Chronic pruritus
Key
clinical points
1. Chronic pruritus (itching that persists for more than 6
weeks) may be caused by inflammatory skin diseases, systemic
diseases, neuropathic conditions, and psychogenic disorders.
2. The presence of a rash does not necessarily indicate a
primary skin disease; lichenification, prurigo nodules, and
excoriations result from rubbing and scratching.
3. The initial evaluation of a patient who has pruritus of
undetermined origin should include a complete blood count with a
differential count, a chest radiograph, and tests of hepatic, renal, and
thyroid function. Patients with itch of undetermined origin should
be reevaluated periodically.
4. In the initial treatment of symptoms, the use of mild
cleansers, emollients, topical anesthetics, and coolants may be helpful.
5. Sedating antihistamines may be used, primarily to help the
patient sleep.
6. Anticonvulsants, antidepressants, and mu-opioid
antagonists appear to be helpful in some forms of chronic itch.
Introduction
Chronic pruritus, which is defined as
itch persisting for more than 6 weeks, is common. It may involve the
entire skin (generalized pruritus) or only particular areas, such as the scalp,
upper back, arms, or groin (localized pruritus). The incidence of chronic
pruritus increases with age.The condition is more common in women than in men.
The causes of chronic pruritus can be
broadly categorized into four major groups: dermatologic causes, systemic
causes (e.g., cholestasis, chronic kidney disease, myeloproliferative
disorders, and hyperthyroidism), neuropathic causes (e.g., nostalgia paresthetica
[a distinctive itch of the upper back] and brachioradial pruritus [a
characteristic itch of the arms, probably caused by spinal-nerve impingement),
and psychogenic causes. Itching of any type may elicit secondary skin changes as a result
of scratching, rubbing, and picking, so the presence of skin findings does not
rule out a systemic cause.
Patients with chronic itch often have
peripheral as well as central neural hyper sensitization. In this state,
sensitized itch fibers overreact to noxious stimuli that usually inhibit itch,
such as heat and scratching. Misinterpretation of non-noxious stimuli also
occurs: touch may be perceived as itch. It is not unusual for patients to
report that just taking off or putting on their bedclothes triggers a bout of
itching.
Pathogenesis
Peripheral and central nervous system
pathway of pruritus: 1. free nerve fiber
endings (unmyelinated C-fibres), 2. epidermis, 3. dermis, 4. subcutaneous fat,
5. peripheral nerve, 6. dorsal root ganglion (location of the cell nuclei of
the first neuron), 7. primary neuron, 8. spinal cord, 9. dorsal horn, 10.
secondary neuron, 11. spinothalamic tract, 12. thalamus, 13. sensorimotor
cortex (postcentral gyrus), 14. motor cortex. The magnification shows the
dorsal horn, where the primary neurons are connected to the secondary neurons.
Interneurons (green) between pain-transmitting fibers (blue) and
pruritus-transmitting fibers (red) can inhibit transmission of itch signals
Induction
Pruritus is triggered by mechanical,
thermal, electrical, and mainly chemical stimulation of cutaneous sensory
C-fibers. The free nerve endings of these unmyelinated nerve fibers in the
epidermis and upper dermis serve as pruriceptors and can be
directly stimulated by the release of mediators. The list of potential
mediators is long, but contains amines (histamine, serotonin), proteases
(papain, kallikrein, tryptase, mucunain), neuropeptides (substance P,
vasoactive intestinal polypeptide – VIP, calcitonin gene-related peptide –
CGRP, neurotensin, melanocyte-stimulating hormone – MSH), bradykinin, opioids
(enkephalin, endorphin, dynorphin), acetylcholine, arachidonic acid metabolites
(prostaglandins), interleukins (IL-2, IL-4, IL-6, IL-8, IL-13, IL-31), and
growth factors (NGF, neurotrophin-4), as well as components of blood platelets
(endothelin-1) and eosinophilic granulocytes (neurotrophins). The free nerve
endings are equipped with specific pruritus-relevant neuroreceptors. These
include the histamine receptor (H1), ion channels (TRPV1), variants of
Mas-related G protein-coupled receptors (Mrgpr), interleukin receptors, and
cannabinoid receptors (CB1, CB2).
Transmission
The afferent pruritus fibers of the skin
are bundled in extracutaneous peripheral nerves that extend to the spinal
dorsal root ganglion and then into the dorsal horn of the spinal cord. There
they are connected to a second neuron, which signals via the tractus
spinothalamicus to the contralateral sensomotoric region of the cortex.
Descending and parallel fibers in the dorsal horn can perform both inhibitory
and excitatory functions. These are mostly myelinized, pain-conducting fibers
that suppress the activity of the pruritus-transmitting neurons via inhibitory
interneurons.
Pathways of Itch from Skin to Brain
Itch originates in the
epidermis and dermal–epidermal junction and is transmitted by small, itch-selective
unmyelinated C nerve fibers. Some of these
fibers are sensitive to histamine, but the majority is not. A complex interplay
among T cells, mast cells, neutrophils, eosinophils, keratinocytes, and nerve
cells (along with increased release of cytokines, proteases, and neuropeptides)
leads to exacerbation of itch.
Cutaneous neurogenic inflammation
Exogenous trigger factors (heat, scratching, irritants,
allergens, ultraviolet light, microbiologic agents) or endogenous trigger
factors (pH changes, cytokines, kinins, histamine, proteases,
neurotransmitters, hormones, stress) may directly or indirectly stimulate nerve
endings from primary afferent neurons. Signals are transmitted to the central
nervous system and thereby affect regions involved in pruritus, pain, somatosensory
reactions (scratching), and probably emotional responses. In addition,
peripheral nerve endings stimulate neighboring afferent nerve fibers in the
dermis and epidermis in a process known as axon reflex. Stimulated release of
neuropeptides results in vascular responses (triple response of Lewis, erythema
by vasodilation, and edema by plasma extravasation), modulation of immunocyte
function (e.g., mediator release from mast cells), and regulation of mediator
release (cytokines, chemokines, growth factors) from keratinocytes and
Langerhans cells.
Clinical Findings
History
Pruritus is a highly subjective symptom and careful
history taking is crucial. It is of prime importance to determine whether the
cause is related to a primary skin disease or systemic disease. It is important
to differentiate between generalized pruritus and localized itch. In the
absence of obvious causative primary skin disease or symptoms or signs
indicating systemic disease, it is essential to carry out a full physical
examination, including lymph node, rectal and pelvic examination. This should
be followed by full blood count, urine examination for sugar, protein and
blood, erythrocyte sedimentation rate, chest X-ray and thyroid, renal and
liver-screening tests. Other routine examination of the stool for occult blood
is a useful and cheap investigation. The possibility that persistent,
generalized pruritus in the absence of skin signs can be an adverse reaction to
a systemic drug should never be overlooked. In the absence of clinical evidence
of primary skin disease, histological examination of a skin biopsy is rarely
helpful and is not recommended as part of the routine work-up. All patients
with generalized pruritus of unrecognized cause should be followed up regularly
as long as the symptom persists. In addition, patients with localized pruritus,
especially in a dermatomal distribution, that present with other sensory
complaints such as a burning sensation, loss of sensation or increased pain
should be evaluated carefully for neuropathic itch.
Cutaneous Lesions
There are common skin lesions that develop in pruritus as
a result of repetitive scratching and rubbing the skin. These lesions are not
considered a primary skin eruption. These
secondary skin lesions of pruritus include excoriations, lichenification, and
hyper- or hypopigmentation.
