doi:10.

1093/brain/awt158

Brain 2014: 137; 313322

| 313

BRAIN
A JOURNAL OF NEUROLOGY

REVIEW ARTICLE

The neurology of itch

Amar Dhand and Michael J. Aminoff
Department of Neurology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0114, USA
Correspondence to: Michael J Aminoff, MD, DSc, FRCP
Room 795-M,
Department of Neurology,
School of Medicine,
University of California San Francisco,
505 Parnassus Avenue,
San Francisco,
CA 94143-0114,
USA
E-mail: aminoffm@neurology.ucsf.edu

Keywords: itch; pruritus; afferent pathways; itch therapy

Introduction
We have all experienced an itch (pruritus). It is a common
phenomenon of remarkable complexity that has received little attention in neurological circles. In the past 15 years, important
advances have occurred in the study of itch. The purpose of this
paper is to review these developments and their clinical
implications.

Itch is an irritative sensation provoking a scratch response that

provides at least temporary relief. It has been thought to serve a
self-protective function, protecting the skin against potentially
harmful agents (Stander et al., 2003). It normally originates in
the skin and transitional tissues, such as the conjunctiva and
anal mucosa (Handwerker, 2010), which it serves to protect
from irritating stimuli, but it can also arise from central or peripheral neurological lesions, as when it follows a stroke or occurs with

Received January 26, 2013. Revised March 26, 2013. Accepted April 8, 2013. Advance Access publication June 22, 2013
The Authors (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

Downloaded from by guest on August 16, 2015

Research over the past 15 years has helped to clarify the anatomy and physiology of itch, the clinical features of neuropathic itch
syndromes and the scientific underpinning of effective treatments. Two itch-sensitive pathways exist: a histamine-stimulated
pathway that uses mechanically insensitive C-fibres, and a cowhage-stimulated pathway primarily involving polymodal C-fibres.
Interactions with pain continue to be central to explaining various aspects of itch. Certain spinal interneurons (Bhlhb5) inhibit
itch pathways within the dorsal horn; they may represent mediators between noxious and pruritic pathways, and allow scratch
to inhibit itch. In the brain, functional imaging studies reveal diffuse activation maps for itch that overlap, but not identically,
with pain maps. Neuropathic itch syndromes are chronic itch states due to dysfunction of peripheral or central nervous system
structures. The most recognized are postherpetic itch, brachioradial pruritus, trigeminal trophic syndrome, and ischaemic strokerelated itch. These disorders affect a patients quality of life to a similar extent as neuropathic pain. Treatment of neuropathic
itch focuses on behavioural interventions (e.g., skin protection) followed by stepwise trials of topical agents (e.g., capsaicin),
antiepileptic drugs (e.g., gabapentin), injection of other agents (e.g., botulinum A toxin), and neurostimulation techniques (e.g.,
cutaneous field stimulation). The involved mechanisms of action include desensitization of nerve fibres (in the case of capsaicin)
and postsynaptic blockade of calcium channels (for gabapentin). In the future, particular histamine receptors, protease pathway
molecules, and vanilloids may serve as targets for novel antipruritic agents.

314

| Brain 2014: 137; 313322

Table 1 Examples of chronic itch conditions by category

Itch category

Representative conditions

Dermatological

Atopic dermatitis
Bullous pemphigoid
Psoriasis
Urticaria
Pruritus ani

Systemic

Cholestasis
Uremia
Hodgkins lymphoma and other malignancy
Polycythemia vera rubra
Graves disease
Iron-deficiency anemia
Diabetes mellitus

Infectious

Human immunodeficiency virus (HIV) infection

Parasitosis (including scabies, trichinosis,
ascariasis, and hookworm)
Varicella
Tinea pedis

Medication-related Mu-receptor opioids

Chloroquine
Neuropathic

See Table 2

Psychiatric

Depression
Delusional parasitosis
Neurotic excoriations

Other

Pregnancy
Itch in the elderly

In some cases, such as uraemia or HIV infection, a specific disorder has multiple
causes for itch, but the disorder has been placed in a single category for simplicity.

instances are unclear, some have suggested that pathological disruption of the antagonistic interaction unmasks normally silent
neuronal pathways that allow a sensory stimulus to evoke a
new sensation, such as a painful stimulus evoking itch (Ma, 2012).

Peripheral biology of itch

In typical circumstances, pruritogens stimulate skin receptors and
activate the peripheral pathway of itch. This provokes a signalling
cascade and action potentials in at least two types of C-fibres.
These nerve fibres conduct the action potential to the dorsal
horn of the spinal cord (Fig. 1).
A key debate is the encoding of itch in the afferent pathway.
Similar to theories on pain, the opposing positions are specificity
theory and pattern theory. Supporters of the specificity theory
argue for modality-specific receptors and peripheral nerves that
constitute a labelled line from the skin to the brain, as originally
articulated in Mullers 1826 doctrine of specific nerve energies.
Proponents of the pattern theory argue that somatic sensations
including itch are generated by receptors and peripheral nerves

