Diagnosis and

Management of
N e u ro p a t h i c I t c h
Jordan Daniel Rosen, BSa,b, Anna Chiara Fostini, MDa,b,c,
Gil Yosipovitch, MDa,b,*

KEYWORDS
 Itch  Pruritus  Neuropathic  Diagnosis  Treatment  Peripheral nerves

KEY POINTS
 Neuropathic pruritus is any injury or dysfunction along the afferent itch pathway that results in a
sensation to scratch.
 Numerous neuropathic itch syndromes, affecting the peripheral and central nervous systems, exist
and should be recognized by clinicians.
 Keys to diagnosis include obtaining a full clinical history and skin examination, imaging, and neuro-
physiologic studies.
 Treatment is challenging and requires tailoring therapies. The most common treatments are GABA-
nergic anticonvulsant medications and topical anesthetics.

INTRODUCTION itch can be distinguished from systemic forms of

pruritus that occur in the absence of direct
Neuropathic pruritus, also known as neuropathic damage to the nervous system. Patients with
itch, is a form of nondermatologic chronic itch. chronic itch frequently suffer from depressed
When defined broadly, neuropathic pruritus refers mood, interrupted slumber, strained interpersonal
to any injury or dysfunction along the afferent itch relationships, and an impaired quality of life.4
pathway that results in a sensation to scratch.1 Neuropathic itch can be challenging for clinicians
Neuropathic itch accounts for 8% to 19% of pa- to diagnose and manage because of the variety
tients affected by chronic pruritus.2,3 Furthermore, of clinical presentations and limited treatment op-
patients with chronic itch owing to neuropathic tions. Recent developments offer improved insight
pruritus tend to have severe pruritus. A retrospec- into the underlying pathophysiology, relevant
tive analysis of 597 patients with chronic pruritus clinical associations, and novel treatment options.
investigated the intensity of itch of different origins
and found neuropathic itch to be of severe inten- PATHOPHYSIOLOGY
sity with a mean of 7.8  1.8 on a numerical scale
of 0 to 10.3 Injury most commonly occurs within Neuropathic itch may develop from a variety of eti-
the peripheral nervous system, or, less commonly, ologies, but the underlying pathophysiology has
within the central nervous system. Neuropathic not been completely ascertained. It is understood

Disclosure Statement: The authors have nothing to disclose.

a
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1475
Northwest 12th Avenue, Miami, FL 33136, USA; b Miami Itch Center, University of Miami Miller School of Med-
derm.theclinics.com

icine, 1475 Northwest 12th Avenue, Miami, FL 33136, USA; c Department of Medicine, Section of Dermatology,
University of Verona, 37126 Verona, Italy
* Corresponding author. 1600 Northwest 10th Avenue, Rosenstiel Medical Science Building, Room 2023A,
Miami, FL 33136.
E-mail address: Gyosipovitch@med.miami.edu

Dermatol Clin 36 (2018) 213–224

https://doi.org/10.1016/j.det.2018.02.005
0733-8635/18/Ó 2018 Elsevier Inc. All rights reserved.
214 Rosen et al

that damage to itch neurons or other cells involved Table 1

in the itch circuitry causes neuropathic itch. Given Causes of neuropathic itch
their vulnerability, damage to the peripheral nerves
is more likely to cause neuropathic itch than cen- Peripheral Nervous Central Nervous
tral nervous system injury. In neuropathic itch, System System
compression, trauma, and other modes of direct Postherpetic Spinal cord disorders
damage to peripheral nerve fibers characteristi- neuralgia Syringomyelia
cally results in a dermatomal distribution of pruri- Small fiber Tumors
tus. However, extensive damage or central neuropathy Abscesses
lesions may cause pruritus that expands beyond Diabetic Transverse myelitis
or involves multiple dermatomes. Moreover, pruri- neuropathic itch Neuromyelitis
tus owing to compression is typically localized to NaV1.7 mutations optica
the corresponding dermatome, whereas nerve fi- Notalgia Brain disorders
ber degeneration can present as either localized paresthetica Stroke
Brachioradial Multiple sclerosis
or generalized pruritus. The location of the insult
pruritus Traumatic brain
and the involvement of other neural pathways
Neuropathic injury
determine whether other symptoms, such as anogenital Abscesses
pain or autonomic changes, are also present. pruritus Scrapie
Allokinesis (itch evoked by light touch) and other Cheiralgia Creutzfeldt-Jakob
forms of hypersensitivity result from peripheral paresthetica disease
and central sensitization of neurons, and are Meralgia Trigeminal trophic
frequently associated with neuropathic itch. paresthetica syndrome
Although the changes in the underlying neural Suprascapular Uremic pruritus
pathway that result in neuropathic pruritus are entrapment
syndrome
not known, the following mechanisms have been
Pudendal neuralgia
proposed: (1) disinhibition of inhibitory spinal
Scalp dysesthesia
interneurons, (2) overactivation of adjacent un- Multilevel symmetric
damaged sensory nerves, (3) hyperexcitation of neuropathic
central itch neurons in the absence of ascending pruritus
signaling, or (4) dysfunction of cortical somatosen- Prurigo nodularis
sory pathways. Recent findings have also impli- Dry eye itch
cated (5) alterations in neuronal ion channels as a Postburn itch
possible mechanism. Scar and keloid Itch

PRINCIPLE DISEASE ENTITIES

acute shingles or PHN.5 Postherpetic itch is
There are multiple ways to group the various etiol- more likely to occur after facial shingles than after
ogies of neuropathic itch. In this article, neuro- truncal shingles.5 The skin changes and sensory
pathic itch is categorized based on the location symptoms of PHN classically present in a single
of the primary insult in the peripheral or central ner- dermatome, but multiple adjacent dermatomes
vous system (Table 1). may also be involved. Risk factors for PHN include
advanced age, immunosuppression, polyneurop-
Peripheral Nervous System
athy, and herpes zoster ophthalmicus or oticus.2
Postherpetic neuralgia Treatment options include anticonvulsants such
Shingles is a neurocutaneous condition caused by as carbamazepine and gabapentin; antidepres-
the reactivation of latent varicella zoster virus in sants such as amitriptyline, desipramine, fluoxe-
somatic sensory ganglia. Nonspecific symptoms tine, or paroxetine; and topical agents such as
(ie, fever, malaise) may present before skin mani- capsaicin or anesthetics.
festations, and the skin manifestations are often
followed by the onset of postherpetic neuralgia Small fiber neuropathies and diabetic itch
(PHN). PHN is classically characterized by allody- Small fiber neuropathies (SFN) are diseases of
nia, pain, and parasthesias. Studies in the last 2 thinly myelinated A-d and unmyelinated C fibers.
decades have provided evidence to support the SFN are characterized by autonomic and sensory
association of neuropathic itch with acute shingles symptoms, such as burning, allodynia, hyper-
and PHN. An epidemiologic study of 586 adults algesia, itch, and excessive sweating. The major
with shingles demonstrated that itch, usually mild diagnostic criterion of SFN is the diminution
or moderate, affected up to 58% of patients with of intraepidermal nerve fiber density (IENF).
 Diagnosis and Management of Neuropathic Itch 215

