SEMINARS I N NEUROI.OGY-VOLUME

12, NO. 4 I)ECEMBER 1992

Pruritus

". . . nothing niari unsettles like a bed of stinging nettles."

-W.S. Gilbert and Sir Arthur Sullivatl rroni "Princess Ida" (1884) An understanding of the rnechanism and n~odulationof itch has eluded investigators for decades. Although closely linked with pain, a modalit) with several scientific periodicals and medical societies to its name, itch has not managed to drum up the same degree of enthusiasm. Much of the problem with itch has been its ineffable, subjective nature, which makes it difficult to quantify and study. Investigators have had to devise creative, indirect methods, such as the measurement of scratching, to obtain objective, quantifiable data. Current evidence suggests that itch is a separate modality, distinct from pain. Our objectives are to review the neurophysiologic data that led to this conclusion and to discuss biochemical and clinical aspects of pruritus, with emphasis on some of the most recent additions to the literature.

QUANTITATION OF ITCH AND SCRATCH

An alternative strategy involves the rneasurement of scratching activity, which is presumably an indirect representation of itch and a more easily quantifiable variable. Most such studies have been performed in sleep laboratories. Various techniques employed have included electroencephalogram, electro-oculograrn, subrnental electromyograrn and forearm muscle potential measurement,j measurement of whole bed vibration along with arm and leg motion meters,"-8 electromagnetic movement detectors,"M-transmitted vibration transducers,' and, most recently, scratch radar. The reproducibility and comparative efficacies of these techniques have yet to be determined. A single standardized model for the experimental induction of itch does not exist. Most investigators agree that to avoid local artifactual influence on the perception of itch, 0.05 cc or less of an injectable pruritogen must be used. Some of the pruritic stimuli used in the study of itch in human subjects include histamine injection,ll-"jiontophoresis, 17-1" or direct application of hi~tamine;'~ di-

"'

rect application of cowhagc (itching powder, a derivative of the plant Mucurla pr~riens);"-'~ injection of tryp~in,??.~"'"radykinin and kallikrein,,' prostaglandins E, and H, (PGE,, PGH,) with and without hi~tamine,'~ synthetic substance p,29,:10 and vasoactive intestinal peptide (VIP),30

T h e measurement of' itch is not an easy task. Investigators have approached this problem in two main ways. Some have tried to measure itch directly, by having patients either answer questionnaires' or diagram the severity of their symptoms. cotnpourld 48/80 (a histamine liberator)," 5-me'I'he visual analogue scale (VAS) is a 10 cm hori- thoxytryptamine, a serotonin receptor agonist;" ~~.~~ of purified zontal line (0 cm representing no itch and 10 cm electrical ~ t i m u l a t i o n ; application being the worst itch imaginable) on which patients bile acids to skin;" and microstimulation of C-nomark (either on paper or with a lever) an assess- ciceptive fiber^.'^.?^." Because animals are unable ment of the severity of their itch. Although the to complete questionnaires accurately or use VAS VAS is popular because it results in numerical val- scales, experimental animal models for itch rely exues, some suggest that patients do not always ac- clusively on measurement of scratching. curately transfer their perception of the itch.' Modifications of this scale include portable comRELATIONSHIP OF ITCH TO PAIN puterized systems for ambulatory recording of subjective symptoms (for example, Pain-Track)." Controversy exists as to the relative reliability of Although itch and pain share common neural these method^.^.^ pathways and at one time were thought to be vari-

Copyright O 1992 by Thieme Medical Publishe rs, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.

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Mark H. Lowitt, M.D., and J e f f r D.Bemhard, M.D.

rnal nerve net, an interweaving of nerve termini from unmyelinated cutaneous nerves.44The point of origin is the terminal cell of the schwann sheath. The nerve endings project past the cell, toward the upper dermis, surrounded by parallel collagen fibers. Once at the dermal-epidermal junction, the nerves and collagen separate and the basal lamina of the nerve joins the basal lamina of the epidermis. These nerves are not homogeneous: adjacent bundles often exchange axons. Adjacent endings may have different destinations and carry different sensory modalities. Free nerve endings have been shown to project irito the epidermis as The epidermal fibers travel to the granular layer where they then proceed laterally. Shelley and Arthur" fourid that nerve endings cluster densely around "itch points" which correspond clinically with areas on the cutaneous surface that are particularly sensitive to pruritogenic stimuli.

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ants of the same sensation, it is now generally accepted that they are distinct sensory modalities. Several observations support this argument. Each has a "peculiar quality which is distinctly recognizable."" Itch and pain can be experienced in the same locatiorl si~nultaneously,with differing intensities. The reflex response to itch is scratching, whereas pain elicits withdrawal. Morphine elicits itch but obliterates pain." Pruritus is produced primarily near the dermal-epidermal junction; pain, but usually not itch, is provoked by deeper stimuli in the skin." Itch cannot be elicited when the dermis and epidermis have been removed, although pain persists in this situation. Most convincing are the neurophysiologic data that suggest that itch and pain are carried by two distinct populations of primary sensory afferents.

ANATOMY AND NEUROPHYSIOLOGY OF ITCH PERIPHERAL NERVE FZBERS

'The exact location of the itch receptor is unknown but it is believed to reside in free nerve endings, which transmit iriformation about itch and aching ("slow") pain when continuous with type C unmyelinated fibers (up to 2 mlsec). Free nerve endings can also transmit information about sharp (or "fast") pain and light touch when part of type SpecuA-delta myelinated fibers (5-30 m/~ec).~O lation on the mechanisms of pain and itch dates to the earliest part of this century. In 1905, Head" described two different systems of sensation, namely, the protopathic system, a diffuse, poorly localized type; and the epicritic system, encompassing more specific, well-defined sensation. In 1938, Bickford" reflected on a gnat bite on his own arm. He noted that a central region at the site of the bite was spontaneously pruritic, but that there was a surrounding area that was "itchy," which could become pruritic with minimal stroking. He suspected that the two sensations were modulated by two separate types of nerve fibers. In retrospect, it has become clear that the protopathic ("itchy skin") and epicritic ("spontaneous itch") systems correspond to C-fiber and A-fiber transmission, respectively, with itch (described as ~~ protopathic) carried mainly by C - f i b e r ~(see later). PRIMARY AFFERENTS IN THE SKIN

Unmyelinated receptors are difficult to study because of' their small size (less than 1 Fm in diameter).4The free nerve endings that serve as the point of initiation of the itch message are located primarily in the upper dermis. Free nerve endings (or penicillate fibers) form the so-called subepider-

