Topical Amitriptyline Combined With Ketamine for the Treatment of Erythromelalgia: A Retrospective Study of 36 Patients at Mayo Clinic

March 2013 | Volume 12 | Issue 3 | Original Article | 308 | Copyright © March 2013

Timothy J. Poterucha BS,a Sinead L. Murphy BS,b Mark D. P. Davis MD,c Paola Sandroni MD PhD,d Richard H. Rho MD,e Roger A. Warndahl RPh,f and William T. Weiss RPhf

aMayo Medical School, College of Medicine, Mayo Clinic, Rochester, MN bAmherst College, Amherst, MA cDepartment of Dermatology, dDepartment of Neurology, eDepartment of Anesthesiology, and fPharmacy Services, Mayo Clinic, Rochester, MN

BACKGROUND: Erythromelalgia is an uncommon neurovascular disorder characterized by redness, increased skin temperature, and pain that usually occurs in the extremities. Treatment remains challenging because of its varying response to medical therapy. The objective of this study was to assess the response of erythromelalgia to compounded topical amitriptyline-ketamine.
METHODS: We retrospectively evaluated 36 patients with erythromelalgia who were treated with compounded topical amitriptyline-ketamine from January 1, 2004, through January 31, 2011.
RESULTS: Thirty-two patients (89%) were female. Mean (standard deviation) age was 44.7 (15.8) years (range, 5-74 years). Patients applied the medication 1 to 6 times per day (median, 5 times). One patient (3%) had complete relief from symptoms, 14 (39%) had substantial relief, 12 (33%) had some relief, 7 (19%) had no relief, and 2 (6%) had local worsening of symptoms. No patients had systemic adverse effects.
CONCLUSIONS: A majority of patients with erythromelalgia (75%) reported improvement in pain with topical application of a compounded amitriptyline-ketamine formulation. The medication was well tolerated.

J Drugs Dermatol. 2013;12(3):308-310.


Erythromelalgia is an uncommon neurovascular disorder characterized by redness, increased skin temperature, and pain that usually occurs in the extremities. It is a heterogeneous disorder, with wide variation in severity and age and time course of onset.1 In addition, it has been reported to occur in areas other than the extremities, including the ears, nose, face, and neck.2 Patients with erythromelalgia have higher morbidity and mortality rates than age-matched controls, and they also have increased risk of myeloproliferative disorders.1
Treatment of erythromelalgia remains challenging because of its varying response to medical therapy, which can result in a trial-and-error approach. Treatments that reportedly have been used for erythromelalgia include aspirin, nonsteroidal anti-inflammatory drugs, opioids, β-blockers, antihistamines, vasodilators, anticonvulsants, antidepressants, clonidine, corticosteroids (oral and topical), lidocaine (topical), mexiletine, and misoprostol, among others. However, according to a retrospective study of 168 erythromelalgia patients by Davis et al,1 few of these treatments are consistently effective.
Recent advances have been made in the understanding of the biochemical basis of erythromelalgia. Mutations in the sodium-channel gene SCN9A cause membrane hyperexcitability in sensory neurons, and these mutations have been associated with familial erythromelalgia.3 Thus, the development of new treatments for erythromelalgia has incorporated study of compounds that block sodium channels,4 including mexiletine (a class 1b antiarrhythmic medication) and topical lidocaine.5,6
In 2006, Sandroni and Davis7 reported successfully treating 4 of 5 patients with erythromelalgia at Mayo Clinic by using topical amitriptyline-ketamine. When applied topically, amitriptyline acts primarily as a sodium channel blocker to dull neuropathic pain. In addition, ketamine has been hypothesized to act through a number of pathways, including binding of receptors for N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, and kainate. These medications may act synergistically to limit transmission of painful stimuli. In addition, the same biochemical effects may prevent vasodilation, thereby reducing the characteristic redness and warmth of the disorder.
In this study, we retrospectively evaluated the outcome of patients with erythromelalgia who received treatment with topical amitriptyline-ketamine at Mayo Clinic (Rochester, MN) since 2004.