Doxepin, a Little Known Super Drug in My Personal Black Bag of Tricks


A while back I was able to completely stop my mastocytosis patient’s chronic hives, which the allergist had been unable to control.

I did it with a drug that has been on the market since 1969 and is taken once a day at a cost of 40 cents per capsule at Walmart pharmacies.

Hives are usually treated with antihistamines like diphenhydramine (Benadryl). My super drug has a 24 hour duration of effect and is about 800 times more potent than diphenhydramine, which has to be taken every fours hours around the clock.

Histamine is involved in allergic reactions, but it also plays a role in stomach acid production. The allergic response happens mostly through stimulation of Histamine 1 receptors and the stomach acid output is regulated mostly via Histamine 2 receptors. Typical antihistamines are blockers of the H1 receptor, or binding site; they don’t do anything except sit there and prevent the real histamine from attaching and starting the allergic chain reaction. While diphenhydramine sits there for 4 hours, loratadine and the other modern, nonsedating (and less itch-decreasing) antihistamines work for 24 hours. Because there is some overlap between H1 and H2 blocking effects, H2 blockers like famotidine can boost the antiallergy effect of the typical H1 blockers. My mastocytosis patient still had hives on diphenhydramine, loratadine and famotidine combined.

But, wait, there’s more…

A much less well known effect of H1 receptor stimulation happens in the central nervous system. An interesting 2013 article explains:

Histamine is an excitatory neurotransmitter in [the] central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressants with sleep-promoting effects, for example, doxepin, promote sleep not through a sedative action but through resynchronisation of [the] circadian cycle. The stimulation of the H1 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the H1 receptor, making it a selective H1 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressants, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients.

American Family Physician writes “Controlled-release melatonin and doxepin are recommended as first-line agents in older adults.” Yet, at least in this country, trazodone is much more commonly used, even though it is less specific in how it helps people sleep.

Doxepin definitely deserves more attention than it is getting.

Hans Duvefelt is a Swedish-born rural Family Physician in Maine. This post originally appeared on his blog, A Country Doctor Writes, here.

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2 replies »

  1. I have the script but am afraid to try it. You know how mast cells can be.

  2. Sadly, another antihistamine with unique attributes for this and many other uses is no longer available, for a long time. Hydroxyzine was a casualty of the unique pharmaceutical business model afflicting our nation’s healthcare.
    Mastocytosis is an unusual hereditary condition involving mast cells, a unique participant of each person’s immune tolerance “apparatus”. It has some odd ways of presenting itself, benefiting from vigilant Primary Healthcare. Kudos to Hans.