C-fibers comprise 70% of primary afferent neurons. Afferent C-fibers fall into three classes: C-mechanoreceptors, cold thermoreceptors, and C-polymodal nociceptors. The C-polymodal nociceptor is the most abundant type, comprising 80% of all C-fiber afferents." In the skin, these nerves are truly polymodal; a single neuron can respond to electrical, mechanical, thermal, and chemical ~ t i m u l i . ' Itch ~ . ~ ~is primarily conveyed by the Cpolymodal nociceptor. Using intraneural microstimulation of ulnar nerves in awake human subjects, investigators have recently isolated individual C-polymodal nociceptive fibers and confirmed that all convey dull or burning pain but only some convey itch.36 'Tuckett and WeiZ4continued investigation of C-fiber subpopulations. They dissected out cutaneous nerves in anesthetized cats, used electrical stimulation to identify the receptive fields of each fiber (2 to 3 mm in diameter), then stimulated each with cowhage. The only C-fiber subtype that responded to cowhage was the polymodal nociceptor. Eighty-two percent of the C-polymodal nociceptors responded to cowhage, and 100% responded to mechanical stimulation and heat. A theory to explain how these fibers convey both pain and itch was presented. The authors suggested a "coactivation" hypothesis in which activation of cowhage-sensitive C-polymodal nociceptors alone might signal itch, but coactivation of this set of fibers along with another population (cowhageinsensitive fibers) might signal pain. "[Wlhether itch or pain is felt would be determined by the relative amounts of activity in these two subpopulations, suggesting a central nervous system (CNS)

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pain arc mediated by "largely overlapping but nor identical populations of C-fibers." The itch-mediating subpopulation of C-polymodal nociceptors is particularly sensitive to histamine. T h e data from these experiments support this hypothesis. It is presumed that the subset of nerves that transmit itch then synapses specifically with itch-friendly (our term) secondary neurons (labeled-lines) in the spinal cord (see later). SPINAL. CORD SYNAPSES

T h e free nerve endings of the C-fibers represent the terminal aspects of neurons whose nuclei reside in the dorsal root ganglia and whose other axoplasmic processes continue, via the dorsal roots, into the spinal cord. T h e peripheral fibers enter the cord and initially travel in the tract of Lissauer, then synapse in the substaritia gelatinosa (laminae 11 and I11 of the dorsal horn)."' T h e dorsal horn is an important integrating center where sensory neurons interact with descending pathways such as the dorsolateral funiculus as well as with spinal interneurons." The interneurons are believed to be part of an inhibitory circuit t.hat interfaces the Cfibers with both A-fiber afferents and descending In his "gate-control theory," Wall49 envisions a system in which small fibers facilitate and large fibers inhibit al'l'erent rioxious stimuli, all in the setting of descending control, with special cells (probably the interneurons) as "gates" that regulate the system." This system accounts for the clinically observed phenomenon of lateral inhibition, in which noxious stimulation of the skin adjacent to a pruritic (or painful) area leads to attenuation of the initial sensation. A child who rubs the skin next to a bruise understands this concept intuitively. Bickford," in 1937, was the first to demonstrate lateral inhibition experimentally. He showed that histamine-induced itch could be inhibited by adjacent application of a painful stimulus.I1 Pinprick stiniulation within the flarc of a histamine-induced itch causes ablation of itch, presumably by the same mechanism.12 In an even more dramatic demonstration of lateral inhibition, in an investigation reported by Graham et al" cowhage was applied to the backs of three patients; pinprick stimulatiori on the chest, within the same dermatome, obliterated the cowhage-induced itch. T h e concept of lateral inhibition nlay explain the basic question of why scratching relieves itch. Scratching of the skin adjacent to a pruritic area may stimulate afferent nociceptive fibers immediately parallel to those conveying itch. The scratched afferent fibers enter the cord and synapse with inhibitory interneurons. These in turn synapse on the original

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mechanism for determining which sensory modality would predominate."'" In contrast, using single fiber recordings in no activation of monkeys, LaMotte et a114~'Vound either A- or C-fiber nociceptive afferents by intradermal histamine. They concluded that an as yet unidentified "chemonociceptor" is responsible for histamine-induced itch. In their review of primary afferent neurons in pain, McMahon and Koltzenburg4' highlight the theory that an otherwise silent subclass of tinmyelinated sensory fibers fires only in the setting of inflammation. An important study by Handwerker et all!' also addressed the question of' how C-fibers carry information about both itch and burning pain. After identifying C-polymodal nociceptive fibers within a cutaneous branch of the radial nerve in human volunteers, the investigators stimulated the receptive field of each fiber with iontophoretically applied histamine, followed by topically applied mustard oil (allyl-isothiocyanate.) Histamine triggered itch, wheal, and flare in one half of the nerve units. Subsequently applied mustard oil induced burning pain in all the histamine-sensitive units as well as four others that showed no response to histamine. No difference in firing patterns ofthe nerves could be detected. These results demonstrated that both histamine and mustard oil excite the same afferent C-fibers in the skin, yet different sensations are induced. Handwerker et all%iscuss b u r hypotheses fix this finding: 1. T h e "specificity hypothesis": Two completely separate populations of C-fibers transmit itch and pain. This theory seems to be refuted by the data; no nerves were selectively sensitive to histamine, and most responded to both forms of stimuli. The authors note that this hypothesis cannot be completely excluded, however, because it is possible that other specific fibers may exist that were simply not found. 2. T h e "intensity hypothesis": A single population of fibers exists, but low intensity stirriuli trigger itch and high intensity stirnul'i trigger pain. No support for this theory was found in these data. 3. T h e "pattern hypothesis": Different stimuli trigger different neural firing patterns. "No clear differential patterns have been found in primary afferents." In addition, there is no evidence to suggest that synapses of these fibers with secondary neurons in the spinal cord are capable of discriminating among different temporal patterns. T~ckett's'~earlier work also refutes this theory. 4. The "variable sensitivity hypothesis": Histaniine-induced itch arid mustard oil-induced

V O L U M E 12, NUMBER 4 DECEMBER 1992

CORTICAL PATHWAYS

Although it is well accepted that cortical activity is important in the perception of itch, understanding of the mechanism is limited. The small body of experimental data derives exclusively from animal research. In 1939, Bradfordso demonstrated that the cerebral cortex exerts an inhibitory effect on scratching in cats. After surgical resection of the frontal cortex, there was a marked accentuation of the scratch r e f l e ~ . ~ Scratching " in cats triggered by intracisternal injection of morphine was not affected by successive ablation of the cortex, thalamus, midbrain, cerebellum, and medulla to the level of the acoustic nuclei.42This finding suggested that the opiate-sensitive "scratch center" lay below the level of the acoustic nuclei (see later). In their 1954 study, Hagbarth and KerP' documented the effect of electric stimulation of' cerebral structures on the itch reflex in cats. They noted that stimulation of' various central structures reduced the size of an afferent volley evoked by a dorsal root stimulus (an itch simulation). The areas that led to this response included the bulbar and midbrain reticular formation, the ventral part of the anterior vermis, the postcentral sensory cortex, the second somatic sensory area, the precentral motor cortex, and the anterior part of the cingulate gyrus. The effect of central stimulation was completely abolished by general anesthesia. It was concluded that synaptic afferent transmission in the spinal cord is influenced by descending pathways from certain cerebral structures.

