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Flushing
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Flushing is defined as visible reddening of the skin over the face, neck, upper portion of the chest, and upper limbs, in association with the sensation of warmth.
Management Strategy
The initial step in the management of a patient with a flushing disorder is to make a specific diagnosis. The first algorithmic step is to distinguish between autonomic neurally-mediated flushing, in which eccrine sweating occurs at the time of the flushing (‘wet flushing’), and direct vasodilator-mediated flushing, in which there is no accompanying eccrine sweating (‘dry flushing’). The dry flushing reactions are further divided into those with prominent dysesthesia and those without.
The most common form of ‘wet flushing’ is thermoregulatory flushing resulting from exercise and/or exogenous heat. A simple measure such as ice chip therapy, as in holding an ice chip in the mouth, can quickly achieve control. Climacteric flushing in women is associated with inappropriate thermoregulation. Hormone replacement therapy is considered the mainstay of treatment. The second major form of ‘wet flushing’ is emotional flushing, which can be managed with oral β-blockers, such as nadolol 40 mg every morning or propranolol between 20 mg and 40 mg twice to three times daily.
The ‘dry flushing’ without dysesthesia is caused by either exogenous or endogenous circulating agents that directly work on the vascular smooth muscle to induce vasodilation. A high-dose nicotinic acid early in the course of therapy for hyperlipidemia can provoke dry flushing. These flushing events can be ameliorated by simultaneous administration of aspirin. All calcium channel blockers can induce flushing as a side effect. An organic nitrate, such as nitroglycerin, can provoke flushing, followed by tolerance after the first week of therapy. Capsaicin in spicy foods, sodium nitrite in cured meats, and sulfites in salads and wines can provoke dry flushing. Alcohol-induced flushing in Asians can be prophylactically addressed with oral administration of aspirin 0.64 g or a combination of H 1 - and H 2 -antihistamines, 50 mg diphenhydramine and 300 mg cimetidine, respectively.
Endogenous circulating agents from underlying malignancies can induce flushing in association with other prominent features. Itching and urticaria should trigger a laboratory work-up for systemic mastocytosis. Flushing following hypertension, pallor, tachycardia, palpitations, and sweating should prompt an investigation for pheochromocytoma. Flushing with diarrhea should encourage a diagnostic test for carcinoid syndrome. Rare malignancies such as renal cell carcinoma, pancreatic cell carcinoma, and medullary thyroid carcinoma should always be on the differential diagnoses as well.
Specific Investigations
First-Line Therapies
Combined versus sequential hormone replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures
Bech P, Munk-Jensen N, Obel EB, et al. Psychother Psychosom 1998; 67: 259–65.
Continuous combined therapy of 2 mg oestradiol (E 2 ) and 1 mg norethisterone acetate (NETA) daily and sequential therapy of E 2 and NETA were both superior to placebo on the Kupperman scale of sweating, hot flushing, myalgia, and vertigo in 105 normal early postmenopausal women.
Even though hormone replacement therapy is the first-line therapy, contraindications can preclude use of this therapy in many women.
Randomized controlled trial of different aspirin regimens for reduction of niacin-induced flushing
Banka SS, Thachil R, Levine A, et al. Am J Health Syst Pharm 2017; 74: 898–903.
Simultaneous administration of aspirin and niacin reduced moderate-to-severe flushing events by a mean of 36.1% in a cohort of healthy adult volunteers.
Aspirin attenuation of alcohol-induced flushing and intoxication in Oriental and Occidental subjects
Truitt EB Jr, Gaynor CR, Mehl DL. Alcohol Alcohol Suppl 1987; 1: 595–9.
A group of 11 Oriental and Occidental subjects with histories of alcohol-induced flushing was compared to a similar ethnic group of non-flushing subjects. Prophylactic administration of oral aspirin 0.64 g 1-h prior significantly reduced facial flushing in the flushing group.
Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study
Layton AM, Schaller M, Homey B, et al. J Eur Acad Dermatol Venereol 2015; 29: 2405–10.
The brimonidine group (once-daily application of brimonidine gel 0.33%) reported significant improvement in patient-reported outcomes on facial redness after 8 days, in comparison to the vehicle group.
Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies
Fowler J Jr, Jackson M, Moore A, et al. J Drugs Dermatol 2013; 12: 650–6.
Once-daily brimonidine tartrate application significantly improved severity of erythema based on Clinician’s Erythema Assessment and patient’s self-assessment, as compared with vehicle application.
Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study
Moore A, Kempers S, Murakawa G, et al. J Drugs Dermatol 2014; 13: 56–61.
Once-daily brimonidine tartrate gel 0.5% for 1 year, equivalent to 345 subject years of exposure, demonstrated similar safety profile, as compared with vehicle. In addition, the durability of the therapeutic effects was maintained without tachyphylaxis in the brimonidine group.
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