Downloaded from by guest on August 16, 2015

a peripheral neuropathy. The sensation may be localized or widespread, commonly outlasts any inciting mechanical stimulus, and is
sometimes accompanied by skin changes. Itchy skin (alloknesis) is
itch that is augmented by light touch or brushing of the skin
around an itching source. Similarly, hyperknesis is itch that is
enhanced when prick is applied to the same surrounding skin
area. Itch is a multidimensional perception with psychological aspects, as exemplified by its induction by thought of an irritating
stimulus (Ikoma et al., 2006). The scratch phenomenon, which
may be painful in other instances, may paradoxically be pleasurable in the setting of itch. Other motor responses to itch include
rubbing or kneading the skin. The local application of cold may
also alleviate itch.
An important distinction is between acute and chronic itch.
Acute itch is the sensation experienced when itch-inducing stimuli
(pruritogens) contact the skin, and usually is relieved by pain
(including scratch) in the surrounding area. Chronic itch is the
persistent sensation that results from various causes in which
pain does not relieve itch, and may actually be perceived as
itch. Table 1 shows some common causes of chronic itch. By analogy to pain, two main mechanisms of chronic itch have been
proposed. Peripheral sensitization is the decreased activation
threshold and increased basal activity of itch-related receptors
and nerve fibres (Potenzieri and Undem, 2012). Central sensitization results from the neuroplasticity that occurs in the spinal cord
and brain such that non-pruritic stimuli are perceived as, or augment, itch. Together, these are the likely mechanisms of alloknesis
and hyperknesis described earlier.
Itch and pain are distinct sensations that interact. The clearest
differentiation is the effector limb of bothwithdrawal for pain
compared with scratch for itch. The interaction between itch and
pain traditionally has been thought to be antagonistic, with pain
dominant over itch (Stander et al., 2003; Binder et al., 2008). This
is most evident when noxious counter-stimuli on the skin suppress
itch sensation, and when opioids inhibit pain but cause itch
(Handwerker, 2010; Schmelz, 2010). The mechanism of this itch
suppression is probably central, as supported by at least two experimental observations: (i) noxious counter-stimuli may be several
centimetres or more away from the itch source, suggesting that
different afferent fibres are activated and their signals integrated
at the spinal cord level (Seo et al., 2009; Davidson and Giesler,
2010); and (ii) secondary hyperalgesia induced by various noxious
stimuli in a skin patch of several centimetres abolishes cowhage or
histamine-induced itch in that area, consistent with a central excitatory state that activates pain and blocks itch (Brull et al., 1999;
Binder et al., 2008).
Unfortunately, a direct antagonistic relation is too simplistic
when pathological lesions are considered. Depending on the location and pathophysiology of the lesion, there are varied manifestations. For instance, herpes zoster neuropathy can produce either
chronic pain or itch, or pain and itch concomitantly (Oaklander
et al., 2002; Ikoma et al., 2006). Further, many central causes of
itch (e.g. spinal cavernous hemangioma) are associated with no
reduction in pain despite very prominent itch (Potenzieri and
Undem, 2012; Lanotte et al., 2013). Lastly, hyperknesis, in
which itch is augmented by pain, also implicates a reversal of
the traditional model. Although the exact mechanisms in these

A. Dhand and M. J. Aminoff

Itch

Brain 2014: 137; 313322

| 315

that are not specific to the stimulus and that deliver a series of
signals modulated and decoded centrally (Craig, 2003).
The strongest evidence for a labelled line for itch came from
studies using microneurography, spinal cord electrophysiology
mapping, and genetic modification techniques. Schmelz et al.
(1997) using microneurography in humans, described a histamine-stimulated itch pathway consisting of mechanically insensitive C-fibres that responded with a temporal profile consistent
with itch as rated by human subjects. These fibres were characterized as slowly conducting thin axons with large innervation
territories on the skin. Subsequently, a complementary histamine-stimulated central pathway for itch consisting of lamina I
spinothalamic tract neurons was mapped in the spinal cord of
cats (Andrew and Craig, 2001). These neurons had distinct conduction velocities and thalamic projections, differentiating them
from pain or temperature projections. In a genetic mouse model,
Sun and Chen (2007) identified a subset of dorsal root ganglion
neurons releasing gastrin-releasing peptide (GRP) and their receptors (gastrin-releasing peptide receptor; GRPR) located in lamina I
of the spinal cord. When GRPR was genetically knocked out or
antagonized pharmacologically, scratching behaviour was inhibited. Most recently, Han et al. (2013) described a set of
MrgprA3-positive neurons in the dorsal root ganglion of mice
that innervate the epidermis and respond to multiple pruritogens.
Ablation of these neurons reduced itch behaviour; conversely,

their excitation, regardless of the stimulus (even when pain-producing, i.e., an algogen), evoked a scratch response.
The labelled-line theory does not explain two experimental observations: (i) the itch pathway may be activated by pain-producing stimuli; and (ii) different pruritogens may activate other
peripheral pathways. The strongest experimental evidence for
the first point was provided by Schmelz et al. (2003) who studied
the response of previously identified itch fibres to capsaicin and
bradykinin, which are algogenic agents. They showed that such
algogens activated mechanically insensitive C-fibres initially
thought to be specific for histaminergic itch.
The second point was fuelled by study of the pruritogen cowhage. Originating from the Hindi term kiwach meaning bad rubbing, cowhage is the common name for barbed hairs of the
tropical plant Mucuna pruriens (Namer et al., 2008). The spicules
cause an intense itch without extended erythema, making it a
useful agent to study non-histaminergic itch. Namer et al.
(2008) used microneurography to study cowhage-induced itch in
humans. They found that cowhage stimulated mechanically responsive or polymodal C-fibres and not the mechanically insensitive fibres related to histamine-induced itch. This finding accords
with observations that cowhage and histamine activate different
spinothalamic neurons in primate spinal cords (Davidson et al.,
2007). Cowhage also activates a subpopulation of A-delta thinly
myelinated fibres in addition to unmyelinated afferents (Ringkamp

Downloaded from by guest on August 16, 2015

Figure 1 Peripheral anatomy of itch. Two itch pathways (histamine in blue, cowhage in red) and the peripheral limb of the pain pathway
(green) are shown. The itch pathways are stimulated by histamine and cowhage skin receptors in the epidermis and dermis, respectively.
Impulses are transmitted primarily via mechanically insensitive C-fibres and polymodal C-fibres, respectively, to secondary neurons in the
dorsal horn. One means of modulation by the pain pathway (depicted only partially) is through a Bhlbb5 interneuron. STT = spinothalamic
tract; Bhlbb5 = transcription factor protein; CMi = mechano-insensitive C-fibres; C-polymodal = polymodal C-fibres.

316

| Brain 2014: 137; 313322

Central biology of itch

The central pathway that mediates itch begins with a synapse in
the dorsal horn from a primary to secondary afferent neuron. The
axons of the secondary cells travel in the contralateral spinothalamic tract and synapse onto third-order neurons in the thalamus,
from which axons project diffusely to cortical and subcortical
regions (Fig. 2).
At the dorsal horn, neurotransmitters such as calcitonin generelated peptide, gastrin-releasing peptide (GRP), substance P, and
glutamate have been implicated in the first itch synapse (Davidson
and Giesler, 2010). In mice, these are theorized to bind to GRPR

