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Alloknesis and hyperknesis—mechanisms, assessment methodology, and clinical implications of itch sensitization

Andersen, Hjalte Holma,b,*; Akiyama, Tasukub; Nattkemper, Leigh Annb; van Laarhoven, Antoinettea,c,d,e; Elberling, Jesperf; Yosipovitch, Gilb; Arendt-Nielsen, Larsa

doi: 10.1097/j.pain.0000000000001220
Comprehensive Review
Global Year 2018

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.

aLaboratory of Experimental Cutaneous Pain Research, SMI, Faculty of Medicine, Aalborg University, Aalborg, Denmark

bDepartment of Dermatology, Itch Center, University of Miami School of Medicine, FL, United States

cHealth, Medical and Neuropsychology Unit, Faculty of Social and Behavioral Sciences, Leiden University, Leiden, the Netherlands

dLeiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, the Netherlands

eDepartment of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands

fDepartment of Dermato-Allergology, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark

Corresponding author. Address: Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7A, A2-203, Aalborg E, 9220, Denmark. Tel.: +45 24 46 45 15; fax: +45 98 15 40 08. E-mail address: hha@hst.aau.dk (H.H. Andersen).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received December 20, 2017

Received in revised form March 06, 2018

Accepted March 13, 2018

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1. Introduction

Chronic itch is a prominent symptom of numerous skin diseases, in addition to certain neuropathic and systemic conditions.136 Common conditions presenting with itch include atopic dermatitis (AD), psoriasis, postherpetic neuralgia, kidney failure, and liver diseases.35,150,160,161 Similar to chronic pain, chronic itch often occurs with additional somatosensory abnormalities.10,35,66,110 As such, patients with chronic itch are often troubled by mechanical itch dysesthesias, warmth-evoked itch exacerbations, pain, stinging, pricking, and/or burning skin sensations.10,35,46,69,141,163 Itch dysesthesias refer to dysfunctional sensory states, in which considerable itch is evoked by light tactile stimuli (eg, from clothing or touch), or by stimuli that would normally induce only mild itching or pain10,22,66,125 (Figs. 1A and B).

Figure 1

Figure 1

As early as 1938, Bickford described that in the immediate surrounds of an itch provocation (such as a histamine skin puncture), an area where innocuous mechanical stimulation produces itch developed. He termed this phenomenon “itchy skin.”32 The alternate, more precise term “alloknesis” was later coined by LaMotte et al. in 1988, when revisiting and extending on Bickford's findings.32,80,82 Moreover, the term “hyperknesis” was proposed to act as an umbrella term which encompasses the state in which there is enhanced itch to normally itch-provoking stimuli or lowered itch threshold to a given stimulus37,80,82,132 (comparable with hyperalgesia for pain65). These dysesthetic states can last for a couple of minutes to hours after an itch provocation or can be a persistent feature, as seen in patients with chronic itch due to AD.10,64,66 Itch-associated dysesthesias, such as mechanical alloknesis and hyperknesis, are noticeably analogue to the dysesthesias found in various experimental and clinical pain conditions.69,125,135 For instance, while patients with painful peripheral neuropathy may report pain in response to light innocuous brush strokes applied to the skin in or around painful areas (allodynia), patients with chronic itch conditions frequently find such stimuli to be itchy (alloknesis).8,64,125

Such somatosensory reactivity patterns are caused by neuronal sensitization, and those signs associated with pain (allodynia and hyperalgesia) have been elaborately studied both mechanistically,124,153 and in diverse clinical cohorts (covered in detail elsewhere20,25,38,87,120). Therefore, much of the present methodological, phenomenological, and mechanistic evidence on mechanical alloknesis and hyperknesis stems from obvious parallels related to pain-associated dysesthesias, in addition to preclinical and human experimental models of itch.8,22,80,82,125,131,133 Notably, the neurophysiology of itch transmission is highly entwined with the nociceptive system, with no clear differentiating features at the peripheral level. This has given rise to different hypotheses explaining how pruriceptive and nociceptive information coming from the same primary afferents is decoded in the central nervous system (see review on the subject83).

In pain research, highly standardized quantitative sensory testing (QST) methodology21,56,93,120,158, combined with diverse human models of sensitization have spawned the notion of potential sensory phenotyping for diagnostic, prognostic, and therapeutic purposes.19,23,25 Similarly, assessment of alloknesis and hyperknesis allows for surrogate measures of neuronal sensitization in itch patients. However, itch-specific QST protocols are much less advanced and studied compared with pain. It remains to be explored whether assessment of itch sensitization correlates is useful for the purpose of subgrouping, for instance, in patients with AD, akin to the sensory phenotyping being used within pain research.25,47,140,159 The purpose of this review is to provide an overview of the definitions, and present evidence regarding assessment techniques and mechanisms of mechanical alloknesis and hyperknesis while linking this evidence to the more familiar concepts of allodynia and hyperalgesia.

