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PubMed1994

Zopiclone as a preoperative night hypnotic: a double-blind comparison with temazepam and placebo.

We have examined the hypnotic effects of zopiclone 7.5 mg and temazepam 20 mg compared with placebo in a double-blind, randomized, clinical study of 60 patients on the night before operation. Evaluation was both subjective (visual analogue scales and a sleep questionnaire), to measure the quality of sleep, and objective (critical flicker fusion, object recall and paired associates tasks), to measure residual impairment. We found that zopiclone was an effective single-dose hypnotic with similar residual effects to the benzodiazepine and it may therefore provide a suitable alternative to benzodiazepines.

Adolescent↗
PubMed1994

Melatonin possesses time-dependent hypnotic effects.

The present study investigated the hypnotic effects of 5 mg melatonin in comparison with placebo when administered at 1200, 1700, 1900 and 2100 hours. Eighteen young adults were studied with the 7/13 ultrashort sleep-wake paradigm after an overnight sleep deprivation. Melatonin was administered according to a double-blind Latin square design. After each administration, melatonin significantly increased sleep propensity, the spectral power in the theta, delta and spindles bands, and subjective sleepiness. It significantly decreased the power in the alpha and beta bands and oral temperature. The latency to maximum effect varied linearly from 3 hours 40 minutes at 1200 hours to 1 hour at 2100 hours. These findings indicate that melatonin possesses a time-dependent hypnotic effect and suggest that endogenous melatonin may participate in sleep-wake regulation.

Adult↗
PubMed2006

Insomnia comorbidity and impact and hypnotic use by age group in a national survey population aged 16 to 74 years.

STUDY OBJECTIVES: To compare age-group differences in somatic/psychiatric comorbidity, impact, and pharmacotherapy associated with sleep disturbance across a broad adult age range. DESIGN: Cross-sectional national mental health survey. SETTING: Adults living in private households in England, Scotland, and Wales. PARTICIPANTS: 8,580 people aged 16 to 74 years. MEASUREMENTS AND RESULTS: Insomnia (4 symptom/syndrome definitions), depression, generalized anxiety disorder, and daytime fatigue were defined from the revised Clinical Interview Schedule. Any insomnia was reported by 37% of the sample, moderate insomnia by 12%, insomnia with fatigue by 13%, and symptoms fulfilling diagnostic criteria for primary/secondary insomnia by 5%. All categories of insomnia were associated with mental disorders, worse physical health, and fatigue to a similar degree in all decade age groups. The associations between insomnia categories and separated, divorced, or widowed marital status were strongest in younger participants. Insomnia categories were of longer reported duration and more strongly associated with worse physical health-related quality of life (SF-12) in older age groups. For participants with any definition of insomnia, benzodiazepine hypnotics were more commonly reported in older age groups. CONCLUSIONS: The association between insomnia and impaired quality of life is most pronounced in older age groups. Associations with physical and mental health status and those with daytime fatigue do not vary in strength between age groups. Older people with insomnia in this population were more likely to be taking benzodiazepine hypnotics.

Adolescent↗
PubMed1983

Pilot pharmacokinetic study of brotizolam, a thienodiazepine hypnotic, using electron-capture gas-liquid chromatography.

Brotizolam, a thienodiazepine hypnotic, can be reliably and sensitively quantitated in human plasma using gas chromatography with electron-capture detection. After addition of an internal standard, samples are directly extracted into an organic solvent, evaporated, reconstituted, and chromatographed at 290 degrees C on a 1% OV-17 column. Sensitivity limits are 0.25 ng of brotizolam/ml of plasma. Six volunteers ingested single 0.25- and 0.5-mg doses of brotizolam on two occasions, and brotizolam concentrations were measured in plasma samples drawn during 24 h after each dose. Peak concentrations averaged 5.5 and 9.2 ng/ml at the two dose levels, and were always attained within 1.5 h after dosage. Elimination half-life averaged 4.4 h (range 2.6-6.9 h) and was independent of dose. Thus brotizolam is a rapidly absorbed hypnotic drug with a short elimination half-life.

