Michael Saco, MD; nodularis: George Cohen, MD Department of Dermatology & Cutaneous Picking the right treatment Surgery, University of South Florida, Tampa (Dr. Saco); Department of Dermatology, University Most patients with localized nodules should receive of Florida, Gainesville topical treatment first. But disappointing results or (Dr. Cohen) specific findings described here could necessitate [email protected] The authors reported no additional or alternative options. potential conflict of interest relevant to this article.

CASE u A 43-year-old woman arrives at your office with persis- Practice tent itching on her arms and legs. For some time, she has used recommendations moisturizing lotions and herbal preparations suggested by her › Start with topical cortico- mother, but they have provided no relief. You note multiple 0.5- steroids under occlusion and to 2-cm firm, excoriated nodules symmetrically distributed on her periodically substitute with elbows and knees bilaterally. She has seasonal allergies and a his- steroid-sparing agents tory of childhood asthma. How would you care for this patient? (calcipotriol ointment or pimecrolimus 1% cream) reating (PN) can be a daunting task for localized for even the most experienced clinician. Prurigo nod- prurigo nodularis. B ules are cutaneous lesions often produced by repetitive › Consider adding oral T scratching—hence the nickname “picker’s nodules”—which antihistamines or may occur as sequelae of chronic pruritus or neurotic exco- montelukast to the initial riations. Thus, PN can be classified as a subtype of neuroder- regimen if a pruritic cause is suspected; alternatively, matitis. The nodules can be intensely pruritic, resulting in an 1,2 consider adding these agents -scratch cycle that can be difficult to break. In this review, if topical therapies alone we examine evidence-based therapies for PN. do not effectively treat the prurigo nodules. C › Turn to oral naltrexone, Key findings with prurigo nodularis gabapentin, or pregabalin Typically, prurigo nodules are firm, hyperkeratotic, pruritic for more widespread or papules or nodules that range in diameter from a few milli- treatment-resistant cases. C meters to several centimeters. The lesions usually have eroded or ulcerated components secondary to repeated excoriation, Strength of recommendation (SOR) which can eventually lead to scarring and changes in pigmen- A Good-quality patient-oriented evidence tation. Patients can have one nodule or hundreds of lesions, B Inconsistent or limited-quality depending on disease severity. The lesions tend to be distrib- patient-oriented evidence uted symmetrically and have a predilection for the extensor C Consensus, usual practice, opinion, disease-oriented surfaces of the upper and lower limbs. The abdomen, posterior evidence, case series neck, upper and lower back, and buttocks are also commonly affected, whereas the face, palms, and flexural areas are rarely involved2-5 (FIGURE 1). The differential diagnosis for PN includes herpetiformis, scabies, , hypertro-