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2. Definitions and terminology

Allodynia and hyperalgesia (the pain-related equivalents to alloknesis and hyperknesis) have been defined and redefined on several occasions.65,90,96–99,124 The present review adheres to the IASP taxonomy task force definitions of 2008 (elaborately described by, eg, Loeser and Treede90,139 and Sandkuhler124). These definitions are not in full agreement with the current IASP definitions (the updated version of the 1994 taxonomy65).

Hyperalgesia (increased pain sensitivity) is characterized as an umbrella term describing all types of increased pain sensitivity, while the term “allodynia” (pain in response to a nonnociceptive stimulus), is restricted to scenarios where the nature of the evoking stimulus is such that it is deemed unable to activate nociceptive primary afferents.97,124,139 This review uses a similar definitional principle for alloknesis and hyperknesis, ie, using hyperknesis if there is doubt as to the prompting stimulus' capability of activating pruriceptive afferents (Figs. 1A and B). This is generally in accordance with the original definitions.80,82

In the literature, conflicting nomenclature is currently being used to describe alloknesis and hyperknesis phenomena. Some studies describe alloknesis solely as itch occurring in response to innocuous (dynamic) tactile stimuli, and hyperknesis only as itch in response to punctate pricking stimuli, which may or may not be considered mildly painful under normal conditions64,112 (Table 1). Other studies denote alloknesis as itch in response to punctate von Frey stimuli, eg, up to 70-mN force1,34,108 (ie, far above the threshold for activating mechanosensitive C-nociceptors). Other reports describe assessments of “mechanical itch sensitivity,” using von Frey filaments in chronic itch patients or after acute itch provocations, omitting the terms alloknesis or hyperknesis.13,76,78,79 Discrepancies exist regarding the extent to which these stimuli are reported to produce itch under normal conditions, and sometimes this is not assessed. It has also been noted that hyperknesis could simply refer to an exaggerated response to chemical stimuli, such as increased itch after histamine, as have been observed in lesional AD skin,55,68,80 but this usage has never caught on. The definitions applied in the present review prevent that a unitary occurrence, such as increased itch sensitivity to punctate mechanical stimuli or chemical itch provocations, as being classifiable as both alloknesis and hyperknesis at the same time, depending on how it is tested (sub threshold vs suprathreshold assessments).

Table 1

Table 1

Recently, “alloknesis” has been used to characterize itch and itch aggravation in response to noxious heat and innocuous warmth stimuli.39,103 Future research might clarify whether gentle warming-induced itch is indeed a type of alloknesis,103 or whether it is an itch-related analogue to inflammatory hyperalgesia. The particular modality-switch dysesthesia, in which itch is evoked in by algogens,64 or exclusively painful stimuli, is not included in current definitions of alloknesis and hyperknesis (Table 1). It has been observed in patients with AD, in healthy subjects with evoked contact dermatitis, and in mice models,64,66,103,112 and is not associated with any specific term. In this review the term “algoknesis” will be applied to describe this sensory phenomenon, which conceivably rely on mechanisms distinct from those of hyperknesis and alloknesis. Itch in response to noxious heat, eg, observed in patients with AD66 will accordingly be characterized as “heat algoknesis.”

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3. Mechanisms of alloknesis and hyperknesis

