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PubMed2002

Napping predicts responsiveness to hypnotics in patients with primary circadian rhythm disorder.

It is hypothesized that one of the primary abnormalities of primary circadian rhythm disorder (PCRD) is the strong link between any episode of sleep and circadian rhythm. To test this hypothesis, the relationship between napping and responsiveness to hypnotics was examined in 12 patients with PCRD. A significant association was found (P = 0.04, chi2 test). Patients with PCRD who napped were all responders to hypnotics. The results suggest a strong link between episodes of sleep and circadian rhythm in some patients with PCRD, and might also suggest the heterogeneity of PCRD. Napping in patients with PCRD may be a predictor for responsiveness to hypnotics. In addition, napping and responsiveness to hypnotics might have a clinical value to differentiate PCRD from secondary CRD.

Adolescent↗
PubMed1996

Prescribing practice and policy for hypnotics: a model of pharmacy audit.

A problem of overprescribing of hypnotic medication ('sleeping tablets') was identified and quantified within a department of health care for older people in a district general hospital. Data on the volume of prescribing were obtained from computerized pharmacy records, and this information was supplemented by a retrospective survey of case notes of 100 patients. Sixty per cent of patients were prescribed a hypnotic at some stage during their hospital stay. Twelve per cent were prescribed a sleeping tablet on admission on an 'as required' basis but never took this medication, suggesting that such prescribing was becoming routine. As part of an ongoing pharmacy audit within the department, a policy was implemented to try to improve prescribing habits. Following this, hypnotic prescribing fell, with the average monthly number of sleeping tablets prescribed falling from 2392 to 734. A further survey of 100 case notes showed overall prescribing had fallen to 25%, although 2% were still prescribed a hypnotic on admission but never took it.

Aged↗
PubMed2005

Isoflurane exerts antinociceptive and hypnotic properties at all ages in Fischer rats.

BACKGROUND: Some anaesthetic agents exhibit an age-dependent analgesic effect, for example nitrous oxide, which is ineffective in newborn rats. We investigated whether a similar time dependency existed for the responses to the volatile anaesthetic isoflurane. METHODS: The analgesic and hypnotic properties of isoflurane at various ages was assessed using four cohorts of Fischer rats aged approximately 7, 16, and 28 days and adults (11-12 weeks old). Intraplantar administration of formalin mimicked inflammatory pain, and its effects were assessed using immunohistochemical (c-Fos staining) and behavioural paradigms. The hypnotic properties of isoflurane were assessed using loss of righting reflex. RESULTS: Formalin administration produced a typical nociceptive response observed both behaviourally and immunohistochemically in all age groups; these nociceptive responses were significantly attenuated by isoflurane 0.5% at each age (P<0.05). Interestingly 7-day-old animals showed a significantly more potent hypnotic response than older animals (P<0.01): with adult rats being most resistant to isoflurane induced hypnosis (P<0.05). CONCLUSION: In contrast to nitrous oxide, isoflurane is an effective antinociceptive agent in neonatal rats. If the data can be extrapolated to clinical scenarios these results suggest that isoflurane may be analgesic in newborns as well as adult humans. In addition, isoflurane is a potent hypnotic, especially in the very young, which is in contrast to the neonate's relative resistance to anaesthesia as assessed by minimum alveolar concentration.

Aging↗
PubMed1991

Subjective versus objective evaluation of hypnotic efficacy: experience with zolpidem.

There is little published literature on the correlation between subjective and objective efficacy of hypnotics. We wanted to determine whether there was a correlation between the patient's subjective evaluation of the efficacy of the hypnotic with the polysomnographic (PSG) findings. We studied 16 patients with chronic insomnia (sleep latency, greater than or equal to 30 minutes; total sleep time, greater than 240 but less than 420 minutes) for 11 nights who took placebos on nights 1 and 2, zolpidem (imidazopyridine) on nights 3-9 and placebo on nights 10 and 11. Patients completed a questionnaire each morning following PSG, which evaluated subjective sleep quality, sleep latency and total sleep time. These data were compared to PSG findings to answer specific questions about sleep latency reduction, efficacy of the hypnotic after a week's use, sleep quality after discontinuing the drug, and any correlation between subjective and objective measures. PSG findings indicated a shortened sleep latency, increased total sleep time, decreased total wake time and increased sleep efficiency when patients ingested zolpidem 30 minutes before bedtime. We found that after 7 nights (nights 3-9) the drug was still effective in reducing sleep latency and increasing total sleep time. Upon withdrawal (nights 10 and 11) sleep returned to baseline (nights 1 and 2). Subjectively, the patients confirmed those findings on the questionnaire, as well as a subjective reduction in the number of awakenings and, interestingly, a subjective increase in the time spent awake after sleep. Many of the objective variables we examined correlated highly with the subjective variables. While on zolpidem, subjects believed and were objectively shown to have a decreased sleep latency, increased total sleep time and decreased time awake before persistent sleep, although they tended to overestimate sleep latency and time spent awake before persistent sleep and underestimated total sleep time. Although the correlation between objective and subjective measures was high for the group, in individual patients there was an impressive difference between the two, and the highest coefficient of variation between a subjective and objective measures was 0.453. No correlations were found with subjective measures of refreshing quality of sleep, decrease in number of awakenings, how sleepy patients felt in the morning or their ability to concentrate in the morning. Thus, we believe the PSG remains the keystone in the evaluation of hypnotic efficacy.

