Regulation of Ca²âº/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal.

Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser(831), increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr(286)) CaMKIIα expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety.

Assessing the cumulative effects of exposure to selected benzodiazepines on the risk of fall-related injuries in the elderly.

BACKGROUND: The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated. METHODS: We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall. RESULTS: For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of flurazepam in the past months was associated with a highly significant increase in the risk of fall-related injuries (HR = 2.83, 95% CI: 1.45-4.34). The cumulative effect of a 30-day exposure to alprazolam was 1.27 (1.13-1.42). For temazepam, the results suggested a potential withdrawal effect. CONCLUSIONS: Mechanisms affecting the risk of falls differ across benzodiazepines, and may include cumulative effects of use in the previous few weeks. Thus, benzodiazepine-specific analyses that account for individual patterns of use should be preferred over simpler analyses that group different benzodiazepines together and limit exposure to current use or current dose.

Comparison of alternative models for linking drug exposure with adverse effects.

Pharmacoepidemiology investigates associations between time-varying medication use/dose and risk of adverse events. Applied research typically relies on a priori chosen simple conventional models, such as current dose or any use in the past 3 months. However, different models imply different risk predictions, and only one model can be etiologically correct in any specific applications. We first formally defined several candidate models mapping the time vector of past drug doses (X (t), t = 1, … ,u) into the value of a time-varying exposure metric M(u) at current time u. In addition to conventional one-parameter models, we considered two-parameter models accounting for recent dose increase or withdrawal and a flexible spline-based weighted cumulative exposure (WCE) model that defines M(u) as the weighted sum of past doses. In simulations, we generated event times assuming one of the models was correct and then analyzed the data with all candidate models. We demonstrated that the minimum AIC criterion is able to identify the correct model as the best-fitting model or one of the equivalent (within 4 AIC points of the minimum) models in a vast majority of simulated samples, especially with 500 or more events. We also showed how relying on an incorrect a priori chosen model may largely reduce the power to test for an association. Finally, we demonstrated how the flexible WCE estimates may help with model diagnostics even if the correct model is not WCE. We illustrated the practical advantages of AIC-based a posteriori model selection and WCE modeling in a real-life pharmacoepidemiology example.

Flexible modeling of the cumulative effects of time-dependent exposures on the hazard.

Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. One example that attracts public attention concerns pharmacoepidemiological studies of the adverse effects of medications. The analysis of such studies poses challenges for modeling the impact of complex time-dependent drug exposure, especially given the uncertainty about the way effects cumulate over time and about the etiological relevance of doses taken in different time periods. We present a flexible method for modeling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. We validated the method in simulations and applied it to re-assess the association between exposure to a psychotropic drug and fall-related injuries in the elderly.

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.

Toxic epidermal necrolysis caused by flurazepam?

Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, but severe cutaneous reactions. Beside cutaneous manifestations, the syndrome is characterised by constitutional sypmtoms with even lethal consequences. Toxic epidermal necrolysis is usually a drug-hypersensitivity syndrome. More than a hundred drugs were suspected to cause toxic epidermal necrolysis. Although benzodiazepines had been suspected in some cases, flurazepam has not been implicated thus far. The authors report a severe, life threatening case of toxic epidermal necrolysis in a young woman suffering from schizophrenia. The most probable cause was flurazepam, a hypnotic agent of the benzodiazepine class.

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.

A review of the safety profiles of benzodiazepine hypnotics.

Although over 20 years of clinical experience with benzodiazepine hypnotics have demonstrated their relative safety, flurazepam, temazepam, triazolam, and quazepam do not have identical safety profiles. Dose-related central nervous system (CNS) depression such as daytime sedation and psychomotor impairment may be expected because they are an extension of the therapeutic action of these agents. Therefore, drug dose is an important factor in determining the expected frequency and severity of these side effects. Also, it is important for a clinician not to assume that these unwanted CNS effects relate only to the length of a drug's half-life. Half-life does appear to be an important determinant of the presence or absence of rebound insomnia.

Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

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.

Differential side effect profile of triazolam versus flurazepam in elderly patients undergoing rehabilitation therapy.

