Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up-to-date. Zaleplon is known to cause central nervous system CNS depression, a rapid condition characterized by shallow breathing, a lower heart rate, and loss of consciousness; this may result in coma and death. Tuck in your inbox Stay connected to Tuck! Benzodiazepines are not recommended for people with obstructive sleep apnea OSA because they cause pronounced muscle relaxation, which can exacerbate symptoms of OSA. Many insurance companies require a prior authorization for this drug. Once a patient stops taking zaleplon, he or she may experience rebound insomnia.
CGI-I is scored from 1 very much improved to 7 very much worsened. CGI-I was assessed at each 4-week study center visit during the week treatment period and at the final visit at week 25 during the run-out period. Patients completed the PMQ each morning upon awakening and recorded their responses via the interactive voice response system or Internet.
The PMQ asks the respondent whether he or she took the study medication the previous evening and assesses the following subjective sleep measures: QOS was measured using a 4-point categorical scale scored as excellent 1 , good 2 , fair 3 , and poor 4. In addition, each respondent assessed the level of next-day functioning by rating the level of morning sleepiness using numerical values from 0 very sleepy to 10 not at all sleepy and by rating ability to concentrate using a 4-point categorical scale scored as excellent 1 , good 2 , fair 3 , and poor 4.
The PMQ was completed daily beginning after the screening visit and continuing through to study termination. Data from this questionnaire were used in various assessments: The ESS was used to determine daytime sleepiness and was completed by each patient at each 4-week study center visit during the week treatment period and at the final visit at week 25 of the run-out period. The scale consisted of 8 items assessing the degree of sleepiness during the performance of everyday activities, each item being scored from 0 would never fall asleep to 3 high chance of falling asleep.
The primary efficacy variable was the score on the PGI Item 1, treatment aid to sleep, assessed at week 12 of the treatment period in the intent-to-treat ITT population. The ITT population consisted of all randomized patients who had received at least one dose of study medication and had undergone at least one post-baseline efficacy assessment. The PGI Item 1 included three ordered categories related to the patient's impression that treatment 1 helped me sleep, 2 did not affect my sleep, or 3 worsened my sleep.
The main secondary efficacy variables were the scores on the following additional assessments performed every fourth week during the treatment period: Tablet-taking behavior was analyzed over each 4-week period of treatment. Measures of daytime ability to function and sleepiness in the morning, provided daily as part of the PMQ, were analyzed on a monthly basis.
Safety was assessed by physical examination during screening and at the last visit, by measurement of vital signs heart rate, supine and standing systolic and diastolic blood pressure during each visit, and by documentation of spontaneously reported or observed adverse events AEs throughout the study. A rebound insomnia effect was defined as a worsening of sleep from baseline values.
Rebound effect was assessed by patients' TST and WASO scores as recorded in the patient's daily questionnaire during the run-out period. A sample size of patients was required in a ratio of 2: Efficacy assessments were analyzed in the ITT population. Safety assessments were analyzed in the population of randomized patients who had received at least one dose of study medication.
In the event of missing assessments of the primary endpoint at week 12, data from the week 16 assessments were used, and for missing assessments of the main secondary PMQ endpoints at month 3, data from the month 4 assessments were used. If assessments were not available for week 12 and week 16, then week 8 values were used, and for missing assessments for month 3 and month 4, month 2 values were used. No other replacements were performed. Unless otherwise noted, all statistical analyses were performed at the 0.
For PGI Item 4, a chi-square test on proportion favorable ratings was used. On the PMQ, for all measurements, the change from baseline was averaged over each month each 4-week period during the treatment period up to week The change from baseline for each PMQ measurement and ESS total score was assessed using analysis of covariance ANCOVA , with treatment group as a fixed factor and the baseline value centered on the grand mean for each group as covariate.
Analysis for a rebound effect was conducted on data from patients who took at least one tablet on the last night of the treatment period. Rebound was also assessed for patients who permanently discontinued the study during the treatment period i. There were no post-baseline data for 2 randomized patients in the zolpidem extended-release group, and thus the ITT population totaled patients. In the zolpidem extended-release group, patients In the placebo group, patients Demographic characteristics of the 2 treatment groups were similar Table 1.
The patients ranged in age from 18 to 64 years, and the majority were white and female. Mean weight of all patients was Baseline disease characteristics were comparable between treatment groups. Mean baseline CGI-S score was 4. Baseline insomnia characteristics recorded from the PMQ during the run-in period were similar between groups Table 2. In the zolpidem extended-release group, The percentage of patients who reported a treatment benefit on the PGI was higher in the zolpidem extended-release group than in the placebo group for all four PGI items at the conclusion of the first 4-week treatment period, and this difference was sustained throughout the entire study.
