Low-dose doxepin (3 and 6 mg) for the treatment of insomnia

Doxepin (Silenor (R)) is a tricyclic antidepressant with a subnanomolar affinity for the H-1 histamine receptor. Recent work has investigated its use at low doses (3 and 6 mg) in patients with primary insomnia. Many agents with H-1 activity have therapeutic limitations, including residual sedation, anticholinergic effects, rapid development of sedative tolerance and weight gain. Low-dose doxepin offers a unique combination of potency and selectivity for H-1, which may prove advantageous in the treatment of insomnia. This article reviews doxepin clinical trials in insomnia and discusses the potential role of this compound in clinical practice. Two Phase II studies and four Phase III studies have investigated low-dose doxepin's efficacy on sleep measures in adult and elderly patients. It was effective on a variety of sleep maintenance parameters with no change to sleep architecture. There was no signal for tolerance, psychomotor impairment, residual sedation, rebound insomnia or discontinuation symptoms. Adverse events were comparable with placebo, the most common being sedation/somnolence and headache. Selective H-1 antagonism is emerging as a novel approach to the treatment of insomnia without the limitation of tolerance, weight gain or the need for the restrictive prescription scheduling required of other hypnotics.