Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics

Hesselink, Jan M Keppel; Kopsky, David J; Bhaskar, Arun

doi:10.2147/jpr.s122765

Cited by 42 publications

(51 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With respect to pain sensation, the outer membranes of keratinocytes and of the sensory neurons that mediate pain are closely associated within the epidermis . Keratinocytes also express numerous receptors and ion channels capable of activating signalling pathways in response to painful chemical, thermal and mechanical stimuli . They also release soluble molecules capable of directly or indirectly stimulating or modulating pain, including small molecules (e.g.…”

Section: Multiple Candidate Structural and Cellular Contributors To Pmentioning

confidence: 99%

Pain mechanisms in hereditary palmoplantar keratodermas

Weinberg

Polydefkis

2019

Br J Dermatol

View full text Add to dashboard Cite

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.

show abstract

Section: Multiple Candidate Structural and Cellular Contributors To Pmentioning

confidence: 99%

Pain mechanisms in hereditary palmoplantar keratodermas

Weinberg

Polydefkis

2019

Br J Dermatol

View full text Add to dashboard Cite

show abstract

“…For instance, we have found that SFN pain patients, in which pathology resides mainly in the skin, are good responders to phenytoin cream. Elsewhere, we have outlined the pathogenesis of neuropathic pain syndromes related to the skin, pointing out the pathological triad of keratinocytes, immune-competent cells, and nociceptors targeted by topical creams containing sodium channel blockers such as phenytoin 22,23…”

Section: First Patent On Topical Formulations Containing Ketamine Andmentioning

confidence: 99%

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design

Hesselink¹,

Kopsky²,

Stahl

2017

JPR

Self Cite

View full text Add to dashboard Cite

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

show abstract

“…The success of this case provoked us to subsequently develop a line of various creams, and we continued to explore amitriptyline cream. We also developed a hypothesis of why topical analgesics would work without systemic resorption, based on 3 different targets in the epidermis: the small nerve endings (nociceptors), the keratinocytes, and the immune-competent cells [11]. All of these cell populations are characterized by a wide population of sodium channels in their membrane, and there is an intense cross-talk between these cells, leading to peripheral sensitization.…”

Section: Patient Number 1: Diabetic Neuropathic Pain Treated With a Tmentioning

confidence: 99%

Topical Compounded Analgesic Treatment in Neuropathic Pain: 8 years of Experience

Hesselink¹,

Kopsky²

2017

Pain Manage Med

View full text Add to dashboard Cite

In our tertiary referral centre, the Institute for Neuropathic Pain, we have treated many patients suffering from localized peripheral neuropathic pain since 2009. We have developed, together with a compounding pharmacist, a base cream as a topical formulation which has enabled us to compound creams based on amongst others amitriptyline, ketamine, clonidine, baclofen, and phenytoin. We have found that many patients profit from such topical formulations and we will describe our experiences using such creams over the last 8 years in this paper, since we first started exploring such topical treatments. We have analysed the efficacy and safety of these topicals, and based on literature, our own online data pool and the patients who had let us know that they benefited from the creams, found sufficient analgesia and positive effects impaired sleep, while the tolerability was excellent. Patients suffering from localized peripheral neuropathic pain, as in diabetic neuropathy, chronic idiopathic axonal polyneuropathy, chemotherapy induced polyneuropathy and small fiber neuropathy, as well as in complex regional pain syndrome, seem especially responsive to such topical approach. Meanwhile, more than 800 Dutch medical doctors have been prescribing one or more of our compounded creams, and patients and medical doctors from abroad frequently contact us to explore the therapeutic options for their patients based on these creams.

show abstract

Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics

Cited by 42 publications

References 79 publications

Pain mechanisms in hereditary palmoplantar keratodermas

Pain mechanisms in hereditary palmoplantar keratodermas

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design

Topical Compounded Analgesic Treatment in Neuropathic Pain: 8 years of Experience

Contact Info

Product

Resources

About