MEDIATORS OF ITCH Since Lewis described the "triple response" of itch, wheal, and flare in response to injury, histamine has been traditionally considered to be the major mediator of pruritus.37Recently, however, it has become increasingly clear that several other substances including neuropeptides and opiates play equally important parts in itch. Although

some pruritic conditions are clearly histamine-dependent (for example, urticaria), many do not respond to antihistaminic therapy. HISTAWE

Three types of histamine receptors are now H, receptors are found in the skin and brain and H, receptors mediate gastric acid secretion.j2 Dermal blood vessels contain both H I and H, receptors, which cause vasodilation; itch and the axon reflex are mediated through the H, rerecently described H, receptor ceptor only.5" occurs in the brain, lung and other tissue.54It primarily acts by central presynaptic negative feedback. In the brain, H, receptors are most dense in the telencephalic areas. The pruritus and wheal and flare of intradermal histamine demonstrate a positive dose-response relationship.'Wo significant difference in itch perception exists between different body parts (forearm, upper arm, and back). Histamine-induced wheal and flare, however, is smaller on the forearm and larger on the back. The reason for this is not clear.'"

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itch-bearing fibers, bearing an inhibitory message, thus down-modulating the pruritic sensation. The secondary neurons often resynapse within lamina V of' the dorsal horn, interact with interneurons, then pass through - the anterior commissure and ascend in the anterolateral pathway (including the spinothalamic tract).'"Fibers then become widely distributed through the brainstem, mainly in the reticular nuclei, the tectal area, and the periaqueductal gray region. From the brainstem, fibers arc projected to the thalamus and cortex via poorly defined pathways.

SUBSTANCE P

Substance P (SP) is an 11-amino acid neuropeptide that plays an important role in pain and itch. It is synthesized in the dorsal root ganglia within the cell bodies of the polymodal nociceptive C-fibers and conducted through the axons to the free nerve endings in the skin.55SP exerts an effect on pain and itch perception at the level of the free nerve endings, the spinal cord, and the cortex. Within the skin, SP is concentrated in the C-fibers in the upper dermis near the dermal-epidermal junction56 in close approximation to the small vessels of the papillary microvasculature." SSPcontaining fibers are most numerous in the lip, fingertip, prepuce, and breast. Occasional intraepidermal fibers are seen57In the spinal cord, SP is abundant in the substantia gelatinosa and trigeminal nuclei." Within the brainstem and brain, SP concentrates in the substantia gelatinosa trigemini, periaqueductal gray, substantia nigra, medial amygdaloid nuclei, and medial preoptic area, among othe r ~Outside . ~ ~ of the nervous system, the greatest concentration of SP is in the gut wall.59 Jesse1 and I v e r ~ e ndemonstrated ~~ that SP is the major excitatory neurotransmitter at the synapse between afferent nociceptive C-fibers and the ascending system. Opiate-containing interneurons are believed to perform a major inhibitory role in the system (see later). In addition to SP, several other less extensively investigated neuropeptides have been localized to the skin and nervous system; they include neuro-

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tensin, calcitonin gene-related peptide, neurokinin krlowrl since the 1930s that iritracisternal morElectrode A, and VIP.57,"'The role of these in pain and itch phine triggers scratching in cats."'" stirnulation of the periaqueductal gray area in rats has yet to be elucidated. laparotinduces analgesia sufficient to perform Exogenously administered SP causes a wheal and flare response, which can be blocked by anti- only." "The discovery of central opiate receptorsfi7 histamines,'\nd SP triggers histamine release resulted in a search for endogenous substances from rat peritoneal mast cells. Therefore some of that would bind to them; the pentapeptide structhe activity of SP in the skin is probably mediated tures of leu- and met-enkephalin were elucidated by histamine released from dermal mast cells." Al- in 1975." Immunohistochemical studies revealed though the notion is still debated to some degree, extensive networks of enkephalin and SP-positive SP is now considered the major mediator of the nerve terminals in the periaqueductal gray region axon reflex vasodilation (flare) seen in many in- as well as the caudal spinal trigeminal nucleus, and flammatory processes." A rrociceptive stimulus on the laminae I, 11, IV, and VII of the dorsal horn. the skin signals afferent transmission to the spinal Notably, the tract of' Lissauer contains much SP but cord via C-nociceptive fibers (mediator: SP). In re- no e n k e p h a l i ~ ~ s . ~ ~ sponse, antidromic signals are sent via surroundThe discovery of the substantial overlap being nerves, also mediated by SP that. is released into tween SP and opiate-containing neurons supports the skin, triggering histarnine release from dermal the spinal interneuron theory espoused rnuch earmast cells. In total, this causes wheal, itch, and lier by Graham et aL21Opiate receptors are present flare." An exhaustive symposium devoted to SP on primary afferent SP-containing nerve termini has been recently reviewed.'j2 ' in the substantia gelatinosa. Short spina1 ~nterneuCapsaicin (trans-8-methyl-N-vanillyl-6-nonen- rons, bearing enkephalins as neurotransmitters, arnide), a derivative of the common pepper plant, deliver an inhibitory presynaptic message to the initially produces erythema and pain when applied primary afferents, thereby acting as the gating cells to the skin or mucous membrane~.~%ftera brief described in Wall's gate-control initial irritation, it is effective in the obliteration of' Opiates affect pruritus at several levels, with itch o r pain in several clinical settings. Capsaicin both excitatory and modulatory effects. Inhibitory applied to the skin depletes SP from sensory effects on itch occur at the spinal level as described n e r ~ e s . ~ " Iimmediate ts effect is to excite C-poly- before. Locally, opiates can trigger mast cell demodal nociceptors. The depolarization of the af- granulation, causing release of histamine, with ferent terminals is due to a nonspecific increase in consequent clinical itch. FK33-824, a met-enkephcationic permeability, particularly to sodium and alin analog, potentiates histamine-induced pruricalcium. In high doses, after the initial depolariza- tus, but its mechanism is not clear.3JWithin parts tion, it blocks C-fiber conduction." Its axonal tox- of the CNS, opiates can trigger itch directly. Inicity with long-term use leads to swelling, degen- tralhecal morphine (given as anesthesia during laeration, and eventually reduction in the number of bor) leads to a severe itch concentrated on the face, C-fibers."' Capsaicin also causes mast cell degran- nlouth, eyes, and especially the no~e.~'.~"his pheulation and depletion within 6 hours. The flare nomenon may result from an enhanced effect on from capsaicin is not blocked by antihistarnincs; the spinal trigeminal nucleus.74Epidural morphine therefore the neuropeptides released by capsaicin can trigger generalized itch.75 probably cause vasodilation directly without the aid Clinically, opiate antagonists exert an imporof h i ~ t a m i n e . ~ ~ tant antipruritic effect. Patients pretreated with In a hscirlating recent study, WallengrenGO rialoxone demonstrate diminution or abolition of demonstrated that SP is involved in contact urti- histamine-induced itch.'"tch/scratch behavior in caria and delayed-type hypersensitivity. Evidence arlirnals can be inhibited by narcotic antagonist^.'^ that the nervous system can modulate immune re- Perhaps the greatest clinical application in this area sponses continues to appear. SP receptors have has been in cholestatic pruritus, a condition in been demonstrated on lymphoid cells, and SY en- which elevated levels of leu- and met-enkephalin hances the proliferation of T lymphocytes.60Fur- have been dem~nstrated.'~-"In 1979, Bernstein ther connections between neuropeptides and im- and Swifts1 treated a patient with primary biliary munity will undoubtedly emerge. cirrhosis with subcutaneous naloxone (0.8 mg). A marked diminution of itch was noted within minu t e ~After . ~ ~ administration of nalmefene, another OPIATES opioid antagonist (20 to 40 mg three times daily), cirrhotic patients experienced a dramatic reducOpiates exert a powerful role in the genesis tion in pruritus." Scores on a VAS pruritus scale and transmission of itch and pain. It has been dropped from 7.6 (0 to 10) to 0.2 at 1, 3, and 6

