Elsevier

Sleep Medicine

Volume 13, Issue 2, February 2012, Pages 133-138
Sleep Medicine

Original Article
Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia

https://doi.org/10.1016/j.sleep.2011.09.006Get rights and content

Abstract

Introduction

The efficacy and safety of doxepin (DXP), a histamine H1 receptor antagonist, was evaluated in elderly adults with sleep maintenance insomnia.

Methods

This was a randomized, double-blind, placebo-controlled outpatient trial. Elderly adults meeting DSM-IV-TR criteria for primary insomnia were randomized to four weeks of nightly treatment with either DXP 6 mg (N = 130) or placebo (PBO; N = 124). Efficacy was assessed using patient self-report instruments and clinician ratings. Patient-reported endpoints included subjective total sleep time (sTST), subjective wake after sleep onset (sWASO), latency to sleep onset (LSO), sleep quality, and a Patient Global Impression scale (PGI). The primary endpoint was sTST at week 1.

Results

DXP 6 mg produced significantly more sTST and less sWASO at week 1 (both p-values <0.0001) than PBO. These significant improvements versus placebo were maintained at weeks 2–4 (all p-values <0.05). There were no significant differences in LSO for DXP 6 mg versus PBO. DXP 6 mg significantly improved sleep quality (weeks 1, 3, and 4, p < 0.05) and several outcome-related parameters, including several items on the PGI, the severity and improvement items of the Clinician Global Impression scale (CGI; weeks 1 and 2) and the Insomnia Severity Index (ISI; weeks 1–4), all versus PBO. There were no reports of anticholinergic effects (e.g., dry mouth) or memory impairment. The safety profile of DXP 6 mg was comparable to that of PBO.

Conclusions

In elderly adults with insomnia, DXP 6 mg produced significant improvements in sleep maintenance, sleep duration, and sleep quality endpoints that were sustained throughout the trial. These data suggest that DXP 6 mg is effective for treating sleep maintenance insomnia and is well-tolerated in 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.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

Acknowledgement

This study (No. SP-0509) was fully-funded and supported by Somaxon Pharmaceuticals, Inc., San Diego, CA.

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