clozapine-related bowel obstruction in the literature, with the most common mechanisms of death being severe impaction leading either to feculent vomiting or bowel necrosis. DISCUSSION: The discussion outlines potential mechanisms and management of clozapine-related constipation.

Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects.

OBJECTIVE: To evaluate the next-day residual effects of the novel hypnotic, gaboxadol, following bedtime dosing in healthy elderly subjects. METHODS: Healthy women (N = 15) and men (N = 10) aged 65-79 years received a single bedtime (22:00 h) dose of gaboxadol 10 mg, flurazepam 30 mg (positive control), and placebo in a randomized, double-blind, crossover study. Measures of information processing and psychomotor performance (choice reaction time, critical flicker fusion, digit symbol substitution, compensatory tracking, body sway), memory (immediate and delayed word recall), and daytime sleepiness (Multiple Sleep Latency Test), as well as subjective ratings (line analog rating scales, Leeds Sleep Evaluation Questionnaire), were obtained starting at 07:00 h the following morning. Adverse events were recorded. RESULTS: Gaboxadol did not show next-day impairments versus placebo on any pharmacodynamic measures whereas the positive control, flurazepam, did show impairments versus placebo on most measures. Gaboxadol showed improvements versus placebo on some measures including subjective rating of next-day alertness/clumsiness on the Leeds Sleep Evaluation Questionnaire. Gaboxadol was generally well-tolerated; there were no serious adverse experiences and no subjects discontinued due to an adverse experience. CONCLUSIONS: A single oral bedtime dose of gaboxadol 10 mg did not have next-day residual effects in healthy elderly subjects, as measured by a range of pharmacodynamic assessments, in contrast to the clear impairments produced by flurazepam 30 mg.

Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries.

BACKGROUND AND OBJECTIVES: Accurate assessment of medication impact requires modeling cumulative effects of exposure duration and dose; however, postmarketing studies usually represent medication exposure by baseline or current use only. We propose new methods for modeling various aspects of medication use history and employment of them to assess the adverse effects of selected benzodiazepines. STUDY DESIGN AND SETTING: Time-dependent measures of cumulative dose or duration of use, with weighting of past exposures by recency, were proposed. These measures were then included in alternative versions of the multivariable Cox model to analyze the risk of fall related injuries among the elderly new users of three benzodiazepines (nitrazepam, temazepam, and flurazepam) in Quebec. Akaike's information criterion (AIC) was used to select the most predictive model for a given benzodiazepine. RESULTS: The best-fitting model included a combination of cumulative duration and current dose for temazepam, and cumulative dose for flurazepam and nitrazepam, with different weighting functions. The window of clinically relevant exposure was shorter for flurazepam than for the two other products. CONCLUSION: Careful modeling of the medication exposure history may enhance our understanding of the mechanisms underlying their adverse effects.

Flurazepam effects on sleep EEG. Visual, computer, and cycle analysis.

Analysis of sleep effects of flurazepam hydrochloride on four normal subjects confirmed that this drug substantially suppresses both REM and stage 4 sleep. Computer analysis disclosed that delta wave amplitude was greatly reduced by flurazepam. However, low density delta wave activity (ie, stage 2 sleep, which was increased in duration beyond the reduction in stage 4), permitted the number of delta waves and the time they occupied per night to remain at baseline levels. This finding suggests that sedative-hypnotics increase total sleep time by slowing the metabolic processes of sleep so that a longer sleep duration is required for the same biological effects. New observations on the induction times of REM and stage 4 effects are also presented. In general, the distortions in sleep EEG produced by flurazepam qualitatively resemble, but are quantitatively greater than, those produced by barbiturates in equivalent hypnotic doses.

Overmedication of the low-weight elderly.

This study analyzes age, weight, and drug doses using cimetidine hydrochloride, flurazepam hydrochloride, and digoxin as tracers. Data were obtained for 1797 patients (mean age, 72 years) filling consecutive prescriptions from a national pharmacy service. With all three drugs, patients with lower weight received substantially higher doses with correlations of weight vs dose, based on milligrams per kilogram of body weight, ranging from -0.34 to -0.40. Because body weight declines with increasing age, lower-weight patients are also older and at greatest risk for drug toxicity. Patients weighing 50 kg or less (n = 155) received milligram-per-kilogram doses that were 31% to 46% higher than the group mean and 70% to 88% higher than patients weighing more than 90 kg. For all three study drugs, as patient weight declines, the mean milligram-per-kilogram dose rose sharply. There was no trend seen toward reducing doses for older patients. Low body weight, in addition to advanced age, is a major risk factor for overmedication. Physicians must recognize the need to reduce drug doses for their low-weight elderly patients.

