Safety of Topical Neuromodulators for the Treatment of Pruritus

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Figure 2. Histopathologic and Fluorescence in Situ Hybridization (FISH) Images

A Hematoxylin-eosin, original magnification × 10 D FISH analysis

Epidermis

B Hematoxylin-eosin, original C TCR-gamma, original magnification × 40 magnification × 40

Dermis

A, Epidermal infiltration of atypical large pleomorphic lymphocytes with analysis. D, The results of FISH analysis using X and Y probes (green and red associated dyskeratotic and apoptotic keratinocytes and partial ulceration; the spots, respectively) revealed that the atypical lymphoid cells in epidermis underlying superficial dermis shows a bandlike lymphohistiocytic infiltrate. (above the curved line) showed a male (XY) host pattern, while dermal cells B, Detail of the large cells with clumped chromatin. C, Most of the large cells (below the curved line) showed a predominant female (XX) donor pattern with show T-cell receptor (TCR)-gamma expression by immunohistochemical scattered male (XY) positive cells.

cases of primary cutaneous GD-TCL, and these patients should Safety of Topical Neuromodulators be assessed for evaluation of potential therapeutic options. for the Treatment of Pruritus The use of ketamine and amitriptyline compounded topically Belen Rubio-Gonzalez, MD for the management of chronic neuropathic pain and itch is in- Jasmine Zain, MD creasing. Topically administered ketamine can provide local Lino Garcia, MS analgesia, but systemic absorption, even at relatively low doses, Steven T. Rosen, MD may be associated with adverse psychotropic effects including Christiane Querfeld, MD, PhD alteration of both internal and external perceptions of reality.1 We present a case of systemic absorption and subsequent toxic Author Affiliations: Department of Pathology, City of Hope, Duarte, California encephalopathy following application of topical amitripty- (Rubio-Gonzalez, Querfeld); Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, California (Zain, Rosen, Querfeld); line, ketamine, and lidocaine for recalcitrant pruritus. Division of Cytogenetics, City of Hope, Duarte, California (Garcia); Department of Surgery, Division of Dermatology, City of Hope, Duarte, California (Querfeld). Report of a Case | A highly functioning man in his 80s with a Corresponding Author: Christiane Querfeld, MD, PhD, Department of history of Parkinson disease presented to the emergency Pathology, City of Hope, 1500 E Duarte Rd, Duarte, CA 91010 ([email protected]). department with slurred speech, ataxia, and altered mental Published Online: September 21, 2016. doi:10.1001/jamadermatol.2016.3117 status. Four days prior to presentation, his dermatologist prescribed several new medications to manage severe intrac- Conflict of Interest Disclosures: None reported. table pruritus secondary to atopic dermatitis for which mul- 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768-3785. tiple standard treatment regimens had failed. The new medi- 2. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous γδ T-cell lymphomas: cations were mycophenolate mofetil (MMF), 500 mg, twice a spectrum of presentations with overlap with other cytotoxic lymphomas. Am daily and a topical medication composed of 10% ketamine, J Surg Pathol. 2012;36(11):1656-1665. 5% amitriptyline, and 5% lidocaine (KAL) compounded in a 3. Berti E, Cerri A, Cavicchini S, et al. Primary cutaneous gamma/delta T-cell lipoderm base to be used twice daily to affected areas as lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol. needed. Following initial application to small test areas with 1991;96(5):718-723. subsequent improvement, the patient gradually increased 4. Talpur R, Chockalingam R, Wang C, Tetzlaff MT, Duvic M. A single-center experience with brentuximab vedotin in gamma delta T-cell lymphoma. Clin coverage with KAL to include most of his upper body on the Lymphoma Myeloma Leuk. 2016;16(2):e15-e19. evening prior to presentation.