Adult↗
PubMed1996

Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse.

The sedative and anesthetic effects of ethanol and propofol when these drugs are coadministered are not known. Accordingly, we investigated the nature of the pharmacological interaction between ethanol and propofol during hypnosis and anesthesia in the mouse. Propofol, ethanol, and mixtures of the two were administered through the tail vein in male CD-1 mice (n = 162). The loss of righting response occurring 10 s after injection and persisting at least 10 s thereafter was defined as hypnosis, and lack of a motor response to tail clamping 60 s after injection was defined as anesthesia. The 50% effective dose (ED50) values for the hypnotic and anesthetic actions of the drugs were determined with quantal dose-response curves, using probit analysis. The pharmacological interactions were identified by the locations of ED50 values on their corresponding hypnosis and anesthesia isoboles. For each drug alone, the hypnotic and anesthetic ED50 values with 0.95 confidence intervals were 16.70 (11.98, 23.20) mg/kg and 25.02 (20.27, 31.29) mg/kg for propofol and 0.88 (0.81, 0.95) g/kg and 1.80 (1.45, 2.23) g/kg for ethanol, respectively. For the drugs in combination, the ED50 values for hypnosis with 0.95 confidence intervals were 6.98 (6.50, 7.49) mg/kg propofol with 0.61 (0.57, 0.66) g/kg ethanol, and for anesthesia were 10.55 (9.76, 11.42) mg/kg propofol with 0.93 (0.86, 1.05) g/kg ethanol, respectively. When plotted isobolographically, we found these combinations to be behaviorally additive both for hypnosis and anesthesia. Although a finding of synergism would have excluded the possibility of an identical mechanism of action for the drugs, elucidation of the molecular basis of the additivity must await further studies.

Anesthetics, Intravenous↗
PubMed1996

Sympatholytic and minimum anesthetic concentration-sparing responses are preserved in rats rendered tolerant to the hypnotic and analgesic action of dexmedetomidine, a selective alpha(2)-adrenergic agonist.

BACKGROUND: The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha(2) agonists after prolonged administration of dexmedetomidine and how the number of available alpha(2) adrenoceptors affects these dexmedetomidine-induced responses was studied. METHODS: The sympatholytic action of acute and chronic (3 and 10 micrograms.kg-1.h-1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micrograms.kg-1.h-1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micrograms.kg-1), doses in the steep part of the dose-response curve. The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg.kg-1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent. RESULTS: After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha(2) adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha(2) adrenoceptor availability in the locus coeruleus. CONCLUSION: Tolerance does not develop for either the sympatholytic or MAC-sparing actions of dexmedetomidine, although it is present for the hypnotic response. The durable quality of the sympatholytic and MAC-sparing responses to dexmedetomidine after chronic treatment is explained by a comparatively larger receptor reserve than is needed for the hypnotic and analgesic responses, which are blunted by the same drug treatment regimen.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1997

Hypnotic effects of low doses of quazepam in older insomniacs.

To evaluate the efficacy and safety of reduced doses of the benzodiazepine agonist quazepam in older insomniacs, 30 men and women > 60 years old with chronic insomnia were randomly assigned to receive 0, 7.5, or 15 mg quazepam. After two placebo nights, each subject received the appropriate dose for seven consecutive nights, which was followed by two placebo recovery nights. Both doses increased total sleep time relative to placebo during the early (nights 1 and 2) and late (nights 6 and 7) treatment phases. The low dose reduced sleep latency during the late phase, whereas the high dose reduced sleep latency in both early and late treatment phases. These observed hypnotic effects for both doses did not diminish over the seven nights of repeated administration. There also was a continued hypnotic effect during the two nights of placebo recovery for both doses. Analyses of plasma concentrations of quazepam and its metabolites suggested the continued drug effects on sleep during recovery are due to the metabolite desalkylflurazepam. In the safety evaluation done by means of adverse drug event assessments and postsleep questionnaires, the adverse events reported were minimal and not drug or dose related.

Aged↗
PubMed1984

Use of sedatives and hypnotics prescribed in a family practice.