in the spinal cord to mediate itch (Sun and Chen, 2007; Sun et al.,
2009). Koga et al. (2011) found that glutamate, not GRP, is the
primary neurotransmitter binding to GRPR. Histamine and cowhage primary afferents do not activate or converge on the same
secondary neuron, suggesting mutually exclusive dual projections
in the spinothalamic tract that mediate itch (Davidson et al.,
2007).
The dorsal horn synapse likely represents the site of modulation
by parallel pain-processing neurons and descending pathways
from the brain. In mice, a population of inhibitory interneurons
(Bhlhb5 neurons) inhibit itch within the dorsal horn, and loss of
these neurons result in persistent itch (Ross et al., 2010). Such
interneurons may represent the mediators between noxious and
pruritic pathways, and serve as the cellular basis of how scratch
inhibits itch (Ross, 2011). This concept is supported by the observation that scratching inhibits spinothalamic neurons during histamine-evoked activity but not spontaneous activity (Davidson
et al., 2009). There is also biochemical evidence that scratching
excites inhibitory interneurons to release glycine and gammaaminobutyric acid and thereby inhibit itch-responsive neurons
(Akiyama et al., 2011).
The evidence for central sensitization in itch is accumulating. In
one study, such sensitization was demonstrated in patients with
atopic dermatitis, who were more likely than healthy subjects to
perceive noxious stimuli as itchy, even though such stimuli usually
reduce itch. Further, when conditioned with histamine, the healthy
participants also reported that noxious stimuli caused itchiness. It
was suggested that the chronic pruriceptive input caused central
sensitization for itch andin consequencepain stimuli caused
rather than inhibited itch (Ikoma et al., 2004). Unlike pain,
study of the molecular mechanisms of central sensitization in
itch pathways is still in its early stages. Nevertheless, it is known
that toll-like receptor 3 (TLR3) induces spinal cord long-term potentiation, resulting in central sensitization and synaptic plasticity.
In mice lacking the Tlr3 gene, there is decreased scratching in
response to both histaminergic and non-histamingeric pruritogens
(Liu et al., 2012).
A number of thalamic nuclei are implicated in the itch pathway.
Cowhage-sensitive itch neurons have a broader thalamic representation than histamine-responsive itch neurons. Both sets of neurons have axons terminating in the contralateral ventral posterior
lateral, ventral posterior inferior, and posterior nuclei, but cowhage
neurons have additional projections to the contralateral suprageniculate and medial geniculate nuclei (Davidson et al., 2012) (Fig.
2). Neuroimaging data suggest an increased activation of thalamic
nuclei including the pulvinar in cowhage itch (Papoiu et al., 2012),
but this was not confirmed in the above electrophysiology studies.
Functional neuroimaging studies (PET and functional MRI) have
been used in humans to study brain regions implicated in itch.
Multifocal regions related to perception, evaluative processes, motivation, attention, emotion, and motor function are involved. This
parallels regions involved in pain processing, though not identically. Specifically, most studies reveal activation of the thalamus,
somatosensory cortex, parietal cortex, motor areas (primary motor
cortex, supplementary motor area, premotor cortex), prefrontal
cortex, anterior cingulate gyrus, insula, and midbrain (Hsieh
et al., 1994; Drzezga et al., 2001; Mochizuki et al., 2003;

Downloaded from by guest on August 16, 2015

et al., 2011). Collectively, these findings suggest that a pruritogen

may activate multiple pathways. Secondly, if one holds to the
specificity theory, these findings support the contention that
there are at least two separate itch pathways (histamine and
cowhage) involved in a sensation experienced as relatively similar
by human subjects. Histamine itch may be more burning and
cowhage itch more stinging in quality, although this is difficult
to distinguish by inexperienced subjects (Handwerker, 2010).
At the molecular level, the division and integration between itch
pathways is even more complex. Each pruritogen activates G protein-coupled receptors (GPCRs) and downstream messengers that
interact with other itch- and pain-signalling systems (Jeffry et al.,
2011). For histamine, three GPCRs (HR1, HR3 and HR4) are implicated in acute itch responses in mice. These receptors activate
phospholipase C, phospholipase A2 and transient receptor potential vanilloid 1 (TPRV1), resulting in elevated intracellular calcium
in skin-specific dorsal root ganglion sensory neurons (Rossbach
et al., 2011). Cowhage cleaves the extracellular domain of protease-activated receptor 2 (PAR2) that activates phospholipase C,
TRPV1 and transient receptor potential ankyrin 1 (TRPA1), leading
to membrane depolarization (Davidson and Giesler, 2010). PAR2
also has a role in peripheral sensitization; when it is stimulated, the
primary sensory nerve endings become more responsive to multiple non-histamine pruritogens (Akiyama et al., 2012). Finally,
chloroquine, another potent pruritogen, interacts with a GPCR
termed MgrprA3 on cells that also express H1R, but likely with
a separate intracellular signalling cascade (Potenzieri and Undem,
2012). Importantly, TRPV1 and TRPA1the receptors originally
found to be responsive to capsaicin and mustard oil, respectivelyare not just pain sensors but also integrate various noxious
stimuli, including those that elicit an itch sensation (Ross, 2011).
There have been attempts to reconcile the labelled line theory
with the findings of non-specificity described above, but the issue
remains unsettled. Many advocate for a mechanism that includes
both labelled lines and pattern decoding. The population-coding
theory suggests that pain and itch labelled lines interconnect
through excitatory and inhibitory interneurons that modulate the
activity of each other, usually in the spinal cord. If pain and itch
fibres are activated together, the sensation of pain alone may then
emerge because inhibition from interneurons and central descending pathways masks itch sensation. However, in patients with
chronic itch, failed crosstalk of these lines creates pro-pain and
pro-itch pathways irrespective of the stimulus (Ma, 2012).

A. Dhand and M. J. Aminoff

Itch

Brain 2014: 137; 313322

| 317

Figure 2 Central anatomy of itch. Histamine (red) and cowhage (blue) itch fibres travel in the spinothalamic tract to the thalamic nuclei

Leknes et al., 2007; Papoiu et al., 2012). In contrast to pain, most

studies, but not all (Papoiu et al., 2012), have shown a lack of
activation of the secondary somatosensory cortex. When cold pain
and itch are experienced simultaneously, there is activation of the
periaqueductal grey, which may serve as a modulator of the sensory input, with accompanying deactivation of the cortico-subcortical network (Mochizuki et al., 2003). Again, there appears to be
a distinction between histamine and cowhage itch as the claustrum, insula, basal ganglia, putamen and thalamus are more activated by cowhage than histamine (Papoiu et al., 2012) (Fig. 2).

Neuropathic itch syndromes

Neuropathic itch results from a lesion in the afferent sensory pathway (Twycross et al., 2003), rather than from a cutaneous lesion
or because of a peripheral stimulus. The site of involvement may
be (i) peripheral nerve and root; (ii) spinal cord; or (iii) brain
(Table 2). Most conditions are chronic itch states accompanied
by other sensory features (paraesthesias, hyperaesthesia,
hypoaesthesia) in a distribution that may suggest the site of the
lesion (e.g., dermatomal for radicular or spinal cord lesions). The
impact of itch on patients quality of life is significant; one study
indicated that chronic pruritus has an impact comparable to that
of chronic pain (Kini et al., 2011).
When a neuropathic itch syndrome is suspected, neurophysiological and pathological studies may help to support the diagnosis
or suggest the underlying pathology. Quantitative sensory testing
may demonstrate abnormal thermal and pain thresholds and itch

intensity experience (Bin Saif et al., 2012). A recent study showed

C-nerve fibre sensitivity to itch and temperature varies in different
body areas (Bin Saif et al., 2012). Skin biopsies, with study of the
intraepidermal nerve fibre density, may also be useful in showing
characteristic neuropathic changes, as is discussed below with
regard to prurigo nodularis, herpes zoster, and notalgia
paraesthetica.