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S E M I N A R S I N NEIJRO1,OGY

months. These patients experienced narcotic withdrawal-like symptoms initially, presunlably a reflection of their baseline elevation of endogenous opiates.

Table 1. Dermatologic Causes of Itch*

dins rnay modulate C-fiber inipulse transmission. Serotonergic compounds have come under recent scrutiny for their role in the rat scratch reflex.3' 5-Methoxytryptamine (5-MeOT) is a serotoriergic agonist with a high affinity for serotonin receptors. Subcutaneous injection of 5-MeOT results in increased hindlimb scratching but intraventricular administration does not. These findings implicate peripheral serotonin receptors in the mediation of the reflex. Peripheral serotonin receptors in humans may therefbre be presumed to play a role in the mediation of itch. Serotonin may initiate the temperature-dependent pruritus experienced by patients with polycythemia vera."

CLINICAL APPROACH TO PRURITUS Deterniining the cause of a given patient's itch may be quite a diagnostic challenge. It is of value to perform a careful physical examination first, to determine if the itch results from a "primary" skin disease. A list of skin diseases in which itching is especially pronlinent is provided in Table 1. Xerosis or dry skin associated with fine scaling may be the most common primary cause of pruritus, especially in elderly patients.85

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Infections Dermatophytosis Folliculitis Human immunodeficiency virus (with and without skin lesions) OTHER PURPORTED MEDIATORS Varicella Early investigators discovered that injection of Infestations Pediculosis several enzymes (endopeptidases) could trigger loScabies calized pruritus, and rriariy believed that these were Inflammatory Atopic dermatitis the pri~riary mediators of itch.'? Trypsin was Bullous pemphigoid considered to be the most effe~tive.~Wallikrein, Contact dermatitis Dermatitis herpetiformis bradykinin, and papain have also been investiDermatographism gated.??." The mode of action of endopeptidases Drug hypersensitivity remains unknowri, but is speculated to involve hisEczema Exfoliative dermatitis t.a~nine.~' Lichen planus Prostaglandins have been implicated in itch as Miliaria well. Iritraderrnal PGE, can elicit itch and flare, but Pityriasis rosea Psoriasis in combination with histamine its effects are much Sunburn greater than merely a d d i t i ~ e . 'It~ has been specuTransient acantholytic dermatosis Urticaria lated that this synergistic action may result from some alteration of the receptivity of the nerve ter- Localized Anogenital pruritus minals.= Overall, however, prostaglandins are not Lichen simplex chronicus Notalgia paresthetica considered major mediators of pruritus. EicosaPrurigo nodularis noid inhibitors do not exert much of a clinical anMiscellaneous tipruritic effect except. in rare cases (for instance, Insect bites Mastocytosis polycythernia vera.) In a recent report, however, Pregnancy-associated that Wallengren and HakansonH"emonstrated Herpes gestationis the axon reflex flare of intradermal bradykinin Impetigo herpetiformis Pruritic urticaria1 papules and plaques of pregnancy and capsaicin can be inhibited by aspirin anti inXerosis domethacin. This finding suggests that prostaglan'Modified from Bernhard.38

The greatest challenge for the diagnostician occurs when the patient complains of itch with no objective skin findings, or with changes derived exclusively from scratching or rubbing. Erosions in linear arrays are suggestive of fingernail-induced injury. Repetitive rubbing or scratching of the skin leads to a thickening and prominence of superficial markings, known as lichenification. If these changes and no other primary lesions are found, a hunt for the cause of the "secondary" pruritus must begin. Systemic disease causing pruritus can be detected in between 10 and 50% of patients with generalized p r u r i t u ~ . ~ V a b l2e lists some of the most frequent underlying conditions associated with pruritus. Itching in these disorders is discussed in detail in several review^.^"" It is generally agreed that a thorough review of systems, physical examination, and basic laboratory data are appropriate.

