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Low Dose Doxepin is Safe and Effective in Chronic Primary Insomnia Patients
Chronic insomnia is prevalent in almost 10% of the adult population, and primary insomnia has been estimated to occur in 25% of all chronic insomnia patients. Although sedative-hypnotics, such as benzodiazepines, are the mainstay in the short-term treatment of primary insomnia, long-term use of these drugs is discouraged due to the high risk of potential adverse drug effects like cognitive impairment, daytime sedation, motor incoordination, and increased risk of falls and accidents. Antidepressants have also been used for treating insomnia, usually in patients with associated psychiatric disorders. Now, Dr.Thomas Roth, at the Henry Ford Hospital Sleep Center, Detroit, USA, and colleagues have reported that Doxepin, a sedative antidepressant, improves sleep in patients with chronic primary insomnia (Sleep, 2007).
Roth et al evaluated the efficacy and safety of doxepin in 67 adults (aged 18-64 yrs) with chronic primary insomnia. Patients were assigned randomly to either doxepin (1 mg, 3 mg, and 6 mg) or a placebo in a crossover study. Patients were given a 5 day or a 12 day drug-free interval between two polysomnographic (PSG) assessments. PSG observations and patient reported measures of sleep were analyzed to assess efficacy of the drug. Adverse events during the treatment period and sedation were noted as measures of safety.
The results showed that the wake time during sleep was significantly reduced by doxepin (3mg and 6 mg) compared to placebo. PSG-defined wake after sleep onset, total sleep time, overall sleep efficiency (SE), and SE in the final third-of-night also significantly improved with all doses of doxepin. The subjective latency to sleep onset was significantly reduced by 6 mg of doxepin. In the safety assessment, all the doses of doxepin were found to be safe and no significant difference was noted in next day residual sedation, reported anticholinergic effects, or memory impairment. Also, the drug did not cause any significant change in the sleep architecture.
In a previous randomized, double-blind, and placebo-controlled trial involving patients with primary insomnia, Hajak et al (Journal of Clinical Psychiatry, 2001) observed that low doses of doxepin (25-50 mg for 4 weeks) were effective in improving sleep and working ability in chronic primary insomniacs. However, they also noted severe rebound insomnia (statistically significant in comparison to placebo) and drug-related side effects (increased liver enzymes, leucopenia, and thrombopenia).
Chronic insomnia is associated with loss of work-hours, frequent accidents, memory impairment, and a higher risk of depression. Doxepin is a drug with an unique potency and selectivity for antagonizing the histamine (H1) receptor at low doses. According to Rodenbeck et al (Psychopharmacology, 2003), the sleep-improving effects of doxepin are mediated at least in part by a normalization of the hypothalamic-pituitary-adrenal axis function.
Dr.Roth and his team have shown that doxepin at low doses (well below those used by Hajak et al) improves the objective and subjective sleep maintenance and duration endpoints that persist into the final sleep hours in patients with chronic primary insomnia, and is also well tolerated.