Given the similarities between itch and pain-evoked dysesthesias, it is natural that aspects of the proposed underlying mechanisms are based on similar experimental approaches and inferences.69,81,125 Experimentally induced alloknesis and hyperknesis typically occur within the region of an itch provocation and in the skin immediately surrounding the provocation site. Consequently, the dysesthesias are referred to as being primary and secondary, respectively. Mechanistically, 2 potentially overlapping sensitization processes exist: sensitization of spinal neurons (central sensitization) and sensitization of the peripheral neurons (peripheral sensitization). In a state of central itch sensitization, pruriceptive spinothalamic tract (STT) neurons respond more vigorously to normal input from pruriceptive primary neurons and mechanosensitive signaling, normally associated with light touch (alloknesis) or mild pain/itch (hyperknesis) converges onto the pruriceptive STT neurons (Figs. 2A and B for models).83,124 The corresponding pain phenomena (ie, secondary allodynia and hyperalgesia) also rely on sensitization of STT neurons.133 These pain dysesthesias do not cross the midline84 or extend beyond a narrow anesthetized strip of skin,73 they are reduced or abolished by myelinated fiber blocks,74,91,165 and are mostly unaffected by ablation of capsaicin-sensitive nociceptors.58,91,165 This all indicates that secondary allodynia and hyperalgesia are segmentally restricted, heterosynaptic, spinal sensitization phenomena which requires peripheral input from myelinated fibers. However, in prolonged inflammatory/neuropathic pain and itch states, additional or entirely different mechanisms potentially relying more on peripheral sensitization, disinhibition, and supraspinal changes may also be involved.23,66,85,124 Strong indirect evidence on the close link between itch and pain-evoked dysesthesias comes from experimental human psychophysical studies. When a conditioning painful stimulation such as an intradermal capsaicin injection,37 or painful transcutaneous electrical stimulation107,108 is preapplied to a skin area, it will exhibit decreased itch sensitivity and reduced itch dysesthesia development long after the spontaneous pain resolves. This may in part be due to the fact that the same neuronal substrates are recruited in the sensitization processes, eg, low-threshold mechanoreceptor (LTM) input to sensitized STT nociceptive and pruriceptive projection neurons is likely responsible for allodynia and alloknesis, respectively. Remarkably, in patients with chronic itch associated with AD, substantial itch and pain can coexist in lesional skin,10,141 and the same is true for robust mechanical hyperalgesia and hyperknesis.10

Figure 2

Figure 2

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3.1. Alloknesis

In nonhuman primates, injection of histamine results in a small number of pruriceptive STT neurons exhibiting increased responses to stroking (alloknesis), or to a punctate skin stimulus (hyperknesis), evoking mild pricking pain sometimes followed by itch in humans.44,130 As outlined above, itch evoked by brush strokes represents a central sensitization phenomenon of wide dynamic range STT neurons likely resulting from an initial PmC or C-mechanoinsensitive–mediated pruriceptive barrage or spinal disinhibition (Fig. 2A and Table 1). This is circumstantially supported by the fact that the primary afferent substrate for light touch is LTMs (Aβ and C-tactile fibers), and that this type of stimulation rarely results in itch under normal conditions. In this context, it is important to note that, in trigeminally innervated areas, very low-intensity mechanical stimuli (such as those used to assess alloknesis or minute vibration of a vellus hair) are sufficient to produce an itch or tickle sensation.11,50 Remarkably, the same trigeminal skin areas exhibit decreased sensitivity to common chemical itch provocations.11,50,92 A recent rodent study quantifying alloknesis by low-intensity von Frey filaments suggested that mechanically evoked itch might be mediated by LTMs, and that such itch is constantly gated by a subpopulation of inhibitory neuropeptide Y+ interneurons also activated by LTM input under normal conditions.34 A follow up study showed that loss of LTM function may be a key driver of alloknesis in xerotic skin by reducing input to the NPY+ iinhibitory interneurons.48 Experiments on allodynia in nonhuman primates show that capsaicin-induced mechanical allodynia occurs in the absence of increased sensitivity of the nociceptive primary afferents,28 whereas STT neurons exhibited enhanced responsiveness to normal input133; thus strongly suggesting central sensitization and subsequent increased convergence to be the driving mechanism. It has recently been shown that not only the STT but also the spinoparabrachial pathway is involved in ascending itch transmission.102 It remains unknown whether these projection neurons are also involved in mediation of itch sensitization. A large proportion of neurons in both the STT and spinoparabrachial pathway expresses the neurokinin-1 receptor.138 When these neurons are selectively ablated, robust inhibition of alloknesis is observed in AD mice,6 thus potentially implicating both ascending pathways.

Notably, areas of alloknesis (and allodynia) rapidly retract when cooling the site of spontaneous itch/pain indicating that at least weak constant pruriceptive C-nociceptor input is required.112,132 This observation aligns with evidence from chronic itch patients where alloknesis is restricted to lesional and perilesional skin.7,64 Pharmacological modulation studies in mice and humans show that the μ-antagonist naltrexone inhibits itch and the development of alloknesis,1,59,117 whereas systemic μ-agonist analgesics generally induce or aggravate itch and exhibit antiallodynic effects.31,75,126 The exact spinal circuitry that mediates secondary alloknesis, hyperknesis, and secondary pain dysesthesias remains to be fully explored. See Peirs et al.113 for a review of recent advances on pain dysesthesias.

