Histamine-1 receptor antagonism for treatment of insomnia

To evaluate the literature regarding the use of histamine-1 (H(1)) receptor antagonists and to describe their role in the treatment of insomnia in adult patients, including the elderly.

Literature was identified via PubMed and Medline through April 1, 2012, using the search terms insomnia and sleep, each individually combined with histamine antagonist, tricyclic antidepressant, trazodone, mirtazapine, doxepin, amitriptyline, nortriptyline, trimipramine, doxylamine, diphenhydramine, and antihistamine.

Data included randomized double-blind trials that statistically evaluated H(1) receptor antagonist treatment in patients with insomnia compared with a placebo control or Food and Drug Administration-approved insomnia treatment. Trials selected evaluated sleep latency, wake after sleep onset, total sleep time, number of awakenings, and/or sleep efficiency in a subjective or objective manner. A total of 65 trials were evaluated, and 16 met inclusion criteria.

With the exception of low-dose doxepin (Silenor-Somaxon), trials evaluating the clinical effectiveness of H(1) receptor antagonists show mixed results and are limited by sample size and generalizability. Large, randomized, appropriately controlled trials are lacking, making it difficult to define the safety and efficacy of these agents. In contrast, low-dose doxepin has been shown to provide consistent sleep benefit compared with placebo.

Over-the-counter antihistamines may have a role for short-term insomnia treatment in younger adults, but tolerance develops rapidly. Mirtazapine should not be used solely for the treatment of insomnia. Sedating antidepressants can be considered after failure of first-line insomnia treatments. Patients taking these agents chronically should be evaluated for continued efficacy and potential harm. Low-dose doxepin may have a unique role in the treatment of insomnia in elderly patients given its tolerability, documented efficacy, and lack of important adverse effects.