Polyneuropathies and itch

Itch is reported to occur in 30% of patients with peripheral
neuropathies, and in one-third of these patients the itch is rated
as moderate to severe in intensity by the response to the item on
itch in the Neuropathy Pain Scale (Binder et al., 2008). The main
peripheral syndromes with prominent itch are summarized in
Table 2.
Although there are multiple causes of itch with HIV infection,
prurigo nodularis (itchy skin nodules) is one cause that probably
relates to the polyneuropathy that occurs in these patients (Singh
and Rudikoff, 2003). In prurigo nodularis, there is a stronger
immunoreactivity of dermal nerves to a neurotrophic agent, p75
low affinity nerve growth factor receptor, than in normal tissue.
This leads to hyperplasia and arborization of unmyelinated nerve
fibres and to increased production of neuropeptides that can result
in an inflammatory reaction (Liang et al., 1999). Pruritus is also a
common side effect of certain chemotherapy agents, especially
platinum compounds (Shepherd, 2003). Paclitaxel-carboplatin
treatment, for example, may cause disabling pruritus, sometimes
accompanied by painful paraesthesias and hyperalgesias, which is

Downloaded from by guest on August 16, 2015

(listed in the left box) usually contralateral to the stimulus. Cowhage neurons project to a broader set of nuclei than histamine neurons
[data derived from Davidson et al. (2012) and Papoiu et al. (2012)]. Thalamic neurons transmit to multiple cortical and subcortical
structures (listed in the right box) with a more diffuse pattern in cowhage itch. These structures are usually activated in a bilateral and
symmetric pattern, except that the insular cortex, claustrum, basal ganglia, and putamen have a minor emphasis contralateral to the
stimulus [data derived from Leknes et al. (2007); Papoiu et al. (2012)]. STT = spinothalamic tract.

318

| Brain 2014: 137; 313322

Table 2 Selected neuropathic itch conditions

Localization

Representative conditions

Peripheral
(receptors,
nerve, root)

Itch associated with polyneuropathies

Postherpetic itch
Brachioradial pruritus
Notalgia paraesthetica
Trigeminal trophic syndrome
Itch associated with keloids or burns

Spinal cord

Inflammatory transverse myelitis

Neoplasms
Cavernous hemangiomas; other vascular
malformations
Post-traumatic Brown-Sequard syndrome

Brain

Ischaemic brainstem and subcortical strokes

Demyelinating inflammatory disorders
Neoplasms
Paraneoplastic disorders
Creutzfeldt-Jakob disease

Postherpetic itch
This disorder, analogous to postherpetic neuralgia, is a chronic itch
state in which refractory itch occurs in a region previously affected
by shingles. In one remarkable case, a 39-year-old woman with
postherpetic itch scratched through the skull into her frontal lobe
after ophthalmic zoster. Quantitative study showed loss in the skin
patch of all sensory modalities except itch, which was enhanced
by histamine. Immunolabelled skin biopsies showed near-complete
loss of epidermal innervation by afferent nerve processes. The
authors suggest that analgesic skin led to a lack of inhibitory
pain signals and hyperactivity of central itch neurons (Oaklander
et al., 2002).

Brachioradial pruritus
Brachioradial pruritus is itchcommonly combined with tingling,
burning, and stingingin the dorsolateral aspect of the upper arm
and is often bilateral. Two predominant mechanisms have been
suggested: (i) sun exposure causing symptoms with seasonal variation; and (ii) intervertebral foraminal narrowing with compression
of nerve roots causing non-seasonal symptoms. The first mechanism was more common in a study of 95 patients (Veien and
Laurberg, 2011).

Notalgia paraesthetica
A peripheral neuropathy of the posterior rami of the thoracic
nerves in the area of the second and sixth vertebrae probably
accounts for this syndrome. Typically, pruritus occurs with or without sensory loss in an area just medial to the scapula border in the
associated dermatomes. Some have attributed this disorder to
spinal nerve root impingement by degenerative changes
(Savk and Savk, 2005). We favour damage to the peripheral
nerves by musculoskeletal compression; such an aetiology is
supported by the finding of a reduced intraepidermal nerve fibre
density in the pruritic region compared with an anatomically
identical non-involved site (Huesmann et al., 2012).

Trigeminal trophic syndrome

This syndrome is characterized by unilateral itch-induced nostril
erosion and ulceration with lower face anaesthesia and paraesthesia after trigeminal nerve surgery, alcohol injection or postherpetic
neuropathy (Nagel and Gilden, 2011). There are also reports of
this condition after stroke, described below. Often exacerbated by
dementia, patients sometimes require complex maxillofacial reconstructions (Bhatti et al., 2008) or protective facemask (Swan et al.,
2009). The mechanism, similar to postherpetic pruritus, is thought
to be absent pain inhibition leading to enhanced itch (Fitzek et al.,
2006).

Keloids and burn scars

Keloids and burn scars commonly lead to itch and pain. For keloids, one study of 28 patients showed that 86% experienced itch
mostly at the edge of the keloid, which has been speculatively
attributed to small nerve fibre dysfunction (Lee et al., 2004).

Spinal cord disorders

Itch is reported in 15% of CNS disorders (Binder et al., 2008),
which are summarized in Table 2. Spinal cord lesions of various
aetiologies may cause chronic itch syndromes. Frequently, there
are accompanying signs of spinal cord dysfunction (e.g., a sensory
level) but, occasionally, itch is the presenting symptom (Lanotte
et al., 2013). Reported aetiologies include neoplasms with or without syrinx (Johnson et al., 2000; Kavak and Dosoglu, 2002), cavernous hemangiomas (Sandroni, 2002; Dey et al., 2005; Lanotte
et al., 2013), transverse myelitis (Bond and Keough, 2003), and
post-traumatic Brown-Sequard syndrome (Thielen et al., 2008). In
these cases, the lesion was usually in the cervical spinal cord, but
in one case it was thoracic (Johnson et al., 2000). A proposed
mechanism is that pathological features of these entities, such as
gliosis and haemosiderin, provoke spontaneous activation of spinal
itch neurons. Quisqualate injections producing similar pathological
changes in the dorsal horn of rats offer a model of this process
(Dey et al., 2005).

