Anaesthesia, 1996, Volume 5 1, pages 1 133-1 I38

REVIEW ARTICLE

Pruritus-itching for a cause and relief?

P. C. A . K A M AND K . H . TAN

Summary
The mechanisms of pruritus, an unpleasant irritation on the skin that provokes an urge to scratch, are reviewed. Whilst
symptomatic treatment is only partially eflective, antihistamines remain the first choice of treatment. However, recent novel
treatment using opiate antagonists, propofol (subhypnotic doses) and serotonin antagonists offer attractive alternaiives.

Key words
Complications; pruritus.

Pruritus or itch is a symptom that can be trivial or signify of both peripheral and central itch specific neurons or is a
a serious underlying disease [I]. Whilst pruritus is closely subliminal form of pain, fail to explain many characteristics
linked with pain [2], it may cause the patient considerable of pruritus.
distress; further, it is poorly understood and managed.
Current research [3] suggests that pruritus is, in fact, a
separate modality distinct from pain. Thus, a logical, Pruritogenic stimuli
systematic and sympathetic approach should be taken A variety of physical stimuli [4, 51 such as pressure, low
towards a patient presenting with pruritus. intensity electrical or punctate thermal stimuli can cause
This article reviews the neurophysiological and clinical pruritus. A latency period between the application of
aspects of pruritus. stimulus and the sensation of pruritus usually occurs [3].
Ever since the description by Lewis [2] of the triple response
(itch, wheal and flare) to injury, histamine is regarded as a
Definition major mediator of pruritus. Pruritus is specifically mediated
Pruritus or itch is a subjective unpleasant and irritating by H I receptors [6] within the epidermis by direct action of
sensation arising from the superficial layers of the skin or histamine on unmyelinated free nerve endings. The primary
the mucous membranes that provokes a n urge to scratch afferents in the skin form a subepidermal nerve plexus with
[4, 51. It is a common symptom in many dermatological the free nerve endings projecting into the epidermis. Many
conditions [ I , 51 and occasionally in occult systemic substances induce pruritus by causing a release of histamine
diseases. To the pain management specialist, pruritus is a from mast cells in the skin [l].
common and distressing side-effect of opioid administration Substance P (SP), a 1 1-aminoacid neuropeptide, may
[4], which can sometimes be worse than the pain. have a n important role in the mediation of pain and
pruritus [7]. Substance P, synthesised in the cell bodies of
the polymodal nociceptive (PMN) C-fibres at the dorsal
Neurophysiology of pruritus root ganglia, is transported through the axoplasm to the
Pruritus is elicited by histamine [ I , 2, 51 and other endo- free nerve endings to modulate both pain and pruritus [7].
genous chemicals [5] which stimulate unmyelinated primary Substance P-containing C-fibres are most abundant near
afferent nerves and spinal neurones projecting through the the junction between epidermis and dermis especially in the
anterolateral quadrant of the brain. Previous theories [5], lips, fingertips, prepuce and breast [8].High concentrations
which propose that pruritus either arises from stimulation of substance P are also found in the substantia gelatinosa

P.C.A. Kam, FRCA, FANZCA, FFARCSI, Senior Lecturer, K.H. Tan, MBBS, Provisional Fellow in Anaesthesia,
Department of Anaesthesia, Royal Prince Alfred Hospital, Missenden Road, Camperdown, N.S.W. 2050, Australia.
Accepted 30 June 1996.

0003-2409/96/ 121 133 + 06 $25.00/0 @ 1996 The Association of Anaesthetists of G t Britain and Ireland 1133
1134 P . C . A . Kam and K . H . Tan

Anterolateral Posterior polymodal nociceptor nerves (PMN) in the epidermo-

column dermal junction transduce the pruritic sensation. Nerve
4 coluinn endings cluster densely around ‘itch points’ which
correspond to areas that are very sensitive to pruritogenic
Spinal cord stimuli. From the P M N nerve endings, pruritus is primarily
conducted (2 m.s ’) by unmyelinated C-fibres to the central
~

C fibre Inhibitory nervous system.