jfponline.com Vol 64, No 4 | APRIL 2015 | The Journal of Family Practice 221 phic lichen planus, perforating disorders, development and perpetuation of the nod- , allergic contact derma- ules. In cases associated with an underlying titis, neurotic excoriations, and multiple psychiatric component, such as delusional keratoacanthomas.4,5 parasitosis, patients often lack insight into PN prevalence and etiology are un- their condition and thus may benefit from known. Although PN can occur at any age, treatment of psychiatric comorbidities.4,7 the typical age range is 20 to 60 years, with z On physical exam, try to find lesions middle-aged women most commonly affect- that have not been traumatized by patients. ed. Patients who develop PN at a younger age They can be useful in uncovering a primary are more likely to have an atopic diathesis.3,4 cause, such as scabies, atopic dermatitis, li- There is ongoing debate regarding chenoid , or simple xerosis. whether PN is a primary cutaneous disease or If a diagnosis cannot be made clinically, a response to repetitive scratching provoked consider obtaining a biopsy of a nontrauma- by a separate cause. PN has been associated tized lesion. Traumatized lesions are typically with a variety of diseases, such as psychiat- unrevealing on histopathology. If the clinical ric disorders, atopic dermatitis, chronic re- assessment of pruritic lesions is indeterminate, nal failure, hyperthyroidism, iron-deficiency laboratory tests that may prove helpful include, anemia, obstructive biliary disease, gastric but are not limited to, thyroid-stimulating hor- malignancy, lymphoma, leukemia, human mone levels, liver function tests, kidney func- Consider immunodeficiency virus (HIV), hepatitis B, tion, a hepatitis panel, and HIV screening. obtaining a and .2,3 With severe refractory pruritus in which a biopsy of a primary cutaneous or systemic cause cannot non-traumatized be determined, evaluate for malignancy—es- lesion, which Use the diagnostic work-up pecially polycythemia, lymphoma, or multi- can help uncover to focus management decisions ple myeloma—by ordering liver function tests scabies, atopic When taking the history, first determine why (including lactate dehydrogenase), a com- dermatitis, patients are picking or scratching. If the le- plete blood count with differential, a basic lichenoid drug sions are pruritic or painful, look for a poten- metabolic panel, a chest x-ray, and possibly a eruption, or tial underlying cause of pruritic symptoms.6 serum protein electrophoresis.7 simple xerosis. If you identify an underlying dermatologic or systemic condition, treat that disorder first.1 For example, adequately treating a patient’s Available treatments atopic dermatitis or hyperthyroidism may If the patient’s pruritic symptoms do not re- quell the pruritic symptoms and potentially solve and an underlying cause cannot be make the prurigo nodules more responsive determined, direct treatment at decreasing to symptomatic treatment or even obviate the pruritus either locally or systemically. Topi- need for such measures. cal therapies, typically associated with fewer If treating the underlying cause of PN adverse effects, are preferable in localized does not provide adequate relief, or if no cases of PN. In more severe, widespread, or cause for pruritic nodules can be found, the recalcitrant disease, systemic agents may be nodules may yet respond to symptomatic necessary. Typical first-line treatments for treatments targeted at decreasing pruritus PN aimed at decreasing pruritic symptoms and inflammation. In contrast, with patients include: who habitually scratch lesions they describe • topical antipruritics, such as ointments as non-pruritic, neurotic excoriations could containing menthol or camphor; topi- be the source of PN, making the nodules less cal corticosteroids, with increased ef- likely to respond to antipruritic therapies.4,7 ficacy under occlusion as seen with z Patient insights. Assessing whether flurandrenolide tape (Cordran tape) patients have insight into their condition is • oral antihistamines, such as prometha- also important. Some patients may be un- zine hydrochloride; oral antidepres- aware that they are repetitively picking and sants, such as doxepin scratching the affected areas and causing the • intralesional corticosteroids—eg,

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triamcinolone acetonide (the con- figure 1 centration used depends on the Classic distribution of prurigo nodules thickness of the lesion and how well the lesion responded to prior injections) • a short course of systemic cortico- steroids, unless the patient has a comorbid condition that could be ex- acerbated by rapid tapering of cortico- steroids (eg, psoriasis).

For patients with concomitant depres- P sion or anxiety, treatment with a selective ho t o s serotonin reuptake inhibitor or anxiolytic, cou 2-4

respectively, may be indicated. With the rt e

8,9 s exception of topical corticosteroids and Geo of: y oral antihistamines,10 the aforementioned

first-line treatments for PN are mostly based rg e e on clinical experience and anecdotal success C ohen, ohen, with no studies to support their use.3 Further- TK M

more, these treatments may be ineffective D 11,12 for many patients. We present our review This patient has markedly ulcerated lesions on his upper back, lower back, and of several studies in the literature examining extensor surfaces of both arms. The face and palms are rarely involved. potential therapies for PN.