Effects of patient age and physician training on choice and dose of benzodiazepine hypnotic drugs.

We conducted a cross-sectional review of all prescriptions (N = 554) for triazolam and flurazepam hydrochloride written by nonpsychiatrists to outpatients at a university affiliated Veterans Administration hospital. We sought to determine whether triazolam, an agent with a short half-life, was used preferentially in older patients (age greater than or equal to 70 years). We also wanted to determine whether dosages of triazolam or flurazepam were lowered in elderly patients. Our findings showed that prescriber level of training was a much stronger determinant of drug choice than patient age. Attending physicians prescribed flurazepam twice as often as interns. Lower dosages of both agents were prescribed more frequently to older patients. Our data suggest that some physicians choose a benzodiazepine hypnotic out of habit rather than application of pharmacologic principles, but reduce doses appropriately when prescribing to elderly patients.

Toxicity of high-dose flurazepam in the elderly.

To assess the potential hazards of flurazepam (Dalmane) therapy of insomnia in the elderly, the relation of dosage and patient age to the frequency of flurazepam-attributed adverse reactions was studied in 2,542 hospitalized medical patients. Adverse reactions, predominantly unwanted residual drowsiness, were reported in 78 flurazepam recipients (3.1%). None of the adverse reactions were serious. The frequency of reported toxicity increased with average daily dose, ranging from 1.3% among those receiving less than 15 mg/day to 12.3% at doses of 30 mg/day or more (p less than 0.001). Toxicity increased with age, progressively from 1.9% among those under 60 to 7.1% among those 80 or over (p less than 0.001). Unwanted effects of high-dose flurazepam were observed much more commonly in the elderly. Only 2.0% of those 70 years of age or older experienced adverse reactions at doses under 15 mg/day, as opposed to 39.0% at 30 mg or more per day. Low doses of flurazepam appear to be safe for elderly individuals, but they are susceptible to unwanted central nervous system depression at high doses.

Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs.

Twenty-six healthy subjects from 19 to 85 yr old took single 15-mg doses of flurazepam (FLZ). Concentrations of desalkylfurazepam (DAFLZ), its principal metabolite, were measured by gas-liquid chromatography in multiple samples drawn 7 or more days after the dose. For the first 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ was detected from 12 hr onward. Its elimination half-life (t1/2) (range, 37 to 289 hr) was longer in elderly than in young men (mean 74 and 160 hr, p less than 0.05), but t1/2 in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withdrawal period, and morning self-ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/ml, P less than 0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single-dose t1/2 correlated with washout t1/2 after termination of FLZ treatment (r = 0.87, P less than 0.01). Clinical self-ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, "deeper" sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of "overshoot" sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported.

Hypnotic efficacy of lorazepam and flurazepam.

In a double-blind crossover study involving 15 insomniac subjects, the hypnotic efficacy of lorazepam, 2 and 4 mg, was compared with flurazepam, 15 and 30 mg, and placebo. Five subjective measures were used: onset, length, and depth of sleep, number of times awakened, and satisfaction with the hypnotic. Lorazepam in 2- and 4-mg doses was comparable in hypnotic efficacy to flurazepam, 30 mg, according to most parameters of measurement. Side effects were minor, although relatively numerous at the 4-mg doses.

Failure to limit quantities of benzodiazepine hypnotic drugs for outpatients: placing the elderly at risk.

PURPOSE: The long-term use of benzodiazepine hypnotics by the elderly is associated with serious side effects, and prescriptions of large quantities of these agents allow such use. Therefore, we determined the quantities of these agents prescribed to outpatients in our Veterans Administration teaching hospital, and the relationship of patient age to total number of doses prescribed per prescription. PATIENTS AND METHODS: Pharmacy and patient records related to 655 consecutive prescriptions for triazolam (Halcion) and flurazepam (Dalmane) were reviewed. Only 266 (41%) of the prescriptions were for 30 or fewer doses, while 178 (27%) were written for 180 or more doses. RESULTS: Thirty-six percent of prescriptions for patients aged 65 years or older were for 180 or more doses, compared with 24% for those aged 45 to 64 years old, and 16% of the prescriptions for patients less than 45 years old (p less than 0.0001). In a multivariate analysis controlling for six other factors related to the total number of doses prescribed, patients aged 65 years or older were still more likely to receive a prescription for 180 or more doses (relative risk 1.9, 95% confidence interval 1.3, 2.8). CONCLUSION: We conclude that inappropriately large quantities of benzodiazepine hypnotics were commonly prescribed, and that patients aged 65 years or older were at greatest risk for receiving such prescriptions.