The excoriations- prurigo nodules – which are excoriated
papules that lead to nodule formation. In many cases, this type of itch is
accompanied by a painful, burning sensation suggestive of a neuropathic
component. Prurigo nodules are frequently associated with emotional stress and
obsessive-compulsive disorder; however, they can be also a manifestation of
itch in patients with atopic dermatitis or chronic renal failure. Such nodules
are usually distributed over extensor aspects of the limbs and upper back.
Lichenification results from continuous rubbing or
scratching and consists of well-developed, thickened plaques with marked
accentuation of skin creases. Lichenified plaques are most commonly distributed
in areas the patient can easily scratch or rub (i.e., nape of neck, below the
elbow, ankle, buttock, and genitalia).
Post-inflammatory hyper pigmentation or hypo pigmentation
can occur in patients with darker skin type because of repeated scratching.
The butterfly sign consists of normal-appearing skin in
the middle of the back outlined by a butterfly pattern of contrasting
hyperpigmentation in areas subjected to persistent scratching, resulting from
the patient's inability to reach the middle of the back.
Shiny fingernails may result from prolonged rubbing.
Some pruritic states have specific clinical patterns.
Despite severe pruritus, chronic urticaria usually does not show secondary skin
lesions associated with scratching. Neuropathic itch in disease entities, such
as postherpetic neuralgia, brachioradial pruritus, and nostalgia paresthetica,
is typically associated with pain and burning sensation. Atopic dermatitis may
also be associated with burning sensation after scratching.
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LABORATORY AND RADIOGRAPHIC
EVALUATION IN PATIENTS WITH PRURITUS OF UNKNOWN ETIOLOGY |
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Basic initial
evaluation |
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-Complete blood
cell count (CBC) with differential and platelet count -Erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP) -Creatinine, blood
urea nitrogen, electrolytes -Liver
transaminases, alkaline phosphatase, bilirubin -Lactate
dehydrogenase (LDH) -Fasting glucose -Thyroid
stimulating hormone (TSH) ± free thyroxine |
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Possible additional evaluation |
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Skin biopsy -Direct
immunofluorescence studies*
-Serum total and/or allergen-specific IgE -Serum ferritin,
iron, total iron binding capacity -Hemoglobin A1c -Parathyroid
function (calcium, phosphate and parathyroid hormone levels) -Stool for
ova/parasites and/or occult blood -Viral hepatitis
panel (including hepatitis B and C viruses) -HIV testing -Anti-tissue
transglutaminase ± epidermal transglutaminase IgA antibodies** -Anti-BP180 and
anti-BP230 bullous pemphigoidIg G antibodies -Anti-mitochondrial
and anti-smooth muscle antibodies -Serum tryptase,
histamine, and/or chromogranin-A levels -Urinalysis with
sediment evaluation -24-hour urine
collection for 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite)
and porphyrins -Serum protein
electrophoresis, serum immunofixation electrophoresis
-Chest X-ray or CT
scan -Abdominal and
pelvic ultrasonography or CT scan -Lymph node ultrasonography -Spinal X-ray or
MRI (for regional pruritus)
-Patch testing -Prick testing for
major atopy and relevant occupational allergens -Age-appropriate
cancer screening (in conjunction with primary care physician) -If hydroxyethyl
starch (HES)-induced pruritus is suspected, electron microscopy of a biopsy
sample from normal-appearing skin * Biopsy perilesional skin or normal-appearing skin (in
vicinity of lesions if present) to assess for bullous pemphigoid and dermatitis
herpetiformis, respectively. ** Often performed in conjunction with serum total IgA;
in patients with IgA deficiency, anti-tissue transglutaminase IgG antibodies
should be assessed. |
Selection of
particular tests beyond the basic initial evaluation is based upon the
patient’s history, physical examination findings, and pruritus severity. The
results of initial testing can also help to direct further evaluation.
Itch Related to Impaired Skin
Barrier Function
Damage
to the stratum corneum and the impaired barrier function that results can
induce itch even without inflammation. Environmental changes (e.g. in pH,
temperature and humidity) may serve as triggers that activate C nerve fibers to
transmit the sensation of itch. Cross-talk between the stratum corneum and
nerve fibers may explain the pruritus associated with impaired barrier
function. Studies have demonstrated that keratinocytes release neuromediators
upon damage to the stratum corneum barrier, and nerve fibers sprout in the
epidermis in response to this damage.
Serine
proteases that activate PAR2 (thereby stimulating itch) are secreted in
response to an increasing (alkaline) stratum corneum pH, which is commonly
noted during barrier damage. This suggests that environmental factors that
increase stratum corneum pH may increase itch perception.
PRURITUS
IN SYSTEMIC DISEASE
Chronic renal disease
Pruritus is one of the most distressing symptoms of
chronic kidney disease (CKD) and it affects 42% of patients on
hemodialysis. Secondary skin changes due
to scratching and rubbing are very common. These include lichenification,
pigmentation, prurigo nodules and eczematization, often secondarily infected.
The back is invariably affected, and the arm bearing the arteriovenous fistula
is also a common site in dialysis patients. Patients with CKD
associated-pruritus often have dry skin, but correction of this by emollients
usually provides minimal relief.
The pathophysiology of CKD-associated pruritus remains
poorly understood but a major role played by the immune and opioidergic systems.
Firstly, itch in CKD is due to derangement of immune system that results in a
pro inflammatory state as immunomodulators such as ultraviolet B light, tacrolimus and
thalidomide alleviate CKD-associated pruritus. Secondly,
itch in CKD is due to an imbalance of the endogenous opioidergic system as
there is an increased ratio of serum β-endorphin to dynorphin A detected in HD
patients, and the ratio increased with the increased intensity of itch. Moreover, a kappa-receptor agonist,
nalfurafine, was shown to significantly decrease itch intensity and
excoriations in HD patients.
The only curative and reliably effective treatment for
renal pruritus is renal transplantation. Important general therapeutic measures
include emollients for xerosis. Secondary eczematization and its accompanying
secondary infection should be treated vigorously. Only UVB phototherapy and
activated charcoal have an established track record for this indication.
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† Typically administered post hemodialysis; daily or
every other day administration of gabapentin/pregabalin has also been
reported. |
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Pruritus is a very early symptom of cholestasis and
frequent complication of many acquired or congenital (Alagill’s disease)
liver diseases. In all cholestatic liver diseases, a common serum mediator was
found, which is autotaxin. Autotaxin (ATX) is a
membrane ectoenzyme that has functions in neuronal development. ATX also
possesses lysophospholipase D activity and cleaves lysophosphatidylcholine
into Lysophosphatidacids (LPA). Accordingly, elevated
levels of LPA were found in the serum of cholestatic patients with pruritus,
allowing for the development of an anti-target therapy. In primary biliary
cholangitis (PBC), pruritus and fatigue are present in about 80% of patients;
these symptoms may precede elevated bilirubin levels.
In addition to autotaxin, endogenous opioids are said to
play a role. Probably decreased hepatobiliary excretion leads to an accumulation
of endogenous opioids.
Patients have elevated plasma opioid levels, and pruritus has been shown to
improve with treatment with μ opioid receptor
antagonists including naloxone, naltrexone, and butorphanol.
Cholestatic pruritus is associated with high plasma
levels of bile salts; however, there is little or no evidence of a correlation
between skin or serum concentrations of bile salts and itching although
administration of cholestyramine, which lowers bile salt levels, does provide
some relief. Thus, combination of both
opioid- antagonist drugs and bile salt-lowering appear reasonable in the management
of pruritus of cholestasis.
