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Cutaneous adverse effects are one of the most frequent adverse events (AEs) associated with the use of BRAF inhibitors, reported in 92% to 95% of patients.1 Such dermatologic reactions include maculopapular eruptions, photosensitivity, verrucous keratoses, keratosis pilaris–like eruptions, keratoacanthomas, and melanocytic proliferations.2 Hand-foot skin reaction (HFSR) occurs in 19% to 60% of patients taking BRAF inhibitors1,3 and presents as tender, erythematous patches on the palms and soles.3 Painful hyperkeratotic plaques develop over pressure points. Although 88% of patients have grade 1 symptoms,4 pain can be severe.
The pathogenesis is unknown, but the reaction is dose dependent and so may be due to direct toxic effects of the drug. It has also been postulated that blockage of receptors for vascular endothelial growth factor and platelet-derived growth factor leads to reduced ability to repair vasculature that is subclinically traumatized in the skin. Previously described therapies include emollient creams, keratolytic creams, topical corticosteroids, pyridoxine, COX-2 inhibitors, phototherapy, and decreased chemotherapy dose.
A man in his 50s with BRAF V600E–mutated metastatic melanoma treated with twice-daily dabrafenib, 150 mg, developed grade 2 HFSR on his feet after 1 week of treatment, which progressed to grade 3 within a month (grading based on Common Terminology Criteria for Adverse Events, v4.03; http://evs.nci.nih.gov/ftp1/CTCAE/About.html). This was his first treatment for metastatic disease. On the palms and soles bilaterally, he had thick, yellow, hyperkeratotic plaques with erythematous borders most pronounced on the weight-bearing areas, including the metacarpophalangeal joints of the hands, heels, and balls of the feet (Figure). These plaques caused significant pain, interfering with performance of activities of daily living.
Thick, yellow, hyperkeratotic plaques with erythematous borders most pronounced on the weight-bearing areas.
Minimal improvement was seen after treatment with topical tazarotene, 0.05%, ointment, lidocaine, 5%, ointment, urea, 40%, ointment, and clobetasol, 0.05%, ointment under occlusion. For pain relief, he required use of long-acting oxycodone, 10 mg, every 12 hours, and oxycodone, 5 mg, every 4 hours, which provided mild pain control. He experienced significant improvement after halting treatment with dabrafenib for 2 weeks and subsequently resuming a reduced-dose dabrafenib regimen at 150 mg/d, but he still required narcotics for pain control.
After 2 weeks of low-dose dabrafenib, he started therapy with pregabalin, 50 mg, 3 times daily. Within a week and without any other change in his lifestyle or activity level, the pain in his feet dramatically decreased to the point where he no longer required narcotics and was able to participate in his previous activities. After 45 weeks, he continued to take pregabalin with continuous pain relief in his feet despite unchanged persistent thickened plaques on the soles, for which the topical therapies provided little therapeutic benefit. Of note, the patient had a lifelong history of bipolar disorder and had been taking bupropion, fluoxetine, lamotrigine, and quetiapine throughout this period.
Pregabalin is an anticonvulsant widely used as first-line therapy for neuropathic pain secondary to a variety of diseases including diabetes, post-herpetic neuralgia, fibromyalgia, and spinal cord injuries. Pregabalin, like gabapentin, binds to voltage-gated calcium channels and decreases synaptic activity; pregabalin exerts its therapeutic effect at lower doses than does gabapentin, and thus patients experience fewer adverse effects with pregabalin. It has been found to be safe, the most common adverse effects being somnolence and dizziness, which frequently resolve within weeks.5
For the present patient, pregabalin provided more effective symptomatic control than narcotics did for pain related to recalcitrant HFSR. Although he had concurrent bipolar disorder, his psychotropic medication regimen remained stable throughout this period, suggesting that pregabalin helped specifically with his peripheral pain. Although peripheral neuropathy has been associated with acral erythrodysesthesia, agents used to treat neuropathic pain have not been reported for use in acral erythrodysesthesia or HFSR. This case report suggests that pregabalin may be useful as a symptomatic treatment for pain associated with HFSR induced by targeted therapies.
Corresponding Author: Jennifer Choi, MD, Department of Dermatology, Yale University School of Medicine, 333 Cedar St, Laboratory for Medicine and Pediatrics 5040, New Haven, CT 06510 (Jennifer.firstname.lastname@example.org).
Published Online: September 24, 2014. doi:10.1001/jamadermatol.2014.2455.
Conflict of Interest Disclosures: Dr Choi serves as speaker for Onyx Pharmaceuticals. Mr Burke serves as a speaker for Bristol-Myers-Squibb, Genentech, and Pfizer (a manufacturer of pregabalin). Mr Burke also serves on the advisory board of Pfizer and Merck. No other disclosures are reported.
Lilly E, Burke M, Kluger H, Choi J. Pregabalin for the Treatment of Painful Hand-Foot Skin Reaction Associated With Dabrafenib. JAMA Dermatol. 2015;151(1):102-103. doi:10.1001/jamadermatol.2014.2455