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.
A Country Doctor Writes: 
Thanks for your insightful piece. Would love to read any reflections on doxepin vs prazosin.
Thank you! I’m wondering what to do with a pt I recently inherited (I’m an NP at a public health clinic seeing mostly homeless-ish folks) who is extremely attached to his doxepin 150mg at night for insomnia & nightmares: soon after he arrived in town, he double-dosed on it, as he tends to take his meds as-needed aka as-wanted, & that combined with his other sedating meds was enough to land him in the ER with altered mental status. The ER docs told him, that’s it, no more doxepin ever. So he’s gone behind the back of our public heath clinic to find another source for it (he admitted this :). Personally, I think if he’s going to take it anyway, plus as far as he’s concerned it’s his one non-negotiable med, we should be the ones prescribing it & trying to monitor his use But that would involve my persuading the psychiatrist & pain doc to stop or decrease what they’re prescribing (too many cooks stirring the pot – that’s one way city medicine is different from country medicine!). It’s complicated.
I’ve had this before too. Make a deal you will still write it if you can short supply it (7 days) and restrict him to one pharmacy. Sometimes the insurance can be helpful with this. Explain its to help him not go “overboard “ but allow him to stay on this particular med. Good luck.
Thank you, Dr. DiLauro! I actually proposed exactly this to him, with weekly pick-up; I spoke first to both psychiatrist & pain doc & they d/c’d the sedating meds they were prescribing, both completely oblivious to the fact that he was also taking doxepin (Rx’d by his old doc in another state).
Unfortunately, he turned me down. But your suggestion is in line with the harm reduction approach we take with our patients. Btw, our psychiatric pharmacist tells me the dose he’s on is typically used for depression; he actually has complex PTSD.
so you want to continue prescribe a tricyclic antidepressant that this guy has already overdosed on once and admitted abuse…. send him to an actual physician please
Unhelpful and shame based.
“scarystupid” is a good name for someone so condescending.
10 mgm of elavil about 5 PM EST and a midnight sleepy time is awaited,
How do you feel about hydroxyzine? We see that much more often than Doxepine.
I had some weird itching of one toe a couple years ago that wouldn’t quit and wasn’t infectious. After topical steroid and Sarna didn’t help, my dermatologist gave me topical Doxepin. It helped.
I also use it to weight gain in depressed patients and the sedation is a good side effect for those having problems sleeping
How do you dose the doxipin? Once daily but how many mgs?
10-20 mg at bedtime.
What dose did you use? As the citation says, it is a selective H1 antagonist at low doses; supposedly the recommended doses for insomnia are 3mg and 6mg, but those doses are available only as brand-name Silenor for about $500 a month. Even topical doxepin can be sedating, so I worry about using the oral form at the generic doses of 5 to 50 times the doses advised for insomnia!
I have only used 10 to rarely 20 mg at bedtime
For this patient hydroxyzine 25 or 50 mg would also be a consideration in this pt due to its sedating effects. Often used in urticaria
I like the TCA’s for chronic pain, itching, insomnia, etc. They do have serious anticholinergic side effects and are deadly in overdoses. I use low dosages and I always get a EKG before I prescribe to look for conduction abnormalities.
As the Senior Consultant at the University of Wisconsin Headache Clinic, I found doxepin to be a highly effective treatment for chronic migraine, with far less anticholinergic effects than its more popular cousin, amitriptyline. Unfortunately, weight gain was predictable and often severe, and sedation was similar to that seen with amitriptyline
As Artie Johnson would say” Very interesting”. Low dose (<6mg) doxepine is not on the BEERS List where as any dose of Diphenhydramine is.
Doxepin when used at 10 mg Q daily or greater for greater than 2-3 years has a 50% risk of Alzheimer’s.
Please show me your reference.
@gerard the psychiatric pharmacists where i work (primary care site within a public mental health clinic) tell me the dose for depression is typically 75-150mg/day
Yes that’s what I was taught. But sleep and hives is different. Like amitriptyline for depression was 150 but sleep and neuropathy a lot less.
Risk? No. Association? Perhaps. Long term anticholinergics and PPI’s have some association with Alzheimer’s, but there is no provable causative relationship.
Great article – thank you for sharing. I am definitely going to use this one !
Silenor (Doxepin in tablet form at 3 & 6 mg strength) is FDA approved for treament of Insomnia. Works well for sleep maintenance insomnia (together with CBT-I i.e. cognitive behavioral therapy for Insomnia) .However Retail price circa $479 & $514 for the 2 dose forms respectively. My practice is limited to Sleep disorders & I frequently use Doxepin 10mg/ml. Have it dispensed with a 1ml syringe with instructions to titrate 3 to 6 mg in 1 mg increments/week (0.3ml to 0.6ml) & stop at effective dose. Comes as a 120mL bottle at a cost of around $27 and would be a 3 months supply!
Works through the H1 blocking effect (as noted above Histamine is a CNS stimulant) that results in the sedating effects. Safe in elderly too at these doses & should not need higher doses as Rx for Insomnia.
Thank you for this very useful post. I will make use of this information with my patients. Especially appreciate the info on how to rx doxepin low-dose for sleep, which I had tried to do years ago but gave up the attempt due to exorbitant cost of the 3mg and 6mg pills.