The unique feature of cholestatic pruritus is that the
itch initially starts in the palms and soles, which is usually not reported in
other diseases and later becomes more generalized. Pruritus in these settings
tends to be generalized, migratory and not relieved by scratching. It is
typically worse on the hands, feet and body regions constricted by clothing,
and it tends to be most pronounced at night. In patients with chronic
cholestasis, pruritus can be an early symptom that develops years before any
other manifestation of the liver disease. It is associated with rubbing rather
than scratching so secondary excoriation, eczematization and infection are less
common than in renal pruritus. Of note,
intractable itch in chronic liver disease may be an indication for liver
transplantation even in the absence fulminant liver failure.
In summary, it is inferred that as yet unknown
pruritogen(s) are produced in the liver and excreted in the bile, and they then
accumulate in the plasma as a result of cholestasis.
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TREATMENT OPTIONS
FOR HEPATIC OR CHOLESTATIC PRURITUS |
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1st line |
Cholestyramine |
4–16 g po
daily Improvement
may be temporary Only
FDA-approved medication for cholestatic pruritus. |
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1st line |
Ursodeoxycholic acid (ursodiol) |
13–15 mg/kg
or 1 g po daily |
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2nd line |
Rifampin |
300–600 mg po
daily (depending upon serum bilirubin level) Increases
hepatic metabolism of bile salts |
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3rd line |
Naloxone |
0.2 mcg/kg/min
iv infusion, preceded by 0.4 mg iv bolus (continue treatment with oral
naltrexone) µ-opioid
receptor antagonist |
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Naltrexone |
25 mg po
twice daily [day 1], then 50 mg po daily µ-opioid
receptor antagonist |
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Nalfurafine |
2.5–5 mcg po
daily κ-opioid
receptor agonist available in Japan |
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4th line |
Sertraline |
50–100 mg po
daily Selective
serotonin reuptake inhibitor |
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Additional medical options |
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Phototherapy |
Especially
broadband- or narrowband-UVB Can be used
in combination with other treatments for an additive effect |
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Bright light therapy |
10 000 lux reflected
toward the eyes for up to 60 minutes twice daily |
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Nalmefene |
Escalating
twice daily po dose: 2 mg [day 1], 5 mg [day 2], 10 mg [day 3], then 20 mg;
further increases as needed to maximum of 120 mg µ-opioid
receptor antagonist |
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Butorphanol nasal spray |
1–2 mg (1 to
2 puffs) daily κ-opioid
receptor agonist and µ-opioid receptor antagonist |
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Ondansetron |
4–8 mg iv or
4–24 mg po daily (equivocal effects in controlled studies) 5-HT3 receptor antagonist |
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Paroxetine |
10–20 mg po
daily Selective
serotonin reuptake inhibitor |
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Dronabinol |
5 mg po
nightly Cannabinoid
B1 receptor agonist |
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Phenobarbital |
2–5 mg/kg po
daily |
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Stanozolol |
5 mg po daily |
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Propofol |
10–15 mg iv
(bolus), 1 mg/kg/h (infusion) |
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Lidocaine |
100 mg iv
daily |
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Thalidomide |
100 mg po
daily |
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Procedural interventions |
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Nasobiliary drainage |
Quick relief
of pruritus; possible complications include cholangitis and pancreatitis |
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Other methods to removal putative
circulating pruritic factors |
Plasmapheresis,
plasma separation and anion adsorption Extracorporeal
albumin dialysis (e.g. MARS [molecular adsorbents recirculating system]) |
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Hematologic Pruritus
Significant pruritus can occur in association
with a number of hematologic diseases.
Iron deficiency
Iron deficiency has been implicated as a cause of
intractable pruritus in the absence of visible skin disease, or even in the
absence of anemia. In patients with iron deficiency plus generalized or
localized pruritus, especially of the perianal or vulvar region, improvement
with iron supplementation has been described. Of note, iron deficiency can be a
sign of polycythemia vera and other malignancies or systemic diseases that
themselves may cause pruritus. The etiology of the iron deficiency should be
determined, including exclusion of a gastrointestinal source of blood loss.
Polycythaemia vera
Pruritus is a common symptom in polycythemic patients. As
many as 50% of untreated patients with polycythemia develop a severe, prickly
and distressing discomfort within minutes of water contact, lasting 15–60 min.
As it frequently occurs after the patient emerges from bathing, it is often
referred to as ‘bath itch’. No visible changes are present in the skin, and the
symptom may be associated with elevated serum and urinary histamine levels.
Water-induced itching may precede development of polycythemia vera by several
years.
Increased cutaneous histamine levels and increased platelet aggregation
have long been suspected to be etiological factors. A mutation in the Janus
kinase-2 gene of polycythaemia vera is also responsible for pruritus and leads
to an increase in CD63-positive, eosinophilic, and basophilic granulocytes in
the blood, which are constitutively activated and promote the degranulation of
mast cells in the skin.
Treatment options include oral aspirin (300 mg once daily
to three times a day), which is first-line therapy and it can provide relief
from pruritus for 12–24 hours. Other options include UVB or PUVA phototherapy
(reports of success), SSRIs (effective in small series), the JAK inhibitor
ruxolitinib (benefit shown in recent studies), intramuscular interferon-α (good efficacy), and oral H1- or H2-receptor
antagonists (variable results). Baths with sodium bicarbonate seem most effective.
Pregabalin (150–300 mg/day, with slow up titration) is another option.
Endocrine disease
Thyroid disease
Severe
generalized pruritus, associated with a warm, moist skin, may be a presenting
symptom of hyperthyroidism. The cause is not known, but it is postulated to
result from a direct effect of thyroid hormone on the skin. This may be due to
increased blood flow, which raises the skin surface temperature, which, in
turn, reduces the threshold to itching. Localized or generalized pruritus may
also be seen in patients with hypothyroidism, but in this case the cause is
usually excessive drying of the skin, which feels cool, and which can lead to
asteatotic eczema accompanied by pruritus.
Diabetes mellitus
Generalized
itching is not a feature of diabetes mellitus. However, localized pruritus,
especially in the genital and perianal areas,is significantly more common in
diabetic women and associated with poor glycemic control, and is due to
mucocutaneous candidiasis. Localized itching of the scalp and lower extremities
in the form of lichen simplex chronicus can also be a manifestation of diabetic
neuropathy, which may respond to topical capsaicin treatment. In addition, truncal pruritus of unknown
origin has been recently reported to be associated to diabetes and diabetic
neuropathy.
Pruritus and Malignancy
Virtually
any malignancy can induce pruritus as a paraneoplastic phenomenon. Persistent,
unexplained pruritus or failure of generalized pruritus to respond to
conventional therapy should warrant evaluation for an underlying malignancy.
Pruritus may be seen in advanced disease or it can be an early sign that is
present for several years before the diagnosis is made. However, the intensity
and extent of pruritus do not correlate with the extent of tumor involvement.
Suggested
mechanisms of tumor-associated pruritus include toxic products from necrotic
tumor cells entering the systemic circulation, production of chemical mediators
of pruritus by the tumor, allergic reactions to tumor-specific antigens,
increased proteolytic activity and histamine release. Pruritus may also
complicate malignant disease that results in obstruction of the biliary tree
(e.g. carcinoma of the head of the pancreas or bile duct), and “central”
pruritus (e.g. due to brain tumors) or pruritus as a consequence of treatment
(e.g. surgery, radiotherapy, cytotoxic chemotherapy) can occur. Localized
pruritus of the nose has been associated with brain tumors.