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3.2. Hyperknesis

The mechanisms of hyperknesis are less clear, and it remains unknown which type of afferents mediate the mild itch resulting from punctate stimuli.11,50,66,67 Hyperknesis is possibly mediated by type-I Aδ fibers through a central mechanism when occurring secondarily to an itch provocation or an actively itchy skin lesion, as is the case for secondary pinprick hyperalgesia (Fig. 2B). On the other hand, itch evoked by pricking stimuli occurs with a 0.5- to 2-second delay,13,66 indicating PmC fibers as the peripheral sensor (Table 1). When pinprick hyperknesis occurs within an active skin lesion or an area pretreated with an itch provocation, additional peripheral contribution is possible.10,64,66 In the case of an inflammatory perturbation, mechanically insensitive afferents can develop de novo mechanosensitivity, and mechanonociceptors respond more vigorously to suprathreshold stimuli.18,99,118 In chronically itchy AD lesions and to a lesser extend beyond the lesions, profound pinprick-evoked hyperknesis occurs, suggesting concomitant peripheral and central sensitization contributions.10,66,76 A subpopulation of nociceptors potentially responsible for punctate mechanically evoked itch is the nonpeptidergic mass-related G-coupled protein receptor D (MrgprD)–expressing C fibers. These terminate very superficially in the epidermis,166 are implicated in nonhistaminergic itch,88 have low mechanical thresholds,154 and are sensitized to punctate stimuli in a mouse model of contact dermatitis.118 The same contact dermatitis model also produces robust pinprick hyperknesis in humans.112 In AD, intralesional and extralesional itch sensitization to chemical provocations (algogens64,66 and pruritogens10,57,68,137) is mechanistically unaccounted for, possibly reflecting protracted cutaneous aberrations. A study has suggested altered transducer expression, eg, increased proteinase-activated receptor-2 (PAR2) on afferent nerve fibers in lesional AD skin.137 It is unlikely that current acute human models of itch sensitization mimic the sensory aberrations associated with prolonged or chronic inflammatory lesional and related skin alterations.8,16,66 Notably, inflammatory heat hyperalgesia is overwhelmingly driven by peripheral sensitization,99 but this is rather different from the sensory abnormalities found in lesional AD skin,66 where normally painful heat stimuli evoke itch, and innocuous warming of the skin often exacerbates ongoing itch.10 The latter observation has been successfully reproduced in rodent itch models and is believed to predominantly occur after provocations with specific pruritogens such as serotonin.5,103 Human surrogate models known to induce subacute peripheral pain sensitization, such as Ultraviolet B-damage (inflammatory) and intradermal nerve growth factor (noninflammatory), both induce mild primary pinprick hyperknesis but have limited impact on chemical itch provocations.16 The well-studied primary mechanical hyperalgesia of these models differs from that of intradermal capsaicin because it is driven by peripheral sensitization and associated with no/limited spontaneous pain. According to one study, the nerve growth factor model does evoke increased sensitivity to cowhage occurring simultaneously with the maximal mechanical hyperalgesia, indicative of sensitization of mechano-sensitive C fibers.72,122

A complicating factor in terms of understanding hyperknesis is that the manner in which itch and pain are differentially encoded (allowing PmC-nociceptors to be both pruriceptive and nociceptive) remains unknown. If the proposed notion of spatial contrast is indeed a crucial encoding component for discrimination between itch and pain,54,83,104,105 then the mechanism for hyperknesis in lesional skin of patients with itch could simply be either highly scattered loss of PmC fibers (as indicated by nerve morphology studies in chronic itch patients115) or sensitization of a small subset of PmC fibers. Both of these scenarios would likely increase itch in response to pinprick stimuli by giving rise to signaling with unusually high spatial contrast.

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4. Quantitative assessment of mechanical alloknesis and hyperknesis

4.1. Animal studies

Alloknesis is documented by eliciting scratching in response to low-intensity mechanical stimuli that would not normally elicit scratching, for instance, in C57BL/6 mice (Table 2).1 After intradermal injection of pruritogens into the rostral back, a very weak von Frey filament (0.7 mN) is applied to the skin area around the injection site. The presence or absence of an evoked hind limb scratch bout directed toward a site of innocuous touch is noted. Touch-evoked scratching is usually observed less than a second after the stimulus. Pharmacological validation of this assessment method has been performed by showing effective abolishment of alloknesis after treatment with opioid antagonists, selective κ-opioid agonists, and H1 histamine antagonists (when the chemical itch provocation is histamine dependent).1,2,59 The onset of alloknesis is often delayed relative to the onset of chemically evoked scratching, implying that substantial constant itch input is required to develop alloknesis. Touch-evoked scratching after innocuous stimuli is also present in experimental mouse models of chronic itch (Table 2). In humans, alloknesis is often assessed by brush strokes (section 4.2) and although brush-evoked scratching has not yet been reported in rodents, pruriceptive signaling in response to brush stimuli is enhanced after an intrathecal injection of morphine in rat pruriceptive trigeminothalamic tract neurons.101