Additional criteria include the signs and symptoms Notalgia paresthetica

of SFN, the presence of normal sural nerve con- Notalgia parestethica is characterized by pruritus,
duction, and/or altered quantitative sensory in a circumscribed area of the back, especially
testing.6 There are various etiologies of SFN, over the medial scapular borders in the mid
which may originate from metabolic, infectious, in- thoracic dermatomes. The classic physical exam-
flammatory, toxic, paraneoplastic, autoimmune, ination finding is a hyperpigmented patch over-
genetic, or idiopathic causes. A recent study of lying the symptomatic area secondary to chronic
41 patients affected by SFN found that 68% of scratching. Paresthesias are also often found in
subjects suffered from mild to severe neuropathic conjunction with pruritus. The changes leading to
itch with an average intensity of 4.79 on a numeric notalgia parestethica can be frequently attributed
scale from 0 to 10.7 In this study, pruritus to radiculopathy of the primary dorsal rami of the
frequently occurred on a daily or near-daily basis, spinal nerves. In one study, approximately 70%
and most often occurred during the evening. The of patients with notalgia parestethica also had
area of the body most commonly afflicted was underlying vertebral column disease.10 Damage
the back (63%), followed by the foot (59%) and to the peripheral nerves by musculoskeletal com-
shin (56%). pression has been proposed as an alternative
Diabetes mellitus is one of the most common explanation.11 Other associations with notalgia
causes of SFN in developed countries. The preva- parestethica include trauma, diabetes mellitus,
lence of pruritus in diabetic subjects is significantly and multiple endocrine neoplasia syndrome type
higher than in nondiabetic subjects (26.3% vs 2A. Therapy usually only provides symptomatic re-
14.6%). Furthermore, in diabetic patients, pruritus lief. Some benefits have been reported with
of unknown origin localized to the trunk occurs capsaicin cream (0.075%–0.100%), 8% capsaicin
more frequently than in those without diabetes patches, topical local anesthetics, oral medica-
(11.3% vs 2.9%).8 This form of pruritus was asso- tions such as gabapentin and antidepressants,
ciated with other characteristics of diabetic poly- and the injection of botulinum toxin type A.2,12
neuropathy, including impaired blood pressure
response in a head-up tilt test, numbness in the Brachioradial pruritus
toes and soles, and Achilles tendon areflexia.8 Brachioradial pruritus is typically localized to a cir-
Neurotropic agents, such as gabapentin, may be cumscribed area on the dorsolateral forearm along
useful in the treatment of this condition, although the C5/C6 dermatomes; however, it may spread to
data are lacking. the shoulders, upper thorax or wrists. Brachiora-
dial pruritus often occurs bilaterally and may be
Gain-of-function mutations in voltage-gated associated with tingling, burning, and stinging per-
sodium channel ceptions. Although brachioradial pruritus is typi-
The voltage-gated sodium channel, NaV1.7, mod- cally localized, generalized pruritus has been
ulates cell excitability and ion channel functioning. described in some cases of brachioradial pruri-
NaV1.7 is widely expressed in the dorsal root gan- tus.13,14 Factors leading to brachioradial pruritus
glion and in sympathetic ganglion neurons and include compression of the spinal cord or cervical
their small diameter axons. A novel clinical syn- radiculopathies, as seen in spinal stenosis.
drome associated with the I739V variant of the Brachioradial pruritus may worsen under exposure
SCN9A gene (which encodes NaV1.7) has been re- to ultraviolet light and warmth, and can be allevi-
ported in 3 patients of the same family.9 In this ated by cooling the area (also known as the
report, the syndromal findings are characterized ice-pack sign). Gabapentin has been described
by paroxysmal itch attacks (involving the shoul- as one of the more effective treatments for bra-
ders, upper back, and upper limbs), followed by chioradial pruritus.15 A recent comparison be-
transient burning pain. The symptoms can be trig- tween treatment approaches in brachioradial
gered by environmental factors such as warmth, pruritus in 49 patients showed meaningful reduc-
hot drinks, or spicy food. Pruritus was also associ- tions of itch with the antidepressants fluoxetine,
ated with impaired superficial sensations, such as amitriptyline, and doxepin.16 Moreover, the com-
hypoesthesia and hypoalgesia in the affected parison found that the most significant reductions
areas. Furthermore, biopsies from 2 of the 3 pa- in itch were associated with the highest itch inten-
tients, demonstrated a significant decrease in sities before treatment, and longer periods of
IENF density, consistent with SFN. Together these therapy.16 Brachioradial pruritus and notalgia par-
findings suggest a neuropathic origin of itch. In estethica may present similarly; however, there are
these patients, the use of pregabalin reduced distinctions that can aid in distinguishing the 2 di-
itch intensity and the frequency of pruritic agnoses. A new study comparing different aspects
episodes.9 of brachioradial pruritus and notalgia parestethica
216 Rosen et al

