Chronic pain in pachyonychia congenita: evidence for neuropathic origin

Brill, Silviu; Sprecher, Eli; Smith, Frances J.D.; Geva, Nirit; Gruener, Hila; Nahman‐Averbuch, Hadas; Defrin, Ruth

doi:10.1111/bjd.16217

Cited by 25 publications

(30 citation statements)

References 45 publications

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“…61 This pain has been described as sharp, burning, throbbing, or tingling sensations in the affected areas of the feet, which is often exacerbated by mechanical force, such as walking or standing. 62,63 The pain seems to be independent of severity of hyperkeratosis. It can be so severe that many individuals will crawl or use a wheelchair to minimize discomfort.…”

Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermentioning

confidence: 98%

“…A survey conducted using the International Pachyonychia Congenita Research Registry revealed that 89% of individuals with PC experience plantar pain and this figure was 97% for those over the age of 10 years who had PC . This pain has been described as sharp, burning, throbbing, or tingling sensations in the affected areas of the feet, which is often exacerbated by mechanical force, such as walking or standing . The pain seems to be independent of severity of hyperkeratosis.…”

Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermasmentioning

confidence: 99%

“…In a subsequent study, 62 individuals with PC completed neuropathic pain questionnaires and underwent quantitative sensory testing. Of these, 86% reported pain in the feet, 62% had higher than normal neuropathic pain questionnaire scores and 55% reported allodynia in the affected region . During quantitative sensory testing, individuals with PC exhibited a higher threshold for detection of both innocuous warm and cool stimuli and mechanical stimuli, and lower thresholds for mechanically evoked pain.…”

Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermasmentioning

confidence: 99%

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Pain mechanisms in hereditary palmoplantar keratodermas

Weinberg

Polydefkis

2019

Br J Dermatol

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Summary Background Palmoplantar keratodermas (PPKs) are a heterogeneous group of skin disorders characterized by thickening of the epidermis on the palms of the hands and soles of the feet. Individuals with PPKs report varying degrees of palmoplantar pain that can severely affect quality of life. Objectives To provide an overview of the scope of pain in hereditary PPKs and highlight candidate mechanisms underlying this pain. Methods In this review, we discuss several forms of hereditary PPKs, with a focus on the incidence, nature, candidate underlying mechanisms and treatment of pain in these conditions. We also synthesize this information with current understanding of the mechanisms contributing to pathological pain in other conditions. Results Pain is a major problem for many, but not all individuals with hereditary PPK. This pain remains poorly understood, inconsistently reported and inadequately treated. The heterogeneity of pain prevalence and presentations across the many forms of PPK suggests that there may exist corresponding heterogeneity in the cellular and molecular mechanisms that drive and shape PPK‐associated pain. Some candidate mechanisms include structural (e.g. fissures and blisters), infectious and immune/inflammatory processes. However, a growing body of evidence also supports the occurrence of localized neuropathic alterations in the affected skin of individuals with PPK, which might contribute to their pain. Conclusions Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to prevention and treatment of pain in individuals with PPK. What's already known about this topic? Pain is a prominent symptom in hereditary palmoplantar keratodermas (PPKs). Pain in patients with PPK can be difficult to treat. Pain mechanisms in PPKs are poorly understood. What does this study add? This study defines multiple potential sources of pain in PPK, including both structural lesions (fissures, blisters) and specific cell types. This review highlights the variability of pain among several forms of hereditary PPK. This study provides mechanistic insights into how neuropathic and inflammatory mechanisms might contribute to pain in some forms of PPK.

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Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermentioning

confidence: 98%

Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermasmentioning

confidence: 99%

Section: Diverse Pain Phenotypes In Hereditary Palmoplantar Keratodermasmentioning

confidence: 99%

See 1 more Smart Citation

Pain mechanisms in hereditary palmoplantar keratodermas

Weinberg

Polydefkis

2019

Br J Dermatol

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“…Pressure on affected areas of the soles is painful, often causing patients to limit their activity. Mechanisms of pain in PC have recently been elucidated with pathologic, functional, and questionnaire studies supporting that pain in PC is neuropathic in nature . With the phenotype of chronic pain and focal hypersensitivity in affected skin, PC is an attractive model system to study expression of NOP‐R distribution and assess whether targeting NOP‐R has potential for the treatment of neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

Nociceptin/orphanin FQ opioid peptide‐receptor expression in pachyonychia congenita

Pan

Schröder

Jostock

et al. 2018

J Peripheral Nervous Sys

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Nociceptin/orphanin FQ opioid peptide (NOP)‐receptor (NOP‐R) is a member of the opioid receptor family. NOP‐R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP‐R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC‐affected) and the arch (PC‐unaffected) of the foot. NOP‐R expression was assessed by immunohistochemistry. Localization of NOP‐R in subsets of epidermal nerve fibers was investigated using the pan‐neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene‐related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aβ fibers (neurofilament H [NFH]). Robust NOP‐R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP‐R peptide. NOP‐R expression in keratinocytes was significantly reduced in PC‐affected plantar skin compared with PC‐unaffected skin. In addition, NOP‐R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co‐expressed NOP‐R. Furthermore, most SP+ fibers also co‐expressed NOP‐R. These findings indicate that NOP‐R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.

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“…The first study to characterize PC pain used pain questionnaires and quantitative sensory testing in 35 patients and concluded that the majority of patients with PC experience pain that has a neuropathic component . In this issue of the BJD , Silviu Brill and colleagues from the Tel Aviv Medical Centre present the results of a second, larger study using pain questionnaires and sensory testing in 62 patients with mutations in KRT6A or KRT16 compared with 45 controls . The authors found an association between PC and moderate‐to‐severe chronic pain, thermal and mechanical hypoaesthesia and mechanical hyperalgesia, as well as reduced conditioned pain modulation, all further supporting the notion that the chronic pain experienced by patients with PC is at least in part of neuropathic origin.…”

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confidence: 99%