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Home , Aquagenic pruritus, Brachioradial pruritus, Cholestatic pruritus, Dimetindene, Itch, Lateral grey column

Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 pharmacologic therapyand neuropsychiatric disorders.It logic disease,, HIV/AIDS,complicationsof ferential diagnosesincludemetabolic disorders,haemato- be asymptomofunderlying systemicdisease(1,2).Dif- ology, butinanestimated 10–50%ofpatientsitmayalso . Itcanarisefromaprimarydermatologic aeti- were parasites. sponse likelytohaveoriginatedwhenmostpruritogens induce scratchinginordertoremoveapruritogen–re- a desiretoscratch. The biologicalpurposeofpruritusisto non-adapting, usuallyunpleasantsensationthatprovokes Pruritus canbedefinedsubjectivelyasapoorlylocalized, INTRODUCTION many. E-mail:[email protected] Heidelberg, Thibautstrasse 3,DE-69115 Heidelberg, Ger- cupational andEnvironmentalDermatology, Universityof Elke Weisshaar, M.D.,DepartmentofSocialMedicine,Oc- Acta Derm Venereol 2003;83Suppl213:5–32 ; ;sensation; the patientappropriately. cian toidentifytheunderlyingcausesandthustreat with pruritusisproposed, whichmayhelpthephysi- cal studies. A precise work-upfor evaluating patients ing from promising casereports anduncontrolled clini- therapeutic conceptsandclarifysomeconfusionaris- topic. However, further effortisneededtodevelopnew past fewyears,reflecting anincreased interest inthis therapeutic studieshasgreatly increased duringthe behind pruritus. The number ofexperimentaland breakthrough inour understandingofthemechanisms mediating pruriticsensationscanberegarded as a second-order withtypical histamineresponses covery ofprimaryafferent neurons and,presumably, velopment ofadequatetherapies.Nevertheless,thedis- and pathophysiologyofpruritushashampered thede- cussed. Lackofunderstandingtheneurophysiology pathophysiology ofpruritusinsystemicdiseasesare dis- diseases are described,andthevariousaetiologies ferent formsofpruritusindermatologicalandsystemic ment ofpruritusare reviewed inthisarticle. The dif- The history, neurophysiology, clinicalaspectsandtreat- 1 ELKE WEISSHAAR Review Pruritus: A Acta Derm Venereol 2003,Suppl.213:5–32 Medicine, Occupational and Envir and Occupational Medicine, Department of Dermatology of Department Pruritus isthemostfrequentlydescribedsymptomin 1,2 , MICHAEL J.KUCENIC , W , ake For ake Key words:itch;mediatorsof onmental Dermatology onmental est University School of Medicine, W Medicine, of School University est , University of Heidelber of University , 1

AND ALAN B.FLEISCHERJR. non-dermatologic fields,and studies donotrecordpruritusasasymptom,especiallyin with currentlyavailabletherapies. ner, theunderlyingcausecorrectedandpruritustreated so thatthepatientcanbeevaluatedinathoughtfulman- way toassemblethemyriadofaetiologiesintofinitegroups tion atsomepointinlife. sonable toassumethateveryoneexperiencesthissensa- physician forminorpruriticconditions.However, itisrea- Samuel Hafenreffer (5). scratch wasintroducedin1660 bytheGermanphysician tus asanunpleasantsensation thatprovokesthedesireto urement ratherthanadisease (4). The definitionofpruri- vulvae, senilepruritusandprurigo, thelatterasadisfig- cured”. fleeting soresandtheitch,fromwhichyoucannotbe will afflict youwiththeboilsofEgyptandtumours, In Deuteronomy(28:26–28),itisstatedthat“theLord priest shallpronouncehimclean”(Leviticus13:36–38). has growninit,theitchishealed.Heclean,and however, inhisjudgmentitis unchangedandblackhair The firstmentionsofpruritusarefoundintheBible:“If, pruritus of History of pruritusremainsunknownforseveralreasons: scess orerysipelas. The overallincidenceandprevalence by cutaneousinfectionsthatcanresultinfolliculitis,ab- as erythema,erosions,excoriationsandcrusts,followed related tospecificdermatosesorinfiltrates. occur indermatologicalandsystemicdiseasesnotdirectly essary diagnostictools,e.g.skinbiopsy. Pruritusmayalso ruled outbytheexperienceddermatologistusingnec- in thesettingofpruritussystemicdiseasesandhastobe in Hodgkin’s disease. This alwaysneedstobeconsidered lated totheunderlyingdisease,e.g.cutaneousinfiltrates a specificdermatologicaldiseaseorinfiltratedirectlyre- skin symptoms(3),andinsystemicdiseasescanresultfrom systemic diseases.Prurituscanalsooccurwithoutvisible that therearedermatologicalfactorscausingpruritusin pects ofpruritusindermatologicaldiseasesandcourse could beconsideredthattherearesystemicorcentralas- are noepidemiologicdatabasesforthisentity, inston-Salem, North Car North inston-Salem, When apatientcomplainsofpruritusthereisrational Hippocrates ofCos(460–377 BC)describedpruritus Severe pruritususuallyleadstosecondarylesionssuch g, Germany g, 1 olina, USA olina, and and (iii) 2

few peoplepresenttoa Department of Social of Department (ii) (i) many there Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 vation byspecificchemicals. Their individualresponsive- cal threshold,responsiveness tothermalstimuliandacti- subgrouped onthebasisofconducting velocity, mechani- chanical, thermalandchemical stimuli. They can be neurons (1).Nociceptive canbeactivatedbyme- aching painevokedbytherecruitmentofunmyelinated ferent inquality(e.g.stinging,pricking)fromthedull, sensation evokedbyactivatingmyelinatedneuronsisdif- psycho-physiological studieshaveshownthatthepainful dicate theirresponsivenesstonoxiousstimuli.Human lations, andhavebeengiventhename‘’toin- tion existinboththemyelinatedandunmyelinatedpopu- are mechanoreceptive.Neuronsthatsignalpainandirrita- and unmyelinatedfibres. The mostrapidlyconductingones sensory neuronsbecauseitdoesnotoverlapinmyelinated ing velocityisausefultoolforclassifyingthefunctionof a greaterspeedcomparedtounmyelinatedfibres.Conduct- myelinated fibresthatallowsactionpotentialstotravelat and slowlyconducting(A- elinated. The formerdivideintorapidlyconducting(A- Neurons canbecategorizedaseithermyelinatedorunmy- mechanisms Basic NEUROPHYSIOLOGY 6 ease. involved inpruritusaccompanyinginflammatoryskindis- genesis remainunclear, includingtheneuromechanisms tus (11, 12),manyaspectsofneurophysiologyandpatho- yielded deeperinsightsintothepathophysiologyofpruri- the casetoday. Though recentexperimentalfindingshave alone relieving,pruritus(10). To agreatextent,thisisstill said thatnoprogresshadbeenmadeinunderstanding,let In 1994,afteracenturyofresearchindermatology, itwas ritus couldhaveaffected history(9). prompt thequestionwhetherMarat’s skindiseaseandpru- the increasingseverityofhispruritus. These circumstances more andradicalviolent,probablyinrelationto sian poor(9). With time,thetoneofhisspeechesbecame cial outcasts,andthereforetoallyhimselfwiththePari- ease causedhimtobeseenasaleper, toidentifywithso- he satinhisbath.ItishypothesizedthatMarat’s skin dis- He wasassassinatedin1793byacounter-revolutionary as scratching whilewritingandeditinghisnewspaper(6–8). bath seekingrelieffrompersistentpruritusandvigorous in particularhewouldspendmostofthedayamedical disease isamatterofspeculation,butduringhislastyears Marat. The exactdateofonsetanddiagnosishisskin and radicalleadersoftheFrenchrevolution,JeanPaul on aphysician,andinthiscaseoneofthemostimpressive In dealingwiththehistoryofpruritusfocushastobe History ofpruritusasaninvestigativetopicisratherpoor. E. Weishaar et al. et Weishaar E. ∆ ) fibres.Itisthecoatingof β ) into accountwhenmodelsof pruritusareused(11, 12).In studies onpruritus(1).Species differences mustbetaken Generally, noparticularly goodanimalmodelexistsfor they formauniquesubsetof spinothalamictractneurons. tinct centralconductionvelocities andthalamicprojections, mine wasfoundincats(12). As theseneuronshavedis- spinothalamic tractneuronsselectivelyexcitedbyhista- mary afferent C-fibres(21).Morerecently, a classof cate thatprurituscanbesubservedbythesespecificpri- extending to85mmonthelowerleg. The findingsindi- estingly, theseC-unitshadalarge innervationterritory tected bymicroneurographyinhumanbeings(21).Inter- duction velocitiesandhistamineresponsivenesswasde- thin ,excessiveterminalbranching,verylowcon- 1997, anewclassofafferent nervefibreswithparticularly in theepidermisofskinandmucousmembrane.In are freeunmyelinatednerveendings(C-fibres)occurring ers oftheskinandmucousmembranes.Itchreceptors distinct sensationsthatinteract. pruritus. Insummary, painandpruritusareprobably two stimulation offasciclesthatevokepaincannotproduce sensations cannotbetransformedtopain,andmicro- inhibited bynoxiousstimuli.Ontheotherhand,pruritic reduce painbutmayinducepruritus,whichcanbestrongly negative affective valence.Itiswellknownthatopioids by chemicalstimuliandtheyinitiatemotorresponse mon features;theyaremultidimensional,induced cordiotomies. Ontheonehand,bothsensationssharecom- when thelateralspinothalamictractisinterruptedby it isabolishedalongwithpainandtemperaturesensations ritus hasbeenconsideredasublimalformofpain,because stood andisthereforecontroversial.Formanyyears,pru- duced experimentalpruritusofthescalp(20). might accountforthereducedsensitivitytohistamine-in- nociceptors and/ordifferent centralprocessingofpruritus one . The lowerinnervationdensityofpruritic determinant ofthemeasureisinnervationterritory (AD)thaninhealthycontrols(19). The main ritic stimuliasseparate. This isbetterinpatientswithatopic tion” ofpruritusreflectstheabilitytoperceivetwopru- the legsandabdomen(18). The “two-pointdiscrimina- the greaterdistributioninarm,followedbyface, of normalhumanskin;theycanbepresentfocally, with fibres mightnotbedistributedevenlyinthehairyportions tion (14–17). As recentlyreported,intraepidermalnerve advances inimmunohistochemistryandsilverimpregna- was laterconfirmedbylightmicroscopywiththerecent ascend closelyunderneaththestratumcorneum(13). This blue stainthattheintraepidermalnervefibresbranchand several stimuli. ness differs: somerespondtosinglestimulionly, othersto The sensationofpruritusarisesfromthesuperficiallay- The neuralrepresentationofpruritusisnotfullyunder- In 1959,itwasshownforthefirsttimeusingmethylene Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 sions, and/orthesurrounding areas,aretouchedacciden- served whenpruriticattacks occurafteraffected skinle- ritic dermatologicaldiseases suchas AD, alloknesisisob- may haveoccurredseveralhours previously. Inmanypru- pruritus inducedbytouching thesiteofaninsectbitethat ous , e.g.aninsectbite(25).Itappearsclinically as lus inducespruritusintheskinsurroundingalocalcutane- and designatesastatewhennormallynon-pruriticstimu- knesis=pruritus) wasfirstdescribedbyBickfordin1938 detected (24). activationstudies,nosubcorticalactivationswere pain seemtosharecommonpathways,butincontrast mine concentrationappliedbypricktesting.Pruritusand graded increaseinrCBFwiththelogarithmofhista- and thecingulategyrus.Severalcorticalareasreflect a significant activationwasfoundintheprefrontalcortex premotor cortex,primarymotorcortex)(24). Additional and theipsilateralcontralateralmotorareas(SMA, cant activationofthecontralateralprimarysensorycortex an intendedaction. Another studydemonstratedsignifi- cal areas(SMA,PM)mayparticipateinthepreparationof affectional aspectsoftheevent(23). The premotoralcorti- gulate cortex(Brodman24)isrelatedtosensorial/ substantiating thattheposteriorsectorofanteriorcin- premotor area(PM)andinferiorparietallobule,thereby cingulate cortex,supplementarymotorarea(SMA), revealed activationofcorticalstructuressuchasanterior bral bloodflow(rCBF)asanindexofneuronalactivity positron emissiontomographymeasuringregionalcere- at themedullaoblongata(1).Recentresultsobtainedby called “prurituscentre”haslongbeenproposedasbeing nervous processingofpruritusandscratching. The so- under investigation,andlittleisknownaboutthecentral (unmyelinated C-fibres)havebeenidentified,theyarestill (22). fibre ascendswithinthecontralateralspinothalamictract line. After synaptictransmissionwiththenextneuron, trol ofthetransmissionoccurpriortocrossingmid- lateral greycolumnofthespinalcord,processingandcon- pruritus. After synapticconnectionwithintheipsi- or thetrigeminalequivalentofbrainstemforheadand entersthroughthedorsalhornforspinaldermatomes via unmyelinatedC-fibresandpossibly A- Pruritic stimulienterthecentralnervoussystem(CNS) processing Central neurophysiological mechanismsofpruritus. be regardedasabreakthroughinourunderstandingofthe rons withsimilarpropertiesbySchmelzetal.(11, 21)can Craig (12)andtheidentificationofprimaryafferent neu- summary, thesecond-orderneuronsfoundby Andrew & The phenomenonofalloknesis(allos=different, Although mostoftheperipheralpathwayspruritus ∆

