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.

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.

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.

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.

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.

Methodology for demonstrating sustained efficacy of hypnotics: a comparative study of triazolam and flurazepam.

To test for sustained hypnotic efficacy, triazolam (0.6 mg) or flurazepam (30 mg) was given to chronic insomniac patients for 7 consecutive nights in parallel, double-blind design. Triazolam at this dose was an effective hypnotic by all usual subjective measures and did not produce appreciable hangover. Flurazepam performed similarly. For either drug, comparison of the mean scores for the first 2 nights with that for the last 2 nights for any of the parameters did not reveal any significant difference. Thus, both triazolam and flurazepam showed sustained efficacy for 1 week at these doses. Some interesting theoretical and practical questions about the measurement of sustained efficacy of hypnotics in situations of repetitive dosing were addressed by the study. While a placebo control is desirable, the results obtained may be uninterpretable. An acute-care hospital setting may not be the ideal setting for doing such studies. There were indications from the study that the first-night results in a hypnotic clinical trial may be atypical.

Comparison of the hypnotic activity of triazolam, flurazepam hydrochloride, and placebo.

Triazolam, 0.4 and 0.8 mg, flurazepam, 15 and 30 mg, and placebo were compared in a double-blind, randomized 5-night crossover study in 25 inpatient insomniacs. These patients all complained difficulty falling asleep; all said they usually slept less than 5 hr a nigh and woke up too early in the morning. Results of the patients' global evaluation of the medications shows that all of the treatments were rated significantly higher than placebo, with the exception of triazolam, 0.4 mg, which was not significantly different from flurazepam, 15 or 30 mg, or from placebo. In subjective evaluation of sleep onset, only triazolam, 0.4 and 0.8 mg, was rated faster than placebo. All 4 active medications increased duration of sleep. Triazolam, 0.8 mg, and flurazepam, 30 mg, were rated as providing deeper sleep than placebo while all treatments except flurazepam, 15 mg, decreased the number of awakenings below that on placebo. A significant dose-response curve was obtained with triazolam and flurazepam for some of the parameters. Very few adverse effects were reported. One patient reported feeling groggy and drowsy on 0.4 mg triazolam while 2 reported nightmares on placebo.

Quazepam and flurazepam: long-term use and extended withdrawal.

Two investigation benzodiazepine hypnotics with long half-lifes, (30 and 15 mg quazepam and 30 mg flurazepam) were evaluated in 47-night sleep laboratory studies. The effectiveness and side effects of these benzodiazepines were assessed during short-, intermediate-, and long-term use. Subjects were also assessed for presence of rebound insomnia during the 15 days following abrupt withdrawal. Quazepam, 15 and 30 mg, and flurazepam, 30 mg, each were effective in sleep induction and maintenance after short- and intermediate-term use. Some loss of effectiveness was noted during long-term use of both doses of quazepam and, to a lesser extent, of flurazepam. Subjective reports of improvement in sleep latency and total sleep time were in general agreement with the objective data. During the 15 nights after abrupt withdrawal of these two long-half-life drugs there was no rebound insomnia, either immediate or delayed. Both drugs exerted carry-over effectiveness on the first 2 to 3 nights after withdrawal; with quazepam this effect persisted throughout the withdrawal period. Quazepam, 30 mg, induced frequent side effects related to sleepiness. Side effects noted with 30 mg flurazepam were less frequent and severe, while the side effects with 15 mg quazepam were minimal. These data suggest that the optimal dose of quazepam is 15 mg.

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.

Withdrawal symptoms after long-term treatment with therapeutic doses of flurazepam: a case report.

A male patient with chronic insomnia experienced withdrawal symptoms when flurazepam (30 mg h.s.), which he had taken nightly for 8 years, was abruptly discontinued. Problems associated with sedative-hypnotic medication and the long-term treatment of chronic insomnia are discussed.

Effect of flurazepam on sleep-disordered breathing and nocturnal oxygen desaturation in asymptomatic subjects.