Adult↗
PubMed1996

Pharmacokinetic-pharmacodynamic modeling of the new steroid hypnotic eltanolone in healthy volunteers.

BACKGROUND: In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers. METHODS: Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model. RESULTS: The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening. CONCLUSIONS: Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

Adult↗
PubMed1978

Clobazam--a new hypnotic?

1 A double-blind randomized trial to compare the relative efficacy of the 1,5-benzodiazepine, clobazam, the 1,4-benzodiazepine nitrazepam, and placebo as hypnotics was carried out. 2 A preference technique was used and the analyses were performed sequentially. 3. The results confirmed that nitrazepam was superior to placebo as a hypnotic but failed to show that clobazam was superior to either placebo or nitrazepam in a ratio of 2:1. Thus, it seems likely that the hypnotic properties of clobazam are minimal. 4 Clobazam is not suitable for use as a hypnotic in hospitalized patients.

Adult↗
PubMed2006

Genetic background differences between FVB and C57BL/6 mice affect hypnotic susceptibility to pentobarbital, ketamine and nitrous oxide, but not isoflurane.

BACKGROUND: Pharmacogenomics has allowed us to identify the mechanisms underlying much of the inherited variability in drug response. There have been several reports of strain-dependent anesthetic actions in rodents, indicating that significant genetic differences exist in the hypnotic and antinociceptive effects of various anesthetics. METHODS: Loss of righting reflex was used to compare the hypnotic action of pentobarbital, ketamine, nitrous oxide and isoflurane between two genetically different populations of mice, C57BL/6 with black hair and Friends virus B (FVB) with white hair. RESULTS: C57BL/6 mice were more susceptible than FVB mice to the hypnotic effects of ketamine, pentobarbital and nitrous oxide. However, the sensitivity to isoflurane did not differ between C57BL/6 and FVB mice. CONCLUSION: Genetic background affects the hypnotic susceptibility to some anesthetic agents in mice. Our results indicate that there may be a different genetic basis for the operation of hypnosis between isoflurane and other anesthetics, such as pentobarbital, ketamine and nitrous oxide.

Anesthetics, Dissociative↗
PubMed1985

L-tryptophan as a hypnotic in special patients.

The authors briefly review prevalence and current treatment trends of sleep disorders in the elderly, underlining the need for the development of a more suitable hypnotic for this population. The use of L-tryptophan (LT) as a physiologic hypnotic in aged responders is considered and the hypnotic effect of 1- to 4-g bedtime doses on ten male inpatients and outpatients aged 30 to 72 years is evaluated. Results suggest a dramatic and sustained relief of insomnia for 3 weeks in 30 per cent of the patients and the absence of side effects in 90 per cent of those who took the agent. The authors conclude that despite its long therapeutic history, L-tryptophan has not been more successful because only a minority of humans appear to be responsive to its hypnotic actions. They point to the need to replicate their current preliminary observations in a larger controlled geriatric population and to delineate biochemical characteristics of LT responders in order to increase LT sensitivity in some patients and convert nonresponders to responders.

Adult↗
PubMed1986

Hypnotics and actual driving performance.

Several related studies of the residual effects of hypnotic drugs on actual driving performance have been conducted using a standard approach and the most recent is described in detail. In it, 12 female formerly diagnosed insomniacs and hypnotic users acted as subjects. They were treated in two separate series with placebo for 2 nights, then hypnotic medication for 8 nights followed by placebo again for 3 nights. In one series, the medication was nitrazepam (10 mg nocte) and in the other, temazepam (20 mg nocte). Eleven subjects completed both series in a double-blind, cross-over (with respect to drugs) design. Their driving performance was repeatedly tested on a 100 km primary highway circuit, in normal traffic, during both the morning and afternoon (10-11 hours and 16-17 hours after drug and placebo ingestion, respectively). Nitrazepam but not temazepam significantly impaired driving performance, the difference lasting throughout the active medication period. These results along with those obtained in the earlier studies are compared to show degrees of driving impairment which follow the use of various hypnotics.

Adult↗
PubMed2006

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11.

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.

Animals↗
PubMed1988

Prevalence, frequency, and duration of hypnotic drug use among the elderly living at home.