Topical therapies matitis.14 Their antipruritic effect, likely re- Calcipotriol vs betamethasone. A prospec- lated to their influence on cutaneous sensory tive, randomized, double-blind study that nerve fibers and inhibition of inflammatory ran right/left comparisons of calcipotriol cytokines, could also explain their efficacy in 15,16 ointment (a vitamin D3 analog) and beta- treating PN. methasone ointment as treatment for PN in A randomized, hydrocortisone-controlled, 9 patients showed that calcipotriol and be- double-blind phase II trial sponsored by No- tamethasone were both effective. However, vartis was designed as a right/left comparison calcipotriol ointment 50 mcg/g was more study between pimecrolimus 1% cream and effective in reducing the number and size of hydrocortisone 1% cream in 30 patients with nodules compared with 0.1% betamethasone non-atopic PN. When applied twice daily, valerate ointment.8 each agent decreased pruritic symptoms and Topical corticosteroids have long been resolved scratch lesions to degrees that were viewed as a first-line therapy for PN.2 Howev- statistically significant. However, an inten- er, given their potential for adverse effects with tion-to-treat analysis revealed no significant long-term use, such as skin atrophy, steroid- differences between pimecrolimus and hy- sparing agents are preferred. Calcipotriol oint- drocortisone.15 In a prospective case series of ment can be useful as both a steroid-sparing 11 patients with PN, 2 out of 4 patients (50%) re- and a keratolytic agent, as it inhibits kerati- ceiving tacrolimus 0.1% ointment and 5 out of nocyte proliferation.4,13 Corticosteroids and 7 patients (71%) using pimecrolimus 1% cream calcipotriol possess anti-inflammatory and experienced a reduction in pruritic symptoms antipruritic properties, likely explaining their and improvement of lesions by 50% or greater efficacy in treating PN.4 with twice daily application of their assigned z Pimecrolimus and tacrolimus. The top- calcineurin inhibitor.16 ical calcineurin inhibitors pimecrolimus and Before prescribing topical calcineurin tacrolimus have been used successfully as inhibitors, inform patients of the black-box steroid-sparing agents in treating atopic der- warning issued by the US Food and Drug

jfponline.com Vol 64, No 4 | APRIL 2015 | The Journal of Family Practice 223 figure 2 Whereas antihistamines exert their an- Thalidomide was effective in this case tipruritic effect by blocking histamine H1- receptors, montelukast decreases pruritic symptoms by antagonizing leukotriene re- ceptors.10 In a prospective study of 12 pa- tients with PN receiving fexofenadine 240 mg twice daily and montelukast 10 mg daily for 4 weeks, 9 of the 12 patients (75%) reported some degree of improvement.10 However, 5 of these 9 patients (56%) achieved only slight improvement. Level of improvement was based on how well the agents reduced the pruritus and lesion number. z Naltrexone. As an opioid antagonist, naltrexone is able to block endogenous opi- ates from binding to central opioid receptors and causing the sensation of pruritus. Ac- cordingly, oral naltrexone can be used to treat Thalidomide effectively resolved this patient’s prurigo nodules shown before (left) PN, as shown in an open-label clinical trial and after (right) treatment. The typical thalidomide daily dose is 50-100 mg for up to in which 9 out of 17 patients (53%) achieved 6 months. high antipruritic effect, defined as a reduc- tion of pruritic symptoms by at least half.18 When selecting naltrexone to treat PN, Administration (FDA) regarding the theoreti- prescribe a daily dose of 50 mg for an average cal increased risk of developing cutaneous of 4.7 months; up to 20 months of treatment malignancy and lymphoma. This warning is may be required. If tachyphylaxis occurs, controversial because in clinical databases, consider increasing the dose to 50 mg twice the incidences of malignancy and lymphoma a day. Most patients should notice some level associated with topical calcineurin inhibitors of antipruritic efficacy and varying degrees of are less than those observed in the general lesion flattening, softening, or healing. How- population.14 ever, exacerbation after therapy discontinu- z Capsaicin. Based on a prospective ation may occur in 41% of patients. Adverse study of 33 patients with PN, topical capsaicin medication effects include fatigue, nausea, may be an effective treatment if administered and dizziness.18 4 to 6 times daily for at least 2 weeks and up z Gabapentin and pregabalin. In re- to 10 months.17 Patients may require up to sponse to a report of a case series in which 0.3% concentration for total resolution of 4 patients with PN responded well to gabap- pruritus. Importantly, capsaicin use may be entin,19 Mazza et al20 conducted a prospective limited by the high application frequency. study of pregabalin treatment for 30 patients with PN. Both gabapentin and pregabalin Systemic therapies inhibit calcium influx and subsequent excit- Fexofenadine and montelukast. Oral anti- atory neurotransmitter release, the mecha- histamines have long been used as a first-line nism by which they likely decrease pruritus treatment for PN. Although clinical experi- in patients with PN.20 In the pregabalin study, ence and anecdotal success support the use 23 out of 30 patients (77%) experienced com- of various antihistamines, evidence-based plete resolution of pruritic symptoms and a literature exists only for fexofenadine and reduction of prurigo nodules in number or the leukotriene receptor antagonist monte- flattening. The recommended dosage of pre- lukast. These oral agents also avoid potential gabalin is 25 mg 3 times daily for 3 months, unwanted effects of topical antihistamines, after which time clinical progress is assessed. which may sensitize skin and increase the If a patient is not lesion-free, continue prega- risk of developing allergic .1 balin at a maintenance dose of 50 mg/d for

