If You Are Having Trouble Sleeping At Night, This Information May Help
Posted on March 5, 2008
» Filed Under Sleep Snoring |
The consequences of insomnia are relatively predictable. Symptoms include waking up feeling tired and unrested, excessive daytime sleepiness, depression, anxiety, and inability to focus on responsibilities or tasks.
Sleep disorders interrupt the sleep of over 40 million Americans every year.4 Consequently, insomnia is an area of particular interest. Due to insomnia’s pervasive nature, there is an incredible need for safe and effective treatments for this condition. One of the several treatment options for insomnia is eszopiclone. Eszopiclone is a nonbenzodiazepine hypnotic agent. It is the active isomer of zopiclone. The manufacturers of eszopiclone claim that it helps people fall asleep quickly, and stay asleep all through the night. To determine the validity of this claim, five experimental trials regarding the efficacy of eszopiclone were evaluated.
The Eszopiclone Studies
The first study, directed by Dr. Martin Scharf5, was a randomized, 2-week, double-blind, placebo-controlled trial conducted on elderly patients diagnosed with primary insomnia. Their ages ranged from 65-85. The diagnosis was made using specific criteria from the Diagnostic and Statistical Manual of Mental Disorders - Forth Edition (DMS IV). The trial was designed to compare the efficacy of eszopiclone versus placebo; in decreasing sleep induction time and increasing total sleep time. Patient data was collected using automated phone surveys. The inclusion criteria were straightforward; patients claiming to get 6.5 hours of sleep a night or less and routinely require more than 30 minutes to fall asleep each night. Qualified study personnel determined the inclusion of each subject, helping reduce classification bias. Medical history interviews were conducted with each patient and consisted of a neurological and physical examination and additional diagnostic tests (serum chemistry, hematology, urinalysis). These ensured that the patient’s insomnia was not secondary; due to comorbid conditions that would influence a persons ability to sleep.
Patients with comorbid conditions or lifestyle choices that would unduly influence sleep were excluded from the study. These efforts maximized the study’s internal validity and reduced selection and confounding bias. After the three-tier randomization, the study’s demographics were homogenous. Two hundred and thirty one patients were randomly assigned into placebo, 1 mg eszopiclone, and 2 mg eszopiclone groups. Each group took their medication nightly before retiring to bed. After they received training on how to operate the interactive voice response system (IVRS), they were given medication with specific instructions and then sent home.
Though the study was unambiguous on patient protocol, any study that uses self-reporting as the sole means of data collection can be weakened. Having 231 different persons responsible to categorize sleep data can introduce significant classification bias. Even though one would hope that any bias introduced by this method would evenly distribute across all test groups, it is difficult to know. Patients were also asked to return to the clinic once a week to receive medication refills and subsequently to fill out quality of life surveys. Patients were initially observed using the IVRS as they recorded their baseline sleep demographics. This was done to assure a functional competence with the system. So while the interactive voice response system could introduce bias, it seems that adequate measures were taken to control for this.
The results for the primary endpoints were significant, especially for patients taking 2 mg of the medication. Eszopiclone significantly decreased sleep induction time ( p = 0.0034). It also increased total sleep time (TST) compared to placebo ( p = 0.0003). The group assigned to 1 mg of eszopiclone did not have results that were as dramatic. The group did have a decrease in sleep induction time, but did not have a significant increase in TST. The group did not significantly differ from placebo in any other category. In other words, 1 mg of eszopiclone helped patients fall asleep, but not stay asleep. The authors also tried to use the results to report the safety of eszopiclone, but they had far too few patients. According to the rule of three, the study was only powered to see adverse events that happen more often than 1 in 77 patients.
Of note, this is the first published study on a sleep medication that has not only reported an improvement in sleep onset and sleep maintenance, but also concurrently reported an improvement in the rating of daytime function. Sleep medicines can induce a state of daytime grogginess, but this was not generally found in eszopiclone. These results were obtained from the quality of life questionnaires.