in 58 patients showed that patients with brachior- this finding may correspond with the presence of
adial pruritus reported stinging and burning more SFN.21 Oral and topical gabapentin, topical corti-
often than those with notalgia parestethica. The costeroids, antidepressants, and pregabalin have
study found that IENF density decreased in the been used in treatment of scalp dysesthesia with
lesional skin of patients with brachioradial pruritus, varying degrees of success.19,22
but not in those with notalgia parestethica. In
the brachioradial pruritus group, structural MRI Multilevel symmetric neuropathic pruritus
abnormalities correlated more frequently with the Multilevel symmetric neuropathic pruritus is char-
localization of symptoms. Additionally, topical acterized by generalized, symmetric, neuropathic
capsaicin was more efficacious in patients with pruritus and scratching lesions, which usually arise
brachioradial pruritus compared with those with in patients in their 60s or older. The cause of multi-
notalgia parestethica.17 level symmetric neuropathic pruritus seems to be
related to multilevel degenerative disc disease of
Neuropathic anogenital pruritus the spine secondary to atherosclerosis and subse-
Anogenital pruritus is defined as an itch localized quent decreased blood flow to the intervertebral
to the anus, perianal, and/or genital skin. Whereas discs.23 The use of low-dose gabapentin, some-
the origin remains unclear in some cases, anogen- times in combination with mirtazapine, has shown
ital pruritus without a primary rash should raise a promising results.23
high index of suspicion of neuropathic itch. In pa-
tients with anogenital pruritis of unknown origin, an Prurigo nodularis
underlying neuropathic disease process is often Prurigo nodularis is a chronic, highly pruritic condi-
found. This supposition is supported by a study tion characterized by the presence of hyperkera-
that found that 16 of 20 patients (80%) with ano- totic, excoriated, pruritic papules and nodules.
genital pruritus of unknown origin had lumbosacral The lesions are classically distributed symmetri-
radiculopathy, representing nerve or nerve root cally. Although contrasting data exist, findings in
compression.18 This study reported positive pa- patients with prurigo nodularis and alterations in
tient outcomes with a steroid and lidocaine nerve dermal and epidermal small diameter nerve fibers
block; however, the use of other treatments used may suggest the presence of a SFN in some
to manage different forms of neuropathic itch are cases.24 Hypoesthesia and paresthesia, as well
also effective in the treatment of neuropathic ano- as burning, tingling, and stinging sensations, may
genital pruritus. be present in patients with prurigo nodularis.25
Randomized, controlled trials are scarce; howev-
Other localized forms of neuropathic pruritus er, some success has been shown with treatments
Other localized neuropathic syndromes character- such as topical steroids, ultraviolet phototherapy,
ized by itch and pain have been reported. These anticonvulsants, cyclosporine, thalidomide, and
syndromes include cheiralgia (hand) paresthetica, aprepitant.26
meralgia (lateral thigh) paresthetica, suprascapular
entrapment syndrome, and pudendal neuralgia. Dry eye itch
Recent findings suggest that dry eye accompa-
Scalp dysesthesia nied with chronic ocular pain and itch is of neuro-
Scalp dysesthesia occurs in the absence of a pathic origin.27 Moreover, there is evidence that
primary cutaneous disorder and presents with peripheral and central sensitization processes
itching, burning, or stinging of the scalp. The may be involved in generating and maintaining
symptoms may be localized or occur diffusely these ocular sensory symptoms.28 Although data
across the scalp. Women account for the vast ma- are lacking, high doses of gabapentin have
jority of patients with scalp dysesthesia. Associa- showed efficacy in treating patients with symp-
tions with psychiatric diseases, cervical spine toms of dryness and ocular pain who are not
diseases, and iatrogenic damage to peripheral responsive to traditional therapies.28
nerves have been described.19 In one study con-
ducted on 15 female patients affected by scalp Scars, postburn itch, and keloids
dysesthesia, 14 had abnormal cervical spine im- Postburn scars, postsurgery scars, hypertrophic
ages. In particular, the most common radiographic scars and keloids can all cause long-lasting pruri-
abnormality was degenerative disk disease, which tus. In these conditions, the pruritus is often asso-
was present in 11 patients and occurred at C5 to ciated with burning or piercing sensations.2 In
C6 in 10 patients.20 Diabetes mellitus has been those who sustain burn injuries, itch is present in
recognized as a risk factor for chronic itch of the about 87% of patients after 3 months, in 70% of
scalp in the geriatric population (odds ratio, 2.1; patients after 1 year, and in 67% of patients after
95% confidence interval, 1.1–9.5; P 5 .037), and 2 years.29 Neurophysiologic and pharmacologic
 Diagnosis and Management of Neuropathic Itch 217

evidence hints at a neuropathic mechanism of pru- prefrontal cortex described symptoms of general-
ritus in patients with chronic burn injury associated ized neuropathic itch.36 Neuropathic itch is infre-
with itch.30 quently associated with prion diseases, such as
Keloids are a form a pathologic scarring consist- scrapie and sporadic Creutzfeldt–Jakob disease;
ing of benign overgrowths of dense fibrous tissue 6 of 31 patients with familial Creutzfeldt–Jakob
that extends beyond the borders of the original disease reported pruritus.37
wound. Symptoms of itch and pain are common Trigeminal trophic syndrome is a condition in
in patients with keloids, and are present in 86% which abnormal sensations, particularly itching,
and 46% of patients, respectively.31 Itch in keloids burning, or stinging, lead to scratching. The asso-
typically involves the border of the keloid, whereas ciated cutaneous sensory loss in trigeminal trophic
pain is more commonly reported in the center of syndrome may permit scratching to continue to
the keloid. The pruritus associated with keloids the point of self-injury. Unfortunately, trigeminal
may be severe; in a recent study, the maximum re- trophic syndrome often remains unrecognized by
ported intensity of itch experienced from a keloid the physician. The most common causes of tri-
was 7.7 on a numerical scale from 0 to 10.31 Allo- geminal trophic syndrome are cerebral vascular
dynia, allokinesis, and abnormal thermal and pain accidents, particularly stroke, and trigeminal nerve
thresholds were also reported in patients. This ablation, often in the context of treatment for tri-
constellation of symptoms may be due to neuro- geminal neuralgia.19,38 Other less frequently
pathic damage.31 Treatment options for scar pru- described causes of trigeminal trophic syndrome
ritus include gabapentin and pregabalin, as well are trauma, herpes zoster, multiple sclerosis, tu-
as topical anesthetics.2 mors, and abscesses.38 Although any of the 3
branches of the trigeminal nerve can be involved,
Central Nervous System the maxillary branch (V2) is the most frequently
Spinal cord disorders affected. Treatment is challenging and includes
Different diseases of the spinal cord may cause the use of protective barrier, carbamazepine, diaz-
itch, including syringomyelia, tumors (typically epam, amitriptyline, and pimozide.38
ependymomas and cavernous hemangiomas), ab- Interestingly, a recent study demonstrated
scesses, transverse myelitis, and neuromyelitis neuropathic changes in multiple gray matter re-
optica.24,32,33 The location and distribution of itch gions of the brain in patients affected by uremic
depends on the site of the primary lesion. In a pruritus. This finding suggests that an underlying
case series of 45 patients affected by neuromyeli- central neuropathy in patients with end-stage renal
tis optica, 12 patients endorsed pruritus, 3 patients disease may specifically involve changes to struc-
reported pruritus as the first symptom of a relapse, tures involved in the cerebral processing of itch.39
and 1 patient reported pruritus as the first symp-
tom of the index episode.32 Pathologic features CLINICAL EVALUATION OF THE PATIENT
of these entities, such as gliosis and hemosiderin,
might provoke spontaneous activation of spinal A thorough history may provide critical information
itch neurons.11 about the origin of pruritus in a patient. In partic-
ular, the characteristics of itch should be investi-
Brain disorders gated in detail. Neuropathic itch syndromes may
Any brain lesion affecting itch neurons can cause be suspected depending on the involved areas,
central neuropathic itch. Central neuropathic the distribution of pruritus, the presence of dyses-
pruritus may be associated with central hypersen- thetic symptoms, or the presence of comorbidities
sitization of nerve fibers, spontaneous firing of (eg, diabetes). For example, one should consider
damaged nerves, and central neuronal deprivation neuropathic origins of itch in patients with local-
of afferent input.34,35 Stroke is the most common ized itch and a history of shingles, or radiculo-
brain lesion associated with neuropathic itch. In pathic itch and back pain in the context of a
particular, infarctions of the lateral medulla can motor vehicle accident. The interview should al-
cause Wallenberg’s syndrome. Wallenberg’s syn- ways include a review of all current, and changes
drome presents with itch, vertigo, nausea, to, medications. The intensity of pruritus may be
dysphagia, dysarthria, ataxia, ipsilateral sensory assessed by subjective scales, such as the visual
loss of the face, and contralateral sensory loss of analog scale or the numeric rating scale. A full
the trunk and extremities.24 Less frequent lesions dermatologic evaluation is fundamental to exclude
associated with neuropathic itch include multiple inflammatory dermatosis as the primary cause of
sclerosis, tumors within or near the brain, ab- pruritus and to assess the presence of lesions sec-
scesses, and infections.12 A case report of a pa- ondary to scratching. Laboratory investigations
tient with traumatic injury to the thalamic and with a complete blood count, erythrocyte
218 Rosen et al

