Section 9: The skin and internal disease
Chapter 47: Pruritus
Introduction
Pruritus (itching) is the predominant
symptom of kin disease and a frequent
manifestation of systemic disease. Itch can be
defined as an unpleasant sensation in the skin
which elicits a desire to scratch. Itch is
classified into 4 types: cutaneous (e.g. scabies,
lichen planus), neuropathic (due to lesions of
afferent pathways of the nervous system e.g.
peripheral neuritis, brain tumours), neurogenic
(due to centrally acting mediators which do
not damage the CNS e.g. opioid peptides in
cholestasis) and psychogenic itching. The
quality of itching varies, ranging from
burning, through pricking, to sensation of
insects crawling over the skin. Pruritus may
occur with or without skin disease and may be
caused by systemic disease.
Pathways of itching
The neurophysiological pathways of
itching start by the itch receptors in the skin.
These are non-specific non-specialized
unmyelinated free nerve endings located close
to the dermal-epidermal junction. Itch is
transmitted from the receptors to unmyelinated
C fibers which enter the dorsal horn of the
grey matter of the spinal cord, synapse there
with secondary neurons, which cross over to
the contralateral spinothalamic tract, and
ascend to the thalamus. There, tertiary
neurones relay itch to the level of conscious
perception in the cerebral cortex.
Table 47.1 Causes of pruritus.
Systemic causes
Chronic uraemia
Cholestasis (primary biliary cirrhosis,
obstructive jaundice, HCV pregnancy
infection)
Polycythemia vera
Iron deficiency anaemia
Malignancy (internal, Hodgkin’s disease,
leukaemia)
Anorexia nervosa
Thyrotoxicosis
Psychogenic
The anterior cingulate cortex is involved
in the recognition of itch sensation at
conscious levels, whilst the premotor cortical
areas participate in intention to scratch, which
go to the skin through descending pathways.
The receptors of itching are also sensitive to
temperature, and this explains the worsening
of itching in a warm environment.
Scratching is a reflex functioning at a
spinal level, modified by higher centers.
Scratching relieves itching for several minutes
after scratching has ceased. This may be due
to suppression of the facilitating circuits that
reinforce itching sensation, or the itching may
damage temporarily the sensory nerve endings
which take several minutes for repair.
Causes of itching
Itching has causes and is accomplished
through mediators. The causes of itching
include skin disease (e.g. scabies, lichen
planus, atopic eczema, psoriasis), systemic
diseases (e.g. chronic renal failure, hepatic
cholestasis, iron deficiency, polycythemia
vera,
systemic
drugs,
thyrotoxicosis,
myxoedema, diabetes mellitus, malignant
diseases and anorexia nervosa), and itching in
clinically normal skin (e.g. aquagenic pruritus,
pruritus of senescence, psychogenic pruritus,
postmenopausal
pruritus,
notalgia
paraesthetica, and brachioradial pruritus). The
causes of pruritus are presented in table 47.1
Skin causes
Urticaria
Eczema (atopic, asteatotic, stasis, contact)
Prurigo (nodularis, pigmentosa, chronic of adults, of pregnancy,
dermographic, actinic, Besnier’s, of HIV infection)
Lichen simplex chronicus
Drug hypersensitivity
Bullous diseases e.g. DH, BP, pregnancy (PUPPP)
Senile pruritus
Neoplastic (mycosis fungoides)
Infestations (scabies, pediculosis, papular urticaria, schistosomal
cercarial dermatitis)
Inflammations (extensive plaque psoriasis, LP, mastocytosis,
eosinophilic pustular folliculitis)
Localized pruritus: ani, scroti, vulvae, nostalgia paraesthetica
Aquagenic pruritus
-515-
Mediators of itching
Mediators of itching are central and
peripheral. Central mediators are released in
the CNS and include opioid peptides (e.g. in
cholestasis). They have a peripheral
augmenting action on histamine itch, in
addition to their pruritic central action.
Peripheral mediators are released in the skin
and include mainly histamine, but other
mediators are also implicated e.g. substance P,
proteases (e.g. kallikrein and chymotrypsin),
cytokines (e.g. IL-2), prostaglandin E2 and
acetyl choline.
Histamine is released by degranulation
of dermal mast cells. There are 3 subclasses of
histamine receptors. H3 receptors occur in the
brain, and H1 and H2, receptors are present in
the skin. H1 but not H2 receptors, are
implicated in histamine-induced itching. Thus,
there is no theoretical basis for use of H2
antagonists (cimetidine, ranitidine) in the
suppression of itching caused by histamine.
Substance P is a neuropeptide usually
present in the skin which increases in itchy
inflammatory dermatoses. It acts by
enhancement of histamine release from mast
cells but not other mast cell mediators.
Substance P is synthesized in the dorsal root
ganglion of nociceptor C fibres and
transmitted peripherally in granules.
A role for IL-2 in the itching of atopic
eczema is proposed: T lymphocytes, an
important source of IL-2, are a feature of the
dermal infiltrate, and ciclosporin, a potent
inhibitor of IL-2 production by T
lymphocytes, causes relief of itching in atopic
eczema. Also, IL-31 is involved in the pruritus
of atopic dermatitis. Prostaglandin E2
enhances itching caused by histamine and
other mediators. Acetylcholine is thought to be
the mediator in aquagenic pruritus and
possibly
atopic
dermatitis.