Cerebral disorders
In the brain, itch syndromes usually have a subcortical or brainstem localization, and are most commonly caused by ischaemic

Downloaded from by guest on August 16, 2015

unresponsive to antipruritic agents, including steroids (Dunphy

et al., 1997). Intriguingly, some polyneuropathies are accompanied by itch suppression. For example, although most patients
with Fabry disease report neuropathic pain due to a small-fibre
neuropathy (Weidemann et al., 2008), they may have a lack of
itch sensation after histamine injection, and indeed note an
absence of itch after mosquito bites (Cable et al., 1982).

A. Dhand and M. J. Aminoff

Itch

Treatment of neuropathic itch

Non-pharmacological therapies
Management of neuropathic itch begins with non-pharmacological
measures used for itch in general, followed by other therapies tried in
a stepwise approach. Non-pharmacological treatments are the mainstay of initial management and should continue even if drug therapies are required. They include behavioural interventions (e.g.,
educating the patient about itch effects, nail-cutting and wearing
protective garments) (Oaklander, 2011), use of moisturizers, wearing loose clothing, and avoidance of warm temperatures (Class IV
evidence) (Twycross et al., 2003). Phototherapy with narrow-band
ultraviolet B has been shown to help in five cases of notalgia paraesthetica, but its use has not been explored in other neuropathic itch
conditions (Class IV evidence) (Perez-Perez et al., 2010).

Pharmacological therapies
As neuropathic itch is often induced without the involvement of
histamine, it is not surprising that antihistamines are generally unhelpful in treatment. Any benefit appears related more to the
somnolent side effects of H1-antihistamines than to a more specific antipruritic effect (Summey and Yosipovitch, 2005).

| 319

There are several medications reported for use in neuropathic

itch. Capsaicin cream and topical anaesthetics such as a lidocaine
patch (Sandroni, 2002) are commonly used initially (Class IV evidence). The mechanism of capsaicin is TRVP1 activation that leads
to receptor desensitization and depletion of substance P from sensory nerve terminals in the skin (Ikoma et al., 2006). In a metaanalysis of six randomized controlled studies testing capsaicin for
diverse itch conditions, there was no convincing evidence in favour
of the treatment. Methodological and statistical problems limited
the validity of these controlled studies. Specifically, it is difficult to
design experiments because the burning sensation induced by capsaicin cannot be masked, making it challenging to find a suitable
placebo to maintain the blinding of patients and investigators
(Gooding et al., 2010). Other topical agents that have been
used with anecdotal claims of benefit include lidocaine 5% gel
(Feramisco et al., 2010), cortisone and tacrolimus (Nakamizo
et al., 2010). The latter activates C-fibres with TRPV1 receptors
through an increase of intracellular calcium ions (Senba et al.,
2004).
As understanding has increased about the aetiologies and
pathophysiology of itch, new therapeutic strategies have emerged,
including anti-seizure medications and antidepressants. Among the
anti-seizure medications, gabapentinwidely used for neuropathic
painis best studied. As indicated previously, scratching excites
inhibitory interneurons to release glycine and gamma-aminobutyric acid and thereby inhibit itch-responsive neurons (Akiyama
et al., 2011). Gabapentin is a structural analogue of gammaaminobutyric acid that is thought to block the alpha2delta subunit
of voltage-dependent calcium channels in dorsal horn postsynaptic
cells. In a randomized control trial of 60 patients with itch following burns, gabapentin was more effective and faster in action than
the antihistamine cetirizine. There was no difference between
gabapentin alone and the combination of gabapentin and cetirizine. All patients receiving gabapentin had become itch-free by 28
days, whereas only 3 of 20 patients receiving cetirizine alone
became itch-free. Furthermore, gabapentin had no reported side
effects, whereas cetirizine caused sedation (Class II evidence)
(Ahuja et al., 2011). Other anecdotal reports describe the efficacy
of gabapentineither alone or in conjunction with topical agents
such as capsaicin or tacrolimusin treating single or a few patients
with itch syndromes such as trigeminal trophic syndrome
(Nakamizo et al., 2010) and brachioradial pruritus (Bueller et al,
1999; Winhoven et al., 2004) (Class IV evidence). Other antiseizure and antidepressant agents were tried for itch by analogy
with their use for treating neuropathic pain. There are anecdotal
reports of antipruritic benefit with pregabalin (Thielen et al.,
2008), lamotrigine (Crevits, 2006), carbamazepine, doxepin,
amitriptyline, nortriptyline and paroxetine (Class IV evidence).
These medications merit more rigorous trials to determine their
efficacy.
In refractory cases, thalidomide or injectable treatments may be
used, depending on the underlying disorder. Thalidomide is an
effective treatment for prurigo nodularis, perhaps due to its suppression of tumour necrosis factor-alpha, which is elevated in
many skin disorders with itch (Summey and Yosipovitch, 2005)
(Class IV evidence). The limiting factors are teratogenicity and
thalidomide-induced peripheral neuropathy. Injectable treatments

Downloaded from by guest on August 16, 2015

strokes. Unilateral pruritus has been described in brainstem, thalamic, subcortical and, rarely, cortical ischaemic strokes (KimyaiAsadi et al., 1999; Seo et al., 2009; Curtis et al., 2012). Similar
to central neuropathic pain, symptoms may develop several days
to weeks after stroke (Kimyai-Asadi et al., 1999). In lateral
medullary ischaemic strokes, in particular, there is a predisposition
to cause facial neuropathic itch that may lead to trigeminal trophic
syndrome (Seo et al., 2009). The latter develops when patients
not only have facial itch, but also hypoaesthesia that results in
scratching to the point of self-injury (Fitzek et al., 2006). The
mechanism of post-stroke pruritus is unclear, but disrupted central
modulatory structures may be involved to produce central
sensitization.
Similar to strokes, neoplasms, especially in the posterior fossa,
may manifest with localized persistent itch of the face or upper
body (Darken et al., 2009). One patient who developed intense
itch of the left face and trunk was found to have a brainstem
paraneoplastic disorder associated with prostate cancer (Berger
et al., 2009). Itch is relatively common in familial CreutzfeldtJakob disease carrying the E200K mutation. Imaging data in
these cases show damage to the midbrain periaqueductal grey
matter suggesting alteration of central itch modulation (Cohen
et al., 2011). In demyelinating disorders, paroxysmal itch may
particularly affect patients with brainstem or spinal cord plaques.
In a study of neuromyelitis optica, 27.3% of patients reported itch
within a week of other symptoms of transverse myelitis that usually involved the central cord. The high frequency, especially compared to itch in multiple sclerosis (4.5%), may be due to more
direct involvement of dorsal horn neurons and peri-aqueductal
pathways (Elsone et al., 2012).