sedimentation rate, thyroid, liver, and renal func- TREATMENT

tion tests are useful in excluding underlying sys-
temic disease. Radiologic studies, specifically Neuropathic itch is a challenging condition for cli-
computed tomography or MRI, are used for nicians to manage. Although it would be ideal to
detecting structural lesions that can impinge on target the source of the disease (eg, compressed
cranial or spinal nerve roots. MRI is particularly spinal cord roots), thereby eliminating the corre-
useful in detecting the imaging abnormalities of sponding sequelae, this strategy is rarely effective
brachioradial pruritus and notalgia paresthetica, or practical. The majority of interventions are not
and can be used to detect lesions of the brain curative. For patients with intractable pruritus, it
and of the spinal cord. Neurophysiologic studies, is important to focus on symptomatic manage-
specifically nerve conduction study and electro- ment and quality of life (Fig. 1). Commonly pre-
myography, are often used to document periph- scribed antipruritic medications, such as
eral nerve damage. However, electromyography antihistamines and corticosteroids, have limited
is insensitive in detecting SFN. In cases of SFN, success in neuropathic pruritus. Alternate agents,
the evaluation of IENF density can be used to such as oral gabapentin and topical capsaicin,
confirm the diagnosis. The technique requires an tend to be the first-line agents in the management
immunofluorescence staining process of a skin of neuropathic pruritus. However, the efficacy of
sample with a primary antibody against the protein pharmacologic treatments is largely based on
gene product 9.5. The IENF densities detected are clinician experience and case reports, and is not
then quantified according to international guide- validated by controlled studies. In addition to med-
lines to determine their signifiance.40 For example, ical treatments, patients may benefit from non-
an IENF density below the fifth percentile of the pharmacologic approaches and therapies. The
corresponding gender and age, in association consultation and coordination of care with other
with a suitable clinical history, suggests the pres- specialists and health care providers is critical
ence of a SFN.40 Additional testing in suspected given the comorbidities associated with the
cases of SFN may include thermal quantitative many conditions that cause neuropathic itch.
sensory testing, which can indicate possible sen-
Topical Pharmacologic Treatments
sory dysfunctions of C nerve fibers that transmit
itch and pain and can serve as a quality marker Topical treatments can be applied in affected
of clinical improvement.2 areas to achieve high local concentrations with

SEVERE ITCH

Topical:
MODERATE ITCH
8% Capsaicin patch

MILD ITCH Oral:

Topical: Gabapentin or
Ke-Am-Li Pregabalin with
Oral: Mirtazapine
Topical:
Gabapentin Carbamazepine
Pramoxine
Lidocaine Pregabalin Invasive:
Ketamine Mirtazapine Botulin Toxin A
Ke-Am-Li Nerve Block
Capsaicin cream IV Ketamine

US
HIC P RURIT
NEU ROPAT
ITY OF
SEVER

Fig. 1. Author’s therapeutic ladder for neuropathic pruritus. IV, intravenous.

 Diagnosis and Management of Neuropathic Itch 219

reduced risks of major adverse effects. During paresthetica,48 trigeminal trophic syndrome,49
localized, less severe, or more acute forms of and, in the authors’ experience, anogenital itch.
neuropathic itch, topical treatments may offer Similar to capsaicin, topical calcineurin inhibitors
more rapid relief. may cause a transient burning sensation. Topical
application is not typically associated with the sys-
Capsaicin temic immunosuppression that can occur with oral
Capsaicin, a metabolite found in chili peppers, is a use of calcineurin inhibitors.
commonly used topical treatment for neuropathic
pruritus. Capsaicin activates the transient receptor Menthol
potential cation channel, subfamily V-1 receptors Menthol, through activation of the TRPM-8 recep-
found on C fibers, causing an intense depolariza- tor, can elicit a cool sensation useful in the relief of
tion. This results in the long-lasting desensitization itch. Although not commonly used in neuropathic
of local nerve fibers and an improvement of pruritic pruritus, patients who report improvement of
symptoms. Capsaicin has shown success in treat- symptoms with cooling of the affected areas,
ing the symptoms of PHN, notalgia paresthetica,41 such as those with brachioradial pruritus (ie, the
brachioradial pruritus,42 and SFN.14 Before ice-pack sign), may experience some relief using
achieving its antipruritic effects, the application topical menthol up to 2%.
of capsaicin is often followed by a hot or burning
sensation that may be brief or last for several Other topical therapies
days. Patients are often very bothered by the A variety of other topical therapies, such as
burning sensation, but compliance may improve gabapentin (10%–12%) and strontium hydrogel
with the preapplication of a local anesthetic such (Tricalm), may be effective in treating neuropathic
as lidocaine42 or a eutectic mixture of local anes- pruritus.20,50 In addition, topical acetylsalicylic
thetic. The administration of nonprescription acid (aspirin) can improve symptoms of neuro-
capsaicin (0.025%–0.100%) normally requires pathic pain51 and, in the author’s experience,
multiple applications to achieve a significant reduce pruritus in PHN and notalgia paresthetica.
reduction in pruritus. We recommend higher
concentrations of topical capsaicin, usually at Oral Pharmacologic Treatments
0.075% to 0.100%.43 Furthermore, 8% capsaicin
patches (NGX-4010) applied for 60 minutes may Many of the medications discussed in this section
produce a greater and longer lasting antipruritic ef- require higher doses to treat neuropathic itch
fect.14,41,42,44 There is even a report of a single 8% compared with the recommended doses for use
capsaicin application abolishing neuropathic pru- in other indications. When using systemic thera-
ritus for more than a year.41,42 pies for the treatment of neuropathic itch, it is
important to use effective dosing to reach thera-
Anesthetics peutic levels. Generally, once a maximum thera-
The effectiveness of topical anesthetics in treating peutic dose has been achieved, medications
neuropathic pruritus varies among patients. How- from a different class may be added to the regimen
ever, the relatively low cost and minimal adverse to achieve further reduction in itch.
effects make them worthwhile treatment modal-
ities to explore. Some success has been reported Anticonvulsants
with the application of the following topical anes- Gabapentinoids are a class of anticonvulsant med-
thetics: eutectic mixture of local anesthetic, lido- ications that includes gabapentin (Neurontin) and
caine, prilocaine, and pramoxine. A combination pregabalin (Lyrica). These drugs are GABA-
of topical 5% to 10% ketamine with 5 amitriptyline aminobutyric acid analogs that act by antagonizing
and 5% lidocaine (KeAmLi), which additionally tar- the alpha-2-delta subunit of voltage-gated calcium
gets ion channels, may improve itch in a variety of channels. Gabapentin is approved by the UD Food
pruritic conditions, including neuropathic pruri- and Drug Administration for the treatment of sei-
tus.45 Ketamine can also be applied topically in zures and PHN,52 and is effective in the treatment
combination with amitriptyline for treatment of bra- of neuropathic forms of itch, such as brachioradial
chioradial pruritus,46 and mild relief of PHN and pruritus, prurigo nodularis, and notalgia paresthe-
notalgia paresthetica.47 tica.53 There are promising case reports regarding
the use of gabapentin in scalp dysesthesia,20 pru-
Topical calcineurin inhibitors ritus associated with traumatic spinal cord injury,54
Topical calcineurin inhibitors are another low-risk and trigeminal trophic syndrome.55 Gabapentin is
option with variable efficacy in neuropathic itch. typically dosed beginning at 300 to 600 mg at night,
Topical tacrolimus applied to effected areas has followed by an increase in dosage every 2 to 3 days
shown some success in treating notalgia as tolerated.56 In our experience for neuropathic
220 Rosen et al