Hodgkin disease
There is a strong
association between pruritus and Hodgkin disease, with nocturnal generalized
pruritus in association with chills, sweating, and fever representing a classic
presentation. Severe, persistent pruritus is predictive of a poor prognosis,
and return of this symptom may portend tumor recurrence. It has been proposed
that pruritus should be added to the list of the “B symptoms” in this disease.
Factors contributing
to pruritus in Hodgkin disease may include eosinophilia and release of
histamine (from basophils), leukopeptidases, or bradykinin. Hepatic involvement
by the lymphoma may occasionally play a role. Production of IL-5 by
Reed–Sternberg cells can lead to eosinophilia, but whether the eosinophil count
correlates with the degree of pruritus is unclear. Therapy should focus on
treatment of the lymphoma, but topical corticosteroids and oral mirtazapine
(7.5–30 mg/day) may be of benefit. A recent case report described improvement
of Hodgkin disease-related pruritus with aprepitant, an NK1 receptor
antagonist.
Non-Hodgkin lymphoma
Pruritus is generally less prevalent in
non-Hodgkin lymphoma than in Hodgkin disease. An estimated 10% of patients with
non-Hodgkin lymphoma suffer from pruritus at some time during their disease
course, often with improvement after successful therapy.
Leukemia
Pruritus is not a
common symptom in patients with leukemia, but when it occurs, it is usually
generalized. Chronic lymphocytic leukemia (CLL) and hypereosinophilic
syndromes, which include patients with eosinophilic leukemia and other
hematologic malignancies, are most often associated with pruritus. In addition,
patients with CLL can develop exaggerated reactions to insect bites. Leukemia
cutis may produce localized symptoms that include pruritus.
Pruritus in HIV Infection and
AIDS
Occasionally,
pruritus is the initial presenting symptom of AIDS. In as many as half of AIDS
patients with pruritus, an additional diagnosis responsible for this symptom is
not identified. However, HIV-infected individuals frequently develop pruritic
dermatoses such as pruritic papular eruption, eosinophilic folliculitis, severe
seborrheic dermatitis, psoriasis, scabies, insect bite reactions, drug
eruptions, xerosis, and acquired ichthyosis. Kaposi sarcoma lesions are
occasionally pruritic. Patients with HIV infection may also have other causes
of pruritus, such as chronic kidney disease, liver disease, and non-Hodgkin
lymphoma.
Severe,
treatment-resistant pruritus is relatively common in HIV-infected individuals,
and a possible correlation between intractable pruritus and increased HIV viral
load has been observed. Immunologic parameters associated with pruritus in HIV
patients include markedly elevated IgE levels, peripheral hypereosinophilia,
and a Th2-type cytokine profile.
Treatment should be
directed at any underlying dermatoses that can be identified (see above).
Topical corticosteroids and antihistamines can be used symptomatically;
antihistamines with anti-eosinophilic potential (e.g. cetirizine) may be more
effective. UVB is an additional therapeutic option and is currently considered
to be safe in HIV-infected individuals. Although antiretroviral therapy (ART)
can lead to improvement in several pruritic dermatologic diseases, a variety of
infectious, inflammatory and neoplastic skin conditions may flare when ART is
started (immune reconstitution inflammatory syndrome). Thalidomide
(100–300 mg/day) is used to treat pruritus and prurigo nodularis in patients
with HIV infection and AIDS, as it is not an immunosuppressant.
DRUG
INDUCED PRURITUS
Virtually any drug
can cause a skin reaction that is associated with pruritus. Pruritic drug
reactions most often present as morbilliform or urticarial eruptions.
Occasionally however, pruritus is the predominant manifestation. Some
medication effects (e.g. hepatotoxicity) that can lead to pruritus have a
relatively long latency period. The primary goal is to identify and discontinue
the offending drug, with supportive antipruritic therapy as needed.
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COMMON DRUGS
CAUSING PRURITUS |
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Pathomechanism |
Medication(s) |
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Cholestasis |
Chlorpromazine,
erythromycin estolate, estrogens (including oral contraceptives), captopril,
sulfonamides |
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Hepatotoxicity |
Acetaminophen,
anabolic steroids (including testosterone), isoniazid, minocycline,
amoxicillin-clavulanic acid, halothane, phenytoin, sulfonamides |
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Sebostasis/xerosis |
β-blockers, retinoids,
tamoxifen, busulfan, clofibrate |
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Phototoxicity |
8-Methoxypsoralen |
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Neurologic |
Tramadol, codeine,
cocaine, morphine*,**, butorphanol*, fentanyl*, methamphetamine |
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Increased serotonin
signaling |
Selective serotonin
reuptake inhibitors (e.g. sertraline, fluoxetine) |
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Increased bradykinin
levels† |
Angiotensin-converting
enzyme (ACE) inhibitors |
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Increased leukotriene
levels |
NSAIDs |
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Histamine analogue |
Betahistine |
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MRGPR§ stimulation |
Chloroquine (pruritus
may be generalized, localized to the hands/feet, or aquagenic) |
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T-cell activation due
to CTLA-4 or PD-1 inhibition |
Ipilimumab, nivolumab,
pembrolizumab |
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EGFR inhibition |
Panitumumab,
gefitinib, cetuximab, erlotinib |
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Selective BRAF or MEK
inhibition |
Vemurafenib,
dabrafenib, trametinib, cobimetinib |
|
Other tyrosine kinase
inhibition |
Sorafenib (especially
scalp pruritus), imatinib, dasatinib, nilotinib |
|
Deposition |
Hydroxyethyl starch |
|
Idiopathic |
Clonidine, gold salts,
lithium, bleomycin |
* Pruritus is more likely with
intrathecal/epidural than systemic administration.
** Also causes non-immunologic release of
histamine from mast cells.
† Pruritus may precede development of
angioedema.
§ MAS-related G protein-coupled receptor
expressed by epidermal C-nerve fibers.
Itch
may also occur as a direct effect of interleukin 2 therapy. CTLA-4, cytotoxic T
lymphocyte-associated antigen 4; EGFR, epidermal growth factor receptor; PD-1,
programmed cell death protein 1.
PSYCHOGENIC PRURITUS
Itching, either localized or generalized, can be a skin
manifestation of psychological disturbance.
Psychogenic
pruritus should be considered when other causes have been excluded. Psychogenic
pruritus may have an intensity that parallels the emotional state. No primary
lesions are seen, and secondary lesions range from lichenification to
excoriations.
Attacks of
nocturnal pruritus associated with a sensation of heat and accompanied by
sweating, are often due to anxiety. Such episodes of pruritus are recently
reported in patients awaiting transplant surgery. Widespread psychogenic
pruritus may result in extensive and disfiguring excoriations and even scarring
to the extent of self-mutilation. Of importance, delusions of parasitosis are
one of the more challenging types of itch that dermatologists encounter. The
patient holds a false belief that they are infested with parasites, although
careful inspection reveals no supporting clinical findings. The patient often
brings “evidence” in the form of collected fragments, although on examination
the material proves to be nonspecific debris. The patients often refuse to see
a psychiatrist. Although rarely successful, psychiatric advice should be
sought. Delusions of parasitosis are classically treated with typical antipsychotic
agents; pimozide is most commonly
used by dermatologists. Olanzapine (5 mg/day) is
another option to treat this severe type of psychogenic itch. It is also self-evident that patients
experiencing severe, persistent pruritus become secondarily depressed, and that
this may itself lower the threshold for pruritus, thus completing a ‘vicious
circle’ of itch, depression and more itch. Although the patient’s sleep pattern
is usually uninterrupted, sedative antipruritics may be utilized as therapy,
because topical agents alone are rarely effective.