fibres. The the H antagonist naltrexonegreatlyreducedalloknesis,whereas the phenomenonofalloknesis.Intwostudies,opiate Central andperipheralmechanismsprobablycontributeto unmyelinated pruritusmediatingnervefibres(33,34). noreceptor unitsgatedbyhistamine-inducedinputfrom ceiving inputfromlow-threshold,fast-conductingmecha- ritus-mediating centralneuronsthroughinterneuronsre- ), alloknesisisexplainedbytheexcitationofpru- (=inductionofpainbyausuallynon-painful on pruritus(26–32).Inanalogywiththeexplanationof considered animportanttoolinpsycho-physicalstudies along theskinsurroundingahistaminestimulus,andis cal stimuli,e.g.asoftbrushorcottonswabbeingstroked ing. Experimentally, alloknesiscanbeinducedbymechani- tally orareinducedbymechanicalfactorssuchascloth- type ofalloknesis. stimuli ofclothingwhileundressingandisinthatwaysome draughts ofairafterundressingorisduetothemechanical be aconsequenceofskintemperaturechangesinducedby self reallycausespruritusisunclear(36). Atmoknesis might erly patientswithaquagenicpruritus(36). Whether airit- common in AD, especiallyinchildren,psoriasisandeld- voked byopenexposureoftheskinafterundressing.Itis ished excitationofmechanoreceptivefibres(29). reduces alloknesis,whichismostlikelyduetothedimin- regardless oftheactiveingredient,abolishesorgreatly Another studyshowedthatapplicationofatopicalagent, pared toapredominantlyperipheraleffect ofcetirizine(27). indicate apredominantlycentraleffect ofnaltrexonecom- major mediators arebrieflyreviewedbelow. lin), eicosanoids,growthfactors andcytokines(1). The ), (, beta-,met-,leu-enkepha- (SP),calcitonin gene-related peptide(CGRP), ), proteases(e.g.tryptases), neuropeptides(e.g. is steadilyincreasing.Itcontains amines(e.g., degranulate mastcells(38). strated, dermalneurogenicinflammationdoesnot mal neurogenicinflammation,but,asrecentlydemon- been assumedthatmastcellactivationplaysaroleinder- has beentermed“neurogenicinflammation”(37).It vasodilatation andproteinextravasationintheskin;this nociceptors leadstoareleaseofneuropeptidesthatinduce ceptive structuresandonbloodvessels. Activation of released duringinflammationexertadualactiononnoci- pruritus. Forexample,vasoactiveinflammatorymediators pathway resultsinnervestimulationandthesensationof lead toacascadeofmediatorreleasewhosefinalcommon Mediators ofprurituspresumablyactonnervefibresor MEDIATORS OFPRURITUS Atmoknesis (atmos=air, knesis=pruritus)isprurituspro- The groupofpotentialchemicalmediatorsislarge and 1

blocker cetirizinedidnot(27,35). These results Pruritus Pruritus 7 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 can causepruritusinpatientswith AD (40). demonstrated thatmastcellmediatorsotherthanhistamine Renal Pruritus”).Inonerecentmicrodialysisstudyitwas a marginal antipruriticeffect (alsoseesection6“Uremic/ levels havebeendetected,yetantihistamineshowedonly example, increasednumbersofmastcellsandhistamine cells isenhanced.Inhaemodialysis-relatedpruritus,for tors inducemastcelldepletionorthetotalnumberof have asecondaryroleindiseaseswhichothermedia- and days. min, whereaspruritusinadiseasestatemaylastforhours wheals andflareswillusuallyonlypersistforupto60 flares. Furthermore,experimentallyhistamine-induced eases (excepturticaria)areaccompaniedbywhealsand tus whodonothaveurticaria.Besides,fewpruriticdis- clinical responsetoantihistaminesinpatientswithpruri- states anddiseasesissuspect,bestprovenbyapoor . Itsmediationinpruritusofotherpruritic induced permeability. proinflammatory reactionsincludingvasodilatation and skin. Their effects coverawiderange,suchasacute SP andCGRParethemost frequently investigatedinthe elinated nervefibreshavebeen identified(46).Ofthese, Over 50describedneuropeptides intheCNSandunmy- Neuropeptides density oraffinity ofthevasculature(45). dothelia –aneffect which mightbeduetolowerreceptor weak directorindirectnon-neurogeniceffect ontheen- fect onnociceptorsandvasculatureisbestexplainedby a tein extravasationislow, however, anditsdifferential ef- unmyelinated C-fibres(44).Itspotencyininducingpro- lieved byaspirin(43).Serotoninisapotentactivatorof taglandins andserotoninproducespruritusthatcanbere- acts histamine-independently(32,42). A mixtureofpros- tus (32,41,42).Inanimalmodelsandhumansitmostlikely Serotonin islesspotentthanhistamineininducingpruri- Serotonin (ii) dilatation ofcapillaries,venulesandterminalarterioles; spot aroundtheinjectionsiteasaconsequenceoflocal jection, includethetripleresponse(39): from eithermastcelldegranulationorintracutaneousin- receptors havenotbeendescribedintheskin).Itseffects, diates itseffects viaH1receptorsintheskin(H Histamine isreleasedduringmastcelldepletionandme- Histamine 8 local axonreflex; result ofwidespreaddilatationarteriolesmediatedby As histamineisreleasedbymastcelldepletion,itmay Histamine playsamajorpartinpruritusofurticariaand E. Weishaar et al. et Weishaar E.

red flushorflareextendingaroundthespotasa (iii)

wheal reductionduetohistamine- (i)

localized red 2

and H 3 of thek-opioidreceptor. TRK-820, arecentlydeveloped the processingofpruritus.Little isknownabouttherole tus, isnotclear. in mastcellactivation,anditsmediatorfunctionofpruri- in all,theroleofneuropeptidesproteinextravasation, mal neuropeptidesaretransmittersofpruritus(51–54). All (50). They alsocontradictotherresultsshowingthatder- nociceptors andthattheyhavenoacutesensoryfunction vasoactive concentrationsofSPandCGRPdonotexcite vasodilatory threshold(51). These findingssuggestthat or pain,eveninmuchhigherconcentrationsabovethe induced markedvasodilatationbutdidnotinducepruritus and proteinextravasation(50).Inonestudy, SP andCGRP capable ofinducinghistamine-independentvasodilatation cells (49). As recentdatahavedemonstrated,SP isalso sels andbyasecondaryreleaseofhistaminefrommast extravasation byadirecteffect onsmallskinbloodves- from mastcellsbyanindirecteffect, andinducesprotein vation. Itinducesflarereactionsbyreleasinghistamine peripherally tothenerveendingsandreleaseduponacti- of nociceptiveC-fibresandterminalsistransported modulation (48). extravasation(47),trophicfunctionandimmuno- suggest thatthe decreasing thepainthreshold (60). These observations treatment. Naloxoneiseffective, butmaycarrytheriskof induced pruritususuallysubsidesaftercessationofthe particularly highincaesareandelivery(61,62).Morphine- also occurasfacialpruritusonly(59,60).Itsincidence is the trigeminalnerve)and/ortowholebody, butcan the injectionsitetotrunk,face(distributionof after 3–7h.Itisdose-relatedandtypicallyspreadsoutfrom or relievemorphine-inducedpruritus,whichoftenoccurs ritus withoutskinlesions. donotprevent jection ofmorphineinparticularmayinduceintensepru- tagonist naloxone(58).Inhumanbeings,intrathecalin- observed whichwasabolishedbytheopiatereceptoran- medullary dorsalhornofmonkeys,facialscratchingwas patients withcholestaticprurituswasintroducedinthe of opiatesledtoscratching(56,57). When plasmafrom mation, painandpruritussensations(55). human skin,whichmaycontributetoneurogenicinflam- be localizedbyimmunohistochemistryonnervefibresof involved. Recently, the central orperipheralstructureopiatereceptorscouldbe regulation ofpruritus,butitisstillnotknowninwhich tides appeartobeinvolvedinthecentraltransmissionand does notleadtoatripleresponse(1).Besides,opioidpep- Morphine induceshistaminereleasefrommastcellsbut Opioids SP isapeptidethatsynthesizedindorsalrootganglia Effects wereseeninanimalswhencentralapplication µ - receptorsystemisinvolved in µ -opioid receptorisoform1A could Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 ing ontheunderlyingdisease. ing mediatormaydiffer ineachtypeof pruritusdepend- interleukin-4 andhistamine. Eachcascadeorpredominat- lease ofvarioussubstances including chymase,tryptase, tic effect and/orleadingtomastcelldepletionandthere- diators functioningtogetherinthesenseofanantagonis- needed. their involvementinthepathomechanismsofpruritus is could playaroleinpruritus,butmoreresearchregarding a pronouncedpro-inflammatoryprofile(74).Cytokines by, ifnotoriginatefrom,aderangedcytokinepatternwith has beensuggestedthatrenalpruritusmightbeconveyed able quantitiesofIL-2and TNF- to secreteIL-8afterantigenstimulation,butnomeasur- mononuclear cellsofpatientswith AD canbestimulated pruritus (72).Othershaveshownthatperipheralblood wasseen,andinthissetting TNF- cant earlypruritogeniceffect withnodetectableaxonic another studyinvestigatingcontrols,aweakbutsignifi- few hours’delayandpeakedbetween6h48(71).In intensity intermittentlocalpruritusthatappearedaftera (70). Inpatientswith AD andcontrols,IL-2inducedalow nophilia occursomedaysafterinitiationofthetreatment ness, dermal T-lymphocyte infiltrateandperipheraleosi- (IL-2) treatmentincancerpatientswherepruritusandred- fects ofcytokinetreatment(69),suchasininterleukin-2 inflammatory skinchangeshavebeenreportedassideef- nificantly reduced(68).Ontheotherhand,pruritusand pruritus, skinlesionsandperipheraleosinophiliaaresig- AD aretreatedwithcyclosporin A thatinhibitscytokines, mycological andviraldiseases(46). When patientswith toimmune blisteringdiseases,allergic contactdermatitis, vation ofcytokinesandlymphokinessuchasin AD, au- In variousdermatologicaldiseasespruritusisduetoacti- Cytokines was efficacious inmodelsofpruritusandpain(67). highlighted loperamide,aperipherallyactingopioidthat dogenous opioidagonists. Animal studieshaverecently is theincreasedCNSneurotransmissionmediatedbyen- nent ofthepathophysiologysyndromecholestasis ritus hasnotyetbeencompletelyclarified(66).Onecompo- role ofserumendorphinlevelsinhepatic/cholestaticpru- (1), thiscannotbeconfirmedforrenalpruritus(65). The as beingaccumulatedinpatientswithhepaticimpairment patients with AD (64). Though thesehavebeenreported mans. this isanewentityofdrugsfortreatingpruritusinhu- tal animalmodel(63).Furtherstudieswillshowwhether sitive andantihistamine-resistantpruritusinanexperimen- k-opioid receptoragonist,didsuppressantihistamine-sen- In summary, pruritus ismostlikelyduetoseveralme- Elevated serumendorphinlevelshavebeenfoundin α

were measured(73).It α

did notinduce • • • • • able tonarrowdownthediagnosis: and ifsomegeneralcluesarepresenttheclinicianwillbe Its onset,durationandnaturehelptodeterminethecause, Important characteristicsofpruritusaregivenin Table I. A precisehistoryprovidesinsightintothediseaseprocess. History EVALUATION OF THE PATIENT 14.Prior diagnosis madebyphysicianorpatient 14.Prior history 13.Travel history 12.Sexual 11 habits, useofcosmetics 10.Bathing Drugs–, ,i.v. drugs 9. Socialhistory–household,personalcontacts, foodhabits,stress 8. Hobbies 7. Occupation 6. Familyhistoryofatopyorskindisease orsimilarpruriticconditions 5. Pastmedicalhistory–,, renal orothersystemicdiseases 4. Atopichistory–eczema,allergic rhinitisandasthma 3. –systemic,topical 2. pruritus of 1. features Historical Patient’s personaltheoryastoaetiologyofthedisease’ 9. Provokingfactors–e.g.water, skincooling,air, exercise 8. Relationshiptoactivities–e.g.occupational,hobbies 7. Location–e.g.generalizedorlocalized,unilateralbilateral 6. Severity–e.g.interferencewithnormalactivities,night-time 5. Duration–e.g.days,weeks,months,years 4. Nature–e.g.prickling,crawling,burning,dysaesthesia 3. Time course–e.g.continuous,intermittent,cyclical,night-time 2. pruritus Onset–e.g.abrupt,gradual,priorhistoryofpruriticepisodes of 1. features Descriptive T able I. . Pets andtheircare duration andonset Medications andtopicals–prescribed,overthecounter, illicit, mastocytosis, rarelyleadtoscratchingandsecondary Severely pruriticdermatoses,suchasurticariaand or othersecondarychanges. dermatological diseasedemonstrateonlyexcoriations Most patientswithpruritusnotrelatedtoaprimary the inaccessibilityfrompatient’s hand. tus, representingtheso-called“butterflysign”dueto spearing isassociatedwithsystemiccausesofpruri- a skindiseaseisresponsibleforthesymptom,whereas Secondary lesionsontheuppermid-backsuggestthat alized pruritus. ing systemicdiseasethanchronic,progressivegener- over onlyafewdaysislesssuggestiveofanunderly- onsetofprurituswithoutprimaryskinlesions systemic disease. Localized pruritusisusuallynotaconsequenceof Descriptive and historical features of pruritus of features historical and Descriptive Pruritus Pruritus 9 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 • • • • • - -U - -A -HIV- - - - Then: -S ------L -B - -E tests: Initial T disclose anundiagnosedsystemicdiseaseandhastobe cal examinationoflymphnodes,liver, spleen,etc.,may of systemicdiseasesmustbeperformed. The generalphysi- phology, distribution,lichenification,xerosisand skinsigns essary. Evaluationofprimaryandsecondarylesions,mor- nails, mucousmembranesandtheanogenitalareaisnec- Careful andcompleteexaminationoftheskin,scalp,hair, Examination 10 able II. Additional radiographic andsonographicstudies cell metabolites Prick testsofmajoratopyantigens andadditives,patchtests Extranuclear antibody(ENA) Antinuclear antibody(ANA) Serum immunoelectrophoresis Serum proteinelectrophoresis Chest X-ray Serum iron,ferritin Parathyroid function(calciumandphosphoruslevels) thyroxine levels) Thyroid functiontest(thyroidstimulatinghormone(TSH)and Fasting ,HbA1C Complete bloodcellcount(CBC)withdifferential leucocytecount skin lesions)causenocturnalwakening. sleep, mostpruriticdiseases(withorwithoutprimary Whereas psychogenicpruritusrarelyinterfereswith the diseaseby5years(75). for Hodgkin’s disease.Pruritusmayprecedeonsetof chills, sweatingandfevermaybeapresentinghistory Nocturnal generalizedpruritusinassociationwith iopathic aquagenicpruritus. bath maybeasignofpolycythaemiarubraveraorid- provoked bytheskincoolingafteremerging froma pruritus mayresemblethecholinergic form.Pruritus ity isimportant.Inassociationwithphysicalactivity, The relationshipbetweenpruritusandphysicalactiv- resenting pruritusintheelderly. Seasonal pruritusfrequentlyoccursas“winteritch”rep- or otherparasitesshouldbeconsidered. When multiplefamilymembersareaffected, behaviour. lesions, butinsteadinvolvepressingandrubbing E. Weishaar et al. et Weishaar E. tool forova,parasitesandoccultblood iver transaminases,alkalinephosphatase, rythrocyte sedimentationrate(ESR) lood ureanitrogen,creatinine rine forsediment,5-hydroxyindolacetic acid(5HIAA)andmast llergy diagnosticapproach: totalIgE,histamine,serotonin Laboratory studies in the evaluation of pruritus of evaluation the in studies Laboratory fixed-point, non-verbalscale(76). Pain track,computerizedsystemwitha7-step-graded, distant pointsbetweenresponsecategories(46).Examples: limited scale,suchas0to10,havingtheadvantageofequi- occasionally, frequently, always. affected patient(46).Examples:pruritus–never, rarely, ployed toassesstheimpactofpruritusonlife quency ofthemeasureddimension. They canalsobeem- search scalesandconsistofdiscretedivisionsthefre- posed toaidetheclinician. pruritus isachallenge.Severalmodalitieshavebeenpro- cal orbiophysicalexamination,measuringtheseverityof scratching and As asubjectivesymptomthatcannotbeverifiedbyphysi- severity pruritus Measuring lesion couldpointtoaspecificdermatologicaldisease. sion, histologicexaminationofanon-specificsecondary is otherwisenormalinappearance(Table III).Onocca- vide informationinpresentationswherethepruriticskin skin biopsyincludingdirectimmunofluorescencemaypro- ology, furtherinvestigationmaybepursued(Table II). A ever, inthesettingofgeneralizedpruritusunknownaeti- There isnogeneralneedforlaboratoryinvestigation.How- investigation Laboratory eoiingauaDepositiondisease Fiberglass dermatitis Deposition granula Fiberglass fragments Urticaria rare eosinophils Oedema inthedermiswithafewor goidwithorwithout spongio- inflammatory cells(excepteosinophils) blood vesselsintheabsenceofother Mastocytosis Increased numberofmastcellsaround Dermatitisherpetiformis dermal papillae Neutrophilic microabscessesinthe Probablediagnoses e.g.drug junction epidermal Eosinophils alongthedermal- Allergic hypersensitivity, with or withoutepidermalchanges Eosinophils inoedematousdermis Histological finding T scales Interval scales Categorical cludes systemicdiseaseandmalignancy. performed carefullywhenthedifferential diagnosisin- clinically normal pruritic skin pruritic normal clinically able III. Histological findings and probable diagnoses in diagnoses probable and findings Histological