Itch stimulus The peripheral fibres travel in the spinal cord through the
tract of Lissauer and synapse in the substantia gelatinosa
where they interact with the spinal interneurones and the
descending pathways [ 1 I]. The inhibitory interneurones link
the C-fibres with both A-fibre afferents and descending
Scratch pathways. The ‘gate control theory’ [ 121 may explain the
phenomenon of ‘lateral inhibition’ (Fig. 1) in which noxious
stimulation of the skin adjacent to a pruritic spot can
Fig. 1. Mechanism of ‘Lateral Inhibition’ attenuate the initial sensation [I 31. Scratching, which
relieves pruritus, is thought to stimulate afferent large fast
conducting A-fibres adjacent to those conducting pruritus
[7]. The A-fibres synapse with the inhibitory interneurones
in the spinal cord and the trigeniinal, amygdaloid, pre-optic and subsequently inhibit the C-fibres, thus reducing the
nuclei in the brain [8]. Whilst substance P can directly pruritic sensation.
induce pruritus, some of the pruritogenic effects are due to The secondary neurones cross through the anterior
substance P-triggered release of histamine from dermal commissure and ascend in the spinothalamic tract to the
mast cells [9]. Other neuropeptides such as neurotensin, reticular nuclei, the tectal nuclei and the periaqueductal
calcitonin gene-related peptide, neurokinin A and vaso- region of the brain stem [7]. The fibres are then projected
active intestinal peptide (VIP) have been implicated as to the thalamus and cortex (Fig. 2). Pruritus may be
pruritogens [7]. integrated and down-modulated by the cerebral cortex.
Proteases such as trypsin, chymotrypsin, kallikrien and Electrical stimulation of various central structures such as
papain can induce pruritus if injected into the epidermis. reticular formation, vermis, post-central sensory cortex and
Natural proteases [5] such as cathepsin found in the the anterior cingulate gyrus can reduce the afferent impulse
epidermis, leucoproteases in the dermis and plasmin in evoked by a pruritic stimulus in cats [14]. The presence of
blood are also pruritogens. Prostaglandins El, E2 [5] are also an opiate-sensitive scratch centre at the floor of the fourth
involved in perception of pruritus by modulating C-fibre ventricle, below the level of acoustic nuclei, is suggested by
transmission rather than as direct stimulants [lo]. the triggering of scratch behaviour when morphine is
Serotonin, acting directly on peripheral serotoninergic injected intracisternally in cats [15]. The frontal cortex
receptors, can induce itch [7]. Opioids which are clinically also appears to have an inhibitory action on scratching in
important pruritogens, appear to act centrally [4], as cats [16].
described in more detail later.
Diseases associated with pruritus
Neural pathways of pruritus Pruritus is a common symptom of many skin disorders,
There is no evidence of specialised receptors for pruritus in usually as a result of histamine release which directly acts
the skin. The current view [7] is that a plexus of free on nerve fibres. Dermatological causes of pruritus include

Pruritogen

Epidermo-dermal
4
Free polymodal nociceptor nerves (PMN)
junction
Spinal cord
4
Lissauer tract

+
Substantia gelatinosa

Spinothalamic tract
Scratch centre

1
Reticular nucleus
Brain Tectal nucleus
.f
Thalamus
Floor of 4th
ventricle

Cortex
/\
Post central sensory; cingulate gyrus

Fig. 2. The neural pathways of pruritus.

