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Carvedilol for the Treatment of Refractory Facial Flushing and Persistent Erythema of Rosacea

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Carvedilol for the Treatment of Refractory Facial Flushing and Persistent Erythema of Rosacea THE CUTTING EDGE: CHALLENGES IN MEDICAL AND SURGICAL THERAPIES SECTION EDITOR: EDWARD W. COWEN, MD, MHSc; ASSISTANT SECTION EDITORS: MURAD ALAM, MD; WILLIAM D. AUGHENBAUGH, MD ONLINE FIRST Carvedilol for the Treatment of Refractory Facial Flushing and Persistent Erythema of Rosacea Chia-Chi Hsu, MD; J. Yu-Yun Lee, MD; Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan Rosacea is a common facial disorder characterized by cen- trofacial erythema, flushing, telangiectasia, edema, pap- ules, pustules, ocular lesions, and rhinophyma in vari- ous combinations.1-4 The skin lesions most commonly affect the convex areas of the nose, cheeks, chin, and fore- head. Rosacea is classified as erythematotelangiectatic (ETR), papulopustular, and phymatous subtypes, and as ocular and granulomatous variants.2-4 The ETR subtype is typified by frequent episodes of facial flushing, telan- giectasias, and persistent centrofacial erythema and may be accompanied by facial edema, burning, or stinging. Severe flushing can cause significant physical discom- fort and emotional stress to the patients, and currently no satisfactory treatments are available. REPORT OF A CASE A48-year-oldwomanpresentedwithfacialflushingwith persistent erythema, and edema accompanied by burn- ing and itchy sensation that were provoked by various Figure 1. Severe erythematotelangiectatic rosacea before carvedilol stimuli, including heat, sun exposure, cold weather, stress, treatment. spicy food, alcohol, and cosmetics. She began to have fa- cial flushing and erythema about 11 years previously, shortly after glycolic acid treatments on the face. Since so many triggering or aggravating factors that she had then, she had visited many dermatology clinics for help, to avoid. She also experienced chronic insomnia and con- and despite treatments with doxycycline, fexofenadine stipation. In March 2009, she came to us for help. Ex- hydrochloride, cetirizine hydrochloride, low-dose pred- amination revealed diffuse fiery red erythema of the cheeks nisolone, topical corticosteroid preparations, metroni- and some background atrophy and telangiectasia of the dazole gel, and pimecrolimus cream in various combi- skin (Figure 1). She was otherwise in good health. Labo- nations, there were only partial beneficial effects. Topical ratory tests, including hemogram and antinuclear anti- and systemic corticosteroids provided better control, but body test, showed no abnormal findings. The clinical di- symptoms would flare or rebound when these treat- agnosis was severe rosacea with a component of steroid ments were discontinued. rosacea. The patient underwent bilateral endoscopic thoracic Despite 4 weeks of treatment consisting of doxycy- sympathectomy for the severe ETR 8 years previously. cline, fexofenadine hydrochloride (60 mg twice a day), The facial symptoms showed a moderate improvement dexamethasone (5 mg/d), aspirin (100 mg/d), clonidine after sympathectomy. But about half a year later, she be- hydrochloride (0.15 mg 3 times a day), and topical hy- gan to experience severe compensatory hyperhidrosis over drocortisone ointment, 1%, and pimecrolimus cream, 1%, the back and legs that necessitated a change of clothing there was only slight clinical improvement. Her face re- up to 6 times per day in summertime. Meanwhile, the mained very warm and red. The temperature of her cheek facial erythema and flushing persisted, and to treat it she was 37°C (ear temperature, 36.3°C). received stellate ganglion block periodically along with oral clonidine hydrochloride, 0.15 mg 3 times daily, for THERAPEUTIC CHALLENGE the next few years. Despite these treatments, she still had a severe hot flush with a burning sensation and persis- Many treatment options are available for rosacea and pro- tent facial erythema that required consistent air condi- vide varying degrees of success,5-12 including topical met- tioning or a fan blowing to the face even in bed. More- ronidazole, oral tetracyclines, azithromycin, ␤-adrener- over, her daily life was very much restricted because of gic blockers,5,6 clonidine,7,8 naloxone hydrochloride,9 ARCH DERMATOL/ VOL 147 (NO. 11), NOV 2011 WWW.ARCHDERMATOL.COM 1258 Downloaded from www.archdermatol.com at , on November 22, 2011 ©2011 American Medical Association. All rights reserved. Figure 2. Dramatic clinical improvement after adding carvedilol, 6.25 mg Figure 3. Minimal facial erythema while maintaining therapy with carvedilol, twice daily for 1 week and 3 times daily for the next week. 6.25 mg 1 to 3 times a day for 16 months. ondansetron hydrochloride,10 as well as vascular laser to 35.9°C. The patient’s own assessment of the clinical therapy and endoscopic thoracic sympathectomy.11,12 severity based on a 10-point visual analog score showed However, severe ETR often responds poorly to treat- a reduction of 9 points (from 10 to 1). Her blood pres- ment. The facial