Diagnostic steps for delusional
parasitosis
NEUROLOGIC
ETIOLOGIES OF PRURITUS AND DYSESTHESIA
A dysesthesia is
defined as an unpleasant abnormal sensation, such as tingling, burning,
numbness, or pruritus; it can be spontaneous or evoked and may result from
abnormalities in the central or peripheral nervous system. Dysesthesias,
including pruritus, are usually localized or regional in distribution and can
affect almost any site. For dysesthesias related to disorders of the CNS, the
location of the abnormality is more important than its cause. In other words, a
stroke, tumor, or multiple sclerosis plaque in the same region of the brain
will generate similar neurologic signs and symptoms.
Neurologic pruritus
most often results from damage, compression, or irritation affecting a nerve or
group of nerves. These neuropathies typically
present with secondary skin lesions due to repeated rubbing or scratching in a
circumscribed area supplied by the afflicted nerve(s). Occasionally, pruritus
of neurogenic origin occurs without neuronal damage, such as increased
endogenous µ-opioids leading to disinhibition of
itch.
Sensory (Mono) Neuropathies
with Pruritus and Dysesthesia
Sensory (mono) neuropathies
that are most often brought to the attention of dermatologists are nostalgia paresthetica
and brachioradial pruritus. Less often, symptoms of meralgia, cheiralgia, or
digitalgia paresthetica require dermatologic assessment. Secondary skin
lesions, if present, include excoriations, crusted papules, hyper pigmentation,
and lichenification; these findings are localized to the area of dysesthesias
that corresponds to the receptive field of one or a few sensory nerves.
Treatment with topical capsaicin (0.025–0.3%)
3–6 times daily for ≥4–6 weeks or a capsaicin 8% patch may be helpful. Other
treatment options include topical anesthetics (e.g. pramoxine, lidocaine),
topical corticosteroids, oral gabapentin/pregabalin, and acupuncture.
Notalgia paraesthetica
Notalgia paresthetica is a fairly common cause of chronic
localized itch, affecting mainly the mid interscapular area especially the
T2–T6 dermatomes, but occasionally with a more widespread distribution,
involving the shoulders, back, and upper chest. Characteristically, patients
complain of persistent burning pruritus. There are no specific cutaneous signs,
apart from those attributed to scratching and rubbing such as mild
lichenification and pigmentation with or without macular amyloidosis. The
current view on etiology is that it is a neuropathic itch due to nerve
entrapment of the posterior rami of spinal nerves arising at T2–T6.
A. Distribution of
dysesthesia in selected neuropathic conditions. The names for these entities
come from Greek terms, e.g. notos = back, meros = thigh, cheiron = hand, algos
= pain. Darker shades indicate more common areas of involvement.
B. B Secondary skin
lesions on the right neck in a patient with cervical osteoarthropathy.
C. C Classic nostalgia paresthetica
with hyper pigmentation on the right upper back at the medial scapular border.
D. D Meralgia paresthetica
presenting as hyper pigmentation and lichenification in a discrete area of
dysesthesia on the anterior thigh.
PRURITUS
VARIANTS
Aquagenic Pruritus
Criteria for the diagnosis of idiopathic aquagenic pruritus
(which is uncommon) are the following: (1) Typically, contact with water at any
temperature or salinityleads to an intense
pricking itch in the exposed skin;
(2) pruritus developing within 30 minutes of water contact and last for as long
as 2 hours without visible skin changes, i.e. in the absence of urticaria or
symptomatic dermographism; and (3) exclusion of chronic skin diseases such as
cutaneous mastocytosis, drug-related pruritus and systemic disorders (e.g.
polycythemia vera).
Typically, symptoms begin on the lower extremities and then
generalize, with sparing of the head, palms, soles and mucosae, mainly in the
middle-aged and elderlyperson. The pathologic mechanism of
aquagenic pruritus is unknown, although elevated dermal and epidermal levels of
acetylcholine, histamine, serotonin and prostaglandin E2 have been described.
Aquagenic pruritus may also be a manifestation of an
adverse drug reaction. Investigation of affected skin has shown elevated
histamine concentrations and increased cutaneous mast cell degranulation, and
the serum histamine concentration is also shown to be raised. The lack of
visible evidence of histamine release can be explained by its slow rate of
release, leading to skin concentrations sufficient to cause itching but below
the threshold for visible vascular changes. However, histamine is unlikely to
be the sole mediator, since antihistamine treatment is generally ineffective, and
there is also evidence of the involvement of acetylcholine, since topical
hyoscine treatment rendered skin unresponsive to water contact. Further
evidence for acetyl choline as a mediator derives from a report of increased
acetyl cholinesterase activity localized to nerve fibres investing eccrine sweat
glands in patients with aquagenic pruritus.
Traditional therapies utilize alkalinization of bath water
to a pH of 8 with baking soda. Treatment with narrowband UVB and PUVA have been
reported as efficacious, with PUVA appearing to be superior to broadband UVB.
Capsaicin cream (0.025%, 0.5% or 1.0%) applied three times daily for a minimum
of 4 weeks can decrease symptoms, but long-term therapy may not be practical.
Pruritus in Scars
Scar remodeling can
last from 6 months to 2 years. Pruritus associated with wound healing is common
and usually resolves over time, but it is occasionally prolonged, especially in
hypertrophic or keloidal scarring. The pruritus in immature or abnormal scars
is most likely a consequence of physical and chemical stimuli as well as nerve
regeneration. Physical stimuli include direct mechanical stimulation of nerve
endings during scar remodeling. Histamine, vasoactive peptides (e.g. kinins),
and prostaglandins E1/E2 may account for a “chemogenic” pruritus. Nerve
regeneration occurs in all healing wounds, and a disproportionate number of
thinly myelinated and unmyelinated C-fibers in immature or abnormal scars may
contribute to increased itch perception. The observation of abnormalities in
small nerve fiber function within keloids has raised the possibility of a small
nerve fiber neuropathy.
Therapy includes
emollients, topical and intralesional corticosteroids, and silicone gel sheets.
Oral antihistamines do not have a significant benefit. Relief of pain and
pruritus associated with giant keloids was observed with oral pentoxifylline
(400 mg 2–3 times daily).
Post-Thermal Burn Pruritus
Approximately 85% of
patients with burns experience pruritus during the healing phase, particularly
when the burns involve the limbs. A gradual decrease in pruritus usually
occurs, but it may persist for years. Reported predictors of pruritus include a
deep dermal burn injury, female gender, and psychological distress. Morphine therapy
may also contribute to postburn pruritus. Emollients, topical anesthetics (e.g.
lidocaine/prilocaine), massage therapy, and bathing in oiled water or with
colloidal oatmeal may be of benefit. In a randomized controlled trial, oral
gabapentin was found to be more effective than cetirizine for post burn
pruritus.
Pruritus of senescence
Although
dry skin is probably the most common trigger, elderly patients can have
idiopathic itch without xerosis. Other possible explanations include
age-related changes in nerve fibers and central disinhibition of itch due to
loss of input from pain fibers. Additional cutaneous changes that may
contribute to pruritus (as well as xerosis) in elderly patients include
decreased skin surface lipids, decreased clearance of transepidermally absorbed
materials from the dermis, decreased sweat and sebum production, and diminished
barrier repair.
Soft white paraffin ointment is cheap, occlusive and has
been shown to accelerate recovery of barrier function in damaged skin. The
patient must be encouraged to apply emollients at least four times daily and,
if necessary, ambient temperature and humidity should be modified. Doxepin 10–20
mg at night is useful in patients in whom there is a significant element of
depression. Corticosteroids, antihistamines and cooling lotions are not
indicated in itching due to xerosis.