The subsequent misuse and abuse of sedatives and hypnotics prescribed to 190 patients of the family practice program at the Medical University of South Carolina was investigated by medical record abstract and patient interviews. Results indicated little misuse and no abuse, with most respondents indicating they took fewer doses than directed. Concerns about dependence were widespread and were most likely in patients who said they never took fewer doses than directed. These patients were also more likely to have side effects. Ten percent of respondents said they had shared their sedative or hypnotic with others, usually relatives. Because of the nature of the population, mostly female and with an average age of 50 years, the results are likely to underrepresent misuse and abuse and to overrepresent concerns with dependence as compared with the general patient population. The results indicate the need for a prospective study to determine the process of becoming a misuser and factors associated with dependency fears.

Adult↗
PubMed2001

Screening for detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine by GC-MS developed using rat liver microsomes.

A gas chromatography-mass spectrometry (GC-MS) procedure for the detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine is presented. The metabolites were first identified in rat liver microsome preparations by GC-MS after isolation and derivatization. Using these GC-MS data, a GC-MS screening was developed for urine as part of the authors' modified systematic toxicologic analysis procedure. After acid hydrolysis of a 2.5-mL aliquot of urine, a further aliquot was added. The mixture was then liquid-liquid extracted at pH 8-9, acetylated, and GC separated. Using mass chromatography with the ions m/z 58, 100, 120, 182, 195, 235, 261, 276, 284. and 293, the presence of new antidepressants, neuroleptics, hypnotics, and their metabolites could be indicated. Positive peaks could be identified by library search using the reference mass spectra recorded during the microsome studies. The intake of therapeutic doses of the following drugs could be monitored in urine: dosulepin, mirtazapine, moclobemide, nefazodone, trazodone, venlafaxine, and zolpidem. Olanzapine and zotepine were detectable in human urine only under steady-state conditions, and low-dose zopiclone was detectable only in overdose. The detection limit was less than 100 ng/mL (signal-to-noise ratio = 3) for the parent drugs.

Animals↗
PubMed1997

The effects of new hypnotic drugs in rats trained to discriminate ethanol.

Several new, non-benzodiazepine hypnotic drugs have recently been marketed (zopiclone, zolpidem) or are in development (zaleplon, SX 3228). These compounds act at benzodiazepine (BZ) (omega) receptors but have mechanisms of action which are not identical to those of benzodiazepines; in particular, zolpidem, zaleplon and SX 3228 have been reported to have selectivity for the BZ1 (omega 1) receptor subtype. In the present study the effects of the four hypnotic drugs were investigated in rats trained to discriminate ethanol (1 g/kg). Comparisons were made with pentobarbital and the benzodiazepines, lorazepam and midazolam. The two benzodiazepines and the barbiturate produced dose-related substitution for ethanol. In contrast, zolpidem, zaleplon, SX 3228 and zopiclone gave rise to only partial (maximum effect 50-67%) substitution, even at doses which greatly reduced rates of lever pressing. The limited ethanol-like effects of zolpidem, zaleplon and SX 3228 may be related to the more selective mechanism of action of these compounds. It is not clear why the effects of zopiclone differed from those of the benzodiazepines.

Acetamides↗
PubMed2001

Sensitivity to the effects of sedative-hypnotics on motor performance: influence of task difficulty and chronic phenobarbital administration.

The present investigation examined sensitivity to the effects of various sedative-hypnotics on motor performance in rats treated chronically with phenobarbital. Eight rats were trained to walk on a rotorod treadmill at low (8 r.p.m.) and high (24 r.p.m.) rotational speeds. Prior to the chronic regimen, phenobarbital, pentobarbital, amobarbital, diazepam and clonazepam produced dose-dependent impairments in motor performance at both speeds. During chronic treatment with phenobarbital (100 mg/kg/day), tolerance was conferred to the effects of all the drugs examined, as evidenced by rightward shifts in their dose-effect curves. For all drugs, the magnitude of this tolerance was generally consistent across the two speeds. Following a 6-week washout period, during which no drugs were administered, dose-effect curves for each drug shifted back toward their original (i.e. pre-chronic) positions. Under all conditions, the doses required for each drug to impair motor performance at the low speed were higher than those required to impair motor performance at the high speed. These data suggest that sensitivity to the motor-impairing effects of sedative-hypnotics is influenced by the difficulty of the behavioral task, but that task difficulty does not modulate the maximal extent to which tolerance and cross-tolerance are expressed.