Table 2

Table 2

Mechanical hyperknesis has not been clearly established in rodents, because of the lack of a standardized method to assess a mechanical itch threshold in naive rodents. Mechanically evoked itch in response to graded stimulation peaks below the force of the mechanical pain threshold in humans (as well as the minimum force normally required to activate PmC-nociceptors).66,147 In addition, the relationship between mechanical force and evoked itch intensity follows an inverted U-shaped curve. One study on alloknesis reported that few scratch bouts were elicited by application of graded von Frey filaments in naive mice,34 but even with the most effectively itch-evoking von Frey filament force (0.7 mN), scratch bouts were only elicited in response to less than 15% of the stimuli. A fundamental translational challange regarding the quantification of itch however, is that animal readouts are always scratch dependent. Oppositely, humans can easily rate an evoked itch sensation, which is so mild that it would rarely elicit an actual scratch. In human studies, this is almost always the case for the mechanically evoked itch in healthy skin.9,10,66,78 Finally, as there are rodent strain differences in mechanical sensitivity,100 the mechanical itch thresholds should be assessed in each strain tested. Outbred mouse strains might not be suitable for preclinical studies of mechanical itch because of their genetic heterogeneity.

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4.2. Human experimental studies

Using human surrogate models of acute and subacute itch, detailed assessments of alloknesis and hyperknesis to mechanical stimuli can be undertaken (Table 2). Intradermal injection, a skin prick, or iontophoretic delivery of a pruritogen such as histamine, mucunain, or serotonin evokes acute itch lasting for 5 to 20 minutes.8,63,132 During or as the itch subsides, the spatial extent of alloknesis and hyperknesis can be assessed by stimulating the skin surrounding the injection site.67,112,132,151 Alloknesis is commonly assessed using light brush, whereas hyperknesis is often assessed with pinprick stimulators or von Frey monofilaments.10,11,67,112 Typically, stimuli are delivered in small increments (0.5-2 cm) following multiple vectors moving from well away from the injection site and toward it. The subjects are asked to notify the investigator when the stimuli turn from producing pure innocuous tactile sensations into itch (alloknesis) or from a pricking/slightly itchy to evoking noticeably more itch (hyperknesis).132 This procedure can be repeated in short succession (as areas of alloknesis and hyperknesis are dynamic) to decrease variability and produce an accurate spatial mapping of the extent of alloknesis or hyperknesis. The drawbacks are that it is (1) time consuming, (2) vulnerable to false positives (a control is always required), and (3) relies on a localized initial itch (making it difficult to apply to endogenously evoked itch in patients). Alternatively, the intensity of the alloknesis and/or hyperknesis can be assessed in the immediate vicinity of an itch provocation.11,64,76,112 Here, the stimulation is conducted several times, with multiple intensities close to the itch provocation/lesional site, but usually not directly on the bleb or wheal. The subject is asked to rate the presence and/or the intensity of the mechanically evoked itch.10,11,64,112 The intensity or simply the presence of alloknesis, can be quantified in response to brush strokes or cotton wool stimuli and the intensity of hyperknesis in response to von Frey or pinprick stimuli.11,64 Evidence suggests that punctate stimuli approximately at, or immediately below the pinprick pain threshold are most effective and also often produce mild itch in unaffected skin. This method is faster than the area approach but does not detect the spatial outline of the assessed dysesthesias and relies on the subject providing an intensity rating rather than simply a shift in perception. On the other hand, the method lends itself more readily to be used, eg, on lesional, perilesional, or nonlesional skin in patients.10,66,76,79 Both methods can be used to assess different itch provocations or interventions and to assess the temporal development of itch dysesthesias. These methods are entirely paralleled by the techniques used in pain research,121,131 where experimentally provoked allodynia and hyperalgesia have been extensively studied. In pain research, these methods have been used, for instance, in an attempt to measure objective correlates of central sensitization,36 or to characterize the peripheral nociceptors involved in induction of long-term potentiation-like pain facilitation.58