flushing, persistent erythema, and dis- sure was reduced from 130/70 mm Hg to 110/60 mm Hg. comfort (burning and itchiness) in our patient were very The symptoms of ETR continued to improve with mini- severe and proved refractory to many of the aforemen- mal facial erythema and only transient flushing episodi- tioned therapies over the course of 11 years. She was in cally without a hot or burning sensation (Figure 3). We desperate need of a more effective treatment to relieve were able to taper and eventually discontinue her fexof- her severe physical and emotional stresses. enadine, dexamethasone, and aspirin in 2 months. As of March 2011, the patient was receiving maintenance SOLUTION therapy of carvedilol (6.25 mg 1-3 times a day), doxy- cycline (100 mg every other day to once a day), and topi- The traditional ␤ blockers nadolol5 and propranolol hy- cal pimecrolimus, 1%, for 23 months without adverse ef- drochloride6 can suppress flushing reactions in some pa- fects. She needed to take only 6.25 mg daily in tients, particularly when associated with anxiety.6 Be- summertime when she could use an air conditioner or cause patients with ETR are often normotensive, some was able to dissipate the body heat by sweating. The pa- patients are less able to tolerate the hypotension and bra- tient was extremely satisfied with this new treatment. dycardia caused by these traditional ␤-blockers. This prob- lem prompted us to find other ␤-blockers that might have COMMENT less hypotensive adverse effects. The frequency of hypo- tension during carvedilol, atenolol, and nadolol therapy Rosacea flushing is often difficult to control by standard for hypertension was 1.8%, 4%, and 1%, respec- treatments for rosacea. Wilkin7 reported that clonidine tively.13-15 Carvedilol is also approved for treating mild- (␣-adrenergic agonist) reduced the malar temperature in to-moderate congestive heart failure and in a study16 was patients with ETR, despite no improvement of redness well tolerated even in elderly patients with low rates of after provocative maneuvers. Although ␤-blockers have hypotension (3.3%) and bradycardia (1.7%). Our pa- not demonstrated objective laboratory evidence for di- tient agreed to have carvedilol added to her current medi- rect effects on cutaneous blood vessels during flushing cations after being informed about the potential adverse episodes, fewer symptoms have been noted in some pa- effects. Carvedilol, 6.25 mg twice a day, was prescribed tients.5,6 The mechanism of ␤ blockers in treating ETR for the first week, followed by 3 times a day thereafter. may be by way of blocking the ␤2-adrenergic receptor on She monitored her blood pressure and pulse rate regu- the smooth muscle of cutaneous arterial blood vessels, larly at home, and no hypotension or bradycardia was resulting in vasoconstriction.4 Moreover, nonselective ␤- noted. blockers also reduce the symptoms of anxiety and tachy- A dramatic improvement in the erythema and telan- cardia that often intensify flushing symptoms.5,6 Carve- giectasia was noted in 2 weeks (Figure 2). The tem- dilol is a nonselective ␤-adrenergic blocking agent with peratures of the cheek and ear were measured before and ␣1-blocking activity and has a ratio of ␣1- to ␤-adreno- after carvedilol treatment. The patient’s cheek tempera- receptor blockade of 1:10.17 For reducing blood pres- ture was reduced by 6.9°C (from 36.9°C to 30.0°C). The sure in patients with mild to moderate hypertension, corresponding ear temperature decreased from 36.2°C carvedilol, 50 mg twice daily, was as effective as pro- ARCH DERMATOL/ VOL 147 (NO. 11), NOV 2011 WWW.ARCHDERMATOL.COM 1259 Downloaded from www.archdermatol.com at , on November 22, 2011 ©2011 American Medical Association. All rights reserved. 17 pranolol hydrochloride, 80 mg twice daily. For facial REFERENCES flushing, the dose of propranolol hydrochloride needed to achieve symptomatic control varied from 20 to 40 mg 1. Crawford GH, Pelle MT, James WD. Rosacea, I: etiology, pathogenesis, and sub- 6 taken 2 to 3 times a day. In our patient, a low dose of type classification. JAmAcadDermatol.2004;51(3):327-341. carvedilol was very effective in treating ETR, with fast 2. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of onset of symptom control. It also allowed tapering and the National Rosacea Society expert committee on the classification and staging eventual cessation of her long-term oral and topical cor- of rosacea. JAmAcadDermatol.2002;46(4):584-587. ticosteroid therapy. She felt that a maintenance therapy 3. Wilkin J, Dahl M, Detmar M, et al; National Rosacea Society Expert Committee. Standard grading system for rosacea: report of the National Rosacea Society Ex- with carvedilol was necessary for control of her facial pert Committee on the classification and staging of rosacea. JAmAcadDermatol. symptoms. 2004;50(6):907-912. Low-dose carvedilol therapy in the present case rep- 4. Lee JY. Rosacea: clinical aspects, pathogenesis and treatment. Dermatol Sinica. resents a novel use of this drug, and the positive effect 2005;23(3):121-130. suggests that carvedilol may be an effective alternative 5.
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