The percentage of patients who obtained a positive evaluation on the CGI-I scale i. The magnitude of these improvements generally increased over the week treatment period. At baseline, both groups had a mean baseline ESS of 7. ESS was overall statistically significantly lower in the zolpidem extended-release group than the placebo group during the double-blind treatment period. Univariate analyses indicated that the groups were statistically significantly different at all time points except month 6 and month 1 trend for significance Table 4.
Over the 6-month period, the mean number of nights per month that tablets were reported as taken was stable in each treatment group. The mean value was slightly higher for patients in the zolpidem extended-release group than for those in the placebo group Table 5. Of note, each patient's average tablet intake per month was based on a minimum required dosing of 3 tablets per week, with the option to take up to a maximum of 7 tablets per week. Of the patients who received at least one dose of study drug, treatment-emergent AEs were reported by patients The majority of AEs were mild or moderate in severity.
The most common AEs occurring at a slightly higher frequency in the zolpidem extended-release group than in the placebo group were headache, anxiety, somnolence, dizziness, fatigue, disturbance in attention, irritability, nausea, and sinusitis Table 6. These AEs were similar in nature to those reported in previous studies and to the known safety profile of zolpidem extended-release. Overall, 57 patients 8.
The AEs most commonly leading to discontinuation in the zolpidem extended-release and placebo groups were psychiatric disorders 3. A total of 30 serious AEs occurred in 25 patients in 2. Potential rebound insomnia was assessed by examining the mean change in TST and WASO scores from baseline on each of the first 3 nights after abrupt discontinuation of study medication during the run-out period. In neither the zolpidem extended-release group nor the placebo group was any worsening from baseline i.
However, no differences between these groups were observed on nights 2 and 3. This study assessed the efficacy and safety of zolpidem extended-release A review of the current literature suggests that this is the longest placebo-controlled study completed thus far of intermittent dosing of an insomnia agent. Non-nightly dosing may offer many advantages over nightly dosing, including decreased drug exposure, increased patient control over therapy, and reduced medication expense.
It is consistent with the prevailing prescribing recommendations for medications in this class and is also the preferred dosing pattern among many patients. Results of the present study confirm the sleep maintenance efficacy of zolpidem extended-release With respect to QOS, the largest benefit obtained in the placebo group 0. Furthermore, the absolute magnitude of the benefits obtained with zolpidem extended-release The primary efficacy parameter, aid to sleep PGI Item 1 , was chosen to capture patients' overall impressions of the medication's ability to improve sleep.
One of the main concerns with developing a longer-acting formulation of a sedative or hypnotic drug is the potential for continuing drug effects after the patient awakens in the morning. Therefore, it is encouraging to note that patient-reported daily measures of morning sleepiness and ability to concentrate were significantly better in the zolpidem extended-release group than in the placebo group for each 4-week interval throughout the entire study.
This is consistent with the pharmacokinetic profile of zolpidem extended-release, which provides higher plasma concentrations beyond 3 h, compared to original zolpidem 10 mg, yet retains a similar elimination half-life, thereby presenting low plasma concentrations at 8 h post-dose. Scores on the ESS were significantly improved with zolpidem extended-release versus placebo in months 2 to 5, and there was a trend for this effect in month 1.
As far as we are aware, this is the first double-blind, placebo-controlled trial demonstrating significant efficacy of an insomnia medication on this measure. This finding lends further support to the conclusion that zolpidem extended-release treatment improved subjective daytime sleepiness in this study. This result is intriguing, however, given that ESS measures were not elevated in this population at baseline and are generally not elevated in adult insomnia patients.
Rebound insomnia—defined as an acute worsening of insomnia symptoms upon discontinuation of medication to a level of severity greater than baseline—was not observed in this study. This result occurred despite the fact that rebound was assessed only in the subset of subjects who had taken study medication on the last night of the double-blind phase, in order to decrease the likelihood that a rebound effect might have been missed by a drug-free period before the run-out phase.
However, it is notable that on the first night of the discontinuation phase, there appeared to be a worsening of TST and WASO compared with the second and third nights in those receiving zolpidem extended-release tablets. The mean number of days that pills were taken was stable over the 6-month period in both treatment groups.
This lack of increase over time in the number of pill-taking nights strongly supports the intermittent dosing model examined in this trial. Neither treatment group attained a mean or median frequency greater than 21 pills per month, or roughly 5 pills per week. Furthermore, given that the study protocol required a minimum of 3 tablets per week, or 12 tablets per month, patients in the zolpidem extended-release group used medication on average an additional 8 to 9 nights of the remaining 16 nights per month that they could have elected to use medication Table 5.