Amobarbital↗
PubMed1976

Is the use of hypnotics, sedatives and minor tranquilizers really a major health problem?

An analysis has been made of individual purchases of hypnotics, sedatives and minor tranquilizers made during 1973 by patients who had bought such drugs either only once (group S, n= 417) or regularly (group R, n=76) during a 16-month period five years earlier from pharmacies in the town of Ostersund, county of Jmtland, Sweden. By 1973, 17% of the patients in each group had either died or moved out of the country and were therefore excluded from the comparison. In group S, 81 patients (23%) bought the above drugs once or more in 1973, while the corresponding figure for group R was 55 (87%). Compared with 1968-69, there was a decrease in the number of prescriptions and also in the number of tablets obtained per individual. Furthermore, the number of tablets per prescription was lower in 1973. Among the drugs prescribed, benzodiazepines dominated during both periods, followed by barbiturates. In 1973 there was a substantial increase in the use of nitrazepam, mostly at the expense of diazepam and combined products. One patient in group S and one in group R showed a tendency to decrease the interval between purchases. The latter was already known to be a drug abuser five years earlier. Without knowing the reason why the drugs were prescribed and to what extent they were actually taken, it is impossible to say whether the other patient should be classified as drug abuser or not. Although the number of patients in this study is limited, it might be concluded that the risk of an occasional user of hypnotics, sedatives and minor tranquilizers living in this area becoming an abuser of such drugs within a five-year period is less than 1/345.

Adolescent↗
PubMed1989

Dependence on sedative-hypnotics: neuropsychological impairment, field dependence and clinical course in a 5-year follow-up study.

Despite some neuropsychological improvement in a group of 30 patients who had been hospitalized for primary abuse of sedatives or hypnotics 4-6 years earlier, the prevalence of intellectual impairment was still increased and about as high as before. As in alcoholic patients CAT scan of the brain showed an increased prevalence of dilatation of the ventricular system, but unlike alcoholics not of widened cortical sulci. Field dependence and visuo-spatial skills during treatment predicted abuse status at follow-up. Patients with improved drug habits had less pronounced withdrawal symptoms during treatment and a better social situation at follow-up than patients without improvement of drug habits. The results suggest that despite some neuropsychological improvement cerebral disorder diagnosed in patients abusing sedatives or hypnotics is often permanent through the years and that neuropsychological status is linked to long-term prognosis.

Adult↗
PubMed2006

The effect of cigarette smoking on the hypnotic efficacy of propofol.

The bispectral index (BIS) was used to examine the hypnotic efficacy of propofol in 25 smokers (20 cigarettes/day for 2 years) and 24 matched non-smokers (same gender, age, height, weight). BIS was recorded at baseline, at four incremental effect-site concentrations of propofol and at loss of consciousness. Compared with non-smokers, smokers were found to have higher BIS values at baseline (mean (SD)) (97 (1) vs 98 (1)), at 0.7 microg x ml(-1) (95 (3) vs 97 (1)) and at 1.1 microg x ml(-1) (89 (6) vs 94 (4)), p = 0.0099, and they lost consciousness at higher propofol concentrations (2.0 (0.4) vs 2.4 (0.8) microg x ml(-1)), p = 0.03, and at lower BIS values (66 (10) vs 60 (10)), p = 0.04. The hypnotic efficacy of propofol is reduced when used at low effect-site concentrations in smokers. This phenomenon may have some impact on the management of smokers undergoing sedation using target controlled infusion systems.

Adult↗
PubMed1981

The use of short- and long-acting hypnotics in clinical medicine.