Brain 2014: 137; 313322

320

| Brain 2014: 137; 313322

include intracutaneous botulinum A toxin (Wallengren and

Bartosik, 2010; Kavanagh and Tidman, 2012), epidural injections
of clonidine and bupivacaine (Elkersh et al., 2003), and stellate
ganglion blocks (Class IV evidence). In one study, botulinum
A toxin was injected into pruritic skin patches at small intervals
(1.5 cm apart) in a dose range of 0.81.4 units per point.
(Wallengren and Bartosik, 2010). It showed moderate and
mostly transient improvement in patients with localized itch,
including notalgia paraesthetica. The proposed mechanism is
modulation of TRPV1 receptors in a similar fashion to capsaicin
to reduce the release of C-fibre neuropeptides (Tugnoli et al.,
2007; Gazerani et al., 2009).

A. Dhand and M. J. Aminoff

Future therapeutic approaches

In the future, multiple therapies may be derived from an appreciation of the itch pathways and mediators described here.
As discussed by Tey and Yosipovitch (2011), novel histamine
receptor antagonists target one of the peripheral histamine receptors (HR4) and show efficacy in histamine-based pruritus models.
Modulators of the protease pathway such as nafamostat mesilate
and tetracyclines target PAR2, which is involved in the cowhage
itch pathway. Cannabinoids that affect the vanilloids, particularly
TRPV1 involved in both histamine and cowhage itch, show promise as treatments for acute and chronic itch. Eventually, dorsal root
ganglion neuron molecules such as GRP, GRPR, and Mrgprs may
become important central targets to inhibit itch.

Neurostimulation treatment

Surgical treatment
Except for a case report of microsurgical decompression in notalgia
paraesthetica (Class IV evidence) (Williams et al., 2010), little has
been published on neurosurgical interventions in the management
of chronic itch syndromes, and the role of such interventions is
unclear at this time.

Other therapies
Certain other therapies, which have been used to treat non-neuropathic itch, may also be tried in patients with otherwise refractory
neuropathic syndromes (Feramisco et al., 2010), although no evidence of efficacy in neuropathic itch has been published. Muopioid receptor antagonists and kappa-opioid receptor agonists
may alleviate pruritus occurring in the context of systemic or
skin diseases. Naloxone has antipruritic effects due to modulation
of mu-opioid sensitive interneurons or wide dynamic range neurons in the spinal cord (Schmelz, 2001). It is an effective treatment
for opioid-induced itch, cholestatic itch, chronic urticaria and
atopic dermatitis (Phan et al., 2010). Nalfurafine and butorphanol
activate cutaneous kappa-opioid receptors without central side effects, and decrease itch especially in patients with uraemia (Reich
and Szepietowski, 2012).

Acknowledgements
We thank Jon Levine, MD, PhD, for reviewing an early version of
the manuscript, and Ms. Kathleen Jee for developing the figures.

References
Ahuja RB, Gupta R, Gupta G, Shrivastava P. A comparative analysis of
cetirizine, gabapentin and their combination in the relief of post-burn
pruritus. Burns 2011; 37: 2037.
Akiyama T, Iodi Carstens M, Carstens E. Transmitters and pathways
mediating inhibition of spinal itch-signaling neurons by scratching
and other counterstimuli. PLoS One 2011; 6: e22665.
Akiyama T, Tominaga M, Davoodi A, Nagamine M, Blansit K, Horwitz A,
et al. Cross-sensitization of histamine-independent itch in mouse primary sensory neurons. Neuroscience 2012; 226: 30512.
Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive
to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4:
727.
Berger JR, Bensalem M, Dalmau J. A brainstem paraneoplastic syndrome
associated with prostate cancer. J Neurol Neurosurg Psychiatry 2009;
80: 9345.
Bhatti AF, Soggiu D, Orlando A. Trigeminal trophic syndrome: diagnosis
and management difficulties. Plast Reconstr Surg 2008; 121: 1e3e.
Bin Saif GA, Alajroush A, McMichael A, Kwatra SG, Chan Y-H,
McGlone F, et al. Aberrant C nerve fibre function of the healthy
scalp. Br J Dermatol 2012; 167: 4859.
Binder A, Koroschetz J, Baron R. Disease mechanisms in neuropathic itch.
Nat Clin Pract Neurol 2008; 4: 32937.
Bond LD, Keough GC. Neurogenic pruritus: a case of pruritus induced by
transverse myelitis. Br J Dermatol 2003; 149: 204205.
Brull SJ, Atanassoff PG, Silverman DG, Zhang J, LaMotte RH.
Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res
1999; 16: 299303.
Bueller HA, Bernhard JD, Dubroff LM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol 1999; 13: 2278.
Cable WJ, Kolodny EH, Adams RD. Fabry disease: impaired autonomic
function. Neurology 1982; 32: 498502.
Cohen OS, Chapman J, Lee H, Nitsan Z, Appel S, Hoffman C, et al.
Pruritus in familial Creutzfeldt-Jakob disease: a common symptom
associated with central nervous system pathology. J Neurol 2011;
258: 8995.
Craig ADB. Pain mechanisms: labeled lines versus convergence in central
processing. Annu Rev Neurosci 2003; 26: 130.
Crevits L. Brachioradial pruritusa peculiar neuropathic disorder. Clin
Neurol Neurosurg 2006; 108: 8035.

Downloaded from by guest on August 16, 2015

Additional treatments for refractory itch include peripheral and

central surface stimulators. Cutaneous field stimulation electrically
stimulates thin afferent fibres. When applied to the affected regions in patients with localized itch, including brachioradial pruritus
and notalgia paraesthetica, there was a 49% reduction of itch
compared to baseline and 40% reduction in itch-related epidermal
nerve fibres (as determined by immunoreactivity) on skin biopsies
(Class IV evidence) (Wallengren and Sundler, 2001). Transcranial
direct current stimulation involves a non-invasive neuromodulator
applied to the scalp to influence neuroplasticity. In a case report, it
was found to improve one patients recalcitrant itch, but not pain,
for 3 months (Class IV evidence) (Knotkova et al., 2013). Further
study of stimulation techniques to relieve intractable itch seem
warranted.

