Doxepin was well tolerated. Reported adverse events were mild or moderate. Headaches and somnolence were reported by >2% of patients. The incidence of adverse events, including next-day sedation, was similar to that of placebo. Additionally, there were no spontaneous reports of anticholinergic side effects, which are associated with higher doxepin doses.4
The second phase III trial examined safety and efficacy of 1, 3, and 6 mg doxepin in patients age ≥65.5 Seventy-six adults with primary insomnia were randomly assigned to receive placebo or doxepin for 2 nights; all patients received all treatments, and each treatment was followed by an 8-hour PSG. Patients taking any doxepin dose achieved objective and subjective improvement in sleep duration and sleep maintenance, which lasted into the final hours of the night. WTDS (primary study endpoint), WASO, TST, and overall SE improved at all doxepin doses compared with placebo, and WTAS and SE at hours 7 and 8 improved at doxepin doses of 3 mg and 6 mg compared with placebo. These findings suggest that doxepin, 3 mg and 6 mg, can help older insomnia patients with early morning awakenings.
In this study, no statistically significant differences were found among placebo and any doxepin doses on VAS, DSST, or SCT or next-day residual sedation. The incidence of side effects was low and similar to that of placebo. Adverse events were mild or moderate; 1 incident of chest pain was reported, but it was determined not to be of cardiac origin and not related to study drug. There were no spontaneous reports of anticholinergic side effects associated with higher doses of doxepin. There were no reports of memory impairment.5
Table 2
Evidence of effectiveness of doxepin for insomnia
| Study | Subjects | Dosages | Results |
|---|---|---|---|
| Roth et al, 20074; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 67 patients age 18 to 64 with chronic primary insomnia | 1, 3, or 6 mg given once daily at bedtime for 2 nights | Improvement vs placebo in PSG-defined WASO, TST, SE, and SE during the final third of the night. 6-mg dose significantly reduced subjective latency to sleep onset. Safety profile of all 3 doses was comparable to placebo. No difference in residual sedation |
| Scharf et al, 20085; phase III, randomized, multi-center, double-blind, placebo-controlled, 4-period crossover, dose-response study | 76 patients age ≥65 with primary insomnia | 1, 3, or 6 mg at bedtime for 2 nights | Reduction vs placebo in WTDS and WASO at all 3 doses. Increase in TST and SE at all 3 doses. No difference in number of awakenings after sleep onset and latency to persistent sleep at all 3 doses. WTAS was reduced only at 3 and 6 mg doses. Patient-reported WTAS was decreased at all doses. Patient-reported latency to sleep onset decreased only with 6 mg. Safety profile of all 3 doses was comparable to placebo and there were no differences among placebo and all 3 doses doxepin in next-day sleepiness or psychomotor function |
| PSG: polysomnography; SE: sleep efficiency; TST: total sleep time; WASO: wake after sleep onset; WTAS: wake time after sleep; WTDS: wake time during sleep Source: References 4,5 | |||
Tolerability
Clinical studies that evaluated the safety of doxepin lasted up to 3 months. Somnolence/sedation, nausea, and upper respiratory tract infection were reported by >2% of patients taking doxepin and were more common than in patients treated with placebo.1 All reported adverse events were mild to moderate.
Doxepin appears to be better tolerated at hypnotic doses (3 mg and 6 mg) than at antidepressant doses (50 to 300 mg/d), although direct comparative studies are not available.2,4,5 Additionally, psycho-motor function assessed using DSST and SCT and next-day sedation assessed using VAS in patients receiving hypnotic doses of doxepin (1 and 3 mg) were the same as placebo. Two studies noted small-to-modest decreases in DSST, SCT, and VAS when doxepin, 6 mg, was administered.1 Patients taking doxepin at antidepressant doses report significant anticholinergic side effects, including sedation, confusion, urinary retention, constipation, blurred vision, and dry mouth. Hypotension also has been reported at antidepressant doses, and there seems to be a dose-dependant cardiotoxicity, with higher incidence of adverse effects occurring at higher doses of the drug.
Severe toxicity or death from overdose is presumably less likely with hypnotic doses of doxepin than with higher doses, although this has not been systematically explored. If an insomniac overdosed on a 30-day supply of an hypnotic dose (3 or 6 mg), he or she would take only 90 to 180 mg of doxepin, which would be unlikely to cause severe toxicity or death.2-4