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What to D.O.

Antidepressants an Ace in the Hole for Urticaria

Pescatore, Richard DO

Emergency Medicine News: July 2019 - Volume 41 - Issue 7 - p 8
doi: 10.1097/01.EEM.0000574796.76204.a0
    antidepressants, urticaria
    antidepressants, urticaria:
    antidepressants, urticaria

    The task of the emergency physician is foremost to stand as the first line and primary responder to life- and limb-threatening emergencies, but we are often faced with quite the opposite—a smoldering or chronic annoyance best left to the primary physician or specialist. Too often, patients present for longstanding complaints after weeks, months, or years of outpatient therapies and diagnostics have fallen short. They seek answers, cures, and compassion, but are typically met with only one of the three, at best.

    It may be antithetical to the crisis call that attracted so many of us to the field, but the ability to offer alternative, advanced, and evidence-based solutions where previous attempts have fallen short is an opportunity for a satisfying experience for patient and clinician alike. Our role as the health care safety net need not be reserved only for those without the means to access regular care; we can also be an informed and expert resource available when traditional routes fail.

    One relatively common but usually benign chronic complaint to darken our doorstep is the patient presenting with chronic or refractory urticaria—hives and itching not responding to topical or systemic therapies that have been recommended or prescribed by their primary physician or on previous emergency department visits. Characterized by the rapidity of its fluctuation, urticaria becomes chronic when wheals fluctuate for six weeks or more or refractory when it fails to respond to classic combination H-1/H-2 therapy.

    Our typical practice of antihistamines or glucocorticoids is met with angst as patients report no success despite multiple rounds of these medications, recommended again and again as the standard cure for urticaria. This is a frequent problem because nearly 40 percent of patients derive little or no relief from classic antihistamines. (Indian J Dermatol.2009;54[3]:275;

    Frustratingly Underutilized

    Understanding and using second-line therapies for refractory urticaria provide effective and satisfying options that have been frustratingly underutilized. The profound antihistamine activity of a number of medications can be harnessed to combat difficult urticaria. Doxepin, a tricyclic antidepressant with potent H-1 and H-2 antihistamine properties, has proven in several investigations to be more effective than diphenhydramine to treat stubborn hives.

    Mirtazapine, a noradrenergic antidepressant with antiserotonin and antihistamine activity, has significant effects on the H-1 receptor and antipruritic activity independent of its histamine activity. (Acta Derm Venereol. 2004;84[6]:482.)

    Doxepin has 800 times more antihistamine activity than diphenhydramine. (J Allergy Clin Immunol. 2011;128[6]:1139; Randomized, double-blind trials comparing it with conventional antihistamines have repeatedly demonstrated doxepin to have improved efficacy and fewer side effects. (J Am Acad Dermatol 1984;11[3]:483.)

    One blinded crossover among patients with chronic urticaria found that doxepin led to partial or total control of pruritus and hives in 74 percent of patients compared with only 10 percent of those receiving diphenhydramine, with fewer than half the sedating effects. (J Am Acad Dermatol. 1985;12[4]:669.)

    Frustratingly, few clinicians utilize doxepin despite guidelines and practice parameters detailing its efficacy and suitability. (Allergy 2014;69[7]:868; The stampede in medicine away from TCAs has clearly come with a cost, where appropriate use is forgotten among fears of ineffectiveness or toxicity.

    Excellent Safety Profile

    Mirtazapine is a newer noradrenergic and specific serotoninergic antidepressant that also has strong H-1-antihistamine properties with an excellent tolerability and safety profile. Several case reports and small trials demonstrated its efficacy in treating severe chronic urticaria, including one report where mirtazapine led to rapid resolution of hives that had shown no response to high doses of ebastine, fexofenadine, hydroxyzine, and cimetidine. (J Am Acad Dermatol 2005;53[5]:916;

    Another patient with refractory pruritus associated with cutaneous malignancy had rapid and sustained relief with mirtazapine, bolstering support for its role in palliative care when patients with progressed malignancies suffer from treatment-resistant pruritus or urticaria. (BMJ Support Palliat Care. 2016;6[1]:119.)

    When considered with multiple drug effects that can be beneficial in the late stages of malignancy, including its role as an antidepressant, orexigenic, and sleep aid, mirtazapine certainly has an important and effective role in refractory and malignancy-related pruritus and urticaria.

    Comfort and comprehension of advanced therapies for benign conditions are far from the siren call of emergency medicine, but such knowledge is endlessly valuable and enduringly useful when patients present having failed outpatient treatment. Doxepin and mirtazapine are excellent and efficacious options to obtain success and make a difference for patients.

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    Dr. Pescatoreis the director of emergency medicine research for the Crozer-Keystone Health System in Chester, PA. He is also the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine: Follow him on Twitter@Rick_Pescatore, and read his past columns at

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