Itch Sensitization? A Systematic Review of Studies Using Quantitative Sensory Testing in Patients With Chronic Itch

Antoinette I.M. van Laarhoven; Jens B. Marker; Jesper Elberling; Gil Yosipovitch; Lars Arendt-Nielsen; Hjalte H. Andersen

Disclosures

Pain. 2019;160(12):2661-2678. 

In This Article

Abstract and Introduction

Abstract

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 [CI: −0.04 to 0.81]). 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.

Introduction

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.[27,82,104] However, chronic itch (defined as lasting more than 6 weeks[107]) is also associated with cutaneous pain and dysesthesias, and profoundly impacts quality of life, eg, by interfering with sleep, attention, and affective functions.[51,82] Chronic itch is the primary sensory symptom in a wide range of skin, neuropathic, systemic, and drug-induced conditions.[107,124] With a point prevalence of chronic itch estimated between ≈5 and 15%, and largely suboptimal treatment options, chronic itch represents a significant socioeconomic burden.[82] 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.[14,15,26,67,113]

Although pain sensitization has been extensively studied in animals, human surrogate models, and patients,[4,98] 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.[21,22,30] 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.[21,22] In addition, in 1955 Shelley and Arthur[103] 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[50,74] (the neuronal encoding remains enigmatic[52,63]), endogenous receptors of mucunain-induced itch,[87,88] spinal circuitry involved in itch transmission/modulation,[2,16,90,109] as well as several novel molecular substrates involved in pruritic signaling[42,73,87,126] has spawned renewed interest in studying whether patients suffering from chronic itch become sensitized akin to what has been shown in chronic pain patients.[5,8,98,127]

Defining Sensitization

Sensitization in the context of pain as well as itch refers to a state of increased responsiveness of nociceptive and pruriceptive neurons, respectively, to their normal or subthreshold afferent input.[34,97,111] In the field of pain research, the molecular mechanisms and behavioral as well as psychophysical manifestations of sensitization have been intensively studied.[64,97,127] Sensitization is usually classified as being either peripheral (affecting primary afferent nociceptors) or central (affecting nociceptors in the central nervous system), and often both may play a role in chronic itch and pain conditions. Particularly, the denotation of central sensitization is associated with ongoing definitional contention,[20,55,97] in part because the underlying pathophysiology is currently not fully understood.[127] Central sensitization may also be aggravated by biopsychosocial factors, such as anxiety, increased attention, and negative expectations.[1,96,116] For this study, the term sensitization is used in the broadest sense. As a proxy of sensitization, an increased psychophysical sensitivity in patients compared to that of healthy controls in response to a controlled somatosensory stimulus (often designed to evoke itch) has often been studied. Although an increased psychophysical sensitivity is plausibly a reflection of increased responsiveness of peripheral and/or central pruriceptive nociceptors, direct evidence hereof is seldomly present in human studies.[34,97] Nevertheless, it can often be inferred whether underlying processes are likely to be manifesting at a peripheral or central level (eg, when stimulating on lesional or nonlesional skin, respectively). Although much is known about mechanisms of pain sensitization, relatively little is known about the mechanisms causing sensitization specifically for itch. They seem to largely, if not entirely, overlap with the processes leading to sensitization for pain.[46,94] A thorough recapitulation of the mechanisms behind neuronal sensitization is beyond the scope of this study and we instead refer to previous excellent reviews.[8,97,101,127]

Probing Sensitization for Itch and Pain

Not only are the underlying mechanisms of sensitization for itch and pain thought to be largely shared, but painful and pruritic stimuli also induce strikingly similar dysesthesic manifestations.[5,98,106] Within and immediately surrounding the area of painful stimuli, allodynia and hyperalgesia may develop.[69,97] Completely analoguous hereto but occurring in the context of itch are alloknesis, describing the state in which an otherwise nonpruritic stimulus, such as light tactile stimuli, provokes a sensation of itch (similar to allodynia),[12,105] and hyperknesis, describing an increased itch response elicited on a normally pruritic stimulus, eg, by means of mechanical probing or a chemical itch provocation (similar to hyperalgesia).[10,17,44] These dysesthesias, suggested constitute signs of sensitization, are not only experimental phenomena—they also occur in (and can be highly bothersome for) patients with acute and chronic itch or pain.[7,44,119] Quantitative sensory testing (QST) for experimental itch and pain sensitivity assessment is multimodal, ie, include thermal, mechanical, electrical, and chemical stimuli. These can be applied to various tissues including muscles, viscera, and skin, with the latter naturally being the most commonly used substrate for QST in chronic itch patients, given that itch exclusively arises from the skin and certain mucosal tissues.[9,107,115] Standardized stimuli can be delivered to assess detection thresholds, itch/pain thresholds, and suprathreshold reactivity corresponding to different transduction receptors, primary afferent populations, and central nervous system pathways.[29,31] With this approach, specific localized or systemic sensory aberrations (eg, reduced thermal detection thresholds in small fiber neuropathy or increased itch responses to mechanical stimuli), can be identified, linked to, and act as proxy measures of an ongoing pathophysiological process.[43,44,66]

Although there is a substantial volume of literature on the study of QST methodology and sensory aberrations occurring in pain patients,[8,9,18,66] QST studies in the field of itch research are rather scarce and often more methodologically heterogeneous. Numerous recent studies have investigated somatosensory sensitivity in patients with chronic itch vs healthy controls. This first systematic review in the field comprehensively summarizes and meta-analytically evaluates whether, and the degree to which, aberrations including sensitization for itch occur in response to somatosensory stimuli in conditions characterized by chronic itch resulting from skin or neurological conditions as opposed to healthy controls.

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