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Background: Doxepin is a tricyclic compound that has been used extensively for the treatment of depressive and anxiety disorders for approximately thirty years. It was noted early to have sedative effects and assist with the improvement of disrupted sleep patterns, but in higher antidepressant doses it was also noted to have significant anticholinergic and antinoradrenergic properties. These properties led to significant dose-limiting side effects, which at times precluded its effective use. Recently, doxepin has seen renewed interest in low doses as an H1 specific antagonist in sleep disorders., Objective: The review seeks systematically to examine currently published data on the use of doxepin for the treatment of insomnia, and its pharmacological basis., Methods: Medline articles showing from a search of 'doxepin and insomnia' were included in the review., Results/conclusion: Currently available data support the use of low-dose doxepin as preferential H1 antagonist for the treatment of primary insomnia. There are likely preferential effects upon sleep maintenance insomnia compared with sleep initiation given the role of histamine in the sleep-wake cycle.

1. Commercial doxepin contains geometric isomers in the proportions Z:E = 15:85. Z-doxepin and its metabolite Z-N-desmethyldoxepin are both active antidepressants, whereas the corresponding E-isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z:E = 15:85, whereas those of N-desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E-N-desmethyldoxepin.