The Mechanism of Action – What Makes SILENOR™ (doxepin HCl tablets) Unique

The human sleep/wake cycle is believed to be governed by two opposing drives: a waking drive that is strongest during the day, and a sleep drive that is strongest at night. Consequently, there are two general ways to improve sleep: increase the drive for sleep or decrease the drive for wakefulness. Both of these drives are impacted by neurotransmitter activity in the brain that fluctuates throughout each 24-hour period. Most of the currently available products that treat insomnia non-selectively increase the sleep drive through mediation of neurotransmitters that act upon the GABA receptor complex in the central nervous system. In contrast, it is thought that SILENOR™ improves sleep predominantly through decreasing the drive for wakefulness by selectively blocking the waking neurotransmitter, histamine.

There is evidence in both animals and humans that histamine release is a key element in maintaining wakefulness. SILENOR™ is a histamine blocker that is more potent than other commonly known histamine-blocking drugs. For example, SILENOR™ is many hundred-fold more potent than Benadryl®. In contrast to the higher does of doxepin (the active ingredient in SILENOR™) used for the treatment of depression (75mg – 300mg), the low dose used in SILENOR™ (1 mg – 6 mg) appears to selectively affect the histamine system without any clinically relevant activity upon other waking neurotransmitter systems. We believe that this relative selectivity for histamine may explain important aspects of the clinical profile we’ve seen with SILENOR™; in particular, in our clinical trials, SILENOR™ patients generally did not exhibit the side effects associated with higher doses of doxepin and other antihistamine products, including anticholinergic effects such as dry mouth, dry eyes, and constipation. SILENOR™, because of its selective activity, may represent a highly directed therapy that promotes and maintains sleep while leaving cognitive and psychomotor functions intact the next morning.