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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 writesControlled-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.

The Art of Clinical Decision Making: Friday Afternoon Dilemmas

The woman had a bleeding ulcer and required a blood transfusion. The hospital discharge summary said to see me in three days for a repeat CBC. But she had a late Friday appointment and there was no way we would get a result before the end of the day. She also had developed diarrhea on her pantoprazole and had stopped the medication. As if that wasn’t enough, her right lower leg was swollen and painful. She had been bed bound for a couple of days in the hospital and sedentary at home after discharge.

She could still be bleeding and she could have a blood clot. There were no openings for an ultrasound until almost a week later. Normally, with the modern blood thinners, we can just start anticoagulation until the diagnosis of a blood clot can be confirmed or disproven. But you don’t do that when somebody has a bleeding ulcer.

The radiology department solved my dilemma by pointing out that the emergency room can order an ultrasound and the department will call in an on-call technician. So that is where my patient had to go. Her blood count was stable and the ultrasound was negative. So now we just have to hope that lansoprazole, which she had taken in the past, but stopped because she didn’t have heartburn, would be effective.

Not long ago, a Friday evening telephone call from a patient with severe nasal pain and a clear discharge after a Covid swab made me think she might have a cerebrospinal fluid leak. She, too, went to the emergency room on my recommendation.

Sometimes I over-explain the reasons I recommend the ER. I will list the types of tests that could help make the diagnosis, the patient only hears “head CT” or “wrist X-ray” and shows up at radiology with no order.

In this part of the country, with sketchy cell phone reception and people not always equipped with land line answering machines, let alone cell phone voice mail, I don’t want to have someone get an imaging test done and be on their way home when I get an abnormal result without being able to reach the patient. I’ve been burned before. And writing “WET READ, PLEASE” doesn’t always result in a call while the patient is still at the hospital.

As so often in medicine, getting the test is only the first step, then there are decisions, interventions and patient education to handle.


Osler said “Listen to your patient, he is telling you the diagnosis”. Duvefelt says “Listen to your patient, he is telling you what kind of doctor he needs you to be”.

BOOKS BY HANS DUVEFELT, MD

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