Topically Applied Midodrine, 0.2%, an Α1-Agonist, for the Treatment Of

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RESEARCH LETTER Table. Summary of Data for 12 Patients

Characteristic No. (%) Topically Applied Midodrine, 0.2%, an α1-Agonist, for the Treatment of Erythromelalgia Age, mean (range), y 57 (26-79) We report the response of patients with erythromelalgia to topi- Female sex 9 (75) a cal midodrine hydrochloride, an α1-agonist. Erythromelalgia White race 11 (92) is a rare syndrome characterized by red, hot, painful feet and Pain level before medicationb hands, sometimes extending proximally. Episodes are gener- Severe 10 (83) ally intermittent, lasting from minutes to hours, but can be Moderate 1 (8) 1 continuous. Although numerous therapeutic regimens have Range of improvement (relief) 2 been described, none is universally effective. Since symp- Complete 0 toms are generally localized, topical treatments might be pref- Substantial 4 (33) 3-5 erable to avoid systemic adverse effects. Some 7 (58) Among the proposed mechanisms for erythromelalgia is None 1 (8) local vasodilatation since increased blood flow has been ob- Worsening of symptoms 0 served in Doppler studies. During symptoms, we have noted Adverse effects of midodrine hydrochloride, 2% that the mean temperature of the toe skin increased by 7.8°C, Nonspecific gastrointestinal tract discomfort 1 (8) and blood flow increased 10.2-fold.1,4 Increase in blood pressurec 1(8) Because vasodilatation may account for the flushing dur- Prior treatment ing an episode, the use of a vasoconstrictor seems reason- Gabapentin 4 (33) able. We hypothesized that midodrine, a vasoactive drug that Trazodone hydrochloride 1 (8) causes vasoconstriction, might be effective. Midodrine, a Combination gel amitriptyline, 2%, and ketamine, 0.5% 9 (75) peripherally acting α1-agonist, activates the α-adrenergic receptors of vessels, resulting in increased vascular tone and a The race/ethnicity of 1 patient (8%) was unknown. reduced blood volume. A patient with erythromelalgia b The level of pain was not documented for 1 patient (8%). responding to oral midodrine has been reported.6 c The increase was documented in 1 of 2 patients whose blood pressure was We used a topical preparation of midodrine for the man- measured consistently. agement of erythromelalgia. We then reviewed reported out- comes among patients with erythromelalgia who received was defined for the purposes of the study, and the data were treatment with topically applied midodrine, 0.2%. derived from interpretation of descriptions in the medical record of how patients reported responding to midodrine, 0.2%. Methods | This study was conducted from November 1, 2011, Further information was obtained from documentation of to November 1, 2013, and was approved by the Mayo Clinic follow-up visits to the department of dermatology after use of Institutional Review Board. Participants were patients in the midodrine, 0.2%. Blood pressure was monitored in 2 patients Department of Dermatology at Mayo Clinic in Rochester, before and after midodrine was prescribed. Minnesota, and provided written informed consent. The clini- cal diagnosis was erythromelalgia; midodrine, 0.2%, was to be Results | Topical midodrine, 0.2%, was prescribed for 12 pa- applied topically, and patients were available for follow-up. tients with erythromelalgia (Table). Most patients had re- Erythromelalgia was defined as the occurrence of red, hot, pain- ceived previously prescribed treatments with no substantial ful feet or hands. Midodrine, 0.2%, in a moisturizing skin cream improvement. Of the 2 patients whose blood pressure was (Vanicream) was compounded at the Mayo Clinic pharmacy and monitored before and after application of midodrine, 0.2%, pre- applied topically 3 times daily during symptoms. scription, 1 had no significant changes, but the other had an After the diagnosis was confirmed, data were abstracted increase in blood pressure. Ten patients (83%) responded to on demographics, adverse effects, and pain level before treat- therapy within minutes (not quantified). ment. Using a verbal rating scale, the patient chose words to describe the sensory qualities of the pain and the overall ex- Discussion | In this study, we summarized self-reported re- perience of the pain. Each word chosen was assigned a rank sponses to a topical preparation of midodrine, 0.2%, that was value and these values were used to determine the pain rat- used as needed. All but 1 patient reported improvement. Topi- ing index that ranges from 0 (no pain) to 5 (excruciating pain). cal midodrine, 0.2%, was well tolerated; only 2 of the 12 pa- Response to medication was graded as complete relief, sub- tients (17%) reported adverse effects. stantial relief (≥50% relief or marked relief), some relief (<50% This study had limitations. The sample with available relief), no change, or worsening of symptoms. The grading scale follow-up was small, available follow-up was documented in