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TABLE Evidence-based therapies for prurigo nodularis

Medication Application frequency/dosing Clinical considerations SOR Betamethasone (topical)8,9 0.1% ointment applied twice daily; Avoid prolonged application of high-potency B increased efficacy under occlusion topical steroids; attempt to alternate or substitute with steroid-sparing agents such as calcipotriol or pimecrolimus Calcipotriol (topical)8 50 mcg/g ointment applied twice May be more efficacious than betamethasone B daily valerate 0.1% ointment Pimecrolimus (topical)15,16 1% cream applied twice daily Discuss FDA black-box warning with patients B before initiating treatment Tacrolimus (topical)16 0.1% ointment applied twice daily Discuss FDA black-box warning with patients C before initiating treatment Capsaicin (topical)17 0.025% to 0.3% strength, applied High application frequency may lead to low C 4-6 times daily compliance Fexofenadine (oral) and 240 mg fexofenadine twice daily; Dose of fexofenadine used in study was much C montelukast (oral)10 10 mg montelukast daily higher than doses typically prescribed for relief of pruritus Naltrexone (oral)18 50 mg/d; may need to increase to High rate of exacerbation (41%) after therapy C 50 mg twice daily if patient discontinuation develops tachyphylaxis Gabapentin (oral)19 900 mg/d for 3 to 4 months; may Higher doses may be needed to achieve C taper to 300-600 mg/d as a therapeutic efficacy maintenance dose Pregabalin (oral)20 25 mg 3 times/d for 3 months; may Appears to be more efficacious overall than C taper to 50 mg/d as a maintenance antihistamines and naltrexone dose

FDA, US Food and Drug Administration; SOR, strength of recommendation.

up to 2 years. Adverse effects typically include Putting Tx options into practice headache, sedation, and dizziness.20 In addition to ruling out potential causes of pruritus and determining the best treatment for each individual with PN, assess for and When to refer to a dermatologist appropriately treat any psychiatric comor- Refer patients to a dermatologist if initial clini- bidities, which are often a psychological com- cal findings suggest a need for further work-up ponent of PN. to rule out primary cutaneous diseases, or if z Localized PN. Start with topical corti- the therapies discussed (TABLE8-10,15-20) yield un- costeroids under occlusion for localized PN. satisfactory results. Dermatologists can pro- To avoid complications of long-term topical vide more advanced treatments that require corticosteroid use, including dermal atro- close monitoring, such as phototherapy,21-24 phy, periodically switch to a steroid-sparing cyclosporine,25 or thalidomide.26-28 Based on agent, such as calcipotriol ointment or topi- multiple case series and case reports, as well cal pimecrolimus. Less evidence is available as our own personal experience (FIGURE 2), to support the efficacy of tacrolimus oint- thalidomide is efficacious in treating PN. How- ment in PN treatment. Topical capsaicin is ever, thalidomide is typically reserved for cases not as practical as other topical treatments that are severe and treatment-recalcitrant due since it needs to be applied 4 to 6 times daily. to the drug’s high cost, teratogenicity (preg- Oral antihistamines and montelukast may be nancy category X), and potentially irreversible added to the therapeutic regimen if there is peripheral neuropathy.29 a chronic pruritic component related to the