NEUROLOGIC DISORDERS AND ITCH Several disorders of the CNS have been associated with pruritus. One report documents severe

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T h e authors speculate as to whether the symptoms result fiom a direct involvement of' a "pruritus area" in the cortex or if' they result from abnorDrug hypersensitivity malities in integration of sensation. In a 1987 reHematologic disorders Iron deficiency anemia port, Shapiro and Braung6reviewed all previously Paraproteinemia rcportcd cases of itch caused by CNS disease. As Polycythemia Vera Hepatic disorders described earlier, he concluded that the cause of Cholestasis pruritus in these cases may lie in the effects "on Drug-induced dcsccrlding pathways which modulate the percepHepatocellular disease Pregnancy-related tion of noxious stimuli." In one group of 77 paObstructive biliary disease tients with brain tumors, 17% had pruritus." Half Human immunodeficiency virus disease of these patients had severe itching of the nose or Malignant disease nostril as well as advanced disease involving the Cutaneous T-cell lymphoma (mycosis fungoides) Hodgkin's disease base of the fourth ventricle. It may be surmised Visceral malignancy that disruption of the opiate system in this location Metabolic and endocrine disorders may be responsible for this distinctive pattern of Carcinoid syndrome Hyperthyroidism itch (see earlier). Hypothyroidism In addition to central neurogenic causes of Systemic mastocytosis pruritus, it is likely that peripheral lesions can be Neurologic disorders Brain abscess involved in localized forms of itch. Notalgia parBrain tumor esthetica is a well-demarcated unilateral pruritus Multiple sclerosis Stroke of the scapular region of the upper back. SecondParasitic infestations ary lichenification and hyperpigmentation may be Psychiatric disorders (uncommon) seen. Because its location corresponds to the pos'Modified from Bernhard.38 terior rami of thoracic nerve roots T 2 through T6, it is believed to be a sensory neuropathy resulting from entrapment of' the fibers in the multifidus paroxysmal bouts of itch in three wornen with mul- spinae muscle where they make a 90" turn." In adtiple sclerosis (MS)." T h e attacks lasted several dition to pruritus, the area exhibits a well-localized Fifty percent of patients minutes and recurred several times a day. Carba- zone of hype~thesia.~" mazepine controlled the symptoms. In two cascs, have sensory loss in the distribution of other pethe distribution appeared segmental, with concur- ripheral nerves." A hereditary version of this conrent hypesthesia. Attacks could sometimes be trig- dition, "hereditary localized pruritus," has been gered by light touch. Relief could occasionally be described in 8 of 15 members of one family.1o0 ohtained by pinching the affected area. It was sug- A recent study demonstrated a marked increase gested that paroxysmal phenomena in MS are due in the nurnber of cutaneous nerves in affected to activation via artificial synapses (ephaptic ac- areas."" Both epidermal and dermal nerves were tivation) between axons in demyelinated areas more abundant than in control skin when stained within the CNS."* The ablation of itch with pinch- with PGP 9.5, a general neural marker. Notably, ing may suggest that lateral inhibition at the level most of these nerves were not detected by S-100 staining. It is not yet clear whether this proliferaof the spinal cord may be playing a role. Unilateral cerebral lesions can be associated tion results from injury to the nerves close to the with contralateral pruritus. One patient with a bas- dorsal roots or if this is merely a secondary reilar artery aneurysm and right internal carotid ste- sponse to frequent scratching. Therapy with emolnosis developed left-sided itch and hypesthesia. lients, topical corticosteroids, and antihistamines is Computed tomographic (CT) imaging revealed le- seldom effective. Alternative treatments have insions of decreased density in the posterior limb of cluded topical capsaicin (0.025% cream, five times the right internal capsule as well as in the frontal per day) with complete relief in 50% of patients within several weeks.Io2 As described earlier, capand temporal lobes near the sylvian fissure." saicin may reduce excitability of peripheral C-fiMasseyWreported on nine patients with unilateral hcrs by depletion of SP and other neuropeptides. pruritus following strokes. Five involved the interTopical EMLA cream (2.5% lignocaine and 2.5% nal capsule and four were in the middle cerebral prilocaine) may also ameliorate pruritus.98 artery distribution. Five patients were treated sucSevere pruritus as a variant of postherpetic cessfully with carbamazepirle or amitriptyline. Anneuralgia has been reportedlo' and ohservcd in our other report described unilateral pruritus in the setting of a right frontal Nocardia brain abs~ess.'~own clinics. Systemic Disorders Associated with Generalized Pruritus

.

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Table 2.

Itch should be attributed to psychogenic causes only after all other medical causes have been carefully excluded. One variety of psycherelated itching has been dubbed "paroxysmal pruritus."lO"his entity is defined as itching without primary lesions, with a paroxysmal pattern, frequently wakening the patient from sleep, and an associated elevated pain threshold (perhaps from lateral inhibition). This itch is often stress-related and is reported to resolve with identification of the underlying stress. Depression is also closely linked with pruritus. In one study, 32% of patients with generalized pruritus had Beck Depression Inventory (BDI) scores consistent with depression, compared with 13.2%of controls.L05 It is difficult to determine whether the pruritus in these cases represents a manifestation of underlying depression or if patients become depressed as a result of their recalcitrant itch. A schizophrenic patient had the delusion that someone could force him to itch by "mental telepathy."ln6This is believed to represent a form of monosymptomatic hypochondriasis, similar to that seen in delusions of parasitosis. One recent report described the unusual case of left hemipruritus in an 83-year-old woman with a negative medical and neurologic work-up. An explosive attack of generalized pruritus was triggered by scratching during a physical examination.105 The lack of a physiologic explanation for this case highlights the difficult overlap between neurogenic and psychogenic pruritus. Cortical influences can have a great effect on the perception of itch. R ~ t h m a described n~~ "physiologic pruritus" as that caused by "weak stimuli of everyday life such as slight rubbing" of clothes or light wind. He observed that one becomes conscious of this itch only when bored or fatigued. He also noted that one's attention can be diverted from minor itch, but that "merely imagining the presence of biting insects may provoke itching and scratching." Lyell admits to "itching violently" during his first few dermatology clinics." Even the wrilirrg of a review article on pruritus can elicit an inordinate amount of itching (personal observations). As described above, cortical inhibition may play a large role in the scratch reflex in animals; cognitive fBctors are certainly involved in control of itch perception in humans. Although many consider scratching an involuntary action, it has been suggested that in certain dermatoses, particularly atopic eczema, psychologic factors play an important role. Scratching in chronic pruritus is purported to contain components of relief, self-punishment, release of tension, and a "dia-

bolical plea~ure.""'~ Kepecs, a psychiatrist, refers to the mixture of pleasure and pain as "algedonic pleasure," the term derived from the Greek algos (pain) ~~ of nocturnal and hedone ( p l e a s ~ r e ) . ' Studies scratching in patients with atopic dermatitis reveal that scratching occurs during sleep, but bouts ofscratching are more frequent and longer while the patient is awake.This phenomenon is ascribed to a conscious "deliberate" component.