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4.3. Clinical studies

Several studies have performed explorative assessments of alloknesis and hyperknesis in patients with chronic itch in both lesional and nonlesional skin areas, as well as before and after experimental itch elicitation (Table 3). Generally, 1 of 2 methods has been applied in previous studies: (1) alloknesis or hyperknesis has been assessed in lesional and/or nonlesional skin of patients using an intensity approach, ie, patients and healthy controls are requested to rate if and how much itch they perceive in response to selected mechanical stimuli (brush, wool fibers, or pinprick)10,66,76,145; and; (2) patients and controls receive an itch provocation, eg, histamine or electrically induced itch, in nonlesional skin (homologous areas for controls), and subsequently the area of alloknesis or hyperknesis is mapped as described in section 4.2.67,149,151 A few studies have used the spatial extent method outlined above only after an experimental itch provocation,149,151 thus excluding the detection of potential baseline differences between chronic itch patients compared with healthy controls. Both chronic itch and pain may lead to generalized somatosensory changes, and therefore even seemingly unaffected areas are not necessarily suitable control areas.10,53,76,78 For instance increased hyperknesis, increased mechanical pain sensitivity, and facilitated itch responses to cowhage provocations were recently observed in nonlesional skin in patients with AD, compared to homologous skin areas in matched controls.10 Particularly, when stimulations are performed in patients with inflammatory skin disorders, barrier alterations must be considered as potential as biasing factors completely unrelated to cutaneous neuronal sensitivity. For instance, pinprick perception might be altered in lichenified skin,10 responses to chemical provocations delivered by iontophoresis might be exaggerated in excoriated areas with reduced barrier integrity, and the temporal profile of evoked itch might be affected by increased or reduced vasomotor reactions to pruritogens by affecting local tissue clearance.11,68

Table 3

Table 3

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5. Applicability of itch dysesthesia assessments

5.1. Mechanical itch dysesthesias in patients

Despite diverse assessment methodology, clinical studies of alloknesis and hyperknesis demonstrate a relatively consistent pattern of results (Table 3). Most studies have been performed in patients with chronic itch due to of AD. When quantifying the spatial extent of alloknesis or hyperknesis after an itch provocation in nonlesional skin, patients with AD do not develop larger areas of mechanical dysesthesias than healthy controls.60,67,149,151 However, it is evident that when using the intensity quantification approach, both robust alloknesis and hyperknesis occur in lesional AD skin,10,64,66,76 whereas good evidence is lacking from other chronic itch conditions. Results from studies applying the intensity quantification approach without previous itch provocations in nonlesional skin of patients with AD are more inconsistent. A single study assessing alloknesis found no evidence of it occurring in nonlesional AD skin.64 Alloknesis has previously been described in case studies of neuropathic itch patients as occurring perifocally, restricted to areas of moderate to severe itch,7,15 and is likely more or less dependent on ongoing spontaneous itch nearby.112,132 With regards to hyperknesis in AD, Ikoma et al. (2004), documented significant lesional and perilesional hyperknesis in response to weighted needle stimulation, whereas van Laarhoven et al. (2007) and Andersen et al. (2017) observed significant hyperknesis in both lesional and nonlesional skin probed using von Frey stimulators (Table 3). Significant inter-individual variability in the severity of hyperknesis seems evident amongst patients with AD, possibly indicating the existence of patient subgroups with high vs low mechanical itch sensitization (Figs. 3A and B).10 Extralesional hyperknesis seems to almost exclusively occur in patients also displaying hyperknesis in lesional skin (Figs. 3C and D).10 In painful peripheral neuropathy, a well-characterized sensory subphenotype is characterized by prominent mechanical hyperalgesia, eg, to pinprick stimuli.25 This particular subgroup is proposed to have increased analgesic responses to sodium-channel blockers and gabapentinoids.25,48

Figure 3

Figure 3

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5.2. Disinhibition as a cause of itch sensitization

Itch, akin to pain, is under both segmental and supraspinal descending inhibitory control.27,95 The former is clearly evident from the itch relief obtainable by homotopic or perilesional counterstimuli such as scratching or heat,14,162 whereas the latter has been shown using conditioned itch modulation paradigms in patients and healthy controls77 (an approach adapted from psychophysical pain research109,156). It is unclear whether blunted responsiveness in either of these endogenous inhibitory systems contributes to itch dysesthesias in chronic itch patients. However, indications of both reduced segmental inhibition70,128,141 (Fig. 2C) and impaired descending itch inhibition have been reported.77 Such assessments have been performed with mostly nonvalidated psychophysical methodology. A recent experimental study in healthy human volunteers indicates that pain-evoked recruitment of descending inhibitory signaling diminishes not only itch but also the development of hyperknesis after electrically induced itch.12 This is in line with evidence from the pain field showing that conditioned pain stimulation reduces the intensity of secondary brush-evoked allodynia,152 after intradermal injection of capsaicin. Given the severity of partially self-inflicted lesions and cutaneous pain coexisting with itch in AD,10,35,110,141 it is not unreasonable to suspect blunted pain-evoked inhibition in this condition as a previous implied.17,66,70 This is likely caused by spinal disinhibition of itch as pain thresholds are usually normal or only marginally decreased.10,114 Validated psychophysical assessment methods are needed before it can be established whether dysfunctional segmental or supraspinal descending itch inhibition is a feature in chronic itch conditions. Reduced descending pain inhibition, measured by conditioned pain modulation (CPM) paradigms, has been found in numerous chronic pain conditions and is implicated in the pain progression.53,111,156,157 Notably, the effect of drugs enhancing endogenous pain inhibition, such as duloxetine, can be predicted by CPM, in that low CPM responses correlate with increased analgesia.159