jfponline.com Vol 64, No 4 | APRIL 2015 | The Journal of Family Practice 225 lesions themselves or an underlying atopic rin inhibitors.) We would also prescribe an diathesis fueling the itch-scratch cycle. oral antihistamine at the start, given that her z Widespread or treatment-resistant history of seasonal allergies and childhood PN. Prescribe naltrexone, gabapentin, or asthma increases her chances of having an pregabalin for more widespread disease or atopic component causing or exacerbating lesions resistant to conservative therapies. If her disease. However, assessing her response you suspect a primary cutaneous disease as to topical therapies before initiating an oral the underlying cause of pruritus or if topical antihistamine would also be an appropriate and oral therapies do not achieve the desired strategy. therapeutic effect, refer to a dermatologist Unfortunately, PN is typically a chronic for further work-up and treatment. and often treatment-resistant disease with dis- z How we would manage the case pre- appointing recurrence rates. As we learn more sented in the introduction. We would start about the pathophysiology of PN, more effec- the 43-year-old on topical corticosteroids tive therapies will hopefully emerge to improve under occlusion and periodically substitute the quality of life for these patients. JFP calcipotriol ointment. (Given the unease that some patients might feel with the black-box warning on topical calcineurin inhibitors, Correspondence we would likely try calcipotriol ointment as a Michael Saco, MD, Department of Dermatology & Cutaneous Surgery, University of South Florida, 13330 Laurel Drive, Oral naltrexone, courtesy before suggesting topical calcineu- Tampa, FL 33612; [email protected] gabapentin, or pregabalin may be needed for References widespread or 1. Moses S. Pruritus. Am Fam Phys. 2003;68:1135-1142. 16. Ständer S, Schürmeyer-Horst F, Luger TA, et al. Treatment of pru- treatment- 2. Jorizzo JL, Gatti S, Smith EB. Prurigo: a clinical review. J Am Acad ritic diseases with topical calcineurin inhibitors. Ther Clin Risk Dermatol. 1981;4:723-728. Manag. 2006;2:213-218. resistant prurigo 3. Lee MR, Shumack S. Prurigo nodularis: a review. Australas J Der- 17. Ständer S, Luger T, Metze D. Treatment of prurigo nodularis with nodularis. matol. 2005;46:211-218. topical capsaicin. J Am Acad Dermatol. 2001;44:471-478. 4. Wallengren J. Prurigo: diagnosis and management. Am J Clin Der- 18. Metze D, Reimann S, Beissert S, et al. Efficacy and safety of -na matol. 2004;5:85-95. ltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Der- 5. Accioly-Filho LW, Nogueira A, Ramos-e-Silva M. Prurigo matol. 1999;41:533-539. nodularis of Hyde: an update. J Eur Acad Dermatol Venereol. 2000;14:75-82. 19. Gencoglan G, Inanir I, Gunduz K. Therapeutic hotline: treatment of prurigo nodularis and lichen simplex chronicus with gabapen- 6. Reamy BV, Bunt CW, Fletcher S. A diagnostic approach to pruri- tin. Dermatol Ther. 2010;23:194-198. tus. Am Fam Physician. 2011;84:195-202. 20. Mazza M, Guerriero G, Marano G, et al. Treatment of pru- 7. Berger TG, Shive M, Harper GM. Pruritus in the older patient: a rigo nodularis with pregabalin. J Clin Pharm Ther. 2013;38: clinical review. JAMA. 2013;310:2443-2450. 