TREATMENT OF ITCH After primary dermatologic disease and underlying illness have been treated or excluded, the need for general symptomatic treatment of itch remains. A combination of modalities is often required. T h e general treatment of itching has been reviewed e1se~here.I'~ Cooling of the skin is an old folk remedy that can be useful in atopic eczema and in other pruritic dermatoses. T h e pathophysiology behind this effect is not well understood. It has been suggested that cold stimuli directly inhibit the activity of the sensory receptors that mediate It is also possible that the effect is mediated centrally, perhaps via lateral inhibition in the spinal cord by temperature-sensitive afferents. Whereas cooling increases the itch threshold, heating the skin is reported to exert the opposite effect."' Winkelmann and Muller" observe that most of the major modalities used in the treatment of itch succeed by converting itch into another sensation. A~ltihistamirlesare an important part of the armamentarium against pruritus, particularly with histamine-mediated disorders such as hives5' One should not expect great efficacy in nonhistaminerelated conditions; controversy exists as to how much the antipruritic action is due merely to the l3 sedative effect. Physical modalities are sometimes effective, including ultraviolet light (UVB, 290 to 320 nm) for renal failure-associated pruritus.l14 Because vibration and transcutaneous electrical nerve stimulation (TENS) have proved effective in some types of pain, several investigators have utilized this modality in the treatment of' itch. In orie study, 14 of 17 patients treated noted a marked relief of itch. Most had a generalized improvement, believed to be secondary to a central effect.'ls Ekblom et al"" tried TENS in treatment of histamine-induced itch. Relief of itching was significant when the stimulation was applied adjacent to the injected histamine, within the same dermatome, and preceding the histamine injection. Although a central effect cannot be excluded, these results are best ex''vl

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PSYCHOGENIC ITCH

plained by the induction of lateral inhibition at the level of the spinal cord (see earlier). In a more recent report, extrasegmental TENS resulted in decrease of itch at a distant site; this finding remains difficult to explai11.l'~ Fjellner"' reported that T E N S worked well initially but not over the long term in patients with generalized pruritus.

FUTURE DIRECTIONS Although much has been learned about itch over the past decade, many of the research questions posed by Tuckett et alx4in 1984 remain to be answered. T h e exact pathophysiology of itch at the level of'the free nerve endings, - the spinal cord synapses, and the cortical pathways -is still podrly understood, and the psychologic factors that contribute so significantly to the experience of itch need further study. More standardized forms of testing for itch and scratch are required. More effective treatment modalities need to be investigated as well.

REFERENCES 1. Lowrie EG, I.azarusJM, Hampers CL, Merrill JP. Some statistical methods for use in assessir~gthe adequacy of hemodialysis. Kidney I n t Suppl 1975;2:s231-42 2. Bergasa NV, Jones EA. Management of the pruritus of' cholestasis: potential role of opiate antagonists. Am J Gastroenterol 1991;86:1404-12 3. Stahle-Backdahl, Wahlgren CF, Hagermark 0. Computerized recording of itch in patients o n rnaintenance hemodialysis. Acta Derm Venereol (Stockh) 1989;69:410-4 4. Wahlgren CF, Ekblonl A, Hagermark 0.Some aspects of the experimental induction and measurement of itch. Acta Derm Venereol (Stockh) 1989;69: 185-9 5. Savin M A , Paterson WD, Oswald I, Adam K. Further studies of scratchingduringsleep. BrJ Dermatol 1975; 93:297-302 6. Felix R, Shuster S. A new method for the measurement of itch and the response to treatment. Br J Dermatol 1975;93:303-11 7. Aoki T, Kushimoto I3, Kobayashi E, Ogushi Y. C o n puter analysis of nocturnal scratch in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980;92:33-7 8. Shuster S. Pruritus a n d its assessment as itch and scratch. Acta Derm Venereol Suppl (Stockh) 1991; 156:45 9. Summerfield JA, Welch ME. T h e measurement of itch with sensitive limb movement meters. Rr J Dermatol 1980; 102:275-81 10. Mustakallio KK. Scratch radar for the measurement of pruritus. Acta Derm Venereol Suppl (Stockh) 1991; 156:44 11. Bickford RG. Experiments relating to the itch sensation, its peripheral mechanism, and central pathways. Clin Sci 1937-1938;3:377-86 12. Cormia FE. Experimental histamine pruritus. I. Influence of physical and psychological factors o n threshold reactivity. J Invest Dermatol 1952; 19:2 1-34 13. Lundeberg T, Bondesson L, Thomas M. Effect of acupuncture o n experimentally induced itch. Br J Dermatol 1987;117:771-7

