RESUMO

GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABAA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABAA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABAA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.

Assuntos

RESUMO

OBJECTIVE: To determine the therapeutic effects of two selective GABA-A agonists, zopiclone and eszopiclone, in the treatment of insomnia. METHODS: This study comprised a phase III, single-center, randomized, double-blind, double-dummy, parallel-group, non-inferiority trial. Patients were randomized to receive zopiclone 7.5 mg or eszopiclone 3 mg, both orally, for four weeks. In total, 199 patients were evaluated during two visits and then followed for at least six weeks. The primary endpoint was the Insomnia Severity Index after four weeks of treatment. Secondary endpoints were obtained through polysomnography data, including total sleep time, sleep latency and sleep efficiency. The frequency of adverse events was also analyzed. ClinicalTrials.gov: NCT01100164. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of eszopiclone over zopiclone. Analysis of objective parameters assessed by polysomnography showed that eszopiclone increased total sleep time and also improved sleep efficiency. The safety profile of both study treatments was similar and the most common events reported in both groups were dysgeusia, headache, dizziness, irritability and nausea. Adverse events were observed in 223 patients, 109 (85.2%) in the eszopiclone group and 114 (87.7%) in the zopiclone group. CONCLUSION: Based on the Insomnia Severity Index at the end of four weeks of treatment, eszopiclone demonstrated efficacy comparable to that of zopiclone in the treatment of insomnia, increasing total sleep time as well as sleep efficiency according to polysomnography.

Assuntos

RESUMO

Eszopiclone is the S-isomer of racemic zopiclone, a cyclopyrrolone with sedative-hypnotic activity that has been available in Europe, Canada, and Latin America since 1987. Eszopiclone acts by binding to the GABA(A) receptor. In contrast to the benzodiazepine (BZD) hypnotics, eszopiclone has more selectivity for certain subunits of the GABA(A) receptor. Oral eszopiclone is rapidly absorbed and extensively distributed to body tissues including the brain. Peak plasma concentrations are attained 1.0-1.6 hours after a 3 mg dose, while the mean elimination half-life is 6 hours. The half-life increases with age to about 9.0 hours in patients 65 years or older. Eszopiclone's pharmacokinetic (PK) profile is not substantially modified in patients suffering from renal failure or mild-to-moderate hepatic impairment, although patients with severe hepatic insufficiency should have a reduced dose. The subjective perception of improved sleep following eszopiclone 2 or 3 mg treatment has been demonstrated in randomized, double-blind, placebo-controlled studies of up to 6 months' duration. In these studies the drug significantly reduced sleep onset latency (SOL), the number of awakenings, and wake time after sleep onset (WASO) whereas total sleep time (TST) and quality of sleep were increased in non-elderly and elderly subjects. Sleep laboratory studies of the effects of eszopiclone have confirmed the drug's clinical efficacy in subjects with chronic primary insomnia. Eszopiclone, unlike BZD hypnotics, does not significantly alter values corresponding to slow wave sleep (SWS or stages 3 and 4) and rapid eye movement (REM) sleep. Rebound insomnia following withdrawal of eszopiclone has been examined in only one study. Discontinuation of the active treatment with 2 mg was followed by rebound insomnia in non-elderly subjects. Three-mg doses of eszopiclone administered for a period of up to 12 months was associated with a sustained beneficial effect on sleep induction and maintenance, with no occurrence of tolerance. The most common side-effects were unpleasant or bitter taste, headache, dyspepsia, pain, diarrhea, dry mouth, upper respiratory infection, urinary tract infection, dizziness, and accidental injury. New adverse events (withdrawal symptoms) including anxiety, abnormal dreams, hyperesthesia, nausea, and upset stomach were recorded in one study on the days following eszopiclone 2 or 3 mg discontinuation. Although dependence and abuse potential have not been formally assessed, unpublished data show that eszopiclone at doses of 6 and 12 mg produces euphoria effects similar to those of diazepam 20 mg in BZD drug addicts. In conclusion, available evidence tends to indicate that eszopiclone is effective and safe for the treatment of chronic primary insomnia in non-elderly and elderly subjects. Tolerance did not occur during active drug administration for a 12-month period. Thus eszopiclone can be efficacious not only during short- and intermediate-term administration but also in patients requiring prolonged regular drug usage.