describe pruritusbyanumberonfixedor

are themostcommonlyemployedre- sis Urticarial stageofpemphi- Arthropod reaction Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 sitive approachtomeasuringpruritusintensity(76). tinuous dataforanalysis. This mayrepresentthemostsen- tion toafewdiscretecategories,therebyprovidingcon- can describetheitchsensationpreciselywithoutlimita- “no pruritus”and“pruritusasbaditcouldbe”.Subjects 100 mm)withdescriptiveanchorsattheextremes,e.g. tinuous scaleisalineofdefinedlength(inmoststudies most commonexampleinpruritusresearch(77). A con- use (80); but thisisnotsuitableforroutinemonitoringinclinical using aninfraredvideocameraprovidinginterestingdata, meters (79).Nocturnalscratchingcanalsobemeasured bed. Limbactivityismeasuredwithmovement-sensitive sured byavibrationtransducerononeofthelegs an electroencephalogramrecordingsleepactivity; mic musclepotentialscanberecordedsimultaneouslywith scratching behaviour scratching • • • Questionnaires measurement Scratch-behaviour scales: Continuous r scratching behaviour; legs, andcarefulanalysisofthisratioprovidesinsightinto nocturnal pruritustendtomovetheirarmsmorethan to gounnoticed. potential forscratchingbehaviourunderneaththecovers turnal bed movements bed turnal cording ofnocturnalscratchingisnotpossible; activated counterstorecordtheirscratching(78),butre- several measurementcharacteristics: lichenification andexcoriationthatvarywidely. There are Clinicians evaluatescratchbehaviourbyregistrationof rarely causescratching(andinsteadrubbingorpressing). cause pruriticdiseasessuchasurticariaandmastocytosis ect observation ect of pruritus of of forexample dailyhabits,physicalactivities onpru- ate otherimportantcharacteristics, suchastheeffect is informativeindescribingpruritus butdoesnotevalu- ogy asamodifiedMcGillPain Questionnaire(85).It cooperation betweendermatology andneurophysiol- found tobereliableandreproducible(81–84). idiopathic urticaria(83)andatopicdermatitis(84) used forevaluatingpatientswithpsoriasis(82),chronic patient. A modifiedformofthisquestionnairehasbeen frequently intenseandamajorsourceofdistresstothe influence uraemicpruritusthattendstobeprolonged, from uraemicpruritus(81),dialysiswasfoundnotto Pain Questionnaire(81–84).In145patientssuffering The Eppendorf Itch Questionnaire Itch Eppendorf The A Index Itch Worcester The sity ofMassachusettsat Worcester (1). questionnaire for uraemic patients and other forms other and patients uraemic for questionnaire (iii)

limb activity meters activity limb

is basedontheshortformofMcGill –expensive,time-intensiveandwiththe

The visualanaloguescale(VAS) isthe

– patientscanbeprovidedwithhand- (iv)

– bodymovementatnightismea-

forearm activity meters activity forearm

was developedattheUniver-

limits thesymptombe- – patientsrespondingto

was developedin (i)

self-report of self-report

(ii) – rhyth- (v)

noc-

di- ( emotional stress,certainfoods,alcohol,contactwithair tus inpatientswith AD, e.g.heatandperspiration,wool, nologic andnon-immunologicstimulimayprovokepruri- disruptive toqualityoflife(88). A number ofbothimmu- constant, butcomesin“attacks”whichcanbesevereand there isnohistoryofpruritus”(87). The sensationisnot AD that“thediagnosisofactive AD cannotbemadeif Others: agnosis, thoughtheinfestationcanbegeneralized(1). regions densewithhairfolliclesmaybeacluetothisdi- diculosis withoutpruritusasasymptom.Pruritusofbody for infestation. encing pruriticsymptomsmayalsoneedtobeassessed Family membersandfriendsofthepatientwhoisexperi- bala (1).Inscabies,pruritustypicallyintensifiesatnight. alized reactiontocomponentsofthemites,eggsorscy- weeks afterinfestationofthemite,andreflectingagener- ity ofthemite.Itcanalsobegeneralized,starting4to6 ing characterduetolocalreactionthepresenceoractiv- Scabies: Infestation dermatology textbooks. the dermatologicaldiseasesmentionedcanbefoundin important problem. A morecomprehensivediscussionof toses inwhichpruritusisacharacteristicfeatureandan This sectionfocusesonthesensationofpruritusinderma- PRURITUS INDERMATOLOGIC DISEASE canis ctenocephalides (lice): : Atopic dermatitis (“swimmers’itch”). tropical bedbug);( pruritogen and ismostlikelynotthepredominant media- indicatesthathistamine cannotbetheonly genesis of AD (90). The minimal ormoderatehelpofanti- both forandagainsthistamine involvementinthepatho- sial findingsinplasmahistamine levelsthereisevidence have notbeenclearlydetermined. Becauseofcontrover- ( atmoknesis lectularius Cimex Despite intensiveresearch,themediatorsofitchin AD nevertheless relatedtoeachothersomedegree(86). (SCORAD index)arenotdirectlyproportional,but vealed thatpruritusandobjective AD severity ing from AD inthreedifferent dermatologycentresre- ritus orantipruritics.Evaluationof108patientssuffer- Insect bite reactions bite Insect

Pruritus inscabiescanbelocalizedandhasaburn- ) andcommoncolds(36,89).

Pruritus issuchanimportantaspectof

It israretomakethediagnosisofpe- = commonbedbug,

= dogflea);schistosomialcercarial ctenocephalides felis ctenocephalides , e.g.mosquitobites;bedbugs cimex tropica cimex Pruritus Pruritus

= catflea, = 11 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 tion in AD (96). trigger factorsarecapableofmodulatingprurituspercep- and inflammatorymediatorsmayexplainwhydifferent fibres expressinghigh-affinity receptorsofvariousimmune pruritus in AD (95,96). The interactivenetworkofnerve keratinocytes orinflammatorycellsareresponsibleforthe thesized andreleasedbycelltypessuchasnervecells, (71). Insummary, itcanbeassumedthatmediatorssyn- cating thatotherunknownmediatorsmightbeinvolved interleukin-2 hasshownmoderatepruriticpotential,indi- cytokines, theymayplayaroleinpruritus. Thus far, only flamed skinin AD containsseveralproinflammatory treatment (pers.comm., Alan B.FleischerJr.). As thein- scores in AD andthereductionofprurituswithtacrolimus significant relationshipbetweenthereductionofEASI cal ). An ongoingstudyshowsthatthereisa proved tobesufficient (oralcyclosporine,topi- calcineurin-related activationof T lymphocyteshavealso ritic potency(94).Othertherapiesthatspecificallyinhibit interleukin-2, -4,-10andinterferon- cytokines from T cellsandmastinvitroincluding selective inhibitoroftheproductionpro-inflammatory of whichhavebeendetectedin AD (50).SDZ ASM 981,a Other studiessuggestapossibleroleofSP andCGRP, both uncontrolled study, butonlyverypoorefficacy in AD (93). shown someantipruriticpotencyinskindiseasesan can causepruritus.Naloxone,anopioidantagonist,has ergic, histamine-independentmechanism. evidence thatprurituscanbeelicitedin AD byacholin- tients witheczema-freepatients(28). These dataprovide with acute AD andamixtureofpainpruritusinpa- burning sensationinhealthypersons,prurituspatients fers fromhealthyskin(28). mayinducea matory ornon-inflammatorystateofatopicskinanddif- vasoactive intestinalpolypeptidedependsontheinflam- that thequalityofsensationevokedbyacetylcholineand demonstrate reliefofpruritusin AD (92).Ithasbeen shown dence-based review, thereislittleobjectiveevidenceto driven (late,morechronic) AD (90). According toanevi- fective in Th2-driven (early, moreacute) AD thanin Th1- ing sedation(91). Antihistamines aremorelikelytobeef- benefit thepatientonlybyacentralmechanismconcern- oids, doxepincream,topical immunomodulators,capsai- pruritus, whichmaybeachieved bytopicalcorticoster- circumscripta): Consequently, themaingoaloftherapyis cessation of scratching inonespot,resulting inathick,lichenoidplaque. (neurodermitis chronicus Severe, paroxysmalpruritus leadstorepeatedrubbingand simplex Lichen AD (88). be borneinmindthaturticarialsymptomscanformpartof tor responsibleforthepruriticsensation,thoughithasto 12 Opioids constituteanotherclassofneuropeptidesthat T reatment withantihistaminesisgenerallythoughtto E. Weishaar et al. et Weishaar E. γ

has shownantipru- the scalpismostfrequently affected site(1). The pru- arms, buttocksandabdomen, butinhospitalizedpatients The mostcommonlyinvolved areasaretheback,legs, caused byheat,skindryness, sweatingorstress(82,99). (82). Exacerbationofitch intensity hasbeennotedas related tohighambienttemperaturesinatropicalclimate and intensityofitchinsomepsoriaticpopulationsmaybe 92% reportpruritusatsometime(1).Higherprevalence in theeveningandatnight(82).Inhospitalizedpatients, seven percentreportthesymptomsonadailybasis–mainly patients suffer fromgeneralizedpruritus(82,99).Seventy- an itchingdisease,studieshaveshownthatupto84%of therapy. ritic diseaseinwhichantihistaminesrepresentacausal mary, urticariaistheonlyknownhistamine-mediatedpru- kocyte migrationandmastcellstabilization(46).Insum- histaminic therapeuticeffects, includinginhibitionofleu- as levocetirizineordesloratadinemayhaveadditionalnon- ery case(46).Newer, multifunctionalantihistaminessuch agents decreaseoreliminatethissensationinalmostev- primary roleinthepruritusofurticariaandH1blocking sions andsmallsuperficialwheals(1).Histamineplaysa or prickling,particularlyintheacutephasewithearlyle- mographism havebeenreported(1). obvious skinlesionsbutonlygeneralizedpruritusorder- sion) hasbeenknowntooccur. Caseswithnoclinically sign (wheal,erythema,itchingafterabriskstroketole- and pruriticdermographismcombinedwiththeDarier’s most commonsymptom(46).Inallforms,asymptomatic mastocytosis inwhichpruritusisoftenprominentandthe Lichen dermatitis: contact allergic and Irritant Urticaria: (also see“Pruritus Therapy”, p.22). cin ,topicalaspirinoracreativecombinationofthese : diseases: Bullous Mastocytosis: rarely seen(46). but inmostcasespruritusissevere,yetexcoriationsare . lesions, especiallyintheearlyphaseofirritantorallergic tus andstingingmayoccurintheabsenceofvisibleskin IgA bullousdermatosisis less severebutnotedtooccur. to secondaryexcoriationsandcrusting.Pruritusinlinear many casesblistersareuncommonlyobservedcompared cially onthescalp(1).Scratchingcanbesointensethatin known foritsburning,stingingor“firey”character, espe- than 3months(98).Pruritusindermatitisherpetiformisis cede thedevelopmentofskinlesionsbyperiodsgreater ther beabsentorintenseandgeneralized(97).Itcanpre-