Anaesthesia, Volume 51, December 1996

 Pruritus 1 135

infections, infestations (e.g. scabies) and inflammatory skin innervated by the trigeminal nerve. A central enkephaliner-
conditions (e.g. eczema, contact dermatitis, psoriasis). gic mechanism [46] has been proposed to explain the
Depression or anxiety may be important predisposing localisation of pruritus over the distribution of the
factors associated with such dermatoses. trigeminal nerve and animal studies suggest the presence
Systemic disease may be detected in 1&50% of patients of an itch centre at the lower medulla with the trigeminal
[ I ] with generalised pruritus. As such, a thorough system nucleus involved in the itch reflex [IS]. The spinal nucleus
review, physical examination and investigations are of the trigeminal nerve which is rich in opioid receptors, is
required to exclude any significant systemic disease [ 1, 51. continuous with the substantia gelatinosa and Lissauer
Pruritus is a distressing complication of cholestatic liver tract at C3.4. Furthermore, the spatial arrangement of
disease [I71 and tends not to be relieved by scratching and the ophthalmic, mandibular and maxillary divisions in the
is difficult to treat. The pathogenesis of pruritus in liver spinal sensory nucleus of the trigeminal nerve is such that
disease has not been clearly elucidated and it is commonly the ophthalmic division is most inferior, thus supporting the
believed that the accumulation of bile salts [I81 in the serum observation that the pruritus of opioid administration is
and tissues act as pruritogens within the peripheral and typically at the nose and upper part of the face.
central nervous system. However, recent evidence [ 191 With epidural or spinal opioids, a segmental distribution
suggests that endogenous opiate or serotoninergic com- of pruritus spreading rostrally from the site of injection is
pounds may be important mediators of pruritus associated frequently observed, suggesting that it is likely due to
with cholestasis [22, 231. cephalad spread of the opioids in the cerebrospinal fluid and
In chronic renal failure, persistent and intractable its subsequent interaction with the trigeminal nucleus and
pruritus may be present in 6 W O % of patients [24] receiving nerve roots [4]. This is supported by the demonstration of
dialysis. The exact aetiology of pruritus in chronic renal the labelled drugs injected in the lumbar subarachnoid
failure is unknown. The mechanisms that have been space migrating rostrally to the ventral surface of the lower
proposed include secondary hyperparathyroidism [25], medulla [4]. The distribution of opioids to the ventral area
increased levels of calcium [26], phosphate [26], magnesium of the lower medulla may be facilitated by the anterior
[27], aluminium [25], vitamin A [28] and increased serum spinal artery which supplies the anterior two-thirds of
histamine level [29] in the blood. Mast cell proliferation the spinal cord [4]. Antagonism of glycine receptors in the
with increased release of histamine has been suggested as a central nervous system by opioids has also been suggested
mechanism [29]. as a mechanism of opioid-induced pruritus [4].
Pruritus may be a symptom of endocrine disorders [30] Hydroxyethyl starch has been reported to cause pruritus
such as diabetes, thyrotoxicosis, myxoedema and post- in 30% of patients receiving it by infusions [48]. Pruritus is
menopausal syndrome. In most of these conditions, pruritus generalised, but with a predilection for the trunk and
is commonly due to mucocutaneous candidiasis [30]. correlated with cumulative dosage. Deposits of hydroxy-
Paroxysmal pruritus associated with multiple sclerosis ethyl starch within dermal macrophages. endothelial cells
[31] is due to activation of artificial synapses between axons and adjacent to nerve fibres can be demonstrated
in the demyelinated areas of the central nervous system. histologically. The pruritus lasts for 8 weeks and does not
Unilateral cerebral lesions such as cerebral tumours [32], respond to conventional antihistamine drugs.
strokes [33] or abscesses [34] can be associated with pruritus, Hydroxyurea therapy, used in the treatment of poly-
presumably due to effects on the descending pathways cythemia rubra Vera, has also been reported to induce
which modulate pruritus. Localised pruritus has been pruritus [49].
reported with peripheral nerve lesions such as postherpathic
neuralgia [35] and notalgia paraesthetica [36], a sensory
entrapment syndrome involving posterior rami of T2-Ta Management
thoracic nerve roots. Determining the cause of pruritus is a diagnostic challenge.
Physical and psychological Factors have to be considered,
with careful examination and investigations carried out to
Pharmacological causes of pruritus exclude any systemic disease. Whilst removal of the cause
Pruritus is a common side-effect of opioid administration is the first priority, treatment is.frequently symptomatic and
[4, 371 and is usually localised to the face, neck or upper not effective.
thorax. The incidence varies widely, from 0-90%, reflecting
the difficulty in investigating this symptom [4]. The
incidence of pruritus is approximately 1 % after systemic Pliysicd methods
administration [4]. 20-93% in patients receiving epidural Cooling of the skin has been a traditional remedy in eczema
opioids [38. 391 and 20-80% in patients receiving intrathe- and other dermatoses. Cold stimuli presumably inhibit the
cal opioids [40.41]. These figures are influenced by several sensory nerve endings that mediate itch [7] or induce lateral
factors. In general, the incidence may [42] or may not [43] inhibition in the spinal cord by stimulation of temperature
be related to the dose of opioids used. The obstetric patient afferent pathways [7]. Vibration and transcutaneous
[42] is more susceptible to pruritus, which may be due to electrical nerve stimulation (TENS) have been used
interaction of oestrogen with opiate receptors [45]. effectively to treat both localised and generalised pruritus.
Morphine [40] and sufentanil [41] appear to be more These beneficial effects may be explained by the induction
pruritogenic than fentanyl [40] and butorphanol, a of ‘lateral inhibition’ in the spinal cord [7]. However, TENS
p-receptor antagonist and x-receptor agonist, appears to be is effective initially but not in the long term in patients with
the least [39]. Although opioids release histamine from mast generalised pruritus.
cells systemically, this does not appear to be the underlying Ultraviolet phototherapy has been used successfully in
mechanism. Usually pruritus is localised to facial areas the treatment of pruritus associated with chronic renal
Antiesthesic/, Volume 51. December 1996
1136 P . C . A . Kam and K . H . Tan
Table 1. Pharmacological management of pruritus in cholestatic jaundice.
Agent Mechanism Disadvantage
First line