Important
mediators and their function in itching are
illustrated in table 47.2.
Itching in systemic disease
Chronic uraemia: Itching occurs in chronic,
but not acute, renal failure, in the majority of
patients, and is severe in only a few. Itching
may be persistent and extensive or transitory
and localized. Dialysis usually does not
improve itching. Factors suggested for the
pathogenesis include abnormal sprouting of
unmyelinated nerve fibres in skin of uraemic
patients, and presence of raised serum
parathyroid hormone levels, due to secondary
hyperparathyroidism. Parathormone is known
to increase tissue mast cells. T-cell derived
lymphokines (IL-2) and opioid peptides are
possible mediators for the itching of uraemic
pruritus, and histamine is improbable because
of absence of relief with the use of
antihistamines. The best treatment for uraemic
pruritus is renal transplantation. Other
effective measures include UVB phototherapy
(narrow band), activated charcoal, and
gabapentin. Emollients are used for the dry
skin. Topical capsaicin 0.025% is effective in
localized uraemic pruritus. It acts by depletion
of substance P from sensory nerve endings.
Cholestasis: Pruritus, which may be
generalized or localized (e.g. to the hands and
feet), is a frequent and distressing symptom of
cholestasis and may precede the onset of
jaundice of any cause. It may be caused by
primary biliary cirrhosis, obstructive jaundice,
HCV infection or pruritus of pregnancy.
Hepatitis C is an important cause of intense
cholestatic pruritus, and should be considered
as a part of the work-up of patients with severe
pruritus. The pathogenesis of cholestatic
pruritus may be the increased plasma levels of
bile salts, or those of opioid peptides.
Naloxone is effective in the treatment of
cholestatic pruritus. Other therapies that may
be effective include cholestyramine (ionexchange resin), phenobarbital combined with
rifampicin,
UVB
phototherapy,
and
plasmapheresis.
Table 47.2 Important mediators and their function in itching.
Mediator
Function in itch
Histamine
Pruritus of urticaria
Acetylcholine
Possibly pruritus of atopic dermatitis
Substance P
Prime mast cells for release of histamine
CGRP
Sensitization of itch receptive neurone terminals
Opioid peptides
Cause central itch, especially in cholestasis
Neurotrophins (nerve growth
Sensitize itch receptive neurons, possible role in atopic dermatitis
factors)
Prostaglandin E
Sensitize itch receptors to histamine
Cytokines
Possible role of IL-2, IL-31 in itch of atopic dermatitis
-516-
Polycythemia
vera:
The
itching
of
polycythemia vera occurs in 50% of patients.
These develop a severe, prickly and
distressing discomfort after water contact
lasting for 15-60 minutes. As it frequently
occurs after the patients emerge from bathing,
it is referred to as ‘bath itch’. Platelet
aggregation has been suggested as a possible
mechanism and source of pruritogenic factors,
including histamine. However, antihistamines
are generally ineffective and treatment with
PUVA or NB-UVB may be effective.
Thyroid disease: The cause of intractable
itching of thyrotoxicosis is cutaneous
vasodilatation which leads to increased skin
surface temperature, which lowers the itch
threshold. The itching of myxoedema is due to
excessive dryness of the skin, and responds to
application of moisturizing creams.
Diabetes mellitus: Contrary to popular belief,
generalized pruritus is not a feature of diabetes
mellitus. However intractable anogenital
itching may occur due to candidiasis.
Localized pruritus of the scalp is also a
recognizable feature of diabetes.
Other diseases: Generalized pruritus may be
caused by malignant diseases and itching may
be migratory. The generalized itching that
occurs in patients with anorexia nervosa is
associated with low body weight and resolves
with weight restoration. Generalized pruritus
may occur in patients having iron deficiency
anaemia.
Itching in normal skin
The skin is apparently normal, apart from
scratch marks. Pruritus may be localized (e.g.
aquagenic pruritus, psychogenic itching,
notalgia paraesthetica, and brachioradial
pruritus) or generalized (e.g. pruritus of
senescence,
psychogenic
itching,
and
postmenopausal pruritus).
Aquagenic pruritus: Contact with water at any
temperature leads to an intense pricking itch in
the exposed skin, without visible change in the
appearance of the skin. Acetylcholine is the
probable mediator. The condition responds
poorly to antihistamines and may respond to
UVB phototherapy or PUVA.
Psychogenic itching: Itching, either localized
or generalized, can be a manifestation of
psychological disturbance. Perianal and, in
women, vulval itching are the commonest
manifestations of localized psychogenic
pruritus. Parasitophobia (delusions of parasitic
infestation of the skin) is a generalized
psychogenic pruritus that can be diagnosed
from the patient’s description of itching due to
insects in the skin. It is treated by antidepressant and anxiolytic drugs (e.g. doxepin
and hydroxyzine), and pimozide (a
phenothiazine) has been advocated for the
treatment of delusion of parasitosis.