Although psoriasisisnottypicallyregardedas This entitymaybeintenselypruritic,stinging

canoccasionallypresentasasymptomatic, These aresystemicandcutaneousformsof

In bullouspemphigoid,pruritusmayei-

Feelings ofpruri- Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 cult todistinguishfrombrachioradialpruritus. skin withoutvisiblechanges. The conditionmaybediffi- eruption sine-eruptionisintensepruritusonsun-exposed and summerpresentswithpruritus.Polymorphiclight T soriasis shouldbesuspectedasaprogressiontocutaneous cally notpruritic,increasingpruritusinlarge plaqueparap- Aquagenic eruption: light Polymorphic nodularis pilaris: rubra Pityriasis Parapsoriasis: the pruritusinthesepatients(1,82). burning components(82). Antihistamines donotrelieve ritus ismostlydescribedashavingtickling,crawlingand stages ofthedisease(101). been describedinsomecases(100),especiallyearly aquagenic pruritus: following criteriahavebeen proposedforthediagnosisof affected 33%reportapositivefamily history(105). The study showsapopulationprevalence of45%,andthose condition oraseveresymptomatic disorder. Onesurvey efficacy (46,102). UVB) andphotochemotherapy(PUVA) havealsoreported steroidal anti-inflammatoryagent),phototherapy(UVA, systemic ,etretinate,benoxaprofen(non- compromising effects. Cyclosporine (3–4.5mg/kgperday), also beusedin AIDS patientswithouthavingimmuno- is requiredtoobtainlong-termbenefit. Thalidomide can tive treatment(46,102). A minimumof3monthstherapy an alternative,butdepigmentationhasbeenreported(46). number oflesions.Combiningwithcryotherapymaybe corticosteroids arelimitedinapplicationowingtothehigh day havebeenreportedassuccessful(104).Intralesional to sixtimesdaily(103)andcalcipotriolointmenttwicea mechanical manipulation.(0.025%to0.3%)four forced byocclusiontoenhancepenetrationandprevent emollients, potentorsuper-potent corticosteroidsrein- der arecomponentstotherapy. Topical therapycomprises causes ofpruritusandresolutiontheunderlyingdisor- vironmental allergens (46,102).Exclusionofthesystemic age ofonsetandcutaneoushypersensitivitytovariousen- diathesis isacontributingfactorcharacterizedbyyoung and eosinophilicdegranulationispresent(46,102). Atopic pruritus (102). An increaseinthenumberofmastcells liberating agents,theymayberesponsibleforthesevere chronic scratching. As theseneuropeptidesarehistamine- whether thisiscausalorsecondaryasaconsequenceof tivity toSPandCGRPcanbeseen(102).Itisnotknown quence ofapruriticsensation(1).Increasedimmunoreac- scratching, whichisusually(butnotalways)theconse- -cell (CTCL)(1,46). Thalidomide (50to200mg/day)maybethemosteffec-

Whereas smallplaqueparapsoriasisistypi-

is characterizedbychronicandsevere (i) can beeitheracommonand trivial

Severe pruritus occurringafterwa-

Moderate toseverepruritushas

This typicallyoccursinspring therapy (107). mizes symptoms,butmaynotbepracticalforlong-term applied 3timesdailyoveraminimumof4weeksmini- (PUVA) (106).Capsaicincream(0.025%,0.5%or1.0%) nm) irradiationororalpsoralenphotochemotherapy reports showefficacy ofsuberythemalUVB(290to320 gastrointestinal haemorrhageisincreased(1).Morerecent ting ofPRV, aspirinmaygivepartialrelief,buttheriskof These haveshownminimaleffectiveness (106).Intheset- include oralcyproheptidine,cimetidineorcholestyramine. to apHof8withbakingsoda,andsystemictreatments ter contactirrespectiveofwatertemperature. sensations provoked by water contact water by provoked sensations 5-hydroxytryptamine andprostaglandinE dermal andepidermallevelsofacetylcholine,histamine, The pathologicmechanismisunknown,althoughelevated gies foraquagenicpruritushavebeenreported(Table IV). the head,palms,solesandmucosae(106).Manyaetiolo- on thelowerextremitiesandgeneralize,withsparingof water temperatureorsalinity. Typically, symptomsbegin with waterandlastforaslong2h(1)irrespectiveof stinging sensationsoccurupto30minfollowingcontact eloproliferative diseases)havebeenexcluded. cluding polycythaemiarubravera(PRV) andothermy- diseases, drug-relatedpruritusandinternaldisorders(in- Skin pathology typically absent typically pathology Skin evident pathology Skin T disease): (Ofuji’s often inimmunocompromisedindividualswith AIDS, disorder wasoriginallyfoundinJapanandisseenmost pustular Eosinophilic well assymptomaticdermatographism. ible skinchanges. This excludesallcausesofurticariaas developing withinminutesofwatercontactwithoutvis- ported (1). able IV. In aquagenicpruritus,prickling,tingling,burningor T Eczematous dermatitis(exacerbation bywatercontact) Aquagenic pruritusoftheelderly(xerosis; maybesubtle) urticaria(secondarytohotwater exposure) Cold urticaria Aquagenic pruritus(idiopathic) Alcohol-induced itchingonhotshowerinsarcoidosis Heat orcoldpruritus Idiopathic haemochromatosis Essential thrombocythaemia Myelodysplastic syndrome Hypereosinophilic syndrome Mastocytosis Hodgkin’s disease Polycythaemia rubravera raditional therapiesutilizealkalinizationofbathwater of pruritus or prickling or pruritus of diagnosis Differential (iii) 2

have beenre- Chronicskin (ii) Pruritus Pruritus

This rare

Pruritus 13 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 decreasing pruritusandskinsymptoms. roxythromycin 300mg/day)arealsoeffective (110) in zole andmacrolideantibiotics(clarithromycin400mg/day, mg dailyisthetherapyofchoice.Dapsone,sulfamethoxa- on thestrikingclinicalappearance.Minocycline100–200 histological featuresarenon-specific,thediagnosisisbased region andneckarethemostaffected bodyareas. As the tion whenhealed(110). The chest,upperback,clavicular pruritic andreddishpapulesthatleavereticularpigmenta- ported. Itischaracterizedbythesuddenonsetofintensely cases affecting otherethnicbackgroundshavebeenre- fects Japanesewomeninspringandsummer. Onlyafew origin. Itwasfirstdescribedin1971(109)andmainlyaf- hood (46). thems canpresentaspruriticrashes,particularlyinchild- tus maybepresentaswell. A widevarietyofviralexan- ralgia, burningorlancinatingpainpredominate,butpruri- cases (46).InacuteHerpeszosterandpost-herpeticneu- tal herpespatientshavelocalpainandpruritusin98%of have apruriticandstingingcomponent:first-episodegeni- (e.g. HIV, malignancy).Herpessimplexinfectionsoften can severelyincreasewhentheimmunesystemisimpaired (3). Moreover, onestudydetectedthatdeathsduetoCTCL CTCL withoutanyskinlesions hasbeendescribedrecently alized pruritusastheonly cutaneousmanifestationof experienced by70–80%of patients (1).Persistentgener- Fungal infections: Fungal Neoplastic V infections: Bacterial Infections pigmentosa: Prurigo identified. Itching maybesoseverethatprimarypustulescannot myeloproliferative diseasesandvisceralcarcinomas(108). 14 ing inprevalence(46). animals (111). Pityrosporumfolliculitishasbeenincreas- workers isdueto verrucosuminfectionfrom pruritus orburningsensations(1).“Barnitch”inrural most importantinfectiousagenttoconsiderinperineal cial fungimaybeintenselypruritic(46).Candidaisthe Cutaneous T-cell lymphoma (CTCL): lymphoma T-cell Cutaneous ritic (112). reported inwhichthepatient’s mainsymptomwasapru- and isgenerallynotpruritic.However, acasehasbeen lesion ofcatscratchdiseasemayresembleaninsectbite secondary syphiliscomplainofthissymptom. The primary trigo maypresentwithpruritus.One-thirdofpatients or Gram-negativebacteria,impetigoandbacterialinter- iral infections: iral E. Weishaar et al. et Weishaar E.

V aricella ischaracterizedbypruritusthat

Inflammatory tineaandothersuperfi-

Folliculitis causedbyGram-positive This isararedermatitisofunknown

Intensive pruritusis not availableat thistime. therapy wouldbereversalof thediseasestate,butthisis reported aseffective inpost-stroke pruritus(116). Ideal as welltopicalmoisturizers andemollients,havebeen tive compoundssuchasamitriptyline orcarbamazepine, changes inperipheralnerve endings.Neurologicallyac- rotic disease,cerebrovascularaccidentsanddegenerative to processesassociatedwithageing,suchasatheroscle- sis. no causeisapparentandmayhavedelusionsofparasito- patients occasionallyhavegeneralizedpruritusforwhich has beenassociatedwithgeneralizedpruritus.Psychotic screen maybeperformed,becausethispsychiatricillness ment becausetopicalsarerarelyeffective. A depression interrupted andmayrequiresedativeantipruriticsfortreat- aggerated (115). The patient’s sleeppatternisusuallyun- intensity thatparallelstheemotionalstateandisoftenex- other causeshavebeenexcluded.Itischaracterizedbyan pruritus andelderlyaretobeconsideredwhen pruritus suchaslice,scabiesandothermites.Psychogenic homes, predisposesthepatienttoinfectionsaetiologiesof drug-induced pruritus.Institutionalizedcare,e.g.nursing pruritis (115). Polypharmacyleadstothepossibilityof erly populationandmaybeaetiologiesofgeneralized ure, diabetesandthyroiddisordersarecommonintheeld- or eruption.Chronicdiseasessuchashepaticrenalfail- ing toascalingoftheepidermisusuallywithnoerythema tion changesandmoistureretentioniscompromised,lead- decrease inskinvascularsupplywithage,lipidcomposi- common (114). Owingtoatrophyoftheintegumentanda pruritus intheelderly, xerosisordryskinmaybethemost rucous epidermalnevus)arecharacteristicallypruritic. exposure. The lesionsinILVEN (inflammatory linearver- and discomfortthatcanbeaggravatedbyheatUV tom inCTCL. which shouldleadtopruritusbeingaddedasaB-symp- were twiceascommonamongthosewithpruritus(113), Darier’s disease: Darier’s Miscellaneous Hereditary Pruritus in aged skin: aged in Pruritus Xerosis Xerosis ritus. xerosis andleadtoeczemacraqueléaccompaniedbypru- tant topicalscontainingalcoholorallergens caninduce sive bathinginhotwater, soaps,detergents anduseofirri- pose towardxerosisandasteatoticdermatitis(46).Exces- andretinoids.HIVinfectionseemstopredis- but generalizedformscanalsobecausedbydrugssuchas Elderly pruritushasbeenspeculatedtooccursecondary is mostcommoninelderlypeople(seebelow),

Patients mayexperienceseverepruritus

Of theaetiologiesforgeneralized Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 plied soonafterandrepeatedlyeachday. . Moisturizingcreams,lotionsorointmentsareap- rubbing orwipingwillexfoliatemoreofthethinnedepi- groin/buttocks. The bodyshouldbeblotteddry, because sponge bathingofodorousregionssuchasaxillaeandthe be restrictedtoonceortwiceweeklywithintermittent lukewarm waterusingmoisturizingsoaps.Frequencymay quent hotorcoldbathingpracticesandinsteadin Pruritus water andabulb syringeafterdefecation. The area isthen structed onhowtoperform a“rectalgargle” withwarm compresses andmeticulous hygiene.Patientscanbein- aggravating factors(119). importance asanxietyanddepression havebeenquotedas replacement therapy(120).Psychiatricscreeningisof be associatedwithadeficiencyoflactobacillusrequiring stools, pHtestingmaybeperformed. A pHof8–10may patients areonchronicantibiotictherapyandhaveliquid to cancer(26patientshadthelatterdiagnosis)(117). If lon andanorectalpathologiesrangingfromhaemorrhoids ritus aniastheirpresentingcomplaint,83(75%)hadco- tional treatment.Inacaseseriesof109patientswithpru- particularly incasesofpruritusanirefractorytoconven- tosigmoidoscopy and/orcolonoscopymaybenecessary, symptoms, includingallergic contactdermatitis(119). Rec- ani hadanunderlyingdermatosisthataccountedfortheir onstrated that34of40patientspresentingwithpruritus not respondtoinitialtreatment,sincearecentstudydem- logic orneoplasticdisease(118). tis, butmaybehelpfulinidentifyingaspecificdermato- diagnosis typicallyshowsnon-specificchronicdermati- cerations, lichenificationandexsudates.Histopathologic nal areatosevereirritationincludingerythema,skinul- ing skinthroughmilderythematouschangeoftheperia- sexually transmitteddiseasesandneoplasticpathology. , psoriasisorlichensclerosisandotherdermatoses, aetiology. These includehaemorrhoids,analfissuresor describes perianalpruritusattributabletoanidentifiable chogenic disordersandradiation.Secondarypruritusani take, poorpersonalhygieneand/oranalseepage,psy- common aredietaryfactorssuchasexcessivecoffee in- cases andmanycauseshavebeenhypothesized(117). More ogy. The incidencerangesfrom25%to95%ofreported the absenceofanyapparentanorectalorcolonicaetiol- patients seekmedicalattention. may bepresentfor5–7weeksuptomanyyearsbefore by aratioof4:1(117). Onsetisinsidiousandsymptoms tion andmalesaremorecommonlyaffected thanfemales and perianalskin.Itoccursin1–5%ofthegeneralpopula- Mild primarypruritusanimay respondtositbaths,cool Patch-testing shouldbeconsideredinpatientswhodo Physical examinationfindingsvaryfromnormalappear- Primary (idiopathic)pruritusanidescribesin T reatment inagedskinshouldincludeavoidanceoffre-

