Original ArticleEfficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia
Introduction
Insomnia is defined as difficulty initiating sleep, maintaining sleep, or nonrestorative sleep accompanied by daytime impairments [1]. Numerous epidemiologic studies have found that the risk of insomnia increases with age [2], [3], [4], [5], [6]. Difficulty maintaining sleep is reported by one-third of all elderly adults and is the most frequent sleep complaint in this population [2], [3], [4], [5], [6]. At the same time, one-fourth of elderly adults with insomnia report waking too early with difficulty returning to sleep (early morning awakenings) [6]. While insomnia is associated with decreased quality of life and impairment in function in general, there are some concerning consequences that are specific to elderly adults, including increased risk of falls and nursing home placement [7], [8], [9].
Benzodiazepines and two of the most frequently used non-benzodiazepine agents in the treatment of insomnia in elderly adults, zolpidem (both immediate and extended-release formulations) [10], [11] and eszopiclone [12], act through facilitation of gamma aminobutyric acid (GABA) neurotransmission. They are classified by the US Drug Enforcement Administration as Schedule IV drugs (drugs with some risk for abuse that can lead to limited physical or psychological dependence). Two over-the-counter antihistamines often used for treatment of insomnia, diphenhydramine and doxylamine, have substantial anticholinergic properties, with the potential to cause cognitive impairment, mydriasis, urinary retention, and constipation, especially among older patients [13]. Additionally, only two of the current therapeutic options, eszopiclone and extended-release zolpidem, are indicated for the treatment of sleep maintenance insomnia [11], [12].
Despite the lack of US Food and Drug Administration (FDA) approval for the treatment of insomnia and the relative lack of efficacy and safety data at hypnotic doses, sedating antidepressants such as trazodone, mirtazapine, and trimipramine are commonly used in clinical practice. However, the limited available data on the use of these agents indicate that, when used for insomnia at antidepressant doses, they are associated with undesirable side-effects such as anticholinergic side effects. Taken together, the limitations of the current approved and unapproved therapeutic alternatives for the treatment of sleep maintenance insomnia in elderly adults suggest that there is a need for additional treatment options.
This study was carried out using low-dose doxepin (DXP). This agent appears to be a selective histamine antagonist (primarily at the H1 receptor) at doses of 3 and 6 mg and has been shown to be effective in improving sleep maintenance parameters with minimal adverse effects in two previous clinical trials in elderly adults with primary insomnia [14], [15]. Additionally, DXP at the doses studied has demonstrated sleep maintenance efficacy in three other trials in adults, with one assessing the effects of 3 and 6 mg in patients with primary insomnia [16], another assessing the short-term effects of DXP at doses of 1, 3, and 6 in patients with primary insomnia [17], and a final one examining the effects of 6 mg using a model of transient insomnia [18]. DXP is the only medication that appears to produce a therapeutic effect on sleep maintenance in the last quarter of the night, while manifesting no clinically significant evidence of morning impairment in careful assessments of next-day effects in chronic insomnia patients [14], [15], [16], [17].
In all of these previous trials, objective sleep laboratory data represented the primary endpoint. The present study included only subjective efficacy endpoints and represents the first trial of low-dose DXP designed to systematically examine patient-reported effects in the outpatient setting.
Section snippets
Methods
This was a randomized, double-blind, placebo-controlled parallel-group study designed to assess the efficacy and safety of DXP 6 mg in elderly adults with chronic primary insomnia across a four-week treatment period. There were 34 sites initially targeted for this study, with 32 of them recruiting at least one patient. An Institutional Review Board approved the protocol for each study site and the study was carried out in accordance with the Declaration of Helsinki and the International
Study population
A total of 525 patients were screened for participation. A total of 255 patients met eligibility criteria and were randomized into the study (125 PBO, 130 DXP 6 mg), with 254 of these patients being included in the ITT analysis set; one randomized subject in the PBO group did not receive study drug and was not included. A total of 237 subjects (93%) completed the study. Demographic and dispositional characteristics of the study sample are presented in Table 1.
Sleep maintenance and duration
sTST was significantly increased for
Discussion
In this 4-week, randomized, placebo-controlled, outpatient trial, the efficacy and safety of DXP 6 mg in generally healthy elderly adults with chronic primary insomnia was assessed. Four weeks of nightly use of DXP 6 mg resulted in significant improvements relative to placebo in patient-reported sleep maintenance (sWASO) and sleep duration (sTST) endpoints that were maintained throughout the trial. In addition to the effects on sleep parameters, DXP treatment resulted in significant improvement
Conclusion
In this study of elderly adults with insomnia, treatment with DXP administered nightly for 4-weeks resulted in significant improvements in sleep maintenance and sleep duration parameters. Given that these effects were sustained throughout the trial, both in this trial, and in two previous long-term trials [15], [16], it appears that there is no evidence of tolerance to the sleep maintenance effects of these low doses of DXP. DXP 6 mg was well-tolerated, with no reports of complex sleep
Conflict of interest
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.09.006.
Acknowledgement
This study (No. SP-0509) was fully-funded and supported by Somaxon Pharmaceuticals, Inc., San Diego, CA.
References (22)
Epidemiology of insomnia: what we know and what we still need to learn
Sleep Med Rev
(2002)- et al.
Sleep disturbances and chronic disease in older adults – Results of the 2003 National Sleep Foundation Sleep in America Survey
J Psychosom Res
(2004) - et al.
Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition
Am J Geriatr Psychiatry
(2003) - et al.
Efficacy and safety of doxepin 6 mg in a model of transient insomnia
Sleep Med
(2010) - American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision....
- et al.
Epidemiology of Sleep: Age, Gender, Ethnicity
(2004) - et al.
Insomnia causes, consequences, and therapeutics: an overview
Depress Anxiety
(2003) - et al.
Insomnia in men-a 10-year prospective population based study
Sleep
(2001) - et al.
Neuropsychological performance in elderly insomnia patients
Aging and Cognition
(1995) - et al.
Treating insomnia in older adults: taking a long-term view
J Am Med Assoc
(1999)
Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II
Sleep
Cited by (72)
Effects of different interventions on insomnia in adults: Systematic review and network meta-analysis
2023, Journal of Psychiatric ResearchPrescription Drugs Used in Insomnia
2022, Sleep Medicine ClinicsAntihistamine safety in older adult dermatologic patients
2022, Journal of the American Academy of DermatologyReview of Select Sleep Medicine Pharmacology: Treatments of Insomnia and Circadian Rhythm Sleep-Wake Disorders
2022, Comprehensive Pharmacology