Postmenopausal pruritus
The commonest presentation of postmenopausal pruritus is
pruritus vulvae, often a manifestation of estrogen deficiency and associated
with mucocutaneous candidiasis and diabetes. It should respond to corrective
hormone therapy, combined if necessary with anti-Candida therapy. Persistent or
episodic widespread itching is occasionally associated with the postmenopausal
syndrome. The itching characteristically evokes rubbing, rather than heavy
excoriation, and is frequently associated with hot flushes. It is especially
troublesome at night, and is usually associated with raised plasma levels of
pituitary follicular and luteal stimulating hormones. These hormones are
unlikely, however, to be the direct cause of the itching and associated
flushing, which are probably attributable to local tissue mediators.
Hormone-replacement therapy with ethinyl oestradiol is usually sufficient to
control postmenopausal pruritus due to this cause, but since systemic estrogen
therapy can be hazardous, expert endocrinological advice should be sought.
Pruritus of atopic dermatitis
The itch of atopic dermatitis is aggravated by scratch
damage, which causes enhanced inflammation (itch–scratch cycle). Itching is
usually worse at night, and is aggravated by contact with wool, sweat, spicy
foods and alcohol. The itching of atopic dermatitis is multifactorial, being
due to dryness, almost invariable in atopic dermatitis sufferers, inflammation
and probably to disturbed regulation of itch traffic in the central nervous
system. In this context, alloknesis (itchy skin) forms a major component of the
itch suffered by the atopic dermatitis patient—explaining, for example, the
paroxysms of itching experienced by patients in response to sweating, sudden
changes of temperature, humidity, undressing or dressingand direct contact with
wool. There is also an increased
population density of sensory nerve fibres in the affected lichenified pruriginous
skin. It is important to distinguish itching associated with inflammatory
changes from that simply due to excessive drying of the skin in patients with
atopic dermatitis. Emollients, which should always be prescribed and which in
many cases may be all that is required, will be inadequate alone where
inflammatory changes are responsible for the itching. Although H1 antihistamines
are of little value in relieving pruritus, but most patients with itchy atopic
dermatitis receive antihistamines, mainly of the sedative type, and are usually
effective—presumably due to their central action. It is now concluded that
sedation is a required component of successful systemic treatment of itching in
atopics, and that, moreover, itching in atopic dermatitis involved a central
component. Systemic antibiotics frequently bring about relief from pruritus.
Staphylococcus aureus behaves as a super antigen leading to T-cell activation, and
also activates dermal mast cells via toll-like receptors. Topical steroids are
frequently effective in suppressing itching in the atopic dermatitis patient.
Corticosteroids are not inherently antipruritic, but suppress the inflammatory
component of the dermatosis thereby alleviating the itching indirectly. They
are especially effective in highly pruritic children with atopic dermatitis
applied by the ‘wet wrap’ technique. Phototherapy is widely used for the
pruritus of atopic dermatitis in older children and adults, especially when it
is intractable and widespread. Both broad-band and narrow-band ultraviolet B is
used, the latter being deemed superior. Immunosuppressives—including systemic
azathioprine and ciclosporin—are highly effective in relieving the itching (and
other signs and symptoms) of chronic atopic dermatitis in selected patients,
probably due to an action on activated CD4+ T-helper lymphocytes. The recent
introduction of topical calcineurin inhibitors, tacrolimus and pimecrolimus,
provides an effective new measure for amelioration of pruritus of atopic
dermatitis. These agents owe their action to downregulation of activated T
cells. Recent work has highlighted the role of interleukin-31 (IL-31) in the
itch of atopic dermatitis and this cytokine is likely to be a target for future
antipruritic therapeutic intervention. Opioid antagonists such as oral
naltrexone may be of value in patients with intensely pruritic atopic
dermatitis.
Treatments for
pruritus of atopic dermatitis
Treatment Level of
effectiveness
1. Emollients
high
2. Topical
steroids
high
3. Sedative
antihistamines medium
4. Topical
calcineurin inhibitors high
5. Narrow-band
UVB phototherapy high
6. Azathioprine high
7. Ciclosporin high
PRURITUS IN PREGNANCY
Pruritus occurs in about 20% of pregnant women. In the
majority of these the itching is localized to the anogenital area, often
secondary to vulvovaginitis due to candidosis, bacterial causes or to
pre-existing dermatoses such as psoriasis and endogenous eczema. However, more
widespread pruritus is also frequent. Important possible causes include scabies
and exacerbation of pre-existing atopic dermatitis or psoriasis. The specific
dermatoses of pregnancy may also present with pruritus. The commonest is pruritic
urticated papules of pregnancy (PUPP; polymorphous eruption of pregnancy), but
the less common pemphigoid gestationis and cholestasis of pregnancy are also
intensely pruritic. No treatment for itching is absolutely safe in pregnancy,
but it is a reasonable assumption that persistent, intense pruritus is itself
prejudicial to healthy pregnancy. The following are deemed the least unsafe
measures in the pruritic pregnant patient:
(i)
Topical—1–2% menthol cream or lotion; 5% urea
cream (for dry skin); benzyl benzoate application (for scabies); topical
steroids (low– moderate potency only);
(ii)
systemic—chlorpheniramine; diphenhydramine;
hydroxyzine;
(iii)
Other—UVB phototherapy.
PRURITUS
IN SPECIFIC LOCATIONS
Scalp Pruritus
Skin disorders
involving the scalp (e.g. seborrheic dermatitis, psoriasis, folliculitis, and
lichen planopilaris) may present with pruritus localized to this area. However,
scalp pruritus also occurs in the absence of any objective changes, most
commonly in middle-aged individuals during periods of stress and fatigue. In
such instances, treatments such as topical corticosteroids and antipruritic
agents have been employed with inconsistent efficacy.
Anogenital Pruritus
Pruritus ani
Pruritus localized to
the anus and perianal skin occurs in 1–5% of the general population, with a
male: female ratio of ~4: 1. The onset is typically insidious, and symptoms may
be present for weeks or years before patients seek medical attention.
Pruritus ani can be
primary (idiopathic) or secondary in nature. Primary pruritus ani is defined as
pruritus in the absence of any apparent cutaneous, anorectal, or colonic
disorder; it accounts for 25–95% of reported cases, depending upon the series.
Possible causes include dietary factors such as excessive coffee intake, poor
personal hygiene, and psychiatric disorders. Secondary pruritus ani has an
identifiable etiology such as chronic diarrhea, fecal incontinence/anal
seepage, hemorrhoids, anal fissures or fistulas, rectal prolapse, primary
cutaneous disorders (e.g. psoriasis, lichen sclerosus, seborrheic dermatitis,
allergic contact dermatitis), sexually transmitted diseases, other infections,
infestations (e.g. pinworms), previous radiation therapy, and neoplasms (e.g.
anal cancer). Pruritus ani (as well as pruritus vulvae or scroti) can also be
neuropathic in origin and be due to compression or irritation of lumbosacral
nerves from prolapsed intervertebral discs, vertebral body fractures, or
osteophytic processes.
Findings on physical examination range from
normal-appearing skin or mild perianal erythema to severe irritation with
crusting, lichenification, and erosion or ulceration. Histologically, a
nonspecific, chronic dermatitis is usually seen, but specific dermatoses (e.g.
lichen sclerosus) and neoplastic disorders (e.g. extramammary Paget disease)
can be excluded.