is definedasprurituslocalizedtotheanus low ratesofsuccess(1). or corticosteroidtopicals,havebeenemployed,albeitwith (20). tors, e.g.proteasesorcentralmechanisms,mustbeassumed pruritus. This providesevidencethatotherlocalmedia- scalp islesssensitivetohistamine-inducedexperimental and fatigue.Despitethehighprevalenceofpruritus, individuals andisfrequentlyrelatedtoperiodsofstress objective changes. This isseencommonlyinmiddle-aged ever, pruritusofthescalpcanoccurinabsenceany efforts toidentifysuchaproblemshouldbemade.How- may presentwithsymptomslocalizedtothescalp,andall paresthetica (122). amyloidosus areinfactdue to, oridenticalwith,notalgia degenerated keratinandthatiswhycasesofmacular skin mayleadtothedepositionofsignificantamounts has tobeconsideredthatrepeatedfrictionortraumathe tosis andfollicularmucinosismaybeintenselypruritic. It cinosis-predominant diseasessuchaslichenmyxedema- hood. Lichenamyloidosis,macularamyloidosisandmu- to beassociatedwithseverepruritusbeginninginchild- milial primarycutaneousamyloidosishasbeenreported and scroti and vulvae Pruritus Fibreglass dermatitis: Fibreglass mucinosis: Amyloidosis, scalp: Pruritic and indecentscratchingoccurred (123).Fibreglassexpo- to diagnosethatinanextreme caseincarcerationforlewd inthic therapy, haemorroidectomy). lying disorder(e.g.extirpationofmalignancy, anti-helm- ondary pruritusaniimproveswithtreatmentoftheunder- such astacrolimusmaybeneededforongoinguse.Sec- ing theriskofatrophogenesis. Topical immunomodulators chenification, patientsmayneedprolongedtreatment,rais- symptoms. However, withlong-standingdiseaseandli- desonide) hasbeenshowntobeeffective incontrolling A mildcorticosteroidcream(,fluocinolone, blotted dry, withavoidanceofrubbingandstringentsoaps. androgenizing effects (46). reported aseffective, butcarries asignificantriskof and thevulva. Topical testosterone propionatehasalsobeen sclerosus andinlichensimplexchronicusofthescrotum months oftenproducesrapidresponseinvulvarlichen clobetasol ointmentappliedtwicedailyfor2weeksto tacrolimus) aresimilartopruritusani. Additionally, nosis andtreatmentoptions(includingtheuseof through repeatedtrauma. The work-up,differential diag- Pruritus isworseatnightandlichenificationmaydevelop that thesearepsychogenicinonly1.3–7%ofcases(121). nally thoughttobepsychogenicillnesses,reportsindicate tating andemotionallydisturbingasanalpruritus(1).Origi- V arious treatments,suchasemollients,antipsoriaticand/

Any pruriticskindisordersuchaspsoriasis This canbesosevere anddifficult

Amyloidosis intheformoffa-

may beascommon,incapaci- Pruritus Pruritus 15 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 quences resultingfromfinancial costsandstresslinkedto tribute topost-burnitching(127). ofchoiceinthetreatment ofburnsandmaycon- pruritus maybeavariantof pruritus.Morphineisthe lagen production(126),supportingtheideathatpost- matory stageofthehealingprocessisaby-productcol- arm wounds(125).Histaminereleaseduringtheinflam- complainofseverepruritus,particularlywithlegor times dailyhasbeenreported(124). giant keloidsusingpentoxifylline(400mg)twiceorthree great benefit. The successful reliefofpainandpruritus sheets orcream.Oralantihistaminesdonotprovideany teroids andinterferons,topicalretinoicacid,siliconegel matory agentssuchastopicalandintralesionalcorticos- abnormal orimmaturescars(1). elling, accountfortheperceptionofpruritusinelevated, chanical stimulationofnerveendingsduringscarremod- It islikelythatalldescribedfactors,includingdirectme- to theincreasedperceptionofpruritus. C-fibres presentinimmatureorabnormalscarscontribute portionate numberofthinlymyelinatedandunmyelinated regeneration occursinallhealingwoundsandadispro- the sensationelicitedbymechanicalstimulation(1). account fora“chemogenic”pruritusthatisseparatefrom taglandin presentinearlywoundsandabnormalscarsmay chemical mediatorssuchashistamine,bradykininandpros- clic AMP anddirecthistaminerelease.Increasedlevelsof latation, thelattermediateseffect ofhistamineviacy- thesis (1). Although bothkininsandPGEpromotevasodi- trophic scarsappearstoparalleltherateofcollagensyn- The increasedhistaminecontentinkeloidsandhyper- flammatory phaseofwoundhealingiswelldocumented. are involved. The roleofhistamineintheearlyandin- cluding kininsandprostaglandinsoftheE-series(PGE) cal mediatorssuchashistamine,vasoactivepeptidesin- tion, heat,negativepressureorsuction.Inaddition,chemi- Physical stimuliincludemechanicalandelectricalexcita- cal, aswellchemicalstimuliandnerveregeneration. ritic sensationinscarsisprobablyaconsequenceofphysi- ing, suchashypertrophicandkeloidalscarring. The pru- discomfort maybeprolongedandhintatabnormalheal- mon andresolvesquickly(1).Occasionally, pruritusand Postburn pruritus: Postburn in Pruritus semble scabies,handdermatitis,folliculitisorurticaria(46). trunk, istypical.Clinically, fibreglassdermatitismayre- parts ofthebody, suchastheupperextremities, faceand skin lesions.Involvementofthehandsandotherexposed and mayprovokesevereprurituswithorwithoutvisible sure iscommoninindustrialandconstructionoccupations 16 Survivors oftenfacepsychological andphysicalconse- Therapy isdifficult, andincludesemollients,anti-inflam- Scar remodellingcanlastbetween6monthsand2years. E. Weishaar et al. et Weishaar E.

associated withnormalhealingiscom-

Approximately 87%ofpatientswith massage therapy(128,129). of showerandbathoilwithcolloidaloatmeal5% anaesthetic (/prilocaine,EMLA),acombination vide adequaterelief(128).Newerreportsfavouratopical topical emollientsandantihistamines,buttheserarelypro- an increaseinpruriticsensations(128). Therapy comprises patients withpruritusthanin thosewithoutit(141,142, shown higherplasmahistamine levelsinhaemodialysis in uraemicpatients(132,140–145). Whereas studieshave been unabletoconfirmthese findings(137–139). failure withorwithoutpruritus (135).Otherstudieshave found betweenthenumberofmastcellsinend-stagerenal renal failureandcontrols(135).Norelationshiphasbeen has beenfoundbetweenpatientsinnon-dialysisend-stage (134–136) hasbeenreported,butnosignificantdifference ous organs (spleen,bone-marrow, bowelwall)andskin without pruritus(132).Proliferationofmastcellsinvari- cells (132,133)inpatientswithpruritusthan degranulated, diffusely spread,andmorenumerousmast cells iscontroversial:studieshavedetectedmainly face andtheshuntarm(74,130). tus, whereasothersareaffected mainlyontheback, About 25–50%ofpatientssuffer fromgeneralizedpruri- vary fromsporadicdiscomforttocompleterestlessness. haemodialysis. The intensityanddistributionofpruritus an independentmarkerofmortalityforpatientson ing dialysis(76,81).Renalpruritushasbeenshowntobe high duringtreatmentandlowestthedayfollow- peaks atnightafter2dayswithoutdialysis;itisrelatively less affected thanpatientsonhaemodialysis(1).Pruritus Patients oncontinuousambulatoryperitonealdialysisare race, durationofdialysisoraetiologytherenalfailure. 9.1% (74). priate. Pruritusinpaediatricpatientsondialysisoccurs term “haemodialysis-relatedpruritus”maybemoreappro- of dialysisadequacy(74).Forthisgrouppatientsthe higher biocompatibilityofdialysisandinatightercontrol The reasonforthisdecreasemightbesoughtinbotha 131), butnowadaysitvariesfromonly15%to20%(74). haemodialysis usedtovaryfrom60%80%(76,130, of pruritusinend-stagerenaldiseaseundergoing to raisedserumurealevels,whichisuntrue. The incidence “Uraemic pruritus”impliesthatthesymptomissecondary the term“uraemicpruritus”isoftenusedsynonymously. tients withchronic(notacute)renalfailure.Unfortunately, Renal pruritusisaparoxysmaloccurringinpa- pruritus renal or Uraemic PRURITUS INSYSTEMICDISEASE Increased plasmahistamine levelshavebeendetected The aetiologyisstillpoorlyunderstood. The roleofmast The occurrenceofrenalpruritusisunrelatedtosex,age, Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 ferentiation comparedtopatients withoutpruritus(74).Be- ritus havebeenfoundto amorepronounced Th1 dif- number inpruriticpatients(155). Patientswithrenalpru- renal pruritus,asthesecells havebeenfoundingreater (155). CD1+cellscancontribute tothedevelopmentof of inflammatoryandpotentiallypruritogenicsubstances leased duringhaemodialysisandmayleadtotherelease phocyte interaction(74,154). Various cytokinesarere- tion, emphasizingtheimportanceof Th1 and Th2 lym- nally, immunologicmechanismshavegainedmore atten- dorphin serumlevelsinhaemodialysispatients(65).Fi- One studystatesthatrenalpruritusisnotrelatedto the durationofdiseaseandunalteredbyhaemodialysis(1). accumulate inrenalfailure.However, thisisunrelatedto concepts. Opioidspotentiallyplayarole,becausethey rently themostfrequentlydiscussedpathophysiological to transplantation(1). patient, butdonotexplaintheabruptnessofresponse pruritus havealsobeenproposedinthechronicdialysis manifestation ofneuropathy(1).Specializedreceptorsfor on dialysisandraisesthepossibilitythatpruritusmaybea haemodialysis patients(152,153). effect of ondansetron,a5-HT3receptorantagonistin since controlledstudieshavefailedtoshowanantipruritic are not(147).Serotonin’s roleremainsunclear, especially dialysis patients(151),whilefreeplasmaserotoninlevels stratum corneumhydrationorsweatsecretion(149,150). the presenceofpruritusdoesnotcorrelatewithxerosis, controversial. mary, theroleofcirculatingPTHinrenalpruritus remains in uraemicpatientswithhyperparathyroidism(76).Insum- injected (76). Additionally, pruritusisnotalwayspresent of PTHintheskinorproduceprurituswhenintradermally tochemical studieshavefailedtodemonstratethepresence symptoms andthePTHlevel(76,148).Immunohis- out, buttherewasnocorrelationbetweenthedegreeof higher indialysispatientswithpruritusthanthosewith- roid hormone(PTH)hasbeenshowntobesignificantly subtotal parathyroidectomyhasbeenreported(1).Parathy- chronic renalfailureanddramaticreliefofpruritusafter membranes moreslowly(1). mulation ofpoorlydialysedcompoundsthatcrossdialysis sufficient relief. perience thatantihistaminetherapyoftenfailstoprovide 147). This findingisinaccordancewiththecommonex- not detectedelevatedplasmahistaminelevels(139,146, histamine levelandseverityofpruritus(140).Othershave 144, 145),norelationshiphasbeenfoundbetweenplasma Opioids andalterationsoftheimmunesystemarecur- Peripheral neuropathyaffects 65%ofpatientswhoare Whole bloodserotoninlevelsareelevatedinhaemo- Xerosis isacommonfindinginuraemicpatients,but Parathyroid glandactivityiscommonlyincreasedin Another hypothesisdescribesapossibleroleofaccu- β -en- - 1–2mg/day(141) -Lidocaine 200mgi.v./day (1) reports: case or -Erythropoietin 36U/kgbodyweight threetimesaweek(145) series case in -Cholestyramine (1) confirmed Effect studies: -Ondansetron 8mgorallyori.v. (152,153,157) controlled in -Naltrexone 50mg/day(159,160) effect Equivocal -Topical capsaicin3–5timesdaily(161,162) -Thalidomide 100mg/day(158) trials: -UVB phototherapy(1) controlled in -Activated charcoal6g/day(1) confirmed Effect T sis, primarysclerosingcholangitis,obstructivecholedocho- commonly associatedentitiesareprimarybiliarycirrho- pruritus Almost allliverdiseasespresentwithpruritus. The most cholestatic or Hepatic these procedures(1,163). effective treatmentsbecausepruritusceasesquicklyafter effective dialysisandrenaltransplantationarethemost pruritus inhaemodialysispatients(161,162).However, capsaicin applicationhasdemonstratedefficacy inrenal to bebeneficialindouble-blindedtrials(1,46). Topical naltrexone 50mg/dayremaincontroversial(159,160). tients inonecontrolledstudy(158),studiesof therapy relievedpruritusinasignificantnumberofpa- in HDpatients(152,153). While thalidomide(100mg) patients (157),butthisisnotverifiedinthelateststudies ful incontinuousambulatoryperitonealdialysisandHD ropoietin (1).Ondansetronhasbeenreportedassuccess- success withketotifen,i.v. heparine,lidocaineanderyth- been usedwithvaryingsuccess(1).Otherreportsstate good resultsincontrolledstudies,butcholestyraminehas renal pruritus(1).Oralactivatedcharcoalhasproduced published therapeuticaloptionsisgivenin Table V. tacrolimus couldeffect renalpruritus. A briefoverviewof explanation astohowtheimmunomodulatoryactivityof to moisturizingproperties.Besides,thereisnoobvious caution asthetherapeuticeffect couldalsohavebeendue vation maybeinteresting,butithastointerpretedwith tients ledtodramaticreliefofpruritus(156). This obser- since a7-daytopicalapplicationoftacrolimusin3pa- esizes animmunologicimpairmentconveyedbyuraemia, ventional materialsare(74). A recentpublicationhypoth- complement andleukocytesarelessactivatedthancon- cacy followingtheuseofhighfluxdialysismembranes, cause oftheimprovedbiocompatibilityanddialysiseffi- able V. Phototherapy withUVB,butnotUVA, hasbeenshown usehasshownonlymarginal efficacy in Therapeutic options in renal pruritus renal in options Therapeutic Pruritus Pruritus 17 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 reducing pruritusinprimary biliarycirrhosis,withbenefit dence tosuggestthatursodesoxycholic acidiseffective in been reportedassuccessful (Table VI). There islittleevi- number ofsystemicantipruritic therapymodalitieshave timately, liver transplantationinend-stageliverfailure. A drawal, interferontherapyforchronichepatitisC,and,ul- derlying causeandincludesgallstoneremoval,drugwith- metenkephalin levels(66). tered serotoninergic neurotransmissionleadingtoelevated to changesinotherneurotransmittersystems,suchasal- -related changesintheopioidsystemmaylead mediated scratchingactivityofcentralorigin.Furthermore, tions indicatethatopiateagonistsinduceopioidreceptor- contributes topruritusofcholestasis(66).Otherobserva- neurotransmission orneuromodulation(tone)intheCNS tends toresultinthespontaneouscessationofpruritus(66). vere cholestasisthedevelopmentofhepatocellularfailure associated withpruritus. Additionally, inpatientswithse- elevated serumconcentrationsofbileacidsarenotalways tion hasbeenreportedtoinducepruritus,ontheotherhand ing arole. While ontheonehandintracutaneousapplica- nisms. Fordecades,bileacidshavebeenpostulatedasplay- are severalmajortheoriesaboutmediatorsandmecha- less acarefulhistoryiselucidated. overlooked eveninpatientswithchronicliverdiseaseun- manifestation ofliverdisease(1). This symptommaybe chronic cholestasis,developingyearsbeforeanyother is mostpronouncedatnight.Itcanbeanearlysymptomin hands andfeet,bodyregionsconstrictedbyclothing, lieved withscratching(169).Itistypicallyworseonthe not associatedwithanyspecificskinlesionandre- drome inchildren(168). tioned asapresentingfeatureofthearteriohepaticsyn- tory ofliverdisease(167).Pruritushasalsobeenmen- within ashorttimecourseandaffect patientswithnohis- cholestatic jaundicepresentingwithprurituscandevelop risk factors(166).Itisemphasizedthatdrug-induced ing forhepatitisCvirusisnotjustifiedintheabsenceof general population. The authorsconcludethatroutinetest- tients withchronicpruritusisequivalenttotheratein recent case-controlstudy, thehepatitisCvirusrateinpa- C-positivepatients(164,165). According toa enced byatleast80%(66).Pruritusisnotedin15%of isreportedby25–70%ofpatientsandexperi- titis. Pruritusasapresentingsymptomofprimarybiliary chronic hepatitisBandautoimmuneactivehepa- coholic cirrhosis,haemochromatosis, Wilson’s disease, titis (1).Lesscommonlyassociatedliverdiseasesareal- drug-induced pruritus),chronichepatitisCandviralhepa- lithiasis, carcinomaofthebileduct,cholestasis(alsosee 18 The treatmentofcholestaticpruritusdependsontheun- Another hypothesisproposesthatincreasedopioidergic The aetiologyofcholestasicpruritisisunknown. There Cholestatic pruritustendstobegeneralized,migratory, E. Weishaar et al. et Weishaar E. PBC: Primarybiliarycirrhosis moting sleep. any therapeuticalbenefitexceptsedatingpropertiespro- in thepathogenesisofpruritus,antihistaminesdonotshow there isnocompellingevidencethathistamineinvolved controlled studiesinpruritusofcholestasis(173,174). As to otheragents(172).Oralnaltrexonewaseffective intwo should berestrictedtopatientswhohavefailedrespond agents suchastheopiateantagonists,useofrifampicin and theadventofmoreeffective second-lineantipruritic tential ofrifampicintoinducesignificanthepatotoxicity, tients withprimarybiliarycirrhosis(172).Giventhepo- tion duetorifampicinmonotherapywasobservedinpa- case report,significantimpairedhepaticsyntheticfunc- quently usedassecond-linetreatment(172).Inarecent trolling pruritusinprimarybiliarycirrhosisandisfre- duce (171).Rifampiciniseffective incon- to bemorepotentthancholestyramineanddoesnotin- ation colesevalem,anewbileacidsequestrantthatappears meta-analysis (170).Currentreportstakeintoconsider- being reportedinonly2of11 trials reviewedinarecent Effect confirmed in case series or case reports: case or series case in confirmed Effect studies: controlled in effect Equivocal trials: clinical controlled in confirmed Effect Iron deficiency: Iron tions, areassociatedwithsignificantpruritus. Haematologic diseases,especiallythemalignantcondi- pruritus Haematologic T thus therelationshipbetween ironreplacementandpruri- (175, 176).Nocontrolledtrials havebeenperformed,and anaemia, havebeendescribed respondingtoirontreatment perianal orvulvalregion, and evenintheabsenceof tus inassociationwithiron deficiency, especially inthe able VI. mintwice/day(242) -Bright lighttherapy(10000lux)reflectedtowardtheeyesupto60 -Stanozolol 5mg/dayp.o.(241) -Phototherapy: UVA, UVB(46) -Phenobarbital 2–5mg/kgbodyweight/dayi.v. (240) -Propofol 10–15mgi.v. (bolus), 1mg/kg -Plasma perfusion(ionresinBR-350)(46) -Ondansetron 4mgor8i.v. or8mgp.o.daily(226,238,239) -Naloxone 0.2 -Naltrexone 50mg/dayp.o.(173,174) - 300–600mg/dayp.o.(233) -Ursodesoxycholic acid13–15mg/kg/dayp.o.,notinPBC(1,170) -Cholestyramine 4–16g/dayp.o.(66) -Thalidomide 100mg/dayp.o.(237) -Nalmefene 2–120mg/dayp.o.(235) Tr eatment of hepatic or cholestatic or hepatic of eatment µ g/kg bodyweightperminutei.v. (234)