Itch

| 321

Jeffry J, Kim S, Chen ZF. Itch signaling in the nervous system. Physiology
(Bethesda) 2011; 26: 28692.
Johnson RE, Kanigsberg ND, Jimenez CL. Localized pruritus: a presenting
symptom of a spinal cord tumor in a child with features of neurofibromatosis. J Am Acad Dermatol 2000; 43: 95861.
Kavak A, Dosoglu M. Can a spinal cord tumor cause brachioradial pruritus? J Am Acad Dermatol 2002; 46: 43740.
Kavanagh GM, Tidman MJ. Botulinum A toxin and brachioradial pruritus.
Br J Dermatol 2012; 166: 1147.
Kimyai-Asadi A, Nousari HC, Kimyai-Asadi T, Milani F. Poststroke pruritus. Stroke 1999; 30: 6923.
Kini SP, DeLong LK, Veledar E, McKenzie-Brown AM, Schaufele M,
Chen SC. The impact of pruritus on quality of life: the skin equivalent
of pain. Arch Dermatol 2011; 147: 11536.
Knotkova H, Portenoy RK, Cruciani RA. Transcranial direct current stimulation (tDCS) relieved itching in a patient with chronic neuropathic
pain. Clin J Pain 2013; 29: 6212.
Koga K, Chen T, Li XY, Descalzi G, Ling J, Gu J, et al. Glutamate acts as
a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. Mol
Pain 2011; 7: 47.
Lanotte M, Panciani PP, Magistrello M, Naldi A, Fontanella M, Ducati A,
et al. Central neuropathic itch as the presenting symptom of an intramedullary cavernous hemangioma: case report and review of literature. Clin Neurol Neurosurg 2013; 115: 4546.
Lee SS, Yosipovitch G, Chan YH, Goh CL. Pruritus, pain, and small nerve
fiber function in keloids: a controlled study. J Am Acad Dermatol
2004; 51: 10026.
Leknes SG, Bantick S, Willis CM, Wilkinson JD, Wise RG, Tracey I. Itch
and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.
J Neurophysiol 2007; 97: 41522.
Liang Y, Marcusson JA, Johansson O. Light and electron microscopic
immunohistochemical observations of p75 nerve growth factor receptor-immunoreactive dermal nerves in prurigo nodularis. Arch Dermatol
Res 1999; 291: 1421.
Liu T, Berta T, Xu Z-Z, Park C-K, Zhang L, Lu N, et al. TLR3 deficiency
impairs spinal cord synaptic transmission, central sensitization, and
pruritus in mice. J Clin Invest 2012; 122: 2195207.
Ma Q. Population coding of somatic sensations. Neurosci Bull 2012; 28:
919.
Mochizuki H, Tashiro M, Kano M, Sakurada Y, Itoh M, Yanai K. Imaging
of central itch modulation in the human brain using positron emission
tomography. Pain 2003; 105: 33946.
Nagel MA, Gilden D. The trigeminal trophic syndrome. Neurology 2011;
77: 1499.
Nakamizo S, Miyachi Y, Kabashima K. Treatment of neuropathic itch
possibly due to trigeminal trophic syndrome with 0.1% topical tacrolimus and gabapentin. Acta Derm Venereol 2010; 90: 6545.
Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M.
Separate peripheral pathways for pruritus in man. J Neurophysiol 2008;
100: 20629.
Oaklander AL. Neuropathic itch. Semin Cutan Med Surg 2011; 30:
8792.
Oaklander AL, Cohen SP, Raju SV. Intractable postherpetic itch and cutaneous deafferentation after facial shingles. Pain 2002; 96: 912.
Papoiu AD, Coghill RC, Kraft RA, Wang H, Yosipovitch G. A tale of two
itches. Common features and notable differences in brain activation
evoked by cowhage and histamine induced itch. Neuroimage 2012;
59: 361123.
Perez-Perez L, Allegue F, Fabeiro JM, Caeiro JL, Zulaica A. Notalgia
paresthesica successfully treated with narrow-band UVB: report of
five cases. J Eur Acad Dermatol Venereol 2010; 24: 7302.
Phan NQ, Bernhard JD, Luger TA, Stander S. Antipruritic treatment with
systemic m-opioid receptor antagonists: a review. J Am Acad Dermatol
2010; 63: 6808.
Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy 2012;
42: 819.

Downloaded from by guest on August 16, 2015

Curtis AR, Oaklander AL, Johnson A, Yosipovitch G. Trigeminal trophic

syndrome from stroke: an under-recognized central neuropathic itch
syndrome. Am J Clin Dermatol 2012; 13: 1258.
Darken RS, Bogitch R, Leonard J, Perry A, McKinstry RC,
Gutmann DH, et al. Brainstem glioma presenting as pruritus in children with neurofibromatosis-1. J Pediatr Hematol Oncol 2009; 31:
9726.
Davidson S, Giesler GJ. The multiple pathways for itch and their interactions with pain. Trends Neurosci 2010; 33: 5508.
Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ. Relief of itch
by scratching: state-dependent inhibition of primate spinothalamic
tract neurons. Nat Neurosci 2009; 12: 5446.
Davidson S, Zhang X, Khasabov SG, Moser HR, Honda CN, Simone DA,
et al. Pruriceptive spinothalamic tract neurons: physiological properties
and projection targets in the primate. J Neurophysiol 2012; 108:
171123.
Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA, Giesler GJ.
The itch-producing agents histamine and cowhage activate separate
populations of primate spinothalamic tract neurons. J Neurosci 2007;
27: 1000714.
Dey DD, Landrum O, Oaklander AL. Central neuropathic itch from
spinal-cord cavernous hemangioma: a human case, a possible
animal model, and hypotheses about pathogenesis. Pain 2005; 113:
2337.
Drzezga A, Darsow U, Treede RD, Siebner H, Frisch M, Munz F, et al.
Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 2001; 92: 295305.
Dunphy FR, Boyd JH, Kim HJ, Dunphy CH, Harrison BR, Dunleavy TL,
et al. A phase I report of paclitaxel dose escalation combined with a
fixed dose of carboplatin in the treatment of head and neck carcinoma. Cancer 1997; 79: 201623.
Elkersh MA, Simopoulos TT, Malik AB, Cho EH, Bajwa ZH.
Epidural clonidine relieves intractable neuropathic itch associated
with herpes zoster-related pain. Reg Anesth Pain Med 2003; 28:
3446.
Elsone L, Townsend T, Mutch K, Das K, Boggild M, Nurmikko T, et al.
Neuropathic pruritus (itch) in neuromyelitis optica. Mult Scler 2012;
19: 4759.
Feramisco JD, Berger TG, Steinhoff M. Innovative management of pruritus. Dermatol Clin 2010; 28: 4678.
Fitzek S, Baumgartner U, Marx J, Joachimski F, Axer H, Witte OW, et al.
Pain and itch in Wallenbergs syndrome: anatomical-functional correlations. Suppl Clin Neurophysiol 2006; 58: 18794.
Gazerani P, Pedersen NS, Staahl C, Drewes AM, Arendt-Nielsen L.
Subcutaneous botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin. Pain 2009; 141:
609.
Gooding SM, Canter PH, Coelho HF, Boddy K, Ernst E. Systematic review
of topical capsaicin in the treatment of pruritus. Int J Dermatol 2010;
49: 85865.
Han L, Ma C, Qin L, Weng H-J, Cui Y, Tang Z, et al. A subpopulation
of nocioceptors specifically linked to itch. Nat Neurosci 2013; 16:
17482.
Handwerker HO. Microneurography of pruritus. Neurosci Lett 2010;
470: 1936.
Hsieh JC, Hagermark O, Stahle-Backdahl M, Ericson K, Eriksson L, StoneElander S, et al. Urge to scratch represented in the human cerebral
cortex during itch. J Neurophysiol 1994; 72: 30048.
Huesmann T, Cunha PR, Osada N, Huesmann M, Zanelato TP,
Phan NQ, et al. Notalgia paraesthetica: a descriptive two-cohort
study of 65 patients from Brazil and Germany. Acta Derm Venereol
2012; 92: 53540.
Ikoma A, Fartasch M, Heyer G, Miyachi Y, Handwerker H, Schmelz M.
Painful stimuli evoke itch in patients with chronic pruritus: central
sensitization for itch. Neurology 2004; 62: 2127.
Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006; 7: 53547.