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5.3. Itch sensitization to nonmechanical provocation modalities

In rodents, innocuous warming aggravates serotonergic but not histaminergic itch.5 Patients with AD consistently report that their itch is worsened by warmth.10,52,143 However, in acute human models of itch, such findings are not reproduced, potentially because studies have almost exclusively relied on histaminergic itch provocations not mimicking itch in AD.14,49 Although studies on itch in response to innocuous thermal stimulation in AD are inconclusive, heat algoknesis has been documented in patients with AD. Heat stimuli in the noxious range applied in lesional skin of patients with AD have been shown to induce itch even when such stimuli were consistently rated as evoking only heat pain in the healthy controls.66 Similar observations have been made in a human model of contact dermatitis itch.112 For electrically induced itch, the evidence is contradictory, with studies showing both no differences in itch ratings between chronic itch patients vs healthy controls, as well as studies showing significant sensitization in itch patients.67,79,164 Itch sensitization to chemical provocations with pruritogens10,68,145 is the most studied phenomenon. Although it is beyond the scope of the current review to summarize this extensive literature, it seems that evidence supports at least 2 central findings: (1) There is limited sensitization to histaminergic itch provocations, perhaps beyond mild sensitization occurring intralesionally,68,144,145 and (2) recent studies indicate increased intralesional and extralesional sensitivity to cowhage-evoked itch.10,57,114 However, a systematic assessment of studies on sensitization to various chemical itch provocations in chronic itch patients is needed before more definite conclusions can be drawn. Notably, algoknesis to chemical pain provocations is well documented. In lesional skin of patients with AD, common algogens such as acetylcholine,61 low-pH solution,66 and bradykinin64 predominantly evokes itch, whereas they mostly or exclusively evokes pain in healthy controls. Conversely, histamine, which is considered a quintessential pruritogen, has been shown to act as an algogen in patients with chronic postherpetic neuralgia.26 Pruriceptive C-nociceptors are prone to tachyphylaxis after repeated chemical stimulations.3,86 Hence, in chronic inflammatory itch conditions, sensitization of pruriceptive units probably include mechanisms by which tachyphylaxis is counteracted, which would contribute to maintaining prolonged itch exacerbations. A proposed mechanism hereof is that local tissue acidosis (associated with inflammation) enhances pruriceptive signaling by co-opting acid-sensing ion channel 3.71

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5.4. Potential implications of itch sensitization

For many patients with chronic itch, alloknesis and hyperknesis are highly bothersome symptoms that prompt, maintain, or worsen scratch bouts and impose behavioral restrictions, including avoidance of wearing certain fabrics or staying away from warm environments.10,29,35,142 It is not clinically feasible to implement microneurographic recordings from peripheral neurons, and assessing sensitization directly in spinal nociceptive circuitry is impossible in humans. Instead, using QST, the severity and spatial extent of itch dysesthesias and hypersensitivity to various sensory stimuli can be psychophysically measured in individual patients.8,10,66,145 Based on case descriptions, mapping of alloknesis/hyperknesis has been found useful as a mean to locate an itch hypersensitive area on normally appearing skin.7,15