Causes ofgeneralizedorlocalized pruri- / h (infusion)(236) Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 Hodgkin’s disease Hodgkin’s nancies (1). of thebrain,buthasnotbeenobservedwithothermalig- the palmsandsolesareasofparticularinvolvement. ease. Inthissetting,pruritustendstobegeneralized,with ing degreesecondarytoextrahepatobiliaryobstructivedis- creased proteolyticactivityandhistamineinvolvement. mour, allergic reactions totumour-specific antigen,in- production ofchemicalmediatorspruritusbythetu- of necrotictumourcellsenteringthesystemiccirculation, ment (1).Suggestedmechanismsincludetoxicproducts pruritus donotcorrelatewiththeextentoftumourinvolve- may beanearlysign(179). The intensityandextentof Pruritus canbeseeninadvancedmalignantdiseaseorit rant evaluationforanunderlyingmalignantdisease(46). pruritus torespondconventionaltherapy, shouldwar- Persistent, unexplainedpruritus,orfailureofgeneralized diseases areincreasedinpatientssuffering frompruritus. epidemiologic studyhasdemonstratedwhethermalignant between cancerandthissymptomisunclear. Noreliable ritus asaparaneoplasticdisorder. The truerelationship are non-pruritic,virtuallyanymalignancycaninducepru- Whereas truecutaneousmetastasesofmalignanttumours pruritus and Malignancy (PRV): vera rubra Polycythaemia ated pruritushasbeensuggested(177). tus. A pathogeneticroleforirondeficiencyinPRV-associ- or othersystemicdiseaseswhichthemselvescausepruri- deficiency canbeasignofPRV, numerousothercancers, tus hastobequestioned.Itconsideredthatiron serotonin re-uptakeinhibitorssuchasparoxetine(46,178). therapy, aspirin,intramuscularinterferon- teroids, systemicH cluding histamine. Treatment comprisestopicalcorticos- ing toserotoninreleaseandotherpruritogenicfactorsin- gation hasbeensuggestedasapossiblemechanismlead- patients withwater-induced pruritus(46).Plateletaggre- tus”). This diagnosismusttherefore be suspectedinall velopment ofPRV byyears(seealso“Aquagenicpruri- count (177). Water-induced pruritusmayprecedethede- lower meancorpuscularvolumeandahigherleucocyte of pruritusatdiagnosiswassignificantlyassociatedwitha had adocumentedhistoryofpruritus(177). The presence fer frompruritus;inthelatestretrospectivecohort48% added tothelistofBsymptoms inthisdisease(1). tumour recurrence(181).It hasbeenproposedthatitbe poor prognosis,andreturnof thissymptommayportend (180). Severepersistent,generalized prurituspredictsa Intense pruritusmayprecede thediagnosisbymanymonths Pruritus ofthenostrilshasbeenassociatedwithtumours Gastrointestinal malignanciescancausepruritusofvary-

has apruritusprevalenceof10–30%. 1 - orH 2 -antihistamines, UVBphoto-

30–50% ofpatientssuf- γ

and selective pruritus. and thuscanleadtoasteatoticeczemaaccompaniedby a frequentcomplication. The skininhypothyroidismisdry, ritus canbeseeninhypothyroidism,butisnotreportedas hormone hasontheskin(1).Localizedorgeneralizedpru- known, butismostlikelyexplainedbytheeffect thyroid presenting symptominhyperthyroidism. The causeisnot Thyroid disease: Thyroid mellitus: Diabetes pruritus Endocrine lymphoma: Non-Hodgkin’s Cholinergic pruritus: Cholinergic 2a: type neoplasia endocrine Multiple syndrome: Carcinoid pruritus: perimenstrual or Premenstrual lignant infiltratesmayproducelocalizedpruritus(46). alized andfoundinthechroniclymphocyticvariant.Ma- pruritus. When itdoesoccur, itismorecommonlygener- at sometimeduringthecourseofdisease. quent (2%). Another 10%ofpatientssuffer frompruritus tions havealsobeendescribed(1). burning orapricklingsensation,althoughpruriticsensa- neuropathy ismorecharacteristicallyassociatedwithpain, of pruritusinductionindiabetesisnotknown.Diabetic to candidiasisordermatophyteinfections. The mechanism certain numberofcasesthismaybeduetopredisposition cantly associatedwithpoordiabetescontrol(182).Ina nificantly morecommonindiabeticwomenandsignifi- pruritus, especiallyinthegenitalandperianalareas,issig- common thaninnon-diabeticpatients(182).Localized symptom ofdiabetescanoccur, but isnotsignificantlymore creasingly severepruritustriggered byphysicalexertion, (46). women andcanbetreatedbyhormonereplacementtherapy pruritus isanoccasionalsymptominperimenopausal to intradermalestrogenhasbeendescribed(183).Episodic (1). Generalizedpruritusrelatedtomensesandsensitivity traceptives orotherhormonaltreatmentiswellrecognized ritus relatedtorecurrentcholestasisinducedbyoralcon- fore theclinicalorbiochemical diagnosiswasmade(184). family members,thepruritus hadbeenpresentlongbe- cally onthebackorcrossingmidline.Inallaffected described ashavinglocalizedpruritusoccurringsymmetri- and notalgiaparaesthetica(1).Inonereport,afamily is but differential diagnosis mayincludelichenamyloidosis in associationwithmultipleendocirineneoplasiatype2a, of themidtoupperbackorscapularareahasbeenreported with orwithoutarash(1). Fewer than5%ofpatientswithleukaemiaexperience

Severe generalizedpruritusmaybethe

Generalized pruritusasapresenting

This canleadtogeneralizedpruritus

This hasbeendescribedas anin-

Pruritus isgenerallylessfre-

Localized pruritus

Premenstrual pru- Pruritus Pruritus 19 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 applied inamoderatepattern. Theoretically, phototherapy can bebeneficial(188),but for thesamereasonshouldbe worsen immunosuppression. PhototherapywithUVBlight corticosteroids shouldbeused withcaution,asthesecan underlying dermatosesifthose canbeidentified. Topical is relativelycommon. Treatment isbestdirectedat the peutic antiviralapproach(187). in-depth analysisand,perhaps,amoreaggressivethera- that thepresenceofthesesymptomsshouldstimulatemore HIV viralloadhasbeenobserved.Finally, it is postulated correlation betweenintractablepruritusandaugmented profile areprognosticallyunfavourable(187). A possible the worstprognosis,andalterationsintype1/2cytokine that hyper-IgE andhypereosinophiliaareassociatedwith analyses ofpatientswithintractablepruritushaveshown phils showenhanceddegranulationinvitro.Immunologic correlated withafasterdeclineinCD4counts(1).Baso- B orCandsystemiclymphoma(185). result ofHIV nephropathy, hepaticfailureduetohepatitis uncommon, butneedtoberecognizedinrenalfailureasa Kaposi sarcomalesionscanalsobepruritic. be generalizedandmayaccompaniedbypruritus. ichthyosis, frequentlylocatedontheextremities,canalso to bemorecommoninthisgroupaswell.Severeacquired in theHIV-infected population. Norwegianscabiestends Insect bitesaremarkedlymoreinflammatoryandpruritic and prurigonodulesasthemostcommonfindings(46). (185). hyperpigmentation andhypopigmentationmayfollow in casesofsevereimmunosuppression(186).Prominent plaques ofthehands,forearms,faceandneck,especially tients, areaccompaniedbyseverepruritus,violaceous photoeruptions, whichmainlyaffect Afro-American pa- usually duetophotosensitizingdrugs(185).Lichenoid in advanceddisease,patientsmaydevelopphotodermatitis, Kaposi sarcoma. As photosensitivityisespeciallyincreased acquired ichthyosis,staphylococcalskininfectionsor eruption, seborrhoeicdermatitis,scabies,drugeruptions, number ofpruriticdermatoses,suchaspapular tified (46).However, thesepatientsarepronetodevelopa never havespecificcausativeorcategoricdiagnosesiden- sentation in AIDS. As manyashalfof AIDS patientsmay ity inHIVpatients(185)andisanoccasionalinitialpre- (AIDS) Pruritus isanimportantcauseofdiscomfortandmorbid- syndrome acquired and infection immunodeficiency HIV in Pruritus to treatmentwithdanazol(1). warm surroundings,anxietyandhotfood.Itmayrespond 20 Severe pruritusunresponsivetosymptomatictreatment Patients haveaugmentedserumconcentrationsofIgE Systemic causes(otherthanHIVitself)arerelatively Eosinophilic pustularfolliculitismayhaveexcoriations E. Weishaar et al. et Weishaar E. is notanimmunosuppressant(192,193). and AIDS iscurrentlythalidomide(50–300mg/day),which tion forpruritusandprurigonodularisinpatientswithHIV trolled clinicaltrials. The mostpromisingtherapeuticop- related pruritus(191),hasnotyetbeenconfirmedincon- ment, andtheantipruriticeffect ofindomethacininHIV- patients withpruriticpapulareruption(190). This treat- to beanefficacious treatmentofpruritusinHIV-infected the disease.Pentoxifylline400mgt.i.d.hasbeenshown larly helpfulinidiopathicpruritusatanadvancedstageof pressant withantihistaminicpotential,asbeingparticu- (e.g. ).Othersfavourdoxepin,atricyclicantide- with anti-eosinophilicpotentialmightbemoreeffective Antihistamines maybeusedsymptomaticallyandthose been foundintheplasmavirallevelsofpatients(189). can increaseHIV replicationbut,sofar, nochangehas Herpes gestationis: Herpes PRURITUS INPREGNANCY Pruritic urticarial papules and plaques of pregnancy of plaques and papules urticarial Pruritic are contraindicatedpriortodelivery. shown mixedresults.Mostofthechemotherapeuticagents cytoxan, cyclophosphamideandplasmapheresishave antihistamines, dapsone,pyridoxine,methotrexate, (0.5 mg/kg/dayofprednisone). Topical corticosteroids,oral pregnancies. partum, butrecurswithincreasedseverityinsubsequent ease resolvesspontaneouslyseveralweekstomonthspost- membranes andpalms/solesareusuallyspared. The dis- a generalizedpemphigoid-likeeruption. The face,mucous progress frompruriticandurticarialpapulesorplaquesto develop duringtheimmediatepostpartumperiod.Lesions occurs typicallyinthesecondorthirdtrimester, butmay vary from1in10,000deliveriesto50,000(1).Onset side ofthelaminalucida.Recentestimatesincidence deposition andcomplementfixationalongtheepidermal mune diseasewithanti-basementmembraneantibody and oralantihistamineshas proved tobeeffective. Occa- ment withmediumtohighpotency topicalcorticosteroids ing arenormalandtheaetiology remainsunknown. Treat- (195). Livertransaminases, hormone levelsandHLAtyp- tion atthedermal-epidermal junctionarenon-existent bullous diseaseandspecific immunofluorescentdeposi- but differs fromherpesgestationisinthatprogressionto ties whilesparingtheface. Vesiculation canbepresent, distensae. Itcommonlyspreadstothetrunkandextremi- postpartum period.Onsetisabrupt,oftenwithinstriae during thelatterpartofthirdtrimesterorimmediate ritic, urticarialorpapulardermatosisthattendstooccur 160 deliveries)(194). This isanidiopathic,intenselypru- the mostcommondermatosisuniquetopregnancy(1in Systemic corticosteroidsarethecornerstoneoftherapy