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DECEMBER 1992

14. LaMotte RH, Simone DA, Baumann T K , et al. Hypothcsis for novel classes of chcmoreceptors mediating chemogenic pain and itch. Pain Suppl 1987;4:S15 15. LaMotte RH. Psychophysical and nel~rophysiological studies o r chemically induced cutaneous pain and itch. T h e case of the missing nociceptor. Prog Brain Res 1988;74:33 1-5 16. Wahlgren CF, Ekblom A. Perception of histamine-induccd itch elicited in three different skin regions. Acta Derrr~1Jenereol (Stockh) 199 1; 7 1:205-8 17. Hardy JL), Wolff HG, Goodell H. Experimental evidence or1 the nature of cutaneous hyperalgesia. J Clin Invest 1950;29: 115-40 18. Heyer G , IIornstein OP, IIandwerker HO. Skin reactions and itch sensation induced by epicutaneous histamine application in atopic dermatitis and controls. J Invest Dermatol 1989;93:492-6 19. IIandrverker HO, Forster HC, Kirchhoff C. Discharge patterns of human C-Cibers induced by itching and burning stimuli. J Neurophysiol 199 1 ;66:307-15 20. Fruhstorfer H, Hermanns M, Latzke L. T h e effects of iherrnal stimulation o n clinical and experimental itch. Pain 1986;24:259-69 21, Graham DT, H, WOlff HG, Nellral involved in itch, "itchy skin," and tickle sensations. J CIin Invest 1931;30:37-49 22. Shelley WB, Arthur RP. T h e neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 1957:76:296-323 23. Tuckctt RP, GreiJY. Response to a n itch-producing substance irr cat. I. Cutaneous receptor populations with myclinatcd axons. Brain Kes 1987;413:87-94 24. Tuckett RP, Wei JY. Response to a n itch-producing suhstance in cat. 11. Cutaneous receptor populations with unmyelinated axons. Brain Res 1987;413:95-103 25. Kajka Itch duration in the involved skin of atopic dermatitis (prurigo Rcsnicr). Acta I k r m Vcncrcol 1967;47: 154-7 26. Medansky RS, Handler RM. Dcrmatopsychosomatics: classificatiorr, physiology, and therapeutic approaches. .J Am Acad Dcrmatol 1981;5:125-36 87. Hagerrnark 0. Studies o n experimental itch induced by kallikrein and bradykinin. Acta Derm Venereol 1974; 54:397-400 28. Hagermark 0, Strandberg K, Hamberg M. Potentiation of itch and flare responses in human skin by prostaglandins E2 and H2 and a prostaglaridin e ~ ~ d o p e r o x ide analog. J Invest Dermatol 1977;69:.527-30 29. Hagermark 0 , Hokfelt I; Pernow B. Flare and itch induced by substance P in human skin. J Invest Dermatol 1978;7 1 :233-5 30. Fjellner B, Hagerrnark 0 . Studies o n pruritogenic and histamine-releasing effects of some putative peptide neurotransmitters. ActaDerm Venereol (Stockh) 198 1; 61:245-50 91. Fjcllncr B. Experimental and clinical pruritus. Acta Derm Venereol Suppl (Stockh) 1981;97:2-34 32. Rerendsen HHG, Broekkamp CLE. A peripheral 5t ~ t l d - l i k ereceptor involved in serotonergic induced hindlimb scratching in rats. E u r J Pharmacol 1991; 194:201-8 33. Edwards AE, Shellow WVR, Wright E l , Digmnan TF. Pruritic skin disease, psychological stress, a n d the itch sensation. Arch Dermatol 1976; 112:339-43 34. Tuckett RP. Itch evoked by clcctrical stimulation of the skin. J Invest Dermatol 1982;79:368-73 35. Varadi D l'. Pruritus induced by crude bile a n d purified bile acids. Experimental production of pruritus in hunlan skin. Arch Dermatol 1974; 109:678-8 1 36. Ochoa J , Torebjork E. Sensations evokcd by intraneural microstirnulation of C nociceptor fibres in human skin nerves. J Physiol (Lond) 1989;415:583-99 37. Keele CA, Armstrong D. Substances producing pain and itch. Baltimore: Williams & Wilkins, 1964:288304 38. Bernhard JD. Cutaneous sensation and the pathophys-

c.

Downloaded by: University of Pennsylvania Libraries. Copyrighted material.

SEMINARS I N NEUROLOGY

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

56.

57.

58. 59.

60. 61. 62. 63. 64. 65.

66. Reynolds DV. Surgery in the rat during electrical analgesia induced by focal brain stirriulation. Science 1969; 164:444-5 67. Snyder SH. Opiate receptors in the brain. N Engl J Med 1977;296:266-7 1 68. Hughes J , Smith TUr, Kosterlitz HW, et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577-1) 69. Hokfelt T, Ljungdahl A, Terenius L, et al. Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkcphalin and substance P. Proc Natl Acad Sci USA 1977;74:3081-85 70. Summerfield JA. Pain, itch and er~dorphins.Br J Dermatol 1981; 105:725-6 71. Weihe E, Nohr D, Hartschuh W. lmmur~ohistochcmical evidence for a co-transmitter role of opioid peptides in primary scnsory neurons. Prog Brain Kes 1988; 74: 189-99 72. Scott PV, Bowcn FE, Cartwright P, et al. Intrathecal morphine as sole analgesic during labour. Br Med J 1980;281:351-3 73. Scott PV, Fischel- HBJ. Spinal opiate analgesia and facial pruritus: a neural theory. Postgrad Med J 1982;58: 53 1-5 74. Ballar~tyneJC, 1.oact1 AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988;33: 149-60 75. Bromage PR, Camporesi EM, Durant PAC, Nielscn CH. Rostra1 spread of epidural morphine. Anesthesiology 1982;56:431-6 76. Bernstein JE, Swift KM, Soltani K, Lorincz AL. Antipruritic effect of an opiate antagonist, naloxone hydrochloride. J lnvest Dermatol 1982;78:82-3 77. Reisner I. T h e pathophysiologic basis of behavior problerns. Vet Clin North Am Small Anim Pract 199 1;2 1: 207-24 78. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988;297:1501-4 79. Jones EA, Rergasa NV. Hypothesis. T h e pruritus of cholestasis: from bile acids to opiate agonists. Hcpatology 1990; 1 1:884-7 80. Bergasa NV, Talbot 'I'L, Alling DW, et al. A controlled trial of naloxonc infusions [or the pruritus of chronic cholestasis. Gastroenterology 1992;102:544-9. 81. Bernstein JE, Swift R. Relief of intractable pruritus with naloxone. Arch Dermatol 1979;115: 1366-7 82. Greaves MW, McDonald-Gibson W. Itch: role of prostaglandins. Br bled J 1973;3:608-9 83. Wallcngren J , Hakanson R. Effects of capsaicin, bradykinin and prostaglandin E2 in the human skin. Br J Dern~atol1992; 126:111-7 84. Tuckett RP, Dennlan ST, Chapman CR, et al. Pruritus, culaneous pain, and eccrine gland and sweating disorders. J Am Acad Dermatol 1984;5: 1000-6 85. Greaves MW. Pathophysiology of pruritus. In: Fitzpatrick TB, Eisen AZ, Wolff K, et a], eds: Dermatology in general medicine, 3rd ed. New York: McGraw-Ilill, 1987:74-8 86. Gilchrest BA. Pruritus. Pathogenesis, therapy and significance in systemic disease states. Arch Dermatol 1982;142:101-5 87. Buchncss MR, Sanchez M. HIV-associated pruritus. Clin Dermatol 1991;9: 1 1 1 - 4 88. Dacus JV. Pruritus in pregnancy. Clin Obstet Gynecol 1990;33:738-45 89. Denrnari ST. A review of pruritus. J Am Acad Dermatol 1986; 14:375-92 90. Lyell A. T h e itching patient. A review of the causes of pruritus. Scot Med J 1972;17:334-47 91. Winkelmann RK, Muller SA. Pruritus. Annu Rev Med 1964; 15:53-64 92. Osterman PO. Paroxysmal itching in multiple sclerosis. Br J Dermatol 1976;95:555-8 93. King CA, Huff FJ, Jorizzo JL. Urlilateral neurogenic pruritus: paroxysmal itching associated with central nervous system lesions. Ann Intern Med 1982;97: 222-3

Downloaded by: University of Pennsylvania Libraries. Copyrighted material.