Chokstyramine bind bile salts in gut unpleasant taste; constipation; malabsorption

Ursodeoxycholic acid Cholestasis diarrhoea
reduce bile salt pool paradoxical itch
Antihistamines H I blockade sedation
Second line

Rifampicin reduce bile salt uptake diarrhoea; nausea; hepatitis

Phenobarbitone enzyme induction encephalopathy
E.uperimenta1

Opiate antagonists block opiate receptors opiate withdrawal

Propofol (subhypnotic dose) inhibit spinal afferents requires administration intravenously
Ondansetron block SHT, receptors constipation; headache

failure. Ultraviolet light (29CL320 nm) is believed to inhibit New treatment strategies
the release of histamine and proliferation of dermal mast Based on the demonstration of increased plasma concen-
cells [50]. trations of methionine enkephalin and leucine enkephalin,
opiate antagonists were used successfully to provide relief
from intractable pruritus in patients with cholestatic
Topical agents jaundice. Naloxone (0.8 mg) was shown to ameliorate
Topical creams or lotions such as calamine may be useful pruritus for 2 h after subcutaneous injection in a patient
for symptomatic relief of pruritus. Topical antihistamines with primary biliary cirrhosis [51]. As naloxone has to be
and corticosteroids are commonly used in dermatological administered parenterally, nalmefene ( 5 mg twice daily), an
conditions. EMLA cream (2.5% lignocaine and 2.5% oral p-antagonist, has been used and demonstrated to be
prilocaine) can also ameliorate pruritus [7]. more potent with a longer duration of action ( 1 2 4 8 h) in
Topical capsaicin cream has been shown to be effective relieving pruritus in patients with cirrhosis [21]. An opiate
in persistent locdised pruritus [30]. Capsaicin, the pungent withdrawal reaction may occur if large doses of nalmefene
constituent of red pepper, is known to excite C-fibres and are used. However, this reaction tends to diminish over
release substance P and calcitonin gene-related peptide. 2-3 days.
This is followed by the depletion of both from the nerve Pruritus associated with epidural or spinal opioids is
fibres, leading to their desensitisation [ 101. Topical capsaicin difficult to treat. Antihistamines (HI antagonists) are com-
(0.025%) cream five times a day may provide relief in 50% monly used, but have a low efficacy as they d o not cross the
of patients with notalgia paraesthetica [7]. blood brain barrier. Opiate antagonists such as naloxone
0.2 pg. kg- I and naltrexone are effective but reduce the
analgesic effects of the epidural or spinal opiates [37].
Propofol has recently been advocated for relieving
Sysremic therapv pruritus associated with cholestasis [52] and opioids [53]
Antihistamines are the first line drugs used in the treatment administered via epidural or spinal routes. It is used in
of pruritus. The HI-receptor antagonists with sedative subhypnotic doses (10 mg bolus or 0.3 pg. kg - I min - I
actions seem to be more effective in the management of infusion) and is believed to act by inhibition of ventral and
histamine-mediated pruritus [5,7]. However, potential side dorsal spinal roots. Despite its proven efficacy, it can only
effects such as anticholinergic effects, paradoxical agitation be used on a short-term basis as it has to be given
and excessive sedation may be undesirable. H2 antagonists parenterally [52]. Overall, propofol has a success rate of
such as cimetidine, on their own, are not effective but may 80% in relieving pruritus induced by epidural morphine for
enhance the H I antagonists when used in combination [5]. 3-6 h, when given as a single bolus, with the added
The management of pruritus associated with cholestatic advantage of reducing postoperative pain [53].
jaundice and chronic renal failure are summarised in Serotonin type 3 receptor antagonists have been
Tables 1 and 2. proposed for the treatment of intractable pruritus

Table 2. Management of pruritus in chronic renal failure.

Treatment Mechanism Comments
Dialysis ? removal of pruritogens not always effective
Phototherapy (UVS light) reduce dermal histamine ? efficacy
TENS ? lateral inhibition only temporary relief
Parathyroidectomy remove parathormone and Ca2+
Antihistamines HIblockade sedation; anticholinergic effects
Erythropoeitin decrease plasma histamine expensive
Oral charcoal bind ‘toxins’ ? efficacy
Cholestyramine bind uric acid ? efficacy

Anaesthesia, Volume 51, December 1996

 Pruritus 1 137

associated with cholestasis [22, 231 and chronic renal failure [21] THORNTON JR, LOSOWSKY MS. Opioid peptides and pri-
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Anntwlie.sio. Volume 5 I. December 1996