This isarare,IgG-mediatedautoim-

is Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 offending agent. induced pruritusentailsimmediate discontinuationofthe be receivedbytopicalcapsaicin (203). Treatment ofdrug- of HES-inducedpruritus(201). Symptomaticreliefmay in thesmallperipheralnerves suggestsacutaneousorigin HES depositsarereleased.In summary, thestorage ofHES can accountforthepruritus(202).Itusuallyceaseswhen may beaconsequenceofhighercumulativedosageand from pruritus(202).HESdepositionincutaneousnerves dependent, transitoryandisgreaterinpatientssuffering and theplacenta(201). Tissue depositionofHESisdose- the skin,liver, spleen,lungandkidney, butnotintheCNS animal studiesdetectedHESdepositsinmacrophagesof pathophysiology isnotcompletelyunderstood.Recent should bestronglyconsideredinpost-ICUpruritus.Its (HES)infusiontherapy(200). This been observedin15–42%ofpatientswhohavereceived anogenital) prurituspersistinguptoseveralmonthshas ritus (199).Severe,generalizedorlocalized(mostly temic administrationofagentscancausenon-specificpru- drugs andtheirpathomechanismsleadingtopruritus.Sys- T fects (suchashepatotoxicity)mayhavealatencyperiod. ized prurituswithoutskinlesions.Somemedicationef- could alsoconsideranadversedrugreactioningeneral- ritic reactionswillbemorbilliformandurticarial,butone can beassociatedwithpruritus(1).Mostcommonly, pru- Any drugcancauseanadversereactionintheskinthat DRUG-INDUCED PRURITUS tum. within 1to2weeksandpruritus2448hpostpar- verse effects thancholestyramine(198).Jaundiceresolves acid levelsandpruritusscoreswithpotentiallyfewerad- dietary fibre,hasshownpromisebyloweringserumbile shown inconsistentresults.Oralguargum,agel-forming holic acid,dexamethasoneandUVBphototherapyhave S-adenosylmethionine, activatedcharcoal,ursodesoxyc- are rare. Treatment ispurelysymptomatic.Cholestyramine, sequent gestation(197).Skinfindingsotherthanjaundice files consistentwithcholestasisandrecurrenceduringsub- ticularly onthesoles,palmsandtrunk–biochemicalpro- or withoutjaundice,whichtendstobeworseatnightpar- of pregnancyisseenin50%affected women. (196). A positivefamilyhistoryofcholestasis ond mostcommoncauseofgestationaljaundicebehind pregnancy ation inliverfunctionresultingcholestasis.Itisthesec- of Cholestasis lution istypicallyseenwithin1to2weekspostpartum. therapy withUVBlightisanothertreatmentoption.Reso- sionally, systemiccorticosteroidsmayberequired.Photo- able VII indicatesthemorefrequentandwell-recognized Features ofthediseaseincludegeneralizedprurituswith

is anestrogen-dependentalter- T spond welltoneurolepticmedicationssuchashaloperidol such asdiazepamandbuspirone.Delusionaldisordersre- psychiatrist. disordersoftenrespondtoanxiolytics derlying disorder, whichitselfmayrequirereferraltoa logic therapymaybetheonlyoption. these patientsdonotrespondtoreasoningandpharmaco- sue andskinas“proof”oftheirparasitosis.Bydefinition, marked self-mutilation.Patientsmaybringshredsoftis- ritic orcrawlingsensationsandthistendstoresultin cally arerationalineveryotherway. They mayfeelpru- (46). Sufferers areusuallymiddle-agedwomenandtypi- which patientshaveafalsebeliefofinfestationtheskin wise knownasdelusionsofparasitosis,isaconditionin of thesetypesbehaviour(204). skin. Obsessive-compulsivedisorderisafrequentcause but haveanexaggeratedresponsetominorirritationofthe reach. Patientslackdelusionsofinfectionorinfestation, is sparingoftheupperback,asthisregiondifficult to tate lesionswithscarring. A diagnosticcluetothedisease be present. lesions rangingfromlichenificationtoexcoriationsmay functioning. Noprimarylesionsareseen,butsecondary patients experienceimpairmentinsocialoroccupational lead topsychologicalstressresultingindepression.Many chological causesispossibleandseverepruritusitselfmay one couldargue thatanoverlappingofphysicalandpsy- Other causesofpruritushavetobecarefullyruledout,but consider thatthisshouldremainadiagnosisofexclusion. schizophrenia, itmaybecalledpsychogenicpruritus.Some cant psychopathology, suchasanxiety, depressionor If onsetofpruritusistemporallyassociatedwithsignifi- DISORDERS PRURITUS INNEUROPSYCHIATRIC . doahcChloroquine, ,Gold salts,Lithium Hydroxyethyl starch 7. Idiopathic , , ,Morphine, 6. Deposition 8-methoxypsoralen 5. Neurologic 4. Phototoxicity Beta-blockers,, Tamoxifen, Busulfan, 3. Sebostasis/Xerosis Oralcontraceptivesandotheroestrogens Valproic acid,Chloroform,oral contraceptives, 2. Hepatotoxicity Medication 1. Cholestasis Pathomechanism able VII. T Monosymptomatic hypochondriacalpsychosis,other- Neurotic excoriationsoftenresultindeep,linearorpunc- reatment ofpsychogenicpruritusvarieswiththeun- Pathomechanisms in drug-induced pruritus drug-induced in Pathomechanisms Butorphanol, Fentanyl Clofibrate Azathioprine, Penicillamine , Tolbutamide,Erythromycin, T estosterone andotheranabolicsteroids Pruritus Pruritus 21 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 acetate resultingin12symptom-freemonths(213). levels T3–T6 withbupivacaineandmethylprednisolone esting singlecasereportofparavertebralblockatspinal lidocaine, cutaneousfieldstimulation(209)andaninter- (212). Otheroptionsincludetopicalcorticosteroids, phy results(211). trapment –unfortunatelywithinconsistentelectromyogra- neurotoxic chemicalsordorsalspinalnervetraumaen- cused onthediseaseasasensoryneuropathysecondaryto cutaneous reflexmechanisms.Morerecentworkhasfo- ing , increaseddermalinnervationandviscero- amyloid. Various aetiologieshavebeenreported,includ- of thepruriticarea. The biopsy specimen canalsocontain thought tobesecondarychronicrubbingandscratching evident onexaminationofabiopsyspecimen,andis the affected area. This isduetomelanophages,whichare nation isawell-circumscribedhyperpigmentedpatchon thesia (210). A characteristicfindingonphysicalexami- ally accompaniedbypain,paraesthesia,and/orhyperaes- pruritus overthemedialscapularbordersandisoccasion- Astwazaturow in1934,ischaracterizedbyfocal,intense pruritus, eachpatientanddisease hastobeseenasunique, lels aspirin’s associationwith painrelief.Inthesettingof Thus far, thereisnospecificanti-pruriticdrugthatparal- PRURITUS THERAPY paraesthetica Notalgia pruritus Brachioradial V be beneficialinobsessive-compulsivedisorder. clic antidepressantsremainuseful(205).Clomipraminecan side-effect profile,buttraditionaltherapiessuchastricy- selective serotoninuptakeinhibitorsbecauseoftheirlow and pimozide.Depressionisincreasinglybeingtreatedwith 22 tion (CFS)andacupuncture(207,209). saicin cream,physicaltherapy, cutaneousfieldstimula- clude non-steroidalanti-inflammatorydrugs,topicalcap- matitis oftheaffected areaisrare. Treatment optionsin- cinity ofthebrachioradialismuscleorigin.However, der- Examination mayrevealexcoriationslocalizedtothevi- mission inthefallandwintermonthsoftemperateclimates. UV lightexacerbatestheconditionandpatientsreportre- cause ofbilateralbrachioradialpruritus(208).Interestingly, recent casereportdescribesaspinalcordtumourasthe impingement maybecontributoryfactors(206,207). A over time,presenceofacervicalribornerveroot brachioradial pruritusremainsanenigma.Solardamage intermittent pruritusoftheflexorsurfaceelbows, ARIOUS T opical capsaicincreamhasbeenreportedassuccessful E. Weishaar et al. et Weishaar E. : Definedasachronic,uncommon, : This condition,firstdescribedby • • tive factorsshouldcomprisethefollowing: Information giventopatientsabouteliminatingprovoca- tronic orthermalcounterstimulation(e.g.itchstopper). physical treatmentmodalitiessuchasphototherapy, elec- ment includestopicaltreatment,systemictreatmentand treatment oftheunderlyingdisease.Symptomatictreat- emphasizing thecause,whichmeansidentificationand The therapyofpruritushasseveralcategories,allthem therapy General cluded ineachsectionforbetterunderstanding. The currentlyavailabletherapeuticoptionshavebeenin- and therearenotherapiesthatworkforallpatients(46). T tency arecurrentlyavailable(Table VIII). large varietyoftopicalcompoundswithantipruritic po- tion drynessandxerosisoftheskinleadingtopruritus. A cific emollientsonaregulardailybasisinordertopreven- T T • • • • • • • do notpenetratethestratum corneum well.EMLA(ligno- tions suchaslignocaineare lesseffective, becausethese agent asbeingsuperiortoany other(46).Earlyprepara- ited. Nocomparativestudies clearlydemonstrateanyone The onsetofactionisusually fast,butthedurationislim- sation andmaygreatlyrelievetinglingdysaesthesia. opical anaesthetic agents anaesthetic opical treatment opical opical treatmentencompassestheapplicationofnon-spe- be helpful. potassium permanganatebathsfor10to15minmay gents suchasbathoilimplemented.Colloidortar not hot),short-lastingshowerswithnon-dryingdeter- A rics; insteadcottonclothing). W T A A A T a coldwashcloth,gentlepressure,etc. interrupt theitch-scratchcycle,suchasapplicationof Follow adviceconcerningadequatemethodsofhowto patient towearclothingwithoutanyrestriction. are moreappropriatefordaytimeuseinenablingthe Rich emollientsmaybeusedatnight,whereascreams dition andinconsiderationofthepatient’s compliance. lected individuallydependingonthepatient’s skincon- specific topicalpreparations.Emollientsshouldbese- Hydrate theskinregularlyonadailybasiswithnon- ake partinrelaxationtherapy. ake controlledphysicalexercise(28). void excessivebathing;thereforetakewarm(notcold, void heat,hotfoods,drinksandotherliquids. void comingintocontactwithdustandmites. void stressandanxiety. ear appropriateclothing(nowoolorsyntheticfab-