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the medical record but was not standardized, the follow-up multibacillary leprosy and recurrent ENL (recurrence 6 weeks criterion of interest was “general improvement” in erythro- after stopping treatment for ENL)3 or chronic ENL (lasting melalgia without obtaining further details, and many >24 weeks)2 were recruited after providing written informed patients were using other medications. Nonetheless, these consent. Patients who were pregnant, had comorbid condi- results suggest that a topical preparation of midodrine, 0.2%, tions, or were allergic to tetracyclines were excluded. is well tolerated and improves symptoms of erythromelalgia. All patients were corticosteroid dependent and did not re- Further investigation is warranted. spond to corticosteroid-sparing agents for almost 18 months, when used alone or in combination (clofazimine, 100 mg, Mark D. P. Davis, MD 3 times a day for 3 months; pentoxifylline, 800 mg, 3 times a Claudia S. Morr, MD day for 3 months; colchicine, 1.5 mg/d, for 3 months; azathio- Roger A. Warndahl, BS Pharm prine, 100-150 mg/d, for 3 months; and hydroxychloroquine, Paola Sandroni, MD, PhD 400 mg/d, for 6 months). Episodes of ENL generally recurred when the prednisolone dose was tapered below 40 mg. Author Affiliations: Department of Dermatology, Mayo Clinic, Rochester, Minocycline, 100 mg/d, was initiated for up to 3 months Minnesota (Davis, Morr); Pharmacy Services, Mayo Clinic, Rochester, Minnesota along with gradual tapering of the prednisolone regimen to dis- (Warndahl); Department of Neurology, Mayo Clinic, Rochester, Minnesota (Sandroni). continuation. No other concomitant drug was administered. Accepted for Publication: February 18, 2015. Baseline tests consisted of complete blood cell count, liver func- Corresponding Author: Mark D. P. Davis, MD, Department of Dermatology, tion, renal function, and antinuclear antibody, as well as chest Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). radiography and ultrasonography of the abdomen. The com- Published Online: May 6, 2015. doi:10.1001/jamadermatol.2015.0511. plete blood cell count, liver function tests, and renal function Author Contributions: Drs Davis and Morr had full access to all the data in the tests were subsequently repeated at 3 and 6 months. study and take responsibility for the integrity of the data and the accuracy of the data analysis. Results | The clinicoepidemiologic profile of the patients is in Study concept and design: Davis, Sandroni. Acquisition, analysis, or interpretation of data: Davis, Morr, Warndahl. the Table. All patients had a bacterial index greater than Drafting of the manuscript: Davis, Morr. 2 after successful completion of 1 year of World Health Critical revision of the manuscript for important intellectual content: Davis, Organization–recommended multidrug therapy for multibac- Warndahl, Sandroni. illary leprosy. Five patients had recurrent ENL, 4 had chronic Statistical analysis: Davis, Morr. Obtained funding: Davis. corticosteroid-dependent ENL, and 1 had chronic corticoste- Administrative, technical, or material support: Davis, Warndahl. roid- and thalidomide-dependent ENL. Four of the patients Study supervision: Davis, Sandroni. with chronic ENL had arthritis, 3 had acute neuritis, 2 had epi- Conflict of Interest Disclosures: None reported didymo-orchitis, and 1 had lymphadenitis. The prednisolone 1. Davis MD, Sandroni P, Rooke TW, Low PA. Erythromelalgia: vasculopathy, regimen was able to be tapered, without relapse, in 3 patients neuropathy, or both? a prospective study of vascular and neurophysiologic after 4 weeks of minocycline treatment and in 5 patients after studies in erythromelalgia. Arch Dermatol. 2003;139(10):1337-1343. 8 weeks of minocycline treatment. Prednisolone treatment was 2. Davis MD, O’Fallon WM, Rogers RS III, Rooke TW. Natural history of erythromelalgia: presentation and outcome in 168 patients. Arch Dermatol. stopped in these 8 patients after 16 to 18 weeks of tapering. Dur- 2000;136(3):330-336. ing 1 year of follow-up, only 2 patients had recurrence of mild 3. Kalava K, Roberts C, Adair JD, Raman V. Response of primary erythromelalgia ENL, which responded to rest and paracetamol (acetamino- to pregabalin therapy. J Clin Rheumatol. 2013;19(5):284-285. phen). On average, there was a decrease in the bacterial in- 4. Poterucha TJ, Weiss WT, Warndahl RA, et al. Topical amitriptyline combined dex by at least 1 log during 1 year of follow-up. Except for with ketamine for the treatment of erythromelalgia: a retrospective study of 36 hyperpigmentation (Figure), gastric pain (2 patients), vomit- patients at Mayo Clinic. J Drugs Dermatol. 2013;12(3):308-310. ing (1 patient), and mild transaminitis (1 patient), no other 5. Sandroni P, Davis MD. Combination gel of 1% amitriptyline and 0.5% ketamine to treat refractory erythromelalgia pain: a new treatment option? adverse effects were observed. Arch Dermatol. 2006;142(3):283-286. 6. Sakakibara R, Fukutake T, Kita K, Hattori T. Treatment of primary Discussion | Minocycline is a second-line antileprosy drug. erythromelalgia with cyproheptadine. J Auton Nerv Syst. 1996;58(1-2):121-122. Besides having antimicrobial activity, it possesses anti- inflammatory and anti-apoptotic properties and causes inhi- Minocycline for Recurrent and/or Chronic Erythema bition of proteolysis, angiogenesis, and collagenase.4,5 Focal Nodosum Leprosum or systemic coinfections have been suggested as a possible risk Erythema nodosum leprosum (ENL) is an immune-mediated factor for the development of leprosy reaction.1 Itcanbehy- complication of leprosy, with an overall prevalence of 24% to pothesized that, apart from possessing a strong bactericidal ef- 50%.1,2 In this pilot study, we evaluate the role of minocy- fect against Mycobacterium leprae, minocycline may prevent cline in recurrent and/or chronic ENL. ENL reactions by treating remote concomitant bacterial infec- tions along with its other therapeutic properties. Methods | This was a prospective pilot study to evaluate the ef- Minocycline has been shown to have a neuroprotective ef- ficacy and safety of minocycline in patients with recurrent fect in conditions such as Parkinson disease, Huntington dis- and/or chronic ENL, undertaken after approval from the In- ease, amyotrophic lateral sclerosis, Alzheimer disease, and spi- stitutes Ethics Committee of the Postgraduate Institute of Medi- nal cord injury.4 By inhibiting microglial activation, minocycline cal Education and Research. After screening, 10 patients with exerts an antinociceptive effect in neuropathic pain, such as pe-

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