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After a neurology consultation to rule out stroke, he was ad- Conflict of Interest Disclosures: None reported. mitted to the hospital, where he demonstrated persistently non- 1. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357-367. focal findings on neurological examination and an oscillating level 2. Poterucha TJ, Murphy SL, Sandroni P, et al. Topical amitriptyline combined of consciousness consistent with delirium. The history of acute with topical ketamine for the management of recalcitrant localized pruritus: mental status change following the recent addition of new ec- a retrospective pilot study. J Am Acad Dermatol. 2013;69(2):320-321. zema medications prompted a dermatology consultation on hos- 3. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical amitriptyline and pital day 2. Recommendations were to continue withholding KAL ketamine in neuropathic pain syndromes: an open-label study. J Pain. 2005;6 (10):644-649. treatment and to obtain a toxicology screen to assess for systemic 4. Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, absorption of the topically applied medications. Amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin lidocaine, and ketamine (2360 ng/mL; normal level, 0 ng/mL) J Pain. 2003;19(5):323-328. along with their respective metabolites including norketamine 5. Poterucha TJ, Murphy SL, Davis MD, et al. Topical amitriptyline-ketamine for the treatment of brachioradial pruritus. JAMA Dermatol. 2013;149(2):148-150. were detected via a mass spectroscopy–based urine toxicology 6. Inan S, Dun NJ, Cowan A. Inhibitory effect of lidocaine on pain and itch using test. Over the ensuing 2 weeks on the inpatient service, the pa- formalin-induced nociception and 5′-guanidinonaltrindole-induced scratching tient’s mental status improved to baseline, and he was discharged models in mice: behavioral and neuroanatomical evidence. Eur J Pharmacol. on hospital day 17 for outpatient management. 2009;616(1-3):141-146. Discussion | Topically formulated amitriptyline and ketamine Novel Chromosome 5 Inversion Associated have shown promising results in clinical trials for treatment of With PDGFRB Rearrangement in Hypereosinophilic neuropathic pain and pruritus.2-4 Whether administered topi- Syndrome cally or systemically, ketamine works by blocking several syn- Hypereosinophilic syndrome (HES) is a rare clinical entity defined aptic receptors, thereby preventing transmission of nerve im- by a persistent absolute eosinophil count (AEC) of 15 000/μL for pulses. Topical amitriptyline, in contrast to its systemic effect longer than 6 months, organ damage, and exclusion of reactive on neurotransmitter-mediated nerve transmission, locally eosinophilia or other hematologic cancers described by the World blocks axonal voltage-gated sodium channels preventing neu- Health Organization.1,2 (To convert eosinophils to ×109/L, mul- ronal depolarization. It is currently thought that the combina- tiply by 0.001.) Skin manifestations are common, affecting up tory effects of amitriptyline and ketamine on the neuronal syn- to 50% of patients with HES. Skin findings include vesicles, pe- apse and axon of sensitized A- and C-fibers work synergistically techiae, angioedema, livedo reticularis, necrosis, gangrene, Ray- to prevent transmission of neuropathic pain and itch, making naud phenomenon, eosinophilic cellulitis and vasculitis, urti- it an attractive treatment strategy for numerous dermatologic caria, symmetrical hyperkeratosis, mucosal ulcerations, and disorders.5 Topical lidocaine has been shown to decrease the pruritus.3 We now know that hypereosinophilia is often associ- transmission of excitatory pain and itch impulses to the dorsal ated with predictable genetic alterations and rearrangements, horn of the spinal cord, making it an additional candidate in the understanding of which is crucial to guiding therapy.We describe treatment of localized pain and pruritus.6 a patient with a novel inversion of chromosome 5 (inv(5)) involv- We present this case to increase awareness of adverse re- ing PDGFRB gene rearrangement and hypereosinophilic syn- actions to topically compounded psychoactive drugs such as drome successfully treated with imatinib. amitriptyline and ketamine, as to our knowledge this has not yet been reported. Elderly patients, or those with pre- Figure 1. Infiltrated Dermal Plaques Before and After Treatment With Imatinib in a Patient With Hypereosinophilic Syndrome existing neurologic illness, especially in the setting of im- paired skin barrier function, may be at an increased risk for sys- A Before treatment with imatinib B After treatment with imatinib temic absorption and consequent encephalopathy. We propose that our patient’s age and atopic dermatitis were the risk fac- tors that predisposed him to systemic absorption, and his Parkinson disease may have contributed to the severity of delirium. Further studies are needed to ascertain the appropri- ate dosing of these medications and to more closely analyze their safety profiles. Clinicians who wish to use these medications should select their patients carefully, use the lowest effective concentration, and consider periodically checking systemic levels to assure optimal patient safety.5

Michael A. Cardis, MD Helena B. Pasieka, MD, MS

Author Affiliations: Department of Dermatology, MedStar Washington Hospital Center, Washington, DC; Department of Dermatology, MedStar Georgetown University Hospital, Washington, DC. Corresponding Author: Helena B. Pasieka, MD, MS, Departments of Dermatology, Medstar Washington Hospital Center and MedStar Georgetown A, This image shows firm, infiltrated dermal plaques on the upper lids, temple, University Hospital, 5530 Wisconsin Ave, Ste 730, Chevy Chase, MD 20745 and malar cheek. B, Interval improvement of the plaques was seen after 2 ([email protected]). months of imatinib therapy. Published Online: September 14, 2016. doi:10.1001/jamadermatol.2016.3118.

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