Brain 2014: 137; 313322

322

| Brain 2014: 137; 313322

Stander S, Steinhoff M, Schmelz M, Weisshaar E, Metze D, Luger T.

Neurophysiology of pruritus: cutaneous elicitation of itch. Arch
Dermatol 2003; 139: 146370.
Summey BT, Yosipovitch G. Pharmacologic advances in the systemic
treatment of itch. Dermatol Ther 2005; 18: 32832.
Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch
sensation in the spinal cord. Nature 2007; 448: 7003.
Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch
sensation. Science 2009; 325: 15314.
Swan MC, Downie IP, Horlock N. Management of trigeminal trophic
syndrome. Plast Reconstr Surg 2009; 123: 11246.
Tey HL, Yosipovitch G. Targeted treatment of pruritus: a look into the
future. Br J Dermatol 2011; 165: 517.
Thielen AM, Vokatch N, Borradori L. Chronic hemicorporal prurigo
related to a posttraumatic Brown-Sequard syndrome. Dermatology
2008; 217: 457.
Tugnoli V, Capone JG, Eleopra R, Quatrale R, Sensi M, Gastaldo E, et al.
Botulinum toxin type A reduces capsaicin-evoked pain and neurogenic
vasodilatation in human skin. Pain 2007; 130: 7683.
Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE,
Szepietowski JC, et al. Itch: scratching more than the surface. QJM
2003; 96: 726.
Veien NK, Laurberg G. Brachioradial pruritus: a follow-up of 76 patients.
Acta Derm Venereol 2011; 91: 1835.
Wallengren J, Bartosik J. Botulinum toxin type A for neuropathic itch. Br J
Dermatol 2010; 163: 4246.
Wallengren J, Sundler F. Cutaneous field stimulation in the treatment of
severe itch. Arch Dermatol 2001; 137: 13235.
Weidemann F, Strotmann JM, Breunig F, Niemann M, Maag R, Baron R,
et al. Misleading terms in Anderson-Fabry disease. Eur J Clin Invest
2008; 38: 1916.
Williams EH, Rosson GD, Elsamanoudi I, Dellon AL. Surgical decompression for notalgia paresthetica: a case report. Microsurgery 2010; 30:
702.
Winhoven SM, Coulson IH, Bottomley WW. Brachioradial pruritus: response to treatment with gabapentin. Br J Dermatol 2004; 150:
7867.

Downloaded from by guest on August 16, 2015

Reich A, Szepietowski JC. Non-analgesic effects of opioids: peripheral

opioid receptors as promising targets for future anti-pruritic therapies.
Curr Pharm Des 2012; 18: 602124.
Ringkamp M, Schepers RJ, Shimada SG, Johanek LM, Hartke TV,
Borzan J, et al. A role for nociceptive, myelinated nerve fibers in itch
sensation. J Neurosci 2011; 31: 148419.
Ross SE. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol 2011; 21:
8807.
Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, et al.
Loss of inhibitory interneurons in the dorsal spinal cord and elevated
itch in Bhlhb5 mutant mice. Neuron 2010; 65: 88698.
Rossbach K, Nassenstein C, Gschwandtner M, Schnell D, Sander K,
Seifert R, et al. Histamine H1, H3 and H4 receptors are involved in
pruritus. Neuroscience 2011; 190: 89102.
Sandroni P. Central neuropathic itch: a new treatment option?
Neurology 2002; 59: 7789.
Savk O, Savk E. Investigation of spinal pathology in notalgia paresthetica. J Am Acad Dermatol 2005; 52: 10857.
Schmelz M. A neural pathway for itch. Nat Neurosci 2001; 4: 910.
Schmelz M. Itch and pain. Neurosci Biobehav Rev 2010; 34: 1716.
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE.
Specific C-receptors for itch in human skin. J Neurosci 1997; 17:
80038.
Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE,
Handwerker HO. Chemical response pattern of different classes of
C-nociceptors to pruritogens and algogens. J Neurophysiol 2003; 89:
24418.
Senba E, Katanosaka K, Yajima H, Mizumura K. The immunosuppressant
FK506 activates capsaicin- and bradykinin-sensitive DRG neurons and
cutaneous C-fibers. Neurosci Res 2004; 50: 25762.
Seo WK, Kwon DY, Seo SH, Park MH, Park KW. Neuropathic pruritus
following Wallenberg syndrome. Neurology 2009; 72: 676.
Shepherd GM. Hypersensitivity reactions to chemotherapeutic drugs. Clin
Rev Allergy Immunol 2003; 24: 25362.
Singh F, Rudikoff D. HIV-associated pruritus: etiology and management.
Am J Clin Dermatol 2003; 4: 17788.

A. Dhand and M. J. Aminoff