Within the pain research area, assessment of sensitization using standardized QST and advanced sensory paradigms, such as temporal summation of pain and CPM, have been shown to be useful, for instance in predicting treatment response to pharmaceutical and surgical interventions.25,47,116,159 Notably, recent studies have shown that mechanistic subgrouping of neuropathic pain patients based on assessment of, eg, mechanical and thermal hyperalgesia may result in improved treatment response rates.47,94 Such studies have not yet been undertaken in patients with chronic itch, but it is clear that centrally acting antipruritics can be of use in otherwise refractory patients.41,117 Moreover, a recent study proposed that prolonged itch and microvascular reactions to cowhage and histamine provocations might act as diagnostic indicators of AD, being of potential value in atypical/mild cases.57 Currently, the clinical utility of assessing alloknesis and hyperknesis as well as itch sensitization in general (eg, sensitization to chemical provocations) remains to be explored. Antipruritic therapeutic measures should focus on reducing local inflammation and targeting the underlying cause when possible. In contrast to chronic pain, chronic itch is mainly regarded as a symptom of an underlying disease rather than as a disease itself. However, chronic itch also presents in absence of any recognized disease processes, often denoted as chronic idiopathic pruritus.30,155 Disease measures such as lesional severity in AD correlates surprisingly poorly with the itch and cutaneous pain that the individual patients report.42,148 An analogue mismatch between pathological findings and pain symptoms is commonly observed in pain conditions.20,51 It could be hypothesized that chronic itch patients with inflammatory dermatoses displaying no signs of itch sensitization, for instance, no alloknesis/hyperknesis nor increased responses to chemical provocation in nonlesional skin, would respond adequately to peripherally acting anti-inflammatory and immune-modulatory drugs. On the other hand, patients exhibiting significant intralesional and extralesional itch sensitization could benefit more from additional therapeutics inhibiting central itch processing as well as sensitization.68 Evidence from the pain field suggests that centrally acting pharmacotherapy inhibiting central hyperexcitability in addition to cognitive behavioral, stress-relief, or exercise therapies might be effective in reducing sensitization. Relevant pharmaceuticals include N-methyl-D-aspartate-receptor antagonists, opioids, tricyclic antidepressants, selective-serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and gabapentinoids.24,25,40,106 Notably, despite a scarcity of randomized controlled trials with itch relieving drugs, both selective-serotonin reuptake inhibitors and gabapentinoids have antipruritic effects in certain itch conditions while opioids (μ-agonists) are well known to induce itch.117 Several studies have associated psychophysical measures of pain sensitization with treatment outcome after both pharmaceutical and surgical interventions.47,94,116,159 Such data are currently lacking in the context of itch, and it is unclear whether similar mechanistic inferences can be drawn from itch sensitivity testing. Although alloknesis and hyperknesis are commonly referred to as prominent features of chronic itch conditions,125,135 they have thus far only been sparsely studied in other chronic itch patients groups than AD.60,66,76,78,145 Assessing the clinical utility of itch sensitivity quantification requires developing a standardized, compact psychophysical test battery designed to detect, and measure itch sensitization in patients.93 Such tests need to be based on, and optimized in accordance with, advances in our mechanistic understanding of itch and itch sensitization to mechanical and other types of stimuli. Concerns have recently been expressed regarding the degree to which the nociceptors responsible for spontaneous pain, for instance in neuropathic conditions, are specifically testable with currently applied sensory assessment protocols.33,127 Data from pain patient cohorts obtained by QST paradigms such as sensory pain thresholds only occasionally correlate well with the reported clinical pain.119,127,134,159 As similar caveats might adhere to itch sensitivity assessments, it is by no means a foregone conclusion that sensory testing is clinically useful in the context of chronic itch.

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6. Conclusion

Cutaneous dysesthesias associated with itch and pain are strikingly similar and can be assessed by similar sensory testing techniques, acting as proxy measures of sensitization. For pain, assessment of allodynia and hyperalgesia are ubiquitous in probing the nociceptive system in preclinical, experimental, and clinical settings. Clinically, this may be used to inform/predict responsiveness to treatment. By contrast, assessment of itch-associated dysesthesias has only been marginally studied. Quantifying alloknesis and hyperknesis provides behavioral or psychophysical proxies measures of itch sensitization that can be performed in animal and human surrogate models of itch, as well as in patients. This review provides a comprehensive overview of (1) the definitions and purported mechanisms of alloknesis and hyperknesis and their analogy to pain sensitization phenomena; (2) the methods by which alloknesis and hyperknesis can be quantified in preclinical, human experimental, and clinical studies; (3) the results derived from studies of alloknesis and hyperknesis in chronic itch patients; and (4) the potential clinical utility and challenges of detecting and measuring itch sensitization. Measuring and distinguishing between alloknesis and hyperknesis with currently available methods is not a trivial task, and much remains unknown regarding neurophysiology of itch sensitization and the interaction between itch and pain. Psychophysical studies in patients suffering from chronic itch have repeatedly shown mechanosensory aberrations compatible with itch sensitization. However, these phenomena have only been sparsely documented in diseases other than AD. Further research needs to examine the mechanisms of itch sensitization, how current assessment methods can be optimized, why sensitization characteristics are pronounced only in certain patients within the same itch condition, and whether these psychophysical tests can be used clinically.

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Conflict of interest statement

The authors declare to have no conflicts of interests.

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Acknowledgements

H.H. Andersen acknowledges support from Spar Nord Fondens Forskningspris 2017 and the EliteForsk 2016 Travel-Stipend granted by the Danish Ministry of Higher Education and Science. Sinead Holden is acknowledged for proof reading the manuscript.

Author contributions: H.H. Andersen and T. Akiyama wrote the initial manuscript draft. All authors commented on and approved the manuscript.

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                    Keywords:

                    Itch; Hyperknesis; Alloknesis; Pain; Central sensitization; Peripheral sensitization; Quantitative sensory testing

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