We assessed the effect of 30 mg of oral flurazepam on sleep-disordered breathing and nocturnal oxygen desaturation by performing a double-blind, placebo-controlled, randomized study. Asymptomatic subjects, 17 men and three women (mean age 49 years, mean weight 79 kg), were monitored for two consecutive nights. Flurazepam was given to 10 subjects on night 1 and to 10 subjects on night 2. Placebo was ingested on the other nights. Polysomnographic determinations included chest wall movement by impedance pneumography, nasal and oral airflow by thermistor probes, and continuous oxygen saturation by ear oximetry. Flurazepam was associated with significant increases in the number of sleep events (p = 0.01), episodes of apnea (p less than 0.01), and total duration of apnea (p less than 0.01). The number of episodes of hypopnea of desaturation did not significantly increase, although the degree of desaturation increased after flurazepam ingestion (p = 0.04). Total sleep time significantly increased (p = 0.04), but could not account for the increased number of events. Sleep stage distribution was minimally altered by ingestion of flurazepam.

A clinical study of flurazepam.

Eleven patients suffering from chronic insomnia were given 30 mg flurazepam for 28 nights. While EEG measures of total sleep time and sleep efficiency were improved, changes in sleep latency and intermittent waking time were small and nonsignificant. Subjective benefits in sleep were confined to the first 2 nights. There was neither increased nor decreased daytime sleepiness. Cognitive functioning was significantly decreased during the first 2 days, and patients were unaware of these changes. Simple motor tasks were relatively unaffected. Desalkylflurazepam concentrations showed significant accumulation over time, but were not predictive of sleep measures or daytime performance in individual subjects. The withdrawal period was characterized by subjectively disturbed sleep and daytime dysphoria.

Daytime sleepiness as a criterion in hypnotic medication trials: comparison of triazolam and flurazepam.

Sleep laboratory hypnotic medication trials typically determine efficacy by examining changes in polysomnographically recorded sleep. We introduce the use of daytime sleepiness, as assessed by the Multiple Sleep Latency Test (MSLT), as a criterion for daytime functioning in such trials. Two benzodiazepine hypnotics, triazolam (0.5 mg) and flurazepam (30 mg), with short and long half-lives respectively, were compared in a multicentered, double-blind crossover study. Results indicated these medications had virtually indistinguishable nocturnal effects, but differed dramatically during the day. Flurazepam decreased sleep latency on the MSLT, whereas triazolam did not. These results could indicate that daytime sleepiness is a concomitant effect of flurazepam.

Effects of flurazepam and zopiclone on the performance of chronic insomniac patients: a study of ethanol-drug interaction.

Three groups of ten middle-aged insomniac patients were treated with placebo, flurazepam, or zopiclone for 12 consecutive days in a study designed to compare the residual daytime effects of long-acting flurazepam and short-acting zopiclone on a variety of cognitive and motor tasks. These effects were examined independently and in combination with ethanol effects. The effects of the drugs on sleep parameters were also subjectively assessed by means of questionnaires during treatment and withdrawal. The study demonstrated persistent performance effects with flurazepam. Testing at the end of the treatment period showed that movement time was impaired in the flurazepam treated group. Flurazepam also enhanced the increment of movement time produced by ethanol. One subject became severely confused when given ethanol after using flurazepam for 12 days. None of these effects were found with zopiclone. The rapid elimination of zopiclone may account for these findings.

Problems in the use of long-acting hypnotics in older patients.

Insomnia and the use of long-acting hypnotic drugs are prevalent in geriatric populations. These drugs have been shown in the laboratory to adversely affect motor performance in the elderly. To examine the clinical significance of these findings, comparisons were made between patients who experienced a fall during their hospital stay and those who did not fall. It was found that patients over 70 years of age who experienced a fall in the hospital were more likely to be receiving flurazepam than the patients who did not fall.

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.

Residual effects of temazepam and other hypnotic compounds on cognitive function.

The morning after effects of taking single doses of three hypnotic compounds were compared in a five-group design, including the three drug conditions (temazepam, flurazepam, barbiturate), placebo, and no capsule controls. Results showed a slight superiority for temazepam over barbiturate on visual-motor and reaction time tasks. On one phase of a cognitive task, the barbiturate and flurazepam groups made more errors than the control groups. Overall, the results indicate an impairment in performance for the group taking barbiturate and a smaller impairment for the flurazepam group. No detectable impairment occurred for subjects taking temazepam.