1 Activity of short- and long-acting benzodiazepines is reviewed with reference to pharmacokinetics and residual sequelae, and to efficacy and adverse effects. 2 Some benzodiazepines may not lead to obvious effects on performance, such as nordiazepam and clobazam, and the persistence of residual sequelae may not relate obviously to elimination half-lives (as with diazepam and possibly flunitrazepam). However, benzodiazepines with mean half-lives less than 8 h may have residual sequelae, whereas hypnotics with mean half-lives greater than 16 h are likely to lead to impared performance and/or anxiolytic effects the next day. 3 Potassium chlorazepate 15 mg, with its long-acting metabolite nordiazepam, would seem to be the drug of choice for insomnia secondary to anxiety. For the insomniac without significant psychopathology, temazepam 10-20 mg, triazolam 0.125-0.25 mg and for occasional use, diazepam 5-10 mg, provide the initial approach. Flurazepam hydrochloride 15-30 mg, nitrazepam 5-10 mg and flunitrazepam 1 mg and above, have persistent residual effects and should be reserved for refractory patients, and for those in whom some impairment of performance the next day would be acceptable. 4 There is little or no evidence to suggest that the proper use of the short-acting hypnotics, triazolam and temazepam, leads to a worsening of sleep on withdrawal. However, some benzodiazepines may lead to disturbances of sleep and/or rebound insomnia, and nitrazepam and flunitrazepam may be implicated.

Anti-Anxiety Agents↗
PubMed1983

Hypnotic efficacy of midazolam in pre-surgical patients: a dose-finding study.

The hypnotic effect of midazolam on the sleep of pre-surgical patients was studied in 99 patients (53 males, 46 females) due to undergo surgery the following day. One tablet of 15 mg midazolam was administered at 21.00 h and a second was given 45 min later if the subject had not fallen asleep, sleep-onset latency being measured from the time the second tablet was taken. Eighty patients required 1 tablet and 19 required 2 tablets. According to the subjective assessment, patients receiving 1 tablet fell asleep in 22.9 +/- 14.9 min and those taking 2 tablets fell asleep in 38.4 +/- 25.3 min (difference significant P less than 0.05). There was no statistically significant difference between the 1- and 2-tablet groups with regard to sleep duration, number of awakenings, overall assessment of the night's sleep, sleep quality and state on awakening. Factors which had a statistically significant influence on the dosage requirement were (a) sex, 30.4% females requiring a second tablet v. 9.4% males; (b) age, the mean age of the 2-tablet group being 36.5 v. 47 years in the lower dose group; (c) weight, patients with lower body weight requiring the higher dosage, mean 57.5 v. 66 kg; (d) current insomnia or a history of sleeping problems; (e) previous use of hypnotics; (f) degree of insomnia, moderate/severe insomnia needing a higher dosage (42% v. 21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Anxiety Agents↗
PubMed1983

Hypnotics and the control of breathing: a review.

Hypnotics are central depressants. In sufficient doses, they suppress respiration, and so their effects on respiration are important considerations in their safety. The paper reviews mechanisms of respiratory control and methods of assessment, the effects of hypnotics on control of breathing and new methods of non-invasive respiratory monitoring.

Anti-Anxiety Agents↗
PubMed1983

Brotizolam as a pre-operative hypnotic.

Efficacy of and tolerance to brotizolam when used as a preoperative hypnotic were studied in two double-blind, randomised parallel group studies. Brotizolam (0.25 and 0.50 mg) was superior to placebo. Efficacy was assessed as good-to-satisfactory in 73.0% of patients with 0.25 mg and in 88.0% with 0.5 mg. A similar assessment was reached in 40.0% of patients with placebo. Brotizolam 0.5 mg was superior to 0.25 mg, and with the higher dose subjective assessments of anxiety were reduced. Efficacy of tolerance to 0.5 mg brotizolam and 2.0 mg flunitrazepam were compared, and both drugs were found to be effective and well tolerated. Brotizolam maintained sleep throughout the night more effectively than flunitrazepam. A dose range of 0.25-0.5 mg brotizolam is recommended as a pre-operative hypnotic.

Adolescent↗