Doxepin
At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness. It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week). It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H receptor of the latter or may have to do with the use of optimal doses. Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H receptor blockade.
Hives
Treatment guidelines for the management of chronic hives have been published. According to the 2014 American practice parameters, treatment involves a step wise approach. Step 1 consists of second generation, H1 receptor blocking antihistamines. Systemic glucocorticoids can also be used for episodes of severe disease but should not be used for long term due to their long list of side effects. Step 2 consists of increasing the dose of the current antihistamine, adding other antihistamines, or adding a leukotriene receptor antagonist such as montelukast. Step 3 consists of adding or replacing the current treatment with hydroxyzine or doxepin. If the individual doesn't respond to steps 1–3 then they are considered to have refractory symptoms. At this point, anti-inflammatory medications (dapsone, sulfasalazine), immunosuppressants (cyclosporin, sirolimus) or other medications like omalizumab can be used. These options are explained in more detail below.