This pill-taking behavior reinforces the notion that patients used active medication, which they judged to be effective, in a selective fashion and did not become increasingly dependent on it over this 6-month period of open access. This lack of escalation in frequency of dosing is also highly suggestive that there would be no escalation over time in the dose itself, although the study design limiting intake to one pill per night precludes drawing any definitive conclusions on this issue.
Nonetheless, the fact of sustained therapeutic effect throughout the trial also indicates that dose escalation would be unlikely. Rather, patients were required to take a dose of study medication at least 3 nights per week. This minimum dosing requirement is an important caveat when considering the frequency of self-administration by patients in this study. It is likely that some patients, during one or more weeks of the study, may have taken one or more doses of study medication solely to adhere to the study protocol and not because of perceived need.
As a result, further studies will be needed to determine how full patient autonomy regarding dosing would affect efficacy, safety, and frequency of dosing outcomes in a long-term study of zolpidem extended-release, or another hypnotic medication. The most frequent AEs experienced in the zolpidem extended-release group, all of which occurred at rates higher than in the placebo group, were central nervous system—related AEs. However, these events were not unexpected, as they are consistent with the pharmacologic effects and known safety and tolerability profile of zolpidem.
Overall, a higher percentage of patients withdrew from the placebo group The only other published 6-month, randomized, placebo-controlled trial of a sedative or hypnotic agent in the treatment of patients with primary chronic insomnia was a study evaluating the efficacy and safety of daily eszopiclone 3 mg. This study differed from the present one, however, in at least one important way: Since sleep parameters are better on pill nights than on non-pill nights, a fixed dosing strategy will maximize efficacy outcomes for the drug-treated group.
Despite this difference, zolpidem extended-release demonstrated comparable therapeutic benefit using a dosage strategy that may better approximate the needs of some patients with chronic insomnia. Potential limitations of this study are the absence of PSG-derived sleep parameters, the exclusive reliance on subjective assessments of next-day functioning and cognitive ability, and the lack of a direct comparison to a nightly control group. Future studies are needed to address these issues.
Another limitation of this study is the lack of an active control group. Studies involving active controls are needed to determine the relative utility of zolpidem and other agents when used on a non-nightly basis. In addition, future studies are needed to determine which patients are best managed with intermittent dosing and when nightly therapy is needed. These benefits were associated with improved subjective next-day functioning, no increase in pill-taking behavior over time, and no rebound insomnia upon drug cessation.
These findings extend those from short-term studies, supporting the safety and efficacy of long-term zolpidem extended-release pharmacotherapy for insomnia. Louis, MO; Helene A. The authors would also like to thank Cherith Marlowe for her editorial assistance. Funding for this editorial support was provided by sanofi-aventis. The authors of this article were fully responsible for the content and editorial decisions and received no financial support or other form of compensation related to the development of this article.
This study was funded by Sanofi-Aventis. Soubrane is an employee of Sanofi-Aventis. National Center for Biotechnology Information , U. Journal List Sleep v. Zammit , PhD, 3 C. Like zaleplon, zolpidem has been linked to CNS depression. There is also a potential for dependence and abuse with zolpidem. Sanofi Aventis has extended the commercial viability of this drug by patenting and selling a controlled-release CR formulation.
The CR medication is delivered in a pill layered with rapid-acting and slow-release components; this allows people with insomnia to achieve sleep easily and stay asleep throughout the night. Importantly, the fast-acting and slow-release layers share the same chemical structure, but the latter contains a blend of inactive ingredients that delay absorption and prolong the hypnotic effect. Ambien CR is available in 6. Eszopiclone is a hypnotic prescribed to help insomnia patients fall asleep more easily and remain asleep throughout the night.
Eszopiclone is manufactured by Sepracor Inc. Lunesta was previously under patent with exclusivity, but as of , the patent has expired and generic versions are currently available. Eszopiclone is available in film-coated tablets. Unlike zaleplon and zolpidem, which have been proven to act on benzodiazepine receptors, the precise action mechanism of eszopiclone is unknown; however, its hypnotic effect suggests interaction with GABA-receptors located near the benzodiazepine receptors, if not the benzodiazepine receptors themselves.
Due to the strength of this hypnotic effect, eszopiclone is a controlled substance and there is potential for abuse of the drug. Unlike other z-drugs and other insomnia medications like triazolam, which are prescribed for up to four weeks, Lunesta has been approved by the FDA for long-term use of six months or more. Long-term trials indicate that Lunesta does not increase tolerance, meaning that patients do not need larger doses to obtain the same effect after long-term use.
Lunesta is touted as superior to competing medications, since it not only initiates sleep but also prevents nighttime waking. Benzodiazepine medications are a class of drugs primarily used to treat anxiety disorders, though their soporific effects often make them suitable as sleep aids. Hence the name, they act on benzodiazepine receptors in the brain, much like z-drugs do. Benzodiazepines carry a much higher risk for dependency and potential abuse than z-drugs.
