Arousability of insomnia patients and healthy volunteers is not impacted by the sleep-specific doses of doxepin (3 MG and 6 MG), but is impacted in healthy volunteers using zolpidem 10 MG.
Durrence H, Roth T, Tran KM, Singh M, Cheng P, Pillai V, and Drake C. Arousability of insomnia patients and healthy volunteers is not impacted by the sleep-specific doses of doxepin (3 MG and 6 MG), but is impacted in healthy volunteers using zolpidem 10 MG. Sleep 2016; 39:A201.
Ability to awaken to external or internal stimuli (arousability) is important. However, arousability is rarely assessed in evaluating hypnotics. An indirect approach to assessing arousability is examining sleep maintenance (SM) and relating wake-after-sleeponset (WASO) to number-of-awakenings (NAW). Decreased NAW reflects a drug's potential for blunting arousal response. Decreased WASO coupled with no decrease in NAW reflects ability to hasten return to sleep. To explore arousability, we evaluated the effects of doxepin (DXP; Silenor®) 3mg and 6mg (i.e. indicated for insomnia). Further, we directly evaluated Auditory Awakening Threshold (AAT) with DXP and zolpidem. Methods: Two placebo-controlled efficacy trials and an AAT trial are reported. Study A was a 12-week trial in elderly insomniacs (DXP 3mg); Study B was a 5-week trial in adult insomniacs (DXP 3mg and 6mg). Study C was a 4-way crossover trial assessing a single dose of DXP 6mg (DXP6), zolpidem 10mg (Z10) and placebo (2 placebo conditions). AAT was evaluated at the Tmax of each active medication and its corresponding placebo. Results: DXP 3mg (Study A and B; p < 0.0001) and 6 mg (Study B; p < 0.0001) significantly decreased WASO across the trials. Importantly, NAW were not decreased at any dose or time point in either study. In Study C, the AAT (expressed as dB) for Z10, was significantly higher (p < 0.0001) than both PBO groups and DXP6, with a mean dB level of 102 (DXP6 83dB, average placebo 81dB). Further, 24 Z10 subjects did not awaken at max AAT (110dB; 4 subjects in all 3 other groups). Conclusion: DXP (3mg, 6mg) improved WASO without altering NAW. Further, DXP6 did not impact AAT; in contrast Z10 increased arousal threshold. These data demonstrate that DXP improved SM without impacting arousability. Further research to determine if this more broadly reflects differences between drugs that work via the sleep (agonist) versus wake (antagonist) system.