The Mechanism of Action – What Makes Silenor^® (doxepin) Unique

At the doses used in Silenor® (doxepin) (3 mg and 6 mg), doxepin’s most potent pharmacological response, histamine H1 blockade, appears to define the action of the drug. Doxepin has long been known as a potent H1 antagonist; receptor binding and functional studies conducted by Somaxon confirm that doxepin has high affinity at human H1 receptors and good selectivity against other central nervous system targets. The receptor binding profile of doxepin suggests that the drug is at least 10-fold more potent as an H1 antagonist than for its other clinically relevant targets. The potency of doxepin at the H1 receptor, coupled with its selectivity versus other central nervous system targets, makes this drug an ideal candidate for use in insomnia when used at low doses. Silenor’s low doses avoid much of the pharmacology of doxepin at antidepressant doses, as supported by the very low incidence of adverse events associated with Silenor.

Silenor Selectivity

Doxepin has activity at re-uptake sites for norepinephrine and serotonin, although it is essentially inactive at the dopamine transporter or at dopamine receptor subtypes studied to date. Studies conducted by Somaxon suggest little or no relevance for 5-HT or dopamine reuptake in the pharmacology of Silenor, although some functional role for the norepinephrine transporter cannot be definitively ruled out. The finding that doxepin is a functional antagonist at 5-HT2a sites suggests that this activity could play a role in doxepin’s sleep promoting effects, as this receptor has been proposed to contribute to the expression of restorative sleep.