39.

iology of pruritus. In: Soter NA, Bader~HP, eds: Pathophysiology of dermatologic diseases, 2nd ed. New York: McGraw Hill, 1991;91-100 Keele CA. Chemical causes o r pain and itch. Annu Rev Med 1970;21:67-74 Guyton AC. Sonlatic sensations: 11. Pain, headache, and thermal sensations. I n : Textbook of medical physiology, 8th ed. Philadelphia: WB Saunders, 1991 :520-3 Ilead H. I ' h c afferent rlervous system froni a new aspert. Brairr 1905;28:99-1 15 Rothman S. Physiology of itching. Physiol Rev 1941; 2 1:357-8 1 Iggo A. Morphology of cutaneous receptors. Annu Rev Neurosci 1982;5: 1-31 Cauna N. T h e free penicillate nerve endings of the hulrian hairy skin. J Anat 1973;115:277-88 Arthur RP, Shelley WB. T h e innervation of human epidermis. J lnvcst Dermatol 1959;32:397-411 Lyrirl B, Hunt SP. Afterent C-fibres: physiological and l~iorhemical correlations. Trends Neurosci 1984;7: 186-8 McMahori S, Koltzcnburg M. T h e changing role of primary afferent neurones in pain. Pain 1990;43:269-72 Sherrington CS. Observations on the scratch-reflex in the spinal dog. J Physiol (1.ond) 1906;34:1-50 Wall PD. T h e gate control theory of pain mechanisms. A re-examination and re-statement. Brain 1978;101: 1-18 Bradford FK. Ablations of frontal cortex in cats with special reference to enhancement of the scratch reflex. J Ncurophysiol 1939;2:192-201 Hagabarth KE, Kerr DIB. Central influences on spinal afferent conduction. J Neurophysiol 1954;17:295307 Herman LE, Rernhard JD. Antihistamine update. Dcrmatol Clin 1991;9:603-I0 Misch KJ, Greaves MW, Black AK. Histarrli~leand the skin. Br J Dermatol; 109:10-3 Arrang I M , Garbarg M, Lancelot JC, et al. Highly potent arrd selective ligands for histamine H3-receptors. Nature 1987;327: 117-22 Greaves MW. Pruritus. In: Campion RH, Burton J L , Ebling FJG, eds: RookIWilliarnsonlEbling Textbook of Dermatology. London: Blackwell Scientific, 1992: 527-35 Hokfelt T, Kellerth J O , Nilsson G, Pernow B. Substar~ce P: localization in the central nervous systern and in some primary sensory neurons. Science 1975; 190: 889-90 Hartschrlh W, Weihe E, Kcinecke M. Peptidergic (neurotensin, VIP, substance P) nerve fibres in the skin. Immunohistochemical evidence of an involvement of neuropeptides ill nociception, pruritus and inflammatiori. Br J Dermatol 1983; 109(Suppl 25): 14-7 Jesse1 TM, Iverserl LL. Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature 1977;268:549-5 1 Berr~steinJE. Neuropeptides and the skin. In Goldsmith LA, ed: Physiology, biochemistry, and molecular biology of the skin, 2nd ed. New York: Oxford LJniversity Press, 199 1:816-34 Wallerigren J. Substance P antagonist inhibits immediate and delayed type cutaneous hypersensitivity reactions. Br J Dermatol 1991;124:324-32 Lernbeck F. Mediators of vasodilatation in the skin. Br J 1)ermatol 1983: 109(Suppl 25): 1-9 Lembeck F. Concluding remarks. In: Substance P and related peptides: cellular and molecular physiology. Ann NY Acad Sci 1991;632:490-3 Lynn B. Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain 1990;41:61-9 Bunker CB, Cerio R, Bull HA, et al. T h e effect of capsaicin application on mast cells in riormal human skin. Agents Actions 1991 ;33: 195-6 Koenigstein H. Experimerital study of itch stimuli in animals. Arch Dermatol Syphilol 1948;57:828-49

383

94. Masscy EW. Unilateral neurogenic pruritus follorving stroke. Stroke 1984; 15:901-3 !)5. Sullivan MJ, Drake ME. Unilateral pruritus and Nocardia brain abscess. Neurology 1984;34:828-9 9ti. Shapiro PE, Braun CW. Unilateral pruritus after a stroke. Arch Dermatol 1987; 123: 1527-30 97. Andreev VC, Petkov I. Skin manifestations associated with tumors of the brain. Br J Dermatol 1975;98:675-8 98. Layton AM, Cotterill J.4. Notalgia paracsthetica-rcport of three cases and their treatment. Clin Exp Dermatol 1991; 16: 197-8 9'1. Pleet AB, Massey EW. Notalgia paresthetica. Neurology 1978:28: 1310-2 100. (:onlings DE, Comings SN. Hereditary localized pruritus. Arch Dermatol 1965;92:236-7 101. Springall DR. Karanth SS, Kirkham N, et al. Synlptorns of notalgia paresthetica may be explained by increased dermal innervation. J Invest Dermatol 1991; Y7:555-61 102. Wallengren .I. Treatment of notalgia parcsthetica with topical capsaicin. J Am Acad Dermatol 1991;24:2868 103. Liddell K. Post-herpetic pruritus. Br Med J 1974;4: 165 104. Arnold HL. Paroxysmal pruritus. J Am Acad Dermatol 1984; 1 1 :322-6 105. Sheehan-Dare RA, Henderson MJ, Cottcrill JA. Anxiety and depression in patients with chronic urticaria and generalized pruritus. Br J Dermatol 1990;123: 769-74 106. Rernhard JD, Gardner MR. Nonrashes. 6. 'l'elepathic pruritus. Cutis 1990;45:59 107. Procacci P, Maresca M. Central pruritus. Case report. I'ain 199 1;45:307-8 108. Graham Dt, Wolf S. T h e relation of eczema to attitude

109. 110. 1 11.

112.

113. 114.

115. 116.

117.

VOLUME 12, NUMBER 4 DECEMBER 1992

a n d to vascular rcactions of thc human skin. J Lah Clin Invest 3953;42:238-54 Kepecs JG, Robin M. Studies o n itching. I. ContribuLiorrs toward an understanding of the physiology oP masochism. Psychosom Med 1955;17:87-95 Bernhard JD. Pruritus: advances in treatment. Adv I)crmatol 199 1;6:57-72