16-18. 8. Wong SS, Goh CL. Double-blind, right/left comparison of 21. Hammes S, Hermann J, Roos S, et al. UVB 308-nm excimer light calcipotriol ointment and betamethasone ointment in the and bath PUVA: combination therapy is very effective in the treatment of Prurigo nodularis. Arch Dermatol. 2000;136: treatment of prurigo nodularis. J Eur Acad Dermatol Venereol. 807-808. 2011;25:799-803. 9. Saraceno R, Chiricozzi A, Nisticò SP, et al. An occlusive dressing 22. Rombold S, Lobisch K, Katzer K, et al. Efficacy of UVA1 photo- containing betamethasone valerate 0.1% for the treatment of pru- therapy in 230 patients with various skin diseases. Photodermatol rigo nodularis. J Dermatolog Treat. 2010;21:363-366. Photoimmunol Photomed. 2008;24:19-23. 10. Shintani T, Ohata C, Koga H, et al. Combination therapy of fexofenadine and montelukast is effective in prurigo nodu- 23. Tamagawa-Mineoka R, Katoh N, Ueda E, et al. Narrow-band laris and pemphigoid nodularis. Dermatol Ther. 2014;27: ultraviolet B phototherapy in patients with recalcitrant nodular 135-139. prurigo. J Dermatol. 2007;34:691-695. 11. Paghdal KV, Schwartz R. Thalidomide and its dermatologic uses. 24. Saraceno R, Nisticò SP, Capriotti E, et al. Monochromatic excimer Acta Dermatovenerol Croat. 2007;15:39-44. light (308 nm) in the treatment of prurigo nodularis. Photoderma- tol Photoimmunol Photomed. 2008;24:43-45. 12. Alfadley A, Al-Hawsawi K, Thestrup-Pedersen K, et al. Treatment of prurigo nodularis with thalidomide: a case report and review of 25. Siepmann D, Luger TA, Ständer S. Antipruritic effect of cyclospo- the literature. Int J Dermatol. 2003;42:372-375. rine microemulsion in prurigo nodularis: results of a case series. J Dtsch Dermatol Ges. 2008;6:941-946. 13. Menter A, Korman NJ, Elmets CA, et al; American Academy of Dermatology. Guidelines of care for the management of psoriasis 26. Orlando A, Renna S, Cottone M. Prurigo nodularis of Hyde and psoriatic arthritis. Section 3. Guidelines of care for the man- treated with low-dose thalidomide. Eur Rev Med Pharmacol Sci. agement and treatment of psoriasis with topical therapies. J Am 2009;13:141-145. Acad Dermatol. 2009;60:643-659. 27. Lan CC, Lin CL, Wu CS, et al. Treatment of idiopathic prurigo 14. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin nodularis in Taiwanese patients with low-dose thalidomide. J inhibitors and lymphoma risk: evidence update with im- Dermatol. 2007;34:237-242. plications for daily practice. Am J Clin Dermatol. 2013;14: 28. Taefehnorooz H, Truchetet F, Barbaud A, et al. Efficacy of thalido- 163-178. mide in the treatment of prurigo nodularis. Acta Derm Venereol. 15. Siepmann D, Lotts T, Blome C, et al. Evaluation of the antipruritic 2011;91:344-345. effects of topical pimecrolimus in non-atopic prurigo nodularis: 29. Wu JJ, Huang DB, Pang KR, et al. Thalidomide: dermatological in- results of a randomized, hydrocortisone-controlled, double- dications, mechanisms of action and side-effects. Br J Dermatol. blind phase II trial. Dermatology. 2013;227:353-360. 2005;153:254-273.

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