Overall this study contributed to help confirm the manufacturer’s claim. Appropriate doses, 2 mg of eszopiclone, could contribute to initiate and maintain sleep. However, it is important to know that polysomnography (PSG) is the gold standard for the measurement of sleep quality, and this trial did not utilize it. This weakens the study’s validity more than any other limitation exposed in this study. The outcomes presented are useful, but truly need collaboration with additional results.
Another eszopiclone study, performed by McCall et al.6, was very similar to the previous article. It was a randomized, 2-week, double-blind, multicenter, placebo-controlled trial designed to compare the efficacy of eszopiclone (2 mg and 1 mg) to placebo in elderly patients. The study had almost identical inclusion and exclusion criteria. However, their methods for sleep evaluation were superior. They used the gold standard of measuring sleep quality, polysomnography (PSG), to determine the efficacy of the study medication. This method measures a variety of facets: eye movement to determine REM sleep, limb movement, the stages of sleep (including how much of each), heart rate using an electrocardiogram, nasal and oral airflow, and pulse oxymetry. This method of sleep analysis is more accurate because the results are not dependant on merely the subjective patient estimation of sleep quality. The results are connected to set baselines, and therefore, very measurable outcomes are available.
Questionnaires were also used to determine the perceived sleep benefit. The data was collected using an interactive voice response system (IVRS). Using dual-method data collection, polysomnography and the IVRS, is ideal in this situation and increases the strength of the study’s results. Treatment compliance was very high as well, 99.3%, which added to the study’s overall validity.
According to polysomnography (PSG) and IVRS data, eszopiclone 2 mg was associated with significantly shorter sleep initiation time and an increase in total sleep time ( p < 0.005 for all). However, unlike the previous study, the results did not reveal a trend toward increased daytime alertness, though eszopiclone patients did report fewer daytime naps ( p = 0.03). The eszopiclone 1 mg group did not experience a significant increase in total sleep time. Though eszopiclone 1 mg did effectively induce sleep, it did not maintain sleep. This study incorporated the same measures to reduce bias as the previous study, and then applied PSG, producing credible results that significantly support the claim.
An additional eszopiclone study, by Zammit et al.7, was also helpful in this analysis. It was another muticenter, placebo controlled, randomized, double blind study. Unlike the previous studies it continued 6 weeks, and this experiment was not designed specifically for the elderly. It included patients from 21-64 years, though all other inclusion and exclusion criteria were, again, almost identical. It did specifically exclude pregnant or lactating females and patients with a history of substance abuse or dependence, and also patients that drank two or more alcoholic beverages a day. Though minor exclusion criteria differences were observed across each study, each criterion arose from the desire to restrict conditions that could influence sleep effectiveness. This uniformity adds strength to each study collectively.
The methodology was strikingly similar, however, the study included a different medication strength, 3 mg, in addition to the standard medication strength of 2 mg, which was almost universal across each trial. This study also used polysomnography in addition to the IVRS collection of data. Similar to the previous experiment, polysomnography was preformed several times throughout the study, and patient surveys were used in conjunction.
The results of the experiment were significant. Eszopiclone 2 mg and 3 mg doses reduced sleep initiation time from an average of 30 minutes to 12 minutes ( p d 0.001). Both doses were also associated with an increase in total sleep time ( p d 0.001) and enhanced quality and depth of sleep ( p < 0.05). The most common side effect was an unpleasant taste, 16.3% in the 2 mg group and 33.3% in the 3 mg group. However, patient compliance at approximately 98.2% seemed unaffected. The study was very thorough and complemented the results obtained from the previous experiments.
Another article, by Krystal et al.8, was a 6-month study on the efficacy of eszopiclone, the longest blinded trial for insomnia ever conducted at the time of its publication. This study was another randomized, placebo-controlled, multicenter, double-blind study. The inclusion and exclusion criteria were similar, again using DMS IV for the primary diagnosis of insomnia and excluding other conditions that might interfere with sleep. Only eszopiclone 3 mg versus placebo was studied. The methodology of this study was similar, though polysomnography (PSG) was not applied, and all data was collected using an interactive voice response system (IVRS). Though this method is not as desirable as including PSG, similar precautions to reduce bias as well as proper patient IVRS education adequately addressed these concerns. This study also included 788 patients; almost triple that of the other trials (Scharf et al.5-231, McCall et al.6-264, Zammit et al.7-308, Sivertsen et al.9-46).
