eszopiclone and ramelteon

Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks.. Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses.. Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves.. Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.

Topics: Acetamides; Azabicyclo Compounds; Eszopiclone; Humans; Hypnotics and Sedatives; Indenes; Infections; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Zolpidem

Hypnotics are commonly use in the treatment of insomnia, and hypnotic use among older adults is more prevalent than with younger adults. Unfortunately, the use of hypnotics is not well studied in the ever-growing geriatric population and the magnitude of the medication benefit is usually not impressive. Insomnia in older adults is usually treated with benzodiazepines, nonbenzodiazepines, and other agents, such as trazodone, valerian, and melatonin. Using appropriately selected agents and therapy initiated with a low dose and careful monitoring of the patient could minimize common unwanted side effects.

Topics: Antidepressive Agents; Azabicyclo Compounds; Central Nervous System Depressants; Eszopiclone; GABA Agonists; GABA-A Receptor Antagonists; Humans; Indenes; Melatonin; Phytotherapy; Piperazines; Pyridines; Sleep Initiation and Maintenance Disorders; Valerian; Zolpidem

Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD.. A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics.. A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants.. The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use.. Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients.

Topics: Acetamides; Adolescent; Adult; Azabicyclo Compounds; Bipolar Disorder; Eszopiclone; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Piperazines; Pyridines; Pyrimidines; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Zolpidem

Topics: Acetamides; Animals; Azabicyclo Compounds; Carcinoma, Basal Cell; Eszopiclone; Humans; Indenes; Piperazines; Pyrimidines; Randomized Controlled Trials as Topic; Skin Neoplasms; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause any cancers. The US Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the four drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. There were eight mentions of incident non-melanoma skin cancers among participants receiving hypnotics but no comparable mentions of cancers among those receiving placebo (P = 0.064, one-tailed). There were also four mentions of incident tumors of uncertain malignancy among those receiving hypnotics but none among those receiving placebo, so combining uncertain and definite malignancies yielded a more significant contrast (P = 0.016). FDA files revealed that all four of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, confirmatory research is needed.

Topics: Acetamides; Animals; Azabicyclo Compounds; Carcinoma, Basal Cell; Causality; Cross-Sectional Studies; Eszopiclone; Follow-Up Studies; Humans; Hypnotics and Sedatives; Incidence; Indenes; Melanoma; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Skin Neoplasms; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration; Zolpidem

Although it has been claimed that insomnia causes an increased risk for depression, adequate controlled trials testing this hypothesis have not been available. This study contrasted the incidence of depression among subjects receiving hypnotics in randomized controlled trials versus those receiving placebo.. The incidence of depression among patients randomized to hypnotic drugs or placebo was compiled from prescribing information approved by the United States Food and Drug Administration (FDA) and from FDA New Drug Application documents. Available data for zolpidem, zaleplon, eszopiclone, and ramelteon were accessed.. Data for 5535 patients randomized to a hypnotic and for 2318 randomized to placebo were compiled. The incidence of depression was 2.0% among participants randomized to hypnotics as compared to 0.9% among those randomized in parallel to placebo (p < 0.002).. Modern hypnotics were associated with an increased incidence of depression in data released by the FDA. This suggests that when there is a risk of depression, hypnotics may be contra-indicated. Preventive treatments such as antidepressant drugs, cognitive-behavioral therapy, or bright light might be preferred. Limitations in the FDA data prevented a formal meta-analysis, and there was a lack of information about drop-out rates and definitions of depression. Trials specifically designed to detect incident depression when treating insomnia with hypnotic drugs and better summarization of adverse events in trials submitted to the FDA are both necessary.

Topics: Acetamides; Azabicyclo Compounds; Cross-Sectional Studies; Depressive Disorder, Major; Drug Prescriptions; Eszopiclone; Follow-Up Studies; Humans; Hypnotics and Sedatives; Incidence; Indenes; Long-Term Care; Odds Ratio; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration; Zolpidem