Tuesday, December 24, 2019

Itch sensitization

van Laarhoven AIM, Marker JB, Elberling J, Yosipovitch G, Arendt-Nielsen L, Andersen HH. Itch sensitization? A systematic review of studies using quantitative sensory testing in patients with chronic itch. Pain. 2019 Dec;160(12):2661-2678.

As well established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch. Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and nonlesional skin, and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available. Of 4667 identified articles, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis [AD]) were found more sensitive than the controls to histamine-evoked itch in lesional skin (standardized mean difference [SMD]: 0.66 confidence interval [CI]: 0.16-1.15), but not nonlesionally (SMD: -0.26 [CI: -0.58 to 0.06]). Cowhage did not evoke more itch in nonlesional skin of patients as compared to the controls (SMD: 0.38). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies. Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than AD are needed to establish whether sensitization is robustly present across chronic itch conditions.

From the paper:

Itch is an unpleasant sensation, distinct from pain, characterized by evoking a desire to scratch the affected area. Most individuals experience occasional acute episodic itch, which usually resolves spontaneously within hours or days. However, chronic itch (defined as lasting more than 6 weeks) is also associated with cutaneous pain and dysesthesias, and profoundly impacts quality of life, eg, by interfering with sleep, attention, and affective functions. Chronic itch is the primary sensory symptom in a wide range of skin, neuropathic, systemic, and drug-induced conditions. With a point prevalence of chronic itch estimated between ≈5 and 15%, and largely suboptimal treatment options, chronic itch represents a significant socioeconomic burden. Notably, the pathomechanisms driving chronic itch in prevalent skin conditions, such as atopic dermatitis (AD), and itch of neurological origin remain largely unknown. Neuronal sensitization occurring both in the periphery and in the central nervous system has been suggested to play a role as has been established for pain. 

Although pain sensitization has been extensively studied in animals, human surrogate models, and patients sensitization for itch has only been sparsely investigated. This is somewhat surprising, given that the first attempts to study histamine skin responses were early in the 20th century and signs of itch sensitization in patients were studied for the first time some decennia thereafter. Cormia et al. meticulously investigated differences in "itch threshold" by serial diluted intradermal histamine injections in patients with chronic itch of various origins vs healthy controls. In addition, in 1955 Shelley and Arthur used various modalities, including mucunain from cowhage spicules and trypsin, to probe itch sensitivity in various pruritic conditions and as well as during extensive array of experimental manipulations. The recent discovery of parallel afferent itch pathways (the neuronal encoding remains enigmatic), endogenous receptors of mucunain-induced itch, spinal circuitry involved in itch transmission/modulation, as well as several novel molecular substrates involved in pruritic signaling has spawned renewed interest in studying whether patients suffering from chronic itch become sensitized akin to what has been shown in chronic pain patients...

The main findings of the present systematic review and meta-analysis support the notion that patients with chronic itch display alterations in somatosensory sensitivity to a wide range of stimulations in lesional skin, whereas findings from nonlesional skin are less clear. Studies have predominantly been conducted in patients with AD, the only itch diagnosis for which aggregated meta-analytic evidence was present. Next, studies are characterized by substantial heterogeneity in terms of recruitment criteria, methodology, outcome reporting, and study design.

Specifically, in lesional skin areas, increased itch responses are observed to chemical pruritogens (predominantly histamine, but also cowhage), algogens (eg, bradykinin), and mechanical as well as thermal stimuli. The observed sensory alterations predominantly take the form of increased itch responsivity as opposed to altered detection and pain thresholds. However, meta-analytic evidence is only conclusive for increased lesional histaminergic itch sensitivity in AD. This is mainly due to a low number of studies for other stimulation modalities and populations other than AD. In nonlesional skin of chronic itch patients, several studies indicate that histaminergic sensitivity is unaltered or decreased. Certain nonhistaminergic provocations, chiefly cowhage, are found to evoke increased itch in nonlesional skin in some, but not all studies. Likewise, several studies suggest generalized punctate hyperknesis in nonlesional skin, but this observation is not uniform across studies. Hence, altered somatosensory processing seems to occur in lesional skin of patients with AD suffering from chronic itch, whereas it remains unclear if and in what way sensory sensitivity is robustly changed in nonlesional skin, in patient groups other than AD, and whether such potential changes correspond to the generalized increased pain sensitivity often reported in chronic pain patients.


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