itch, doses as high as 3600 mg/d may be tolerable. however, current research is lacking with regards
Pregabalin has demonstrated success in the treat- to the use of selective serotonin reuptake inhibi-
ment of prurigo nodularis.57 Pregabalin is dosed tors and selective serotonin and norepinephrine in-
beginning with 50 mg twice daily and may be hibitors in neuropathic itch. Treatment-resistant
increased to a maximum total dose of 450 mg/ neuropathic pruritus may respond to a combina-
d.56 Despite similar mechanisms of action, a trial tion of gabapentin and mirtazapine because it re-
of pregabalin or gabapentin can be prescribed if duces neural hypersensitization. Other
a patient does not respond to the other agent. antidepressants such as fluvoxamine and duloxe-
Sedative neurologic symptoms are the most com- tine72 have also been reported to reduce pruritus.
mon side effects of both gabapentin and pregaba-
lin, but are generally well-tolerated by patients57 Neurokinin-1 inhibitors
and subside with continued treatment. Patients Neurokinin-1 (NK1) receptors are found
also often experience increased appetite, weight throughout the body and the neural system. NK1
gain, constipation, and, less commonly, swelling receptors bind the neuropeptide substance P.
of the lower legs. The kidneys eliminate both gaba- Substance P is involved in the transmission of
pentin and pregabalin, so drug levels must be fol- pain and itch, and is suspected of playing a role
lowed closely in patients with impaired renal in the pathogenesis of pruritic conditions. Aprepi-
function.58 Additionally, it is important to monitor tant, an NK1 receptor inhibitor, is indicated for
for symptoms of withdrawal if either medication is the treatment of chemotherapy-induced nausea
discontinued abruptly.59 and vomiting. Aprepitant has also demonstrated
Although not as widely used as the gabapenti- efficacy in the treatment of a variety of pruritic con-
noids, 2 additional anticonvulsants, oxcarbazepine ditions, such as paraneoplastic itch73 and prurigo
and carbamazepine, have been used in the treat- nodularis.74 In addition, a case report of a woman
ment of neuropathic pruritus. In a small number with brachioradial pruritus showed improvements
of patients, oxcarbazepine has demonstrated in pruritus and pruritic lesions within 1 week of
some success in the treatment of notalgia pares- receiving 80 mg/d of aprepitant.75 The adverse ef-
thetica60 and brachioradial pruritus.61 Carbamaze- fects of aprepitant are typically well-tolerated by
pine has been used to treat neuropathic itch in patients76; however, aprepitant is an inhibitor of
multiple sclerosis,62 PHN, trigeminal trophic CYP3A4 and can interact with other medications.
syndrome,63 and brachioradial pruritus.64 The Novel NK1 receptor inhibitors, such as serlopitant
pharmacodynamics of carbamazepine and oxcar- and tradipitant, have a higher affinity for brain NK1
bazepine are not entirely understood, but are receptors and are possibly more effective in treat-
believed to involve antagonism of voltage-gated ing neuropathic itch.
sodium channels found on neurons.65 Variations
Opioids
in the gene (SCN9A) encoding the voltage-gated
Itch transmission is associated with activation of the
sodium 1.7 receptor (NaV1.7) have been linked
mu-opioid receptor and antagonism of the kappa-
with a familial form of peripheral neuropathic
opioid receptor. It has, therefore, been postulated
itch.66 Interestingly, monoclonal antibodies to
that mu-opioid receptor antagonists and kappa-
NaV1.7 may be effective in the treatment of this
opioid receptor agonists may make for capable
type, as well as other forms of neuropathic itch.67,68
treatments of pruritus.77 At night, 1 to 4 mg of intra-
nasal butorphanol, an opioid with mixed activity,
Antidepressants
can reduce symptoms in patients with treatment-
Tricyclic antidepressants offer an additional thera-
resistant chronic itch.78 However, clinical evidence
peutic approach to neuropathic itch. Amitriptyline
advocating for the use of opioid medications in pa-
has been reported useful in the treatment of PHN
tients with neuropathic itch is lacking.
itch, trigeminal trophic syndrome, notalgia pares-
thetica,69 and brachioradial pruritus.70 To minimize Ketamine
adverse effects, amitriptyline is typically given at Ketamine is an NMDA receptor antagonist that,
night, beginning at a low dose of 5 to 10 mg, and when administered intravenously, can be used to
then titrated upward. Patients may not experience treat neuropathic pain.79 In the author’s experi-
benefits from the medications until 6 to 8 weeks of ence, patients with severe intractable neuropathic
treatment. pruritus may also benefit from intravenous keta-
Selective serotonin reuptake inhibitors and se- mine (0.5 mg/kg).
lective serotonin and norepinephrine inhibitors
are used to treat certain types of pruritus. The se- Oral lidocaine analogs
lective serotonin and norepinephrine inhibitor, mir- The use of the lidocaine analog, mexiletine, has
tazapine, can be used to treat neuropathic pain71; been reported to improve cholestatic pruritus.80
 Diagnosis and Management of Neuropathic Itch 221