Details of consumption of hypnotic drugs derived from a nationally representative sample of elderly people were analysed in terms of the prevalence, duration, and likely frequency of use. Of 1020 randomly selected subjects aged 65 and over 16% (166) reported using (mainly benzodiazepine) hypnotic drugs, and of these 89% reported having taken such a drug the night before the interview. Most of these users (73%) had been taking hypnotic drugs for more than one year, with 25% reporting drug use for more than 10 years. These results suggest that for most elderly users of hypnotic drugs, patterns of consumption encourage the development of cumulative effects and benzodiazepine dependence.

Aged↗
PubMed1999

Association between delta waves during sleep and negative symptoms in schizophrenia. Pharmaco-eeg studies by using structurally different hypnotics.

We examined the effects of benzodiazepine (BZD) hypnotics and zopiclone (ZPC), a nonbenzodiazepine hypnotic, on sleep and psychiatric symptoms in schizophrenia, as well as the clinical correlates of these variables. Seven male schizophrenic patients chronically taking neuroleptics together with BZD were studied. We replaced BZD with ZPC and performed polysomnography (PSG) and Brief Psychiatric Rating Scale (BRPS) scoring before and after an 8-week ZPC treatment. The replacement of BZD with ZPC increased the mean amplitude of high-amplitude low-frequency delta waves on the frontal derivation recognized by period-amplitude analysis, and it decreased the BPRS negative-symptom score. Under the BZD treatment, the negative-symptom score correlated inversely with the mean amplitude of high-amplitude low-frequency delta waves. This correlation was weak and not significant under the ZPC treatment. Therefore, delta waves during sleep have a close correlation to negative symptoms in schizophrenia, and such a correlation could be influenced by hypnotics. Although these are preliminary findings, it was suggested that, compared with BZD, ZPC might be a beneficial hypnotic in regard to both sleep and negative symptoms of chronic schizophrenic patients.

Adult↗
PubMed2002

Tolerance and sensitization to the hypnotic effects of alcohol induced by chronic voluntary alcohol intake in rats.

The effect of a chronic alcohol exposure on the development of tolerance to the depressive effects of alcohol were examined in male Wistar rats that voluntary self-administered alcohol. A free-choice drinking procedure based on the limited access paradigm and the addition of glucose that implies an early availability of the alcoholic solution was used (Alcoholism Primary Praecox procedure). Alcohol induced sleep time (3.5 g alcohol per kg i.p.) was measured at 90 days (after 2 months of alcohol consumption) or at 60 + 90 days old (1 or 2 months of alcohol consumption). The psychomotor performance was also evaluated by means of an 80 degrees inclined screen test. Subjects that had been tested for the hypnotic effects at both 60 and 90 days showed a higher intake of alcoholic solution than the animals only tested at 90 days. The same consumption increase was observed in the glucose group. No significant differences between groups were observed in the inclined screen test. Tolerance to the hypnotic effects of alcohol was observed at 90 days. On the other hand, no significant differences between alcohol and control groups (glucose or water) were observed in the sleep time at 60 days. In the alcohol-drinking rats tested for two trials (60 and 90 days), sensitization instead of tolerance to the second hypnotic alcohol injection was seen. Tolerance to the hypnotic effects of alcohol observed after chronic voluntary alcohol consumption may provide animal models of alcoholism based on limited access to sweetened alcoholic solutions with construct validity.

Alcohol Drinking↗
PubMed1978

A retrospective analysis of analgesics and sedative-hypnotics in hospitalized obstetrical and gynecological patients.

In a retrospective analysis, the dose per patient day (DPPD) of controlled analgesics and sedative-hypnotics dispensed to inpatients at a women's hospital in the United States were studied from October 1974 through September 1975. Obstetric patients received as many analgesics (1.872 DPPD) as did gynecologic patients (1.945 DPPD). Percodan and meperidine were the most frequently dispensed oral and parenteral analgesics (0.673 and 0.526 DPPD) respectively. Obstetric patients received greater quantities of sedative-hypnotics (0.453 DPPD) than did gynecologic patients (0.311 DPPD). Secobarbital and pentobarbital were the most frequently dispensed oral and parenteral sedative-hypnotics (0.161 and 0.015 DPPD), respectively. A decline in the use of barbiturates was observed toward the end of the study year, with a corresponding increase in the use of the non-barbiturate sedative-hypnotics. It is recommended that intrapartum administration of analgesics and sedatives be carefully evaluated in view of their possible depressant effects on the fetus/newborn.

Analgesics, Opioid↗
PubMed1997

Patterns of hypnotic drug prescription in Italy. A two-week community survey.