Diagnosis and treatment of outpatient insomnia by psychiatric and nonpsychiatric physicians.

Insomnia is commonly encountered in general medical practice, but little is known about how primary care physicians manage this problem. We reviewed medical records describing 536 patient encounters in which either triazolam (Halcion) or flurazepam (Dalmane) was prescribed for outpatient use. Only 12% of the progress notes written by internists or surgeons contained even a remote reference to sleep, whereas 74% of psychiatrist's notes contained at least some sleep symptom documentation. In a multivariate analysis including the number of medical and psychiatric diagnoses, patient age, and physician gender, only the prescriber department was independently associated with the presence of symptom documentation. We also found that 30% of the prescriptions written by internists or surgeons were for inappropriately large quantities of these drugs (180 or more doses) compared with 6% of the prescriptions written by psychiatrists. We conclude that the evaluation of insomnia by nonpsychiatrists is often incomplete and that hypnotic drugs may be inappropriately prescribed by these physicians. Further efforts are needed to improve the management of insomnia by primary care physicians in the outpatient setting.

Effects of flurazepam and zolpidem on the perception of sleep in normal volunteers.

In previous studies we have reported that the benzodiazepine hypnotic triazolam and the nonbenzodiazepine zolpidem increase the likelihood that insomniacs will report having been asleep when awakened by an electronic tone of progressive intensity. It has not been known, however, whether this occurs with normal sleepers. In the present study we have administered placebo, flurazepam 30 mg and zolpidem 10 mg to 15 normal sleepers and awakened them with an electronic tone at five points across the night. In contrast to previous reports with insomniacs, both compounds made only modest improvements in sleep. When all time points were combined, subjects reported having been asleep in 40.3, 42.9 and 47.9% of the trials on placebo, flurazepam and zolpidem, respectively (ns). Subjects were accurate in their estimate of total time asleep, and this accuracy was not influenced by the drugs. Similarly, there were no effects on a variety of questions related to dreaming and other cognitive activity during sleep. These results suggest that the effects of these hypnotics, which have been described previously in insomniacs, are not found in normals. Further studies will be necessary to clarify whether such effects in insomniacs are related to the clinical efficacy of hypnotics.

Decreased expression of gamma-aminobutyric acid type A/benzodiazepine receptor beta subunit mRNAs in brain of flurazepam-tolerant rats.

The expression of GABAA/benzodiazepine beta subunit mRNAs was studied in cerebral cortex, hippocampus, and cerebellum of flurazepam-treated rats. Immediately following 4 wk of treatment, beta 2 and beta 3 subunit mRNAs were significantly reduced in cerebellum and hippocampus, whereas only beta 2 was decreased in cortex. These decreases had largely reversed 48 h following flurazepam treatment. After 2 wk of treatment, both beta 2 and beta 3 mRNAs were reduced in cerebellum, and beta 3 mRNA was reduced in hippocampus, but neither was changed in cortex. Four hours after an acute flurazepam treatment, the only change was a decrease in beta 3 mRNA in hippocampus. These results indicate that the expression of GABAA receptor beta subunit mRNAs in different brain regions is differentially regulated during chronic flurazepam treatment, and some changes occur within hours after a single large dose.

High-dose benzodiazepines in the treatment of severe neurotic anxiety.

There has been a paucity of research in the use of high-dose benzodiazepines in the treatment of severe neurotic anxiety. The author presents five cases, three with excellent and two with poor outcomes. The English and Fench language literature is reviewed and reveals evidence that high-dose benzodiazepines may be useful in the treatment of certain neurotic patients. However, the lack of controlled studies is noted. The author poses several questions important to the future of research on benzodiazepines.

Insomnia in the elderly.

Insomnia is common in the elderly population. Difficulty in initiating and maintaining sleep affects nearly half of all patients over the age of 65, representing an increased prevalence in older versus younger patients. Nocturnal sleep time is decreased, frequent awakenings occur, and daytime napping is common. Age-related changes in sleep physiology correlate with the subjective complaints of disturbed sleep. Multiple etiologies for insomnia in the elderly have been described. Management strategies must include attention to both nonpharmacologic and pharmacologic aspects of care, especially with respect to the altered pharmacokinetics and pharmacodynamics associated with advanced age. Reassessing therapy is essential to promote the end goal of improvement of the elderly patient's quality of life.

Adverse reactions to triazolam, flurazepam, and placebo in controlled clinical trials.