Oral mexiletine can treat other pruritic conditions Nonpharmacologic Treatments

as well, and is a potential therapeutic option for
Psychological interventions
the treatment of neuropathic itch.81
Adopting a holistic approach to address the cogni-
Future tive and emotional components of neuropathic
Further exploration of the neuropathic itch itch may be considered. Although there are limited
pathway and development of pharmacologic data on the psychological management of these
agents targeting receptors, neurokinin 1 inhibitors, patients, it may be useful as an additional therapy
ion channels such as transient receptor potential to control the itch–scratch cycle and improve qual-
channels (transient receptor potential cation chan- ity of life. Cognitive behavior therapies include
nel, subfamily V), Mas-related G-protein coupled habit reversal training and relaxation training.92
receptor, may yield future clinical applications. The goal of habit reversal training is to alter
dysfunctional behavior by teaching patients to
Invasive Treatments replace negative behaviors with neutral actions.
This technique consists of awareness training,
Botulinum toxin A practicing a competing response whereby a pa-
A small number of case series have suggested tient replaces the dysfunctional behavior, and
that injection of botulinum toxin A decreases pru- increasing motivation to better control scratch-
ritus in patients with notalgia paresthetica.82,83 ing.93 Habit reversal training has been shown to
Treatment involves a series of injections of 1 to have positive effects on the treatment of some
5 U of botulinum toxin A at each of several points compulsive anxiety-related disorders and in the
within the affected area, each point being located decrease of frequency of scratching in patients
1 to 2 cm apart. Botulinum toxin may decrease with itch-related dermatoses.93 Relaxation training
pruritus through the reduction of cholinergic includes progressive muscle relaxation and auto-
transmission or release of substance P along genic training. Progressive muscle relaxation con-
itch pathways. The authors have had some suc- sists of exercises that determine the tension of
cess with this treatment; however, such benefits certain muscle groups, followed by the subse-
were not substantiated in a 20-patient double- quent relaxation of those muscles. Autogenic
blinded controlled study.84 It is also speculated training is known to reduce stress and anxiety in
that botulinum toxin A may be useful in other different somatic diseases, and consists of asking
forms of neuropathic itch, such as brachioradial subjects to concentrate mentally on certain body
pruritus.85 perceptions.93 Biofield therapy with healing touch
was reported to be effective in treating a patient
Interventional therapies
affected by intractable central neuropathic itch.36
Interventional treatments, such as targeted nerve
Healing touch involves touching or placing one’s
blocks or modulation of specific neural structures,
hands above the body to facilitate healing. It has
provide alternative treatment strategies in selected
shown efficacy in reducing itch in patients with
patients with refractory neuropathic itch. There
pain, as well as reducing stress, anxiety, and
have been reported benefits with peripheral nerve
chronic pain in oncologic patients.36,94–96
stimulation in a case of notalgia paresthetica,86
and with targeted nerve blocks in cases of post- Physical therapy and exercise
herpetic itch87 and notalgia paresthetica.88 Addi- Strengthening and stretching exercises could be
tionally, a paravertebral injection of a mixture of considered an adjunctive treatment in certain
triamcinolone acetonide and lidocaine has been neuropathic itch conditions, especially those
reported to reduce pruritus in patients suffering related to nerve impingement or compression.
from neuropathic anogenital pruritus.18 Given the This intervention was applied in a case report of
limited evidence and the inherent risks of surgery, 2 individuals affected by notalgia paresthetica;
neurosurgical decompression is rarely indicated. A the individuals both had a reduction in itch after
less invasive, nonsurgical alternative is transcuta- the implementation of a muscle stretching and
neous electrical nerve stimulation. Transcuta- strengthening program.97
neous electrical nerve stimulation has been
shown to partially relieve pruritus in those with SUMMARY
localized notalgia paresthetica,89 burn pruritus,90
or brachioradial pruritus.89,91 Potential future treat- Given the variety of presentations, extensive
ments for neuropathic itch may include trans- differential diagnoses, and limited number of
cranial direct current stimulation, repetitive definitive treatments, neuropathic itch is often diffi-
transcranial magnetic stimulation, or epidural mo- cult to diagnose and a challenge to treat. Manage-
tor cortex stimulation. ment frequently requires trials with different
222 Rosen et al

treatments and the care of an interdisciplinary 16. Wachholz PA, Masuda PY, Pinto A, et al. Impact of
team of health care providers. Although neuro- drug therapy on brachioradial pruritus. An Bras Der-
pathic itch is often a debilitating and consuming matol 2017;92:281–2.
condition for patients, awareness among clinicians 17. Pereira MP, Luling H, Dieckhofer A, et al. Brachiora-
and patients remains limited. It is important for dial pruritus and notalgia paraesthetica: a compara-
future research to aid in validating the efficacy of tive observational study of clinical presentation and
current treatments and to continue to guide the morphological pathologies. Acta Derm Venereol
development of novel therapeutic options. 2018;98(1):82–8.
18. Cohen AD, Vander T, Medvendovsky E, et al. Neuro-
REFERENCES pathic scrotal pruritus: anogenital pruritus is a symp-
tom of lumbosacral radiculopathy. J Am Acad
1. Yosipovitch G, Goodkin R, Wingard E, et al. Neuro- Dermatol 2005;52:61–6.
pathic pruritus. Itch: Basic Mech Ther 2004;27: 19. Shumway NK, Cole E, Fernandez KH. Neurocutane-
231–40. ous disease: neurocutaneous dysesthesias. J Am
2. Stumpf A, Ständer S. Neuropathic itch: diagnosis Acad Dermatol 2016;74:215–28.
and management. Dermatol Ther 2013;26:104–9. 20. Thornsberry LA, English JC. Scalp dysesthesia
3. Mollanazar NK, Sethi M, Rodriguez RV, et al. Retro- related to cervical spine disease. JAMA Dermatol
spective analysis of data from an itch center: inte- 2013;149:200–3.
grating validated tools in the electronic health 21. Valdes-Rodriguez R, Mollanazar NK, González-
record. J Am Acad Dermatol 2016;75:842. Muro J, et al. Itch prevalence and characteristics
4. Kini SP, DeLong LK, Veledar E, et al. The impact of in a Hispanic geriatric population: a comprehensive
pruritus on quality of life: the skin equivalent of study using a standardized itch questionnaire. Acta
pain. Arch Dermatol 2011;147:1153–6. Derm Venereol 2015;95:417–21.
5. Oaklander AL, Bowsher D, Galer B, et al. Herpes 22. Sarifakioglu E, Onur O. Women with scalp dysesthe-
zoster itch: preliminary epidemiologic data. J Pain sia treated with pregabalin. Int J Dermatol 2013;52:
2003;4:338–43. 1417–8.
6. Devigili G, Tugnoli V, Penza P, et al. The diagnostic 23. Ward RE, Veerula VL, Ezra N, et al. Multilevel sym-
criteria for small fibre neuropathy: from symptoms metric neuropathic pruritus (MSNP) presenting as
to neuropathology. Brain 2008;131:1912–25. recalcitrant "generalized" pruritus. J Am Acad Der-
7. Brenaut E, Marcorelles P, Genestet S, et al. Pruritus: matol 2016;75:774–81.
an underrecognized symptom of small-fiber neurop- 24. Misery L, Brenaut E, Le Garrec R, et al. Neuropathic
athies. J Am Acad Dermatol 2015;72:328–32. pruritus. Nat Rev Neurol 2014;10:408–16.
8. Yamaoka H, Sasaki H, Yamasaki H, et al. Truncal pru- 25. Iking A, Grundmann S, Chatzigeorgakidis E, et al. Pru-
ritus of unknown origin may be a symptom of diabetic rigo as a symptom of atopic and non-atopic diseases:
polyneuropathy. Diabetes Care 2010;33:150–5. aetiological survey in a consecutive cohort of 108 pa-
9. Devigili G, Eleopra R, Pierro T, et al. Paroxysmal itch tients. J Eur Acad Dermatol Venereol 2013;27:550–7.
caused by gain-of-function Na v 1.7 mutation. Pain 26. Fostini AC, Girolomoni G, Tessari G. Prurigo nodula-
2014;155:1702–7. ris: an update on etiopathogenesis and therapy.
10. Savk E, Savk SO. On brachioradial pruritus and no- J Dermatolog Treat 2013;24:458–62.
talgia paresthetica. J Am Acad Dermatol 2004;50: 27. Crane AM, Feuer W, Felix ER, et al. Evidence of cen-
800–1. tral sensitisation in those with dry eye symptoms and
11. Dhand A, Aminoff MJ. The neurology of itch. Brain neuropathic-like ocular pain complaints: incomplete
2013;137:313–22. response to topical anaesthesia and generalised
12. Oaklander AL. Neuropathic itch. In: Carstens E, heightened sensitivity to evoked pain. Br J Ophthal-
Akiyama T, editors. Itch: mechanism and treatment. mol 2017;101:1238–43.
Chapter 7. Boca Raton (FL): CRC Press/Taylor & 28. Andersen HH, Yosipovitch G, Galor A. Neuropathic
Francis; 2014. p. 89–118. symptoms of the ocular surface: dryness, pain,
13. Zeidler C, Lüling H, Dieckhöfer A, et al. Capsaicin and itch. Curr Opin Allergy Clin Immunol 2017;17:
8% cutaneous patch: a promising treatment for 373–81.
brachioradial pruritus? Br J Dermatol 2015;172: 29. Vitale M, Fields-Blache C, Luterman A. Severe itch-
1669–71. ing in the patient with burns. J Burn Care Rehabil
14. Kwatra SG, Stander S, Bernhard JD, et al. Brachior- 1990;12:330–3.
adial pruritus: a trigger for generalization of itch. 30. Goutos I. Neuropathic mechanisms in the pathophys-
J Am Acad Dermatol 2013;68:870–3. iology of burns pruritus: redefining directions for ther-
15. Weisshaar E, Szepietowski JC, Darsow U, et al. Eu- apy and research. J Burn Care Res 2013;34:82–93.
ropean guideline on chronic pruritus. Acta Derm Ve- 31. Lee S-S, Yosipovitch G, Chan Y-H, et al. Pruritus,
nereol 2012;92:563–86. pain, and small nerve fiber function in keloids: a
 Diagnosis and Management of Neuropathic Itch 223