Evaluation includes a
thorough history, complete cutaneous and general physical examination, and
psychiatric screening. The latter is of importance considering that anxiety and
depression may be aggravating factors for pruritus ani. Patch testing should be
considered to exclude allergic contact dermatitis. Rectosigmoidoscopy and/or
colonoscopy may be necessary, especially in patients with recalcitrant pruritus
ani, in order to detect underlying conditions ranging from hemorrhoids to
cancer. The possibility of pinworm infection should be considered, particularly
in affected children. In patients receiving chronic antibiotic therapy who have
liquid stools with a pH of 8–10, Lactobacillus replacement
therapy is recommended.
While secondary
pruritus ani usually improves with treatment of the underlying disorder,
management of primary disease can be very challenging. Mild cases often respond
to sitz baths (e.g. with astringents such as black tea), cool compresses, and
meticulous hygiene using water-moistened, fragrance-free toilet paper or a
bidet. The area is then dried with blotting or a fan, with avoidance of rubbing
and alkaline soaps. Application of zinc oxide paste can help to protect the
skin from further irritation and friction.
A mild corticosteroid cream (class 6 or 7) is
often effective in controlling symptoms. However, with greater disease severity
or the presence of lichenification, more potent topical corticosteroids and
prolonged treatment may be required, raising the risk of cutaneous atrophy.
Topical calcineurin inhibitors, including use on a rotational basis with
topical corticosteroids, may be helpful when longer courses of therapy are
necessary.
Pruritus vulvae and scroti
These common
disorders, which may be incapacitating and emotionally disturbing, are solely
psychogenic in only 1–10% of patients. Like pruritus ani, patients with
pruritus of the vulva or scrotum typically complain of symptoms that are worse
at night, and repeated rubbing or scratching leads to lichenification. The
evaluation, differential diagnosis, and treatment options are similar to those
for pruritus ani.
Acute pruritus of the
vulva or scrotum is often related to infections such as candidiasis, but allergic
or irritant contact dermatitis should also be considered. Chronic pruritus in these sites may be caused by
dermatoses (e.g. psoriasis, atopic dermatitis, lichen sclerosus, lichen
planus), malignancy (e.g. extramammary Paget disease, squamous cell carcinoma),
or atrophic vulvovaginitis. Scrotal pruritus secondary to lumbosacral
radiculopathy has also been described. In general, irritation related to
cleansing and toilet habits needs to be addressed, as well as treatment of any
identifiable underlying cause.
MANAGEMENT OF PRURITUS
Pruritus can significantly impair the quality of life in
affected individuals. Acute itch may lead to agitation and difficulty
concentrating, while chronic itch can have sequelae such as depression and
decreased sexual desire or function. Obviously, the most important step is to
identify and treat the fundamental cause of the itch, whether it is primarily
in the skin or of a systemic origin. At the same time, patients require
symptomatic relief. Thus far, no specific
antipruritic drugis capable of relieving itch irrespective of its origin. Thus,
individualized management of each patient and pruritic disease process is
necessary. General measures and specific treatments that can be selected
according to the patient’s complaints.
General Measures
Patient education and elimination of
provocative factors are important.Pruritus is temperature
dependent, and therefore wearing light soft breathable clothes(no wool or rough
fabrics), keeping the bedroom cool, using light bedclothes and keeping the
working environment as cool as possible are all helpful measures. A cool shower
before retiring may allow sleep. Avoid excessive
bathing (lukewarm baths or showers with syndets), using emollients on a daily
basis with application immediately after bathing, and managing dermographism if
present. Elderly patients are especially prone to xerosis, and restricting full
bathing to once or twice weekly, with interim sponge bathing of odorous regions
such as the groin and buttocks, may be helpful. Patients can be taught methods
of interrupting the itch–scratch cycle, such as application of a cold washcloth
or gentle pressure, and the nails should be kept short. Cooling lotions,
such as calamine lotion or topical 1% menthol in 90% ethanol is of significant
value in the symptomatic relief of histamine-induced pruritus, probably due to
activation of cold-sensitive TRP channels on afferent nerve terminals. Of note a
subset of patients with chronic itch reports that hot showers alleviate their
itch for several hours. Controlled physical exercise,
relaxation therapy, and minimization of exposure to dust and heat as well as of
stress and anxiety are beneficial.
Topical Antipruritic Treatments
There is a lack of controlled studies for most topical
antipruritic treatments. Many topical agents are claimed to be effective for
pruritus; however, few claims are supported by more than anecdotal evidence.
Although capable of relieving pruritus due to inflammatory skin disease,
corticosteroids are not intrinsically antipruritic. Antihistamines are only
antipruritic if the pruritus is caused by histamine, as in urticaria. However,
a number of pharmacologic mechanisms offer promising avenues for treatment of
itch.
Barrier Creams and Combination Therapies
Emollients and barrier repair creams often reduce
pruritus through improved barrier function. They help the stratum corneum to
retain water and provide an exogenous barrier to prevent trans epidermal water
loss. Such barrier creams are often effective treatments for itch associated
with dry skin and atopic dermatitis. Restoration of the barrier minimizes
fissuring and reduces exposure of C nerve fibers. Atopic dermatitis patients
treated with ceramide-dominant emollients demonstrate improved transepidermal
water loss and overall severity of skin disease. Lipids, occlusives, and
humectants also reduce damage to skin by decreasing contact between skin
proteins, lipids, and surfactants. Acidifying the stratum corneum may also
reduce itch. High pH solutions increase the swelling of the stratum corneum,
change lipid rigidity, and increase secretion of serine proteases, suggesting
that neutral or acidic pH solutions are less damaging.
Topical Salicylates
Clinical trials have shown that applying a topical salicylic acid
solution to the skin relieves itch. Topical salicylic acid is a common
keratolytic agent and may also increase hydration and soften the stratum
corneum by decreasing its pH.
Topical Immunomodulators
Although topical immunomodulators, such as tacrolimus and
pimecrolimus,
are used primarily for atopic dermatitis, these medications are promising
antipruritic treatments in other dermatologic diseases as well such as chronic
irritative hand dermatitis, seborrheic dermatitis, lichen sclerosus, anogenital
pruritus and prurigo nodularis. Tacrolimus and pimecrolimus have both been
shown to directly affect C nerve fibers.
Coolants and Counter-Irritants
A distinct subset of sensory neurons may directly sense
changes in temperature via receptors of TRP ion channels on cutaneous nerve
endings. These include vanilloid receptors, such as TRPV1, which respond to
warmth and capsaicin.
These receptors act synergistically with other receptors involved in itch, such
as PAR-2 and SP receptor (Neurokinin 1). These receptors are targets for
treatment of itch. Other receptors from the same family include cold receptors,
such as TRPM8. Menthol may reduce itch
via TRPM8 receptors in keratinocytes and nerve fibers. Menthol 1% cream is
popular with patients who have pruritic skin; however, higher concentrations
can induce skin irritation. Those patients who report that cold showers and ice
relieve their itch tend to respond extremely well to treatment with menthol.
Capsaicin
Topical capsaicin,
the active compound in the chili pepper, causes release of neuropeptides, including
SP, from C nerve fibers. The exact mechanism is not fully understood; however,
prolonged application of capsaicin to the skin depletes stores of SP,
desensitizes neurons, and abolishes pruritus at the site of application.
Capsaicin activates the vanilloid receptor TRPV1, which is abundant in the
epidermal layer of the skin. Several reports have supported capsaicin's value
for localized, chronic pruritic disorders, particularly those of neuropathic
origin, including brachioradial pruritus, nostalgia paresthetica, postherpetic
itch as well as pruritus associated with CKD, psoriasis and atopic dermatitis.