Adverse reactions were evaluated from 45 double-blind controlled clinical trials involving triazolam 0.25 mg (N = 731), triazolam 0.5 mg (N = 2004), flurazepam 30 mg (N = 899), and placebo (N = 1771). Excessive CNS depression was the most frequent adverse effect, reported in 14.2% of trials with triazolam 0.25 mg, 19.5% with triazolam 0.5 mg, 23.9% with flurazepam 30 mg, and 6.4% with placebo. With the exception of orolingual complaints associated with flurazepam, all other categories of adverse reactions were equally or more frequent with placebo than with active medications. Unusual or excessive adverse reactions were not reported.

Comparative efficacy of estazolam, flurazepam, and placebo in outpatients with insomnia.

The efficacy and safety of estazolam, an investigational triazolobenzodiazepine, and flurazepam were compared in 65 insomniac outpatients. Patients completed sleep questionnaires each morning. Global evaluations demonstrated that both treatments were significantly superior to placebo. However, estazolam was preferred over flurazepam in a global rating that reflected how well rested and refreshed the subjects felt on arising. Improvement in complaints of difficulty in going to sleep showed only a trend toward significance favoring estazolam and flurazepam over placebo. Residual daytime drowsiness and fatigue accounted for approximately 70% of all side effects with both active treatments. Significantly more side effects occurred with flurazepam than with estazolam. Flurazepam-treated patients had a significantly more severe rating of adverse reactions than did placebo-treated patients.

Clinical uses and advantages of low doses of benzodiazepine hypnotics.

The most common adverse effects associated with the use of benzodiazepine hypnotics are residual daytime effects (daytime sedation and daytime performance decrements), anterograde amnesia, and rebound insomnia. Studies show that these adverse effects are related to dose. Hence, benzodiazepine hypnotics should be used in low doses so as to minimize or prevent these common adverse effects. It is now generally accepted that benzodiazepines should not be administered long-term for the treatment of chronic "idiopathic" insomnia. Two noncontinuous sleep disturbances, insomnia in the elderly and transient insomnia in young and middle-aged adults, are probably the most acceptable indications for the use of benzodiazepines. Low doses of short- and intermediate-acting benzodiazepines (triazolam and temazepam) are efficacious in the treatment of insomnia in the elderly, and preliminary evidence suggests that they are efficacious in the treatment of transient insomnia in young and middle-aged adults.

Survey of hypnotic drug use in nursing homes.

The prescribing patterns for hypnotic medications were surveyed in 765 patients of three skilled-nursing facilities and two intermediate-care facilities. Seven per cent of the patients received a hypnotic routinely; an additional 3 per cent had as-needed orders for a hypnotic medication. Temazepam, flurazepam, and triazolam were, in descending order, the three most commonly prescribed hypnotics and accounted for 79 per cent of the hypnotic prescriptions. The average duration of use for triazolam, temazepam, and flurazepam was 11 weeks, 24 weeks, and 82 weeks, respectively. Seventy-six per cent of the flurazepam prescriptions were given seven days a week; 31 per cent of these prescriptions were for 30 mg doses. Medications that were not hypnotics but did have sedative side-effects were prescribed with bedtime orders for 11 per cent of the patients. The three most commonly prescribed drugs in this class were diphenhydramine, thioridazine, and haloperidol. Possible explanations for the lower frequency of hypnotic use observed in this study as compared to the frequencies reported in the literature are discussed, as are possible hazards of high-dose and long-term use of hypnotics.

Bedtime flurazepam and the human circadian rhythm of spontaneous motility.

Sixteen male students received bedtime placebo and flurazepam 30 mg at home in a counter-balanced double-blind, crossover design. For 24 h after each treatment the subjects' spontaneous motor activity was recorded each 15 min with an unobtrusive actometer, worn as the subjects attended classes. The circadian activity curves were submitted to cosinor analyses. The 24 h post-flurazepam activity was a mean of 15.1% lower than post-placebo activity (P less than 0.025). On the average, both the nocturnal through and the daytime peak of motility dropped; the latter change was greater, reducing by a mean of 19.4% the amplitude of the circadian rhythm of activity (P greater than 0.01). the timing, or phase, of the rhythm was not shifted. Although the drug did not consistently modify reports of subjective feelings on the Profile of Mood States (POMS), 13 subjects correctly discriminated drug from placebo sessions (P less than 0.05). A bedtime dose of 30 mg of flurazepam appears to significantly reduce spontaneous human motility that night and during the next day. Activity recording revealed an important residual, behavioral effect of the drug which was not reflected in POMS reports of subjective feelings, suggesting that activity recording may provide a more sensitive measure for psychotropic drug effects.