controlled study. J Am Acad Dermatol 2004;51: the management of recalcitrant localized pruritus:
1002–6. a retrospective pilot study. J Am Acad Dermatol
32. Elsone L, Townsend T, Mutch K, et al. Neuropathic 2013;69:320–1.
pruritus (itch) in neuromyelitis optica. Mult Scler J 48. Ochi H, Tan L, Tey H. Notalgia paresthetica: treat-
2013;19:475–9. ment with topical tacrolimus. J Eur Acad Dermatol
33. Zhao S, Mutch K, Elsone L, et al. An unusual case of Venereol 2016;30:452–4.
’itchy paralysis’: neuromyelitis optica presenting 49. Nakamizo S, Miyachi Y, Kabashima K. Treatment of
with severe neuropathic itch. Pract Neurol 2015;15: neuropathic itch possibly due to trigeminal trophic
149–51. syndrome with 0.1% topical tacrolimus and gaba-
34. Yosipovitch G, Samuel LS. Neuropathic and psycho- pentin. Acta Derm Venereol 2010;90:654–5.
genic itch. Dermatol Ther 2008;21:32–41. 50. Papoiu AD, Valdes-Rodriguez R, Nattkemper LA,
35. Binder A, Koroschetz J, Baron R. Disease mecha- et al. A novel topical formulation containing stron-
nisms in neuropathic itch. Nature reviews. Neurology tium chloride significantly reduces the intensity and
2008;4:329. duration of cowhage-induced itch. Acta Derm Vene-
36. Curtis AR, Tegeler C, Burdette J, et al. Holistic reol 2013;93:520–4.
approach to treatment of intractable central neuro- 51. Kingery WS. A critical review of controlled clinical tri-
pathic itch. J Am Acad Dermatol 2011;64:955–9. als for peripheral neuropathic pain and complex
37. Cohen OS, Chapman J, Lee H, et al. Pruritus in fa- regional pain syndromes. Pain 1997;73:123–39.
milial Creutzfeldt-Jakob disease: a common symp- 52. Neurontin(R) [package insert]. New York: Pfizer Inc;
tom associated with central nervous system 2017.
pathology. J Neurol 2011;258(1):89–95. 53. Maciel AAW, Cunha PR, Laraia IO, et al. Efficacy of
38. Curtis AR, Oaklander AL, Johnson A, et al. Trigemi- gabapentin in the improvement of pruritus and qual-
nal Trophic Syndrome from stroke. Am J Clin Derma- ity of life of patients with notalgia paresthetica. An
tol 2012;13:125–8. Bras Dermatol 2014;89:570–5.
39. Papoiu AD, Emerson NM, Patel TS, et al. Voxel- 54. Crane DA, Jaffee KM, Kundu A. Intractable pruritus
based morphometry and arterial spin labeling fMRI after traumatic spinal cord injury. J Spinal Cord Med
reveal neuropathic and neuroplastic features of 2009;32:436–9.
brain processing of itch in end-stage renal disease. 55. Sawada T, Asai J, Nomiyama T, et al. Trigeminal tro-
J Neurophysiol 2014;112:1729–38. phic syndrome: report of a case and review of the
40. Lauria G, Bakkers M, Schmitz C, et al. Intraepider- published work. J Dermatol 2014;41:525–8.
mal nerve fiber density at the distal leg: a worldwide 56. Leslie TA, Greaves MW, Yosipovitch G. Current
normative reference study. J Peripher Nerv Syst topical and systemic therapies for itch. In:
2010;15(3):202–7. Cowen A, Yosipovitch G, editors. Pharmacology of
41. Andersen HH, Sand C, Elberling J. Considerable itch. Handbook of experimental pharmacology, vol.
variability in the efficacy of 8% capsaicin topical 226. Berlin: Springer; 2015. p. 337–56.
patches in the treatment of chronic pruritus in 3 pa- 57. Matsuda KM, Sharma D, Schonfeld AR, et al. Gaba-
tients with notalgia paresthetica. Ann Dermatol pentin and pregabalin for the treatment of chronic
2016;28:86–9. pruritus. J Am Acad Dermatol 2016;75:619–25.
42. Misery L, Erfan N, Castela E, et al. Successful treat- 58. Zand L, McKian KP, Qian Q. Gabapentin toxicity in
ment of refractory neuropathic pruritus with capsaicin patients with chronic kidney disease: a preventable
8% patch: a bicentric retrospective study with long- cause of morbidity. Am J Med 2010;123:367–73.
term follow-up. Acta Derm Venereol 2015;95:864–5. 59. Ehrchen J, Ständer S. Pregabalin in the treatment
43. Papoiu AD, Yosipovitch G. Topical capsaicin. The of chronic pruritus. J Am Acad Dermatol 2008;58:
fire of a ‘hot’ medicine is reignited. Expert Opin Phar- S36–7.
macother 2010;11:1359–71. 60. S‚avka E, Bolukbasib O, Akyolb A, et al. Open pilot
44. Andersen HH, Arendt-Nielsen L, Elberling J. Topical study on oxcarbazepine for the treatment of nota-
capsaicin 8% for the treatment of neuropathic itch lgia paresthetica. J Am Acad Dermatol 2001;45:
conditions. Clin Exp Dermatol 2017;42:596–8. 630–2.
45. Lee HG, Grossman SK, Valdes-Rodriguez R, et al. 61. Mataix J, Silvestre J, Climent J, et al. Brachioradial
Topical ketamine-amitriptyline-lidocaine for chronic pruritus as a symptom of cervical radiculopathy. Ac-
pruritus: a retrospective study assessing efficacy tas Dermosifiliogr 2008;99:719–22 [in Spanish].
and tolerability. J Am Acad Dermatol 2017;76:760–1. 62. Yamamoto M, Yabuki S, Hayabara T, et al. Paroxysmal
46. Poterucha TJ, Murphy SL, Davis MD, et al. Topical itching in multiple sclerosis: a report of three cases.
amitriptyline-ketamine for the treatment of brachiora- J Neurol Neurosurg Psychiatry 1981;44:19–22.
dial pruritus. JAMA Dermatol 2013;149:148–50. 63. Bhushan M, Parry E, Telfer N. Trigeminal trophic syn-
47. Poterucha TJ, Murphy SL, Sandroni P, et al. Topical drome: successful treatment with carbamazepine.
amitriptyline combined with topical ketamine for Br J Dermatol 1999;141:758–9.
224 Rosen et al