Notalgia paraesthetica: This is a common
cause of localized persistent pruritus.
Characteristically, patients complain of
persistent burning pruritus localized to the
mid-scapular area, but may extend to the
scalp. Mild lichenification and pigmentation
may be seen. The current view is that it is a
type of sensory neuropathy. Capsaicin cream
may be effective.
Brachioradial pruritus: This is a common
sunlight-induced chronic pruritus, localized to
the outer aspects of the elbow, and adjacent
lower and upper arms. Oral gabapentin and
topical capsaicin cream may be effective.
Pruritus of senescence: Generalized pruritus,
associated with extensive excoriation, occurs
in 50% of those in the seventh decade or
beyond. Itching results from excessive dryness
(xerosis of the skin) caused by decreased
sebum production and failure to retain water
by the ageing skin. Treatment is with
emollients, that should be applied at least 4
times daily. Antihistamines are not indicated
in itching due to xerosis.
postmenopausal itching: The generalized
itching of postmenopausal women, which is
troublesome at night, characteristically evokes
rubbing rather than scratching and is
controlled by ethinyl oestradiol replacement
therapy, which is also effective in the
treatment of localized genital pruritus resulting
from oestrogen deficiency.
Itching in atopic dermatitis
The itching of atopic eczema 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. Paroxysms of itching may
be experienced by patients in response to
sudden changes of temperature, humidity,
undressing or dressing. The itching of atopic
eczema is multifactorial being due to dryness,
inflammation and probably to disturbed
regulation of itch traffic in the CNS.
Mediators of itching are both peripheral
-517-
(histamine, mast cell mediators other than
histamine, IL-2 from T-lymphocytes), and
central (opioid peptides). Topical treatment of
atopic eczema includes emollients for dryness,
topical corticosteroids and tacrolimus (a
topical T-cell immunosuppressant). Systemic
treatment includes sedative antihistamines,
UVB phototherapy, PUVA, and oral immunosuppressive drugs (azathioprine, ciclosporin).
All these topical and systemic agents are
highly effective in relieving the pruritus of
atopic
dermatitis,
except
sedative
antihistamines which have a medium effect.
Investigation of generalized pruritus
This includes blood picture, renal,
hepatic and thyroid function tests, stools for
occult blood, and inquiry about a history of
drug intake.
Treatment of pruritus
It is important to identify and treat the
cause of itching, whether it is primarily in the
skin or of a systemic origin. At the same time,
patients require symptomatic relief. Pruritus is
temperature-dependent and the patient should
be advised to wear light clothes and keep his
environment as cool as possible. Pruritus due
to dry skin, especially prevalent in elderly
people, may respond to emollients as aqueous
cream. H1 antihistamines and topical
corticosteroids should not be used in the
absence of visible inflammatory changes in
the skin.
Low-sedation antihistamines are the
treatment of choice for urticaria, while
sedating antihistamines are better used for
atopic eczema. Topical capsaicin is effective
in localized pruritus e.g. post-herpetic
neuralgia,
prurigo
nodularis,
notalgia
paraesthetica and brachioradial pruritus.
Intractable itching may be treated with
naloxone
or
doxepin,
a
tricyclic
antidepressant.
Paroxetine, a selective serotonin reuptake
inhibitor, may have a place in the treatment of
intractable itching, including that of advanced
cancer. Naloxone is effective in pruritus of
cholestasis. Gabapentin is effective in uraemic
pruritus. Tables 47.3, 47.4 illustrate the mode
of action of topical and systemic antipruritics,
respectively.
Table 47.3 Topical antipruritic medications.
Topical antipruritic
Mode of action
Calamine
Cooling
Menthol
Activation of cold-sensitive channels on
afferent nerve terminals
Capsaicin
Depletes neuropeptides of afferent nerve
terminals
Doxepin
Tricyclic, also potent H1 antihistamine
Corticosteroids
Calcineurin inhibitors
Local anesthetics
Anti-inflammatory, indirectly
antipruritic
Down-regulate activated T cells in skin
Cause temporary loss of all skin
sensation at site of application
Table 47.4 Systemic antipruritic medications.
Drug
Mode of action
H1 antihistamines
Inverse agonist at the H1 receptor
Doxepin
Tricyclic, and potent H1 antihistamine
Naltrexone
Paroxetine
Opioid receptor antagonist
SSRI
Mirtazapine
Serotonergic and noradrenergic
antidepressant
Prevents release of neurotransmitters
from nerve terminals
Gabapentin
-518-
Comment on usage
Short lived relief
Short lived relief
Burning sensation in early stages
of treatment
Effective in itching of atopic
eczema, causes drowsiness
Ineffective in itching of clinically
normal skin
Relieve itching of atopic
dermatitis
Risk of contact allergic
sensitization
Comment on usage
Effective in urticaria, controversial
in atopic dermatitis and other
pruritic dermatoses
May be effective in pruritus of
atopic dermatitis
Effective in pruritus of cholestasis
Effective in pruritus of internal
malignancy
For intractable nocturnal pruritus
Effective in uraemic pruritus