BACKGROUND: In Italy a number of studies have been published on psychotropic drug use in general practice and community settings. However, the present study is the first Italian study to focus on hypnotic drug prescriptions in a large community sample. METHOD: Data were collected from 145 of the total of 404 pharmacies of five large cities in north-eastern Italy. All consecutive patients presenting a prescription for a hypnotic drug were interviewed by the pharmacists during a two-week period. RESULTS: The pharmacists interviewed 7/44 consecutive patients. The highest prevalence of prescriptions for hypnotic drugs was found in the elderly and in women. The majority (96%) of prescriptions were for benzodiazepines, with lorazepam and triazolam accounting for 50%. Short-acting and ultra-short-acting benzodiazepines were more frequently prescribed for sleep induction by general practitioners (GPs) than by psychiatrists and other physicians. Frequently the benzodiazepine used as a hypnotic was also prescribed for day time sedation. Approximately 72% of subjects reported they had been taking the prescribed drug for one year or more. CONCLUSIONS: In Italy benzodiazepines are the most frequently prescribed drugs for sleep induction; as they are widely prescribed for elderly people by GPs often for long periods of time, educational programmes and guidelines on the rational use of benzodiazepines in general practice are needed.

Adult↗
PubMed2006

Three decades of antidepressant, anxiolytic and hypnotic use in a national population birth cohort.

BACKGROUND: Psychotropic medication use is common and increasing. Use of such drugs at the individual level over long periods has not been reported. AIMS: To describe antidepressant, anxiolytic and hypnotic drug use, and associations between such medication use and common mental disorder, over a 22-year period. METHOD: Questions about psychotropic medication use and symptoms of common mental disorder were asked of more than 3000 members of the 1946 British birth cohort at multiple time points between ages 31 and 53 years. RESULTS: Prevalence of any antidepressant, anxiolytic or hypnotic use increased significantly from 1977 (30.6 per 1000) to 1999 (59.1 per 1000) as the cohort aged. Less than 30% with mental disorder used antidepressants, anxiolytics or hypnotics. Previous use of antidepressant, anxiolytic or hypnotic was a strong predictor of future use during an episode of mental disorder (odds ratios 3.0-8.4); this association became weaker over time. CONCLUSIONS: Pharmacotherapy is infrequently used by individuals with common mental disorder in Britain; this has not changed in the past three decades.

Adult↗
PubMed2006

Ethanol-induced hypnotic tolerance is absent in N-methyl-D-aspartate receptor epsilon 1 subunit knockout mice.

Recent pharmacological studies suggest that N-methyl-D-aspartate (NMDA) receptors play an important role in neuroadaptive processes in the development of tolerance to addictive drugs, such as opioids, amphetamine, and cocaine. In the present study, we investigated the contribution of the NMDA receptor to ethanol-induced hypnotic tolerance using NMDA receptor epsilon1 subunit knockout mice. Hypnotic sensitivity to a single injection of 3, 3.5, and 4 g/kg ethanol was not significantly different between wild-type mice and NMDA receptor epsilon1 subunit knockout mice. In contrast, although wild-type mice displayed hypnotic tolerance after repeated administration of 4 g/kg ethanol for 4 consecutive days, no change in the duration of hypnosis was observed in knockout mice. No significant differences were observed in blood ethanol clearance between wild-type and knockout mice on day 4. Our results indicate epsilon1 subunit containing the NMDA receptor might be involved in the development of ethanol-induced hypnotic tolerance.

Animals↗
PubMed2005

Interaction between thiopental and fentanyl in mice is different between hypnotic and lethal doses.

Much is known about the interaction of intravenous anesthetics and opioids at the therapeutic level, but less is known regarding their combined lethal effect, leaving some uncertainty regarding the window of safety for their clinical use. We set out to document the type of interaction between thiopental and fentanyl for both the hypnotic effect (loss of righting reflex) and lethal effect in mice. Hypnotic and lethal dose-response curves were constructed for thiopenthal alone and in combination with fentanyl (0.8 microg/kg, each based on five to seven subgroups of six to ten ICR mice. The dose of fentanyl was that needed to double the lag time to tail flick following a noxious stimulus (the equivalent of human analgesia). While fentanyl did not change the median effective hypnotic dose of thiopental (8.9 mg/kg [95% confidence interval {CI} 8.0-9.9 mg/kg] alone versus 7.8 mg/kg [95% CI 6.7-8.7 mg/kg] in combination), it significantly reduced its median lethal dose from 71.8 mg/kg (95% CI 68.3-74.8 mg/kg) to 64.5 mg/kg (95% CI 63.7-65.2 mg/kg). Most remarkably, it increased the slope of the curve from 0.17 (95% CI 0.10-0.36) to 0.61 (95% CI 0.24-1.10), virtually eliminating the difference between the non-lethal and lethal ranges. We conclude that the type of interaction between thiopental and fentanyl is stronger for the lethal effect than for the hypnotic effect. This may become relevant to clinical situations in humans when higher doses of thiopental are used.

Anesthetics, Intravenous↗