64. Tait CP, Grigg E, Quirk CJ. Brachioradial pruritus 81. Wood GJ, Akiyama T, Carstens E, et al. An insatiable
and cervical spine manipulation. Australas J Derma- itch. J Pain 2009;10:792–7.
tol 1998;39:168–70. 82. Weinfeld PK. Successful treatment of notalgia pares-
65. Ambrósio AF, Soares-da-Silva P, Carvalho CM, et al. thetica with botulinum toxin type A. Arch Dermatol
Mechanisms of action of carbamazepine and its de- 2007;143:980–2.
rivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. 83. Wallengren J, Bartosik J. Botulinum toxin type A for
Neurochem Res 2002;27:121–30. neuropathic itch. Br J Dermatol 2010;163:424–6.
66. Martinelli-Boneschi F, Colombi M, Castori M, et al. 84. Maari C, Marchessault P, Bissonnette R. Treatment
COL6A5 variants in familial neuropathic chronic of notalgia paresthetica with botulinum toxin A: a
itch. Brain 2017;140:555–67. double-blind randomized controlled trial. J Am
67. Lee J-H, Park C-K, Chen G, et al. A monoclonal anti- Acad Dermatol 2014;70:1139–41.
body that targets a Na V 1.7 channel voltage sensor 85. Kavanagh G, Tidman M. Botulinum A toxin and bra-
for pain and itch relief. Cell 2014;157:1393–404. chioradial pruritus. Br J Dermatol 2012;166:1147.
68. Kornecook TJ, Yin R, Altmann S, et al. Pharmaco- 86. Ricciardo B, Kumar S, O’callaghan J, et al. Periph-
logic characterization of AMG8379, a potent and eral nerve field stimulation for pruritus relief in a pa-
selective small molecule sulfonamide antagonist of tient with notalgia paraesthetica. Australas J
the voltage-gated sodium channel NaV1. 7. Dermatol 2010;51:56–9.
J Pharmacol Exp Ther 2017;362:146–60. 87. Yamanaka D, Kawano T, Shigematsu-Locatelli M,
69. Yeo B, Tey HL. Effective treatment of notalgia pares- et al. Peripheral nerve block with a high concentra-
thetica with amitriptyline. J Dermatol 2013;40:505–6. tion of tetracaine dissolved in bupivacaine for intrac-
70. Barry R, Rogers S. Brachioradial pruritus–an enig- table post-herpetic itch: a case report. JA Clin Rep
matic entity. Clin Exp Dermatol 2004;29:637–8. 2016;2:43.
71. Mattia C, Paoletti F, Coluzzi F, et al. New antidepres- 88. Goulden V, Toomey P, Highet A. Successful treat-
sants in the treatment of neuropathic pain. A review. ment of notalgia paresthetica with a paravertebral
Minerva Anestesiol 2002;68:105–14. local anesthetic block. J Am Acad Dermatol 1998;
72. Kouwenhoven TA, van de Kerkhof PCM, Kamsteeg M, 38:114–6.
et al. Use of oral antidepressants in patients with 89. Wallengren J, Sundler F. Cutaneous field stimulation
chronic pruritus: A systematic review. J Am Acad Der- in the treatment of severe itch. Arch Dermatol 2001;
matol 2017;77(6):1068–73.e7. 137:1323–5.
73. Ständer S, Luger TA. NK-1 antagonists and itch. In: 90. Hettrick HH, O’Brien K, Laznick H, et al. Effect of
Cowan A, Yosipovitch G, editors. Pharmacology of transcutaneous electrical nerve stimulation for the
itch. Handbook of experimental pharmacology, vol. management of burn pruritus: a pilot study. J Burn
226. Berlin: Springer; 2015. p. 237–55. Care Res 2004;25:236–40.
74. Ständer S, Siepmann D, Herrgott I, et al. Targeting 91. S‚avk E, S‚avk Ö, S‚endur F. Transcutaneous electrical
the neurokinin receptor 1 with aprepitant: a novel nerve stimulation offers partial relief in notalgia par-
antipruritic strategy. PLoS One 2010;5:e10968. esthetica patients with a relevant spinal pathology.
75. Ally MS, Gamba CS, Peng DH, et al. The use of J Dermatol 2007;34:315–9.
aprepitant in brachioradial pruritus. JAMA Dermatol 92. Tey HL, Wallengren J, Yosipovitch G. Psychosomatic
2013;149:627–8. factors in pruritus. Clin Dermatol 2013;31:31–40.
76. Keller M, Montgomery S, Ball W, et al. Lack of effi- 93. Schut C, Mollanazar NK, Kupfer J, et al. Psycholog-
cacy of the substance P (neurokinin 1 receptor) ical interventions in the treatment of chronic itch.
antagonist aprepitant in the treatment of major Acta Derm Venereol 2016;96:157–63.
depressive disorder. Biol Psychiatry 2006;59: 94. Wilkinson DS, Knox PL, Chatman JE, et al. The clin-
216–23. ical effectiveness of healing touch. J Altern Comple-
77. Tajiri K, Shimizu Y. Recent advances in the manage- ment Med 2002;8:33–47.
ment of pruritus in chronic liver diseases. World J 95. Danhauer SC, Tooze JA, Holder P, et al. Healing
Gastroenterol 2017;23:3418. touch as a supportive intervention for adult acute
78. Dawn AG, Yosipovitch G. Butorphanol for treatment leukemia patients: a pilot investigation of effects on
of intractable pruritus. J Am Acad Dermatol 2006;54: distress and symptoms. J Soc Integr Oncol 2008;
527–31. 6:89.
79. Maher DP, Chen L, Mao J. Intravenous ketamine in- 96. Kemper KJ, Fletcher NB, Hamilton CA, et al. Impact
fusions for neuropathic pain management: a prom- of healing touch on pediatric oncology outpatients:
ising therapy in need of optimization. Anesth Analg pilot study. J Soc Integr Oncol 2009;7:12.
2017;124:661–74. 97. Fleischer AB, Meade TJ, Fleischer AB. Notalgia par-
80. Watson W. Intravenous lignocaine for relief of intrac- esthetica: successful treatment with exercises. Acta
table itch. Lancet 1973;301:211. Derm Venereol 2011;91:356–7.