Applied Evidence

Prurigo nodularis: Picking the right treatment

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With severe refractory pruritus in which a primary cutaneous or systemic cause cannot be determined, evaluate for malignancy—especially polycythemia, lymphoma, or multiple myeloma—by ordering liver function tests (including lactate dehydrogenase), a complete blood count with differential, a basic metabolic panel, a chest x-ray, and possibly a serum protein electrophoresis.7

Available treatments

If the patient’s pruritic symptoms do not resolve and an underlying cause cannot be determined, direct treatment at decreasing pruritus either locally or systemically. Topical therapies, typically associated with fewer adverse effects, are preferable in localized cases of PN. In more severe, widespread, or recalcitrant disease, systemic agents may be necessary. Typical first-line treatments for PN aimed at decreasing pruritic symptoms include:

  • topical antipruritics, such as ointments containing menthol or camphor; topical corticosteroids, with increased efficacy under occlusion as seen with flurandrenolide tape (Cordran tape)
  • oral antihistamines, such as promethazine hydrochloride; oral antidepressants, such as doxepin
  • intralesional corticosteroids—eg, triamcinolone acetonide (the concentration
    used depends on the thickness of the lesion and how well the lesion responded to prior injections)
  • a short course of systemic corticosteroids, unless the patient has a comorbid condition that could be exacerbated by rapid tapering of corticosteroids (eg, psoriasis).

For patients with concomitant depression or anxiety, treatment with a selective serotonin reuptake inhibitor or anxiolytic, respectively, may be indicated.2-4 With the exception of topical corticosteroids8,9 and oral antihistamines,10 the aforementioned first-line treatments for PN are mostly based on clinical experience and anecdotal success with no studies to support their use.3 Furthermore, these treatments may be ineffective for many patients.11,12 We present our review of several studies in the literature examining potential therapies for PN.

Topical therapies
Calcipotriol vs betamethasone. A prospective, randomized, double-blind study that ran right/left comparisons of calcipotriol ointment (a vitamin D3 analog) and betamethasone ointment as treatment for PN in 9 patients showed that calcipotriol and betamethasone were both effective. However, calcipotriol ointment 50 mcg/g was more effective in reducing the number and size of nodules compared with 0.1% betamethasone valerate ointment.8

Topical corticosteroids have long been viewed as a first-line therapy for PN.2 However, given their potential for adverse effects with long-term use, such as skin atrophy, steroidsparing agents are preferred. Calcipotriol ointment can be useful as both a steroid-sparing and a keratolytic agent, as it inhibits keratinocyte proliferation.4,13 Corticosteroids and calcipotriol possess anti-inflammatory and antipruritic properties, likely explaining their efficacy in treating PN.4

Pimecrolimus and tacrolimus. The topical calcineurin inhibitors pimecrolimus and tacrolimus have been used successfully as steroid-sparing agents in treating atopic dermatitis.14 Their antipruritic effect, likely related to their influence on cutaneous sensory nerve fibers and inhibition of inflammatory cytokines, could also explain their efficacy in treating PN.15,16

A randomized, hydrocortisone-controlled, double-blind phase II trial sponsored by Novartis was designed as a right/left comparison study between pimecrolimus 1% cream and hydrocortisone 1% cream in 30 patients with non-atopic PN. When applied twice daily, each agent decreased pruritic symptoms and resolved scratch lesions to degrees that were statistically significant. However, an intention-to-treat analysis revealed no significant differences between pimecrolimus and hydrocortisone.15 In a prospective case series of 11 patients with PN, 2 out of 4 patients (50%) receiving tacrolimus 0.1% ointment and 5 out of 7 patients (71%) using pimecrolimus 1% cream experienced a reduction in pruritic symptoms and improvement of lesions by 50% or greater with twice daily application of their assigned calcineurin inhibitor.16

Before prescribing topical calcineurin inhibitors, inform patients of the black-box warning issued by the US Food and Drug Administration (FDA) regarding the theoretical increased risk of developing cutaneous malignancy and lymphoma. This warning is controversial because in clinical databases, the incidences of malignancy and lymphoma associated with topical calcineurin inhibitors are less than those observed in the general population.14

Capsaicin. Based on a prospective study of 33 patients with PN, topical capsaicin may be an effective treatment if administered 4 to 6 times daily for at least 2 weeks and up to 10 months.17 Patients may require up to 0.3% concentration for total resolution of pruritus. Importantly, capsaicin use may be limited by the high application frequency.

Systemic therapies
Fexofenadine and montelukast. Oral antihistamines have long been used as a first-line treatment for PN. Although clinical experience and anecdotal success support the use of various antihistamines, evidence-based literature exists only for fexofenadine and the leukotriene receptor antagonist montelukast. These oral agents also avoid potential unwanted effects of topical antihistamines, which may sensitize skin and increase the risk of developing allergic contact dermatitis.1

Whereas antihistamines exert their antipruritic effect by blocking histamine H1-receptors, montelukast decreases pruritic symptoms by antagonizing leukotriene receptors.10 In a prospective study of 12 patients 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.

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