Eszopiclone was again associated with a significant increase in total sleep time, approximately 40 minutes longer per night, and almost a 50% improvement in sleep latency ( p d 0.003). This study was specifically analyzing the long-term efficacy of eszopiclone, so the resulting data uniquely contributed.
The last article, by Sivertsen et al.9, was a randomized, placebo-controlled, 6-week, double blinded study conducted on older adults diagnosed with primary insomnia. This experiment was similar in several instances, but unique in many more. The trial was conducted using zopiclone, rather than eszopiclone - the active isomer. While the dose was somewhat adjusted to compensate, zopiclone 7.5 mg is equivalent to eszopiclone 3.75 mg, the quantity and delivery is different from the other experimental trials. Also, rather than comparing zopiclone to placebo alone, they also compared zopiclone to cognitive behavioral therapy (CBT). Inclusion and exclusion criteria were once more extremely similar. Polysomnography and sleep diaries were used to collect patient data and baseline measurements were taken on each patient. However, this time the results were considerably different. CBT proved to be more effective than drug therapy, and zopiclone was found only marginally more effective than placebo. Though this trial aimed for a power of 80%, less patients completed the study than originally projected (46 in total, 16 in the zopiclone group, 12 in the placebo group), thus increasing the possibility for a beta error. Though a slight improvement over placebo was noticed, these results are incongruent with previous outcomes. An increase in the number of patients studied would likely resolve this variation.
In many ways these experimental trials were parallel in execution. As mentioned previously, inclusion and exclusion criteria were in many instances identical. In each experimental trial patient demographics were homogeneous with minor exceptions, and every study, except one, had enough participants to claim adequate power. Undeniably the research possessed various flaws. Notably, criteria were very similar; as a result outcomes only apply to a specific population - the primary insomniac. Secondary insomnia was not addressed. Also, the most prominent side effect, unpleasant taste, could have compromised the blinding of the patients, leading to bias. Additionally, a considerable amount of data was collected and categorized by the patients themselves, perhaps introducing data bias. However, it seems that adequate measures were taken to control for this, and four out of five experimental trials achieved similar outcomes. Overall, the results verified the manufacturers claim: that eszopiclone helps people fall asleep quickly, and stay asleep all through the night.
If you enjoyed reading my article here, be on the look-out for my subsequence articles coming up, the next one being on “Stress”. For more information about healthy alternative choices in other areas of your life, just go the links below in my resource box today.
References
1.Micromedex. Insomnia. thomsonhc.com/hcs/librarian/ND_PR/Main/SBK/1/PFPUI/IpTTfb29MatKs/ND_PG/PRIH/CS/4AA997/ND_T/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/57C9EE/ND_B/HCS/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/81/ContentSetId/75/SearchTerm/insomnia/SearchOption/BeginWith. Accessed November 17, 2007.
2.NHLBI, National Heart Lung and Blood Institute. Insomnia. nhlbi.nih.gov/health/dci/Diseases/inso/inso_whatis.html. Accessed November 17, 2007.
3.NHLBI, National Heart Lung and Blood Institute. Insomnia. nhlbi.nih.gov/health/dci/Diseases/inso/inso_signsandsymptoms.html Accessed November 17, 2007.
4.NIH, National Institutes of Health. Sleep Disorders. fda.gov/womens/getthefacts/sleep.html Accessed November 17, 2007.
5.Scharf M, Erman M, Rosenberg R, et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep. Jun 1 2005;28(6):720-727.
6.McCall WV, Erman M, Krystal AD, et al. A polysomnography study of eszopiclone in elderly patients with insomnia. Curr Med Res Opin. Sep 2006;22(9):1633-1642.
7.Zammit GK, McNabb LJ, Caron J, Amato DA, Roth T. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin. Dec 2004;20(12):1979-1991.
8.Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. Nov 1 2003;26(7):793-799.
9.Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA. Jun 28 2006;295(24):2851-2858.
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