Unfortunately, compliance is poor because initial application causes an
intense, transient burning sensation at application sites; however, this usually
resolves after using the medication for a few days or with application of a
topical anesthetic.
Topical Anesthetics
Pramoxine
Pramoxine is
a topical anesthetic that reduces itch, especially when applied to facial
areas, by blocking the transmission of nerve impulses. Pramoxine inhibits histamine-induced itch and
CKD-associated pruritus.
Polidocanol
Polidocanol is a nonionic surfactant with both local
anesthetic properties and moisturizing effects. In an open-label study, a
combination of 5% urea and 3% polidocanol (Lauromacrogol) was found to
significantly reduce pruritus in patients with atopic dermatitis, contact
dermatitis, and psoriasis.
Systemic Antipruritic Treatments
Antihistamines
Pruritus due to histamine is mediated exclusively via H1
receptors; H2 antihistamines are ineffective in relieving pruritus.
First-generation (classic) H1 antihistamines have marked sedative and atropine-like
(anticholinergic) actions. Second generation (minimal- or low-sedation) H1
antihistamines have lower lipophilicity and consequently are associated with
less drowsiness and other unwanted side effects. H1 antihistamines are widely
used for this purpose. Second generation H1 antihistamines are the treatment of
choice for the itch of urticaria. In the itch of atopic dermatitis,
first-generation H1 antihistamines are widely prescribed and any effectiveness
for this or other causes of pruritus being probably attributable to their
sedative properties.
Opiate Antagonists and Agonist–Antagonists
μ-opioid receptor agonists can cause generalized
pruritus. μ-Opioid antagonists, such as naloxone and
naltrexone,
have been used for the treatment of pruritus associated with cholestasis, uremia,
and dermatologic diseases. μ-antagonists are associated with significant side
effects including hepatotoxicity, nausea and vomiting, difficulty sleeping, and
reversal of analgesia, among others. Κ-Receptor agonists also inhibit
μ-receptor effects. The novel κ agonist, nalfurafine (TRK-820), has been shown
to be effective in treatment of severe uremic pruritus. Thus, κ agonists are a
promising treatment for severe itch.
Butorphanol is
a commercially available opioid agonist-antagonist analgesic with both
κ-agonist activity and μ-antagonist activity.
Intranasal butorphanol is an effective treatment for many patients with
chronic, severe, and intractable pruritus due to systemic diseases and
inflammatory skin diseases.
Antidepressants
The oral antidepressant and selective noropinephrine
re-uptake inhibitor, mirtazapine,
has been shown to relieve itch in some patients. Unlike other SSRIs,
mirtazapine is a central presynaptic α2 noradrenergic inhibitor and specific
serotonergic antidepressant. Mirtazapine is a safe medication without serious
side effects and may be an effective alternative for the treatment of nocturnal
pruritus.179 It
has been shown to be effective when used to treat systemic pruritus as well as
pruritus of inflammatory skin diseases and in particular nocturnal itch using a
low dose of 15 mg at night. A recent open-labeled study showed paroxetine and
fluvoxamine,
both selective serotonin reuptake inhibitors, to be efficient in the treatment
of chronic itch.
Thalidomide
Thalidomide has
shown antipruritic efficacy in treatment of inflammatory skin diseases, such as
prurigo nodularis, actinic prurigo, eczema, and idiopathic elderly pruritus. It
is especially useful in pruritus associated with multiple myeloma and
lymphoproliferative disease. The
antipruritic activity of thalidomide
could be related to several mechanisms, including inhibition of TNF-α
synthesis. Although TNF-α does not have any direct pruritogenic effect, it is
elevated in many pruritic dermatoses. Thalidomide may also act directly as a
peripheral and central nerve depressant. The major adverse effects of
thalidomide are peripheral neuropathy and teratogenicity.
Neuroleptics
Gabapentin is
a structural analog of the neurotransmitter γ-aminobutyric acid and has been
used as an anticonvulsant; however, its mechanism of action in the CNS is
poorly understood. Studies have shown that gabapentin is effective for
treatment of brachioradial pruritus, multiple sclerosis-induced itch, and other
types of neuropathic itch as well as uremic itch. Gabapentin appears to alter
sensation and pruritus associated with itch related to nerve damage in
dermatologic and systemic disease. Gabapentin may inhibit central itch
pathways, as it does in pain. Pregabalin is
a neuropathic pain medication that has a similar structure and function to
gabapentin with fewer side effects and can reduce neuropathic itch or alter the
sensation of itch in systemic diseases.
Substance P Antagonist
Aprepitant, an
oral drug that antagonizes the effect of SP on neurokinin type 1 receptor has
recently been shown to be effective against pruritus associated with the Sézary
syndrome.
Nonpharmacologic Treatments for Itch
Phototherapy
Narrow band UVB is an effective for treatment of
pruritus. Phototherapy decreases the population density of mast cells by
inducing apoptosis, causes peripheral nerve dysfunction, and reduces divalent
cations in the skin. Phototherapy is an effective treatment for itch associated
with atopic dermatitis, psoriasis, and CKD. Remissions may last for as long as
18 months.
Cutaneous Field Stimulation and Acupuncture
Cutaneous field stimulation (CFS) is a new technique that
electrically stimulates afferent fibers, including nociceptive C fibers. In
patients with localized itching, CFS significantly reduces patient-reported
itch and causes degeneration of epidermal nerve fibers. However, CFS is only
practical for localized disease. In addition, acupuncture at the correct points
showed a significant reduction in type I hypersensitivity itch in both healthy
volunteers and patients with atopic eczema.
Behavioral Therapy Targeting the Central Nervous System
Stress and other psychogenic factors are important in
chronic itch. Stress reduction using holistic approaches such as meditation,
yoga and mindfulness may have adjunctive role in reducing itch intensity.
|
GENERAL MEASURES FOR THE
TREATMENT OF PRURITUS AND DYSESTHESIA |
|
Skin care |
|
·
Twice daily
application of a moisturizing cream or ointment ·
Warm (not
hot) baths/showers ≤ once daily, with minimal use of a mild soap/non-soap
cleanser, and followed immediately by moisturizer application; especially in
winter, consider limiting use of soap to odorous regions such as the axillae
and anogenital area ·
Avoid wool
and other rough fabrics ·
Keep nails
cut short |
|
Topical |
|
·
Cooling
agents/counterirritants: e.g.
menthol, camphor, capsaicin ·
Anesthetics: e.g. pramoxine, lidocaine, prilocaine, polidocanol,
palmitoyl ethanolamine ·
Anti-inflammatory agents: corticosteroids, calcineurin inhibitors |
|
Systemic medications |
|
·
Antihistamines: especially if there is a component of dermographism or
urticaria; otherwise limited efficacy beyond sedative effects; consider
doxepin (beginning with 10–25 mg at bedtime) ·
Neuromodulators: gabapentin, pregabalin ·
Antidepressants: SSRIs (e.g. fluoxetine, paroxetine, sertraline,
venlafaxine), tricyclics (e.g. amitriptyline, doxepin), mirtazapine ·
Opioid antagonists/agonists: e.g. naltrexone, butorphanol nasal spray ·
Other: thalidomide (especially for prurigo nodularis),
aprepitant (NK1 receptor antagonist) |
|
Physical modalities |
|
·
Phototherapy: UVB (broadband or narrowband), PUVA, UVA, UVA-1 ·
Acupuncture |
|
Psychological approaches |
|
·
Behavior
modification therapy, biofeedback ·
Support
groups |
NK1,
neurokinin 1; PUVA, psoralen plus UVA; SSRI, selective serotonin reuptake
inhibitor.