Benzodiazepines are not recommended for people with obstructive sleep apnea OSA because they cause pronounced muscle relaxation, which can exacerbate symptoms of OSA. Benzodiazepine medications act quickly — typically within 10 days — but most physicians urge patients to gradually wean themselves off the drug; those who abruptly stop taking the drug have reported depression and anxiety, as well as physical withdrawal symptoms like nausea and vomiting.
Triazolam is primarily used as a sedative to treat patients with severe insomnia. Triazolam was originally manufactured by Pharmacia and Upjohn and branded as Halcion; however, the patent and exclusivity rights have expired, and several generic versions are available. These include Apo-Triazo, Hypam, and Trilam, as well as other named used in non-English-speaking countries.
Triazolam is available in 0. The maximum dose per day should not exceed 0. Doctors urge people not to take triazolam unless they plan on sleeping for the next seven to eight hours. Triazolam is indicated for short-term treatment of insomnia, and should not be used for longer than three consecutive weeks. In clinical studies, triazolam successfully decreased sleep latency the time it takes to fall asleep at night , increased overall sleep duration, and reduced nighttime waking in insomnia patients.
As a result, this medication may not be suitable for people with jobs that require them to work early in the morning, particularly if their duties involve use of vehicles or heavy machinery. Temazepam is used to treat sleep-onset and sleep-maintenance insomnia. The drug was first patented in , and became available in the U. It is most commonly marketed under the name Restoril; other trade names include Euhypnos, Normison, Remestan, and Temaze. The maximum daily dosage for Restoril is 30 mg, but as little as 7.
Restoril is a short-term insomnia medication, and is classified as a Schedule IV controlled substance under the Convention of Psychotropic Substances. As a result, it carries high risks of dependency and abuse. Most people who take Restoril will notice an improvement in their insomnia symptoms after as little as one week. The pills are designed to induce sleepiness for at least seven or eight hours, and those who wake up too soon may experience difficulty remembering or concentrating on things until the effects wear off.
Estazolam is a short-term insomnia medication used to help patients fall asleep and remain asleep throughout the night. It is also often used to induce sleep prior to medical operations. Estazolam was first created by Upjohn in the s, and is currently marketed under the names ProSom in the U. The standard maximum dose for adults is 2 mg per day, but a dosage of 1 mg or 0. Pregnant women and people with liver failure or disease should not use estazolam.
It also interacts with other medications, including HIV protease inhibitors, sodium oxybate used to treat excessive daytime sleepiness , and clozapine used to treat schizophrenia. In addition to the side effects listed above, some people who take ProSom report severe side effects related to their mood and psychological well-being.
These include increases agitation and aggression, and changes in regular behaviors. Ramelteon is classified as a melatonin agonist, which means that it acts on melatonin receptors in the brain; melatonin is a hormone produced in the pineal gland that helps regulate natural hour sleep cycle, also known as circadian rhythm.
It does not act on benzodiazepine receptors or other GABA receptors, resulting in less of a hypnotic effect. The current patent is set to expire in Spring , and a generic version of Rozerem has already been approved by the FDA. Due to its mechanism of action and minimal hypnotic effects, ramelteon has not been shown to cause dependency, and no potential for abuse has been reported.
Ramelteon is not a controlled substance, but is currently available by prescription only. Physicians will typically direct patients to take one tablet 8 mg half an hour before they plan to sleep. The most common side effects are dizziness and sleep, and few adverse health effects have been reported. In most cases, insomnia symptoms will improve after seven to 10 days of regular use. Studies are still being conducted to determine if ramelteon is more effective than standard melatonin supplements, which are available over-the-counter and produce a similar, sleep-inducing effect.
Suvorexant is classified as a sedative-hypnotic , as well as an orexin agonist because it acts on orexin receptors. Orexin also known as hypocretin is a neuropeptide that regulates feelings of wakefulness, arousal, and hunger. Suvorexant essentially blocks orexin neuropeptides from bonding, suppressing wakefulness and inducing sleepiness in the process. The newest medication on our list, Belsomra received FDA approval in and became available in the U.
Belsomra is available in 10 mg tablets, with a maximum recommended dosage of 20 mg per day. Like Rozerem, Belsomra should be taken 30 minutes before bedtime, and patients should not take the drug unless they plan to sleep for at least seven hours. Belsomra has been shown to produce limited dependency, and the potential for abuse has been noted.
As a result, suvorexant is classified as a controlled substance. People with liver failure or impairment should not take Belsomra, and studies have linked the drug to fetal health problems during pregnancy.