Patients (aged 65 years or older) who were hospitalized for rehabilitation therapy after a cerebrovascular accident or other acute debilitating condition participated in a 6-week controlled clinical trial. After a 2-week period of receiving nightly single-blind placebo, patients were randomly allocated to receive either triazolam (0.125 mg) or flurazepam hydrochloride (15 mg) nightly under double-blind conditions. For the final 2 weeks, patients again received single-blind placebo. The study groups' were comparable in their performance on four psychomotor tests done in the morning during the initial placebo period. Triazolam-treated patients showed subsequent improvement on the tests, consistent with practice effects, whereas flurazepam recipients showed performance impairment during treatment. Triazolam-flurazepam differences were significant in the card-sorting and arithmetic tests, and they approached significance for the Purdue pegboard test. Blind ratings by physical therapists indicated significant impairment among flurazepam recipients in their capacity to cooperate with and participate in the rehabilitation tasks; the impairment persisted into the post-treatment placebo period. Similar flurazepam-triazolam differences, although not significant, were reported by occupational therapy and nursing staff members. The findings suggest that the kinetic differences between flurazepam and triazolam may have clinical implications in elderly patients undergoing rehabilitation therapy.

Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal.

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.

Clinical safety of flurazepam and midazolam during 14-day use in chronic insomniacs.

Data from evening questionnaires, reports of side effects, laboratory findings, and all-night respiratory measurements were collected on the 99 chronic insomniacs examined in this multicenter study. These data were used to compare the clinical safety and desirability of a benzodiazepine hypnotic with a very short half-life, midazolam 15 mg, with a hypnotic with a longer half-life, flurazepam 15 and 30 mg; both compounds were compared with a placebo control. There were 2 prestudy placebo nights followed by 14 consecutive nights of treatment. Of the 107 patients accepted, 99 completed the study. No marked adverse reactions were found in any area for any group. There was no increase in sleep apneas during the treatment period for any group. Results of this study provide additional evidence of the safety of benzodiazepine hypnotics.

Psychomotor performance in chronic insomniacs during 14-day use of flurazepam and midazolam.

Four skills performance (psychomotor) tasks, including simple and choice reaction time, divided attention, and vigilance, were given to 99 chronic insomniacs to determine whether the use of midazolam 15 mg, or of flurazepam 15 or 30 mg, compared with placebo would produce next-day impairment throughout a 14-day treatment period. Tests were administered during 2 baseline days and on treatment days 1 and 2 (early interval), 7 (middle interval) and 13 and 14 (late interval). Compared with placebo, performance on all four tasks was impaired by flurazepam 30 mg. The deficits associated with flurazepam 15 mg were roughly half the magnitude of those produced by flurazepam 30 mg, but these changes did not reach statistical significance for single response measures at single time intervals. Midazolam showed no consistent pattern of performance effects; however, for divided attention tracking error, there was a significant decrement. The placebo group showed flat performance curves or improved performance as a result of learning (practice effect).

Cognitive performance and mood in patients with chronic insomnia during 14-day use of flurazepam and midazolam.

The 99 chronic insomniacs examined in the present multicenter study were given three cognitive tasks (reading comprehension, addition, and digit symbol substitution test [DSST]) as well as the Hopkins Symptom Checklist (HSCL) and the Profile of Mood States (POMS) in order to evaluate the effects of flurazepam (Dalmane) 15 and 30 mg, midazolam 15 mg, and placebo on cognitive performance and mood. Subjective evaluation of performance was also obtained. A significant person in the patient's life was also asked to evaluate the patient's mood before and during the 14-day treatment interval. After a 20-day washout, next-day performance and mood were evaluated after placebo nights -1 and 0 (baseline) and after treatment nights 1, 2 (early interval), 7 (middle interval), and 13 and 14 (late interval). Analysis of variance (ANOVA) on changes from baseline indicated no significant between-groups treatment effects for reading comprehension or any of the mood variables at any interval. Patients on flurazepam 30 mg performed less well compared with other groups even though, after completion of the tasks, this group believed that they performed as well as those on the other regimens. Performances by flurazepam 15 mg, midazolam, and placebo groups were similar. Significant others tended to rate high-dose flurazepam patients more negatively. High-dose flurazepam patients had a significant change on the DSST and addition tasks due to treatment after the first night, and change in performance remained significantly impaired for the DSST task relative to that of the other groups thereafter.