decrease painandpruriticsen- Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 considered (216). an increasedriskofallergic contactdermatitisneedstobe have beenreportedwithpromethazine(46). With , are coveredandyoungchildrentreated.Intoxications ness andxerostomiaoccurwhenlarge partsofthebody its antipruriticpotency(46).Sideeffects suchasdrowsi- in theUSA,despitenocontrolledstudieshavingproved minergic activity(46).Diphenhydramineiswidelyused too, hasantipruriticpotency, mostlikelyduetoantihista- eczema andcontactdermatitis(214,215)., dermatoses suchaslichensimplexchronicus,nummular modest antipruriticeffects in AD andothereczematous no effect wasseenin AD (30).Doxepinhasdemonstrated ritus severity(29)dependingontheunderlyingcauseas tactile, mechanical,heatand painsensationsexceptcold. tion oftheepidermiswithareturn ofallsensationssuchas Discontinuation ofcapsaicin wasfollowedbyreinnerva- results fromthedegeneration ofepidermalnervefibres. to arecentstudy(217),hypalgesia producedbycapsaicin a directeffect onthesmallskin bloodvessels. According by anindirecteffect andinducingplasmaextravasationby vasodilators releasinghistaminefromcutaneousmastcells ropeptides suchassubstanceP, oneofthe mostpowerful lease andsecondarilyinhibitsthereaccumulationofneu- including thepepperplants.Capsaicinenhancesre- botanical speciesofthenightshadefamily(solanacea) Capsaicin Capsaicin antihistamine topical The thol andcamphor(46). to bemorepotentantipruriticagentsthanpramoxine,men- , lidocaineandsimilaranaestheticsarelikely ease (e.g.notherapeuticbenefitwasseenin AD) (30). (29). The therapeuticeffect dependsontheunderlyingdis- aesthetic withurea,alsoknownforitsantipruriticpotency (29). Effectiveness canbeimprovedbycombininganan- in localizedpruriticstatessuchasnotalgiaparaesthetica in experimentallyinducedpruritusandmaybesufficient caine/-prilocaine cream)hasshownantipruriticpotency Pimecrolimusandothers - Miscellaneous:, ,Capsaicin, Tacrolimus, Crotamiton, -Antihistamine: , promethazin, dimetindene, doxepin -Anaesthetics: benzocaine, lidocaine, prilocaine/lidocaine,pramoxine -Cooling agents:shakelotions(e.g.calamine,alcohol) -Coal tar:gels,shampoos,bathadditives,solution,cream,ointment -Corticosteroids: groupIto VII potency -Emollients T able VIII. is anaturallyoccurringalkaloidfoundinmany T opical treatment modalities treatment opical

dimethindene mayimprovepru- application-site pruritus. of inflammatorydiseases.Sideeffects areburningand be lesseffective thantacrolimusindecreasingthepruritus tients with AD wasnoted(94).Pimecrolimusislikelyto recent controlledstudy, animprovementofpruritusinpa- matory cytokinesfrom T cellsandmastinvitro.Ina flammatory skindiseases.Itselectivelyinhibitspro-inflam- macrolactam derivativedevelopedforthetreatmentofin- T with continueduse. ing, pain,erythemaandirritation,allofwhichdecrease large skinareas(161).Sideeffects includestinging,burn- effect. Ithasbeenshowntobeasafetreatmentevenon and needtobeapplied35timesdailyformaximum (32). Available concentrationsrangefrom0.025%to0.3% in patientswith AD theresultshavebeencontroversial cessful invariousdermatologicdisorders(Table IX),but T Effect confirmed in case series or case reports: case or series case in confirmed Effect trials: clinical controlled in confirmed Effect T Pimecrolimus application-site adverseevents(218). pruritus anderythemaarethemostcommonlyreported safety appearssuperiortocorticosteroidagents.Burning, inflammatory andantipruriticeffects (218).Long-term is asafeandefficient treatmentin AD, showingrapidanti- pruritus. Controlledtrialsindicatethattopicaltacrolimus pression of T-cell invasionandmediators thatcanprovoke T which allowsforgreaterpercutaneouspenetration. more potentthancyclosporine.Itissubstantiallysmaller, the macrolidecyclosporine,butisapproximately100times inhibiting T-lymphocyte activationinafashionsimilarto acrolimus acrolimus opical capsaicintherapyhasbeenreportedasbeingsuc- able IX. acrolimus reducespruritusviathemodulationandsup- -Pityriasis rubrapilarisrelatedpruritus (253) -PUVA associatedpruritus(252) -Apocrine chromohydrosis(251) -Hydroxyethyl starch-inducedpruritus (203,249) -Nummular eczema(249) -Lichen simplexchronicus(249,250) -Chronic prurigo(250) -(103,249,250) -Aquagenic pruritus(107) -Peripheral pain(248) -Pruritic psoriasis(246,247) -(207) -Haemodialysis-related pruritus(161,162) -Notalgia paraesthetica(212) -Post-mastectomy painsyndrome(245) -Diabetic neuropathy(244) -(Chronic) postherpeticneuralgia(243) Indications for topical capsaicin therapy capsaicin topical for Indications is amacrolideagentandexertsitseffects by (SDZ ASM 981)isthefirstascomycin Pruritus Pruritus 23 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 cal dermatology. show whetherstrontiumnitratemightalsobeusefulinclini- a directeffect ontheCfibres.Furtherinvestigationswill cantly (222). The mechanismisunclear, butmaybedueto nitude anddurationofhistamine-inducedpruritussignifi- and analgeticeffects whentopically appliedinaplacebo- Sangre deGrado,showedantipruritic,anti-inflammatory Zangrado Crotamiton 24 T lotion comparedtoitsvehicle(46). not showasignificantantipruriticpotencyofcrotamiton effective inamelioratingpruritus. A double-blindstudydid ecdotal reportsbysomepatientsthatthisagentishighly experimental model(42). Other studieshavenotconfirmedthisindetailahuman eral nociceptiveeffect ofsalicylicacidonpruritus(221). chronicus (221). A possiblemechanismcouldbeaperiph- cumscribed pruritus,suchasoccursinlichensimplex pruritic potencyinpatientssuffering fromlocalizedcir- dichloromethane solutionhasindicatedasignificantanti- effect (219,220),topicalapplicationofanaspirin/ Gy Cn Ot T Tn T H Ds DH H Pr N N N opical applicationof Whereas systemicaspirindoesnothaveanyantipruritic a h R F 2 y l n r 2 1 o a a a a u r -e - a n c u i d l l l x K b o E. Weishaar et al. et Weishaar E. a a r c m t o l l d a g e r s n n i x o l o x - e d , n p t e e t t 8 e s c o x i i o s i 3 f g p t 2 h h o n n e e o i m X r e o 0 n i i r t n e d n s s n t r r e i i e t t e . i o d e c a a g n , anextractofthe Amazonian ethnomedicine n r e o m m S e a s n y t is aneffective scabicide. There havebeenan- i i t i n n e s o e e r t n o e s s i m d s i c S S s 5 ( O a d Mn H H P R I I m A A κ n m e f - e e e r e p 1 i i n n f u r H h - e d l s s r , u e d m o strontium nitrate strontium r i e t t s i i c t t a o i i T e c H p u b t a a c c g - - h u t o c i t m m h c i a t i i 3 i d i 2 s a t n i n n n e o o t r , e i v i p n i i o i f f i r o n n r r o H n n n w e n l l e t a m e i n a a n o e e i e c s b l c o 3 s c m m i m r r e o o y e e f t a r r o r g ) p d h r p m m e e f r e c f i l e b o t u c c c t c y t l o c o a a a l i t e e y e l a , m o v o r e a t t c r p p p m - o i n c i p n t c a o p a t t t t a i r k o o t i e o y t p o n l h y n o n i a p s r r r h n t o t p r - - s d a h a o r s b 2 1 c g r e e a g o k y l o u u - o o b b f i o t a n n p e c n r l l

f d i o o i e t k reduced themag- i i n s a a r s c c c t a f e n k p t i k k e l d n c a d e r n a a ( e o e m µ d d t r m p r d A - e i g a m n r u o o l i e n h c c a t n c a t t i e t i e i o b n a o m o n p c c i d r t t y y t u c o o i p t s v y r e c e c i ) e r t a f y i l r u p l i s n n h c i b e c t r i , a o - l n offer significanttherapeuticpotentialinthefuture. vanilloid receptorantagonism(223). This substancemay controlled study. These actionsappeartobemediatedby mechanisms ofactionisgivenin Table X. mary ofsystemicdrugswithantipruriticpotencyandtheir can beusedinthetreatmentofpruritus(225). A briefsum- lation ofpruritus.Someneurotropicandpsychotropicdrugs nism, demonstratingthepowerfulcentralnervousmodu- effects mayworkprimarilybyplacebomecha- patients inonestudy(224).Manysystemicdrugswith in pruritusarefairlymarkedandwereachieved66%of erty ormechanismrelatedtosedation.Placeboresponses Most drugswithantipruriticpotencyactcentrallybyaprop- treatment Systemic type throughvariableabsorptionbetweenindividuals,route availability ofserotoninreceptorantagoniststhe5-HT sis. Another problemisthewidevariationinbio- tion instudydesignrestrictsthepotentialformeta-analy- cancer (32,152,153,157,179,226–228). The widevaria- uraemic, hepatic,opioid-inducedpruritusandin been reportedwithvariablesuccessinthetreatmentof ? C ( C a c P H P I P P P P U V v A p A N N 2 n ( c i a h o r s r o o h h r 1 r a t t 6 e e 5 Serotonin receptorantagonistsofthe5-HT f t u u y r o o o r l l t s o o i l r u u 3 i b 7 y y i h r r n a c s i p t p o c l l r r i i ) o o l ) c c o i m h e e i g t i i o o a u o b c y u y u c d c s s s o o r g t s c m l t t i t s t s e i i g p e k a a e d d s h h c a r d n e , a r i e s s n e e e a a , m i n e u o n e i i t c r i l r r e e n a s s o r c i x r d s m m i a z m m m , , c a n d c i r c t u e g h d y ( o g i p r a a i i i o m l a 9 t a o c e e v a a r t t i a r i r t s n i i 0 o a n , s i n a r a o i t t p k m r v d ) e a i t a i i n s t s u e s s s s i i s e o d t l e e c n o a , y r , i b n i r u e n o s y e d m r a c H r p e m s y d i d n t i a h u ( l s h s p i ( I e 9 d o o a s r b e 1 c V ( r v l o 3 e i e g 2 r o a i a p 7 e s i l , a t ) x s e 2 d n r a r 8 e i i s e a p n u a c 5 e c s a ) c e s r s i r i r e ) s h s y e e c s i m o e r ( t , , n x r r ? u s i c o ( a f h i c b t ) s 2 a i o n , c o , a u r , s 5 r h i r b n r o l i r c h 8 i l s u e c e p a u o o ) , x i n l t i s u n l s i o a a a o o s i g ( c i m l s u n d 1 t d , d t s i s 5 p h i n r a i s 8 l p e s e ( i p e o c 2 e , n e r p r a a 0 m a c 1 d p l p s l o 5 i 9 e r c e p e n ) u d 2 r a s h u s t r i , , t a i t s i i g i 1 ( g p c o e c 2 o 9 t o a r n a 5 i i s 3 , d l m d 5 e ( , s e e n s ) a e ( 2 r f o 2 r m n f ( 5 y t e ? 5 i 6 a l c ) p 4 e b ) t , 3 t r ) i

i o t p p l o type have i i p r r s f a u u , h r r r y y i i t l t u a u c s s t , i i n c ) 3 Downloaded By: [Akademiska Sjukhuset] At: 12:55 5 October 2007 humans, butfurtherinvestigationisnecessary. may representanewentityofdrugsfortreatingpruritusin -resistant pruritusinananimalmodel(63). This substance shown antipruriticactivityinantihistamine-sensitiveand synthesized tor modulatestheperceptionofitch. TRK-820 isanewly acting substances. patients withmultidrugtherapy, especiallyincentrally nists mayposeapotentialriskwhenusedinseverelyill (232). no effect onmaximalpruritusintensityandonsettime creases experimentalhistamine-induced pruritus,buthas renal pruritus(46). According toreports, acupuncturede- ment ofpruritusvulvae,allergic contactdermatitisand matitis (231). tion butdonothaveanybeneficialeffects oncontactder- neous fieldstimulationtreatmentsreducetheitchsensa- ing theskin(230).Interestingly, singleandrepeatedcuta- hibitory mechanismsthatarenormallyactivatedbyscratch- ous fieldstimulationactsthroughendogenouscentralin- ritus didnothaveanybenefit.Itissuggestedthatcutane- allel withthereliefofitch.Patientsgeneralizedpru- the numberofepidermalnervefibreswasreducedinpar- ing experiencedsufficient relief.Skin biopsiesshowedthat open-label uncontrolledstudy, patientswithlocalizeditch- afferent fibres includingC-fibres(209,230).Inarecent ous fieldstimulationisanewtechniquestimulatingthin as ittendstodeclinewithcontinuedtherapy(46).Cutane- purposes (230). The effect maybe apartialplaceboeffect, found inagedskin,butnotsufficient forpracticalclinical been reportedasbeneficialintypesofpruritussuchthat sis, polycythaemiarubraveraandprurigonodularis. toses, pruritusrelatedtouraemia,primarybiliarycirrho- therapy haveshownmostbenefitininflammatoryderma- light(UVA,modalities UVB,UVA/UVB) andPUVA treatment Physical nin syndrome(229). Application of5-HT serotonin tootherreceptors,increasestheriskofseroto- of serotoninsimultaneously, hencepresentingexcessive tor andfunctionallyincreasingsystemicCNSlevels nyl (229).Perhaps,blockingonetypeofserotoninrecep- bination withotherdrugssuchasmirtazapineandfenta- type wereappliedinchemotherapyinducednauseacom- curred whenserotoninreceptorantagonistsofthe5-HT warns oftheserotoninsyndrome,becausetwocasesoc- but cannotdefinitelybeexcluded. A recentpublication ritus, suchasforexamplerenalpruritus,appearsunlikely, for serotoninreceptorantagonistsindifferent typesofpru- of administrationanddoseprescribed.Insummary, arole Experiments inanimalssuggestthatthe Acupuncture hasbeenreportedassuccessfulinthetreat- T ranscutaneous electronicnervestimulation(TENS)has κ -opioid receptor-selective agonistthathas 3

receptor antago- κ -opioid recep- 3 select patientsbenefitfromphysicaltreatmentmodalities. A anaesthetics, macrolideimmunomodulatorsandcapsaicin. cal treatmentsrangingfrommoisturizerstotopical are alwayssignificant,andmanypatientsbenefitfromtopi- Patient educationandeliminationofprovocativefactors and thattherearenotherapiesworkforallpatients. pruritus, eachpatientanddiseaseshouldbeseenasunique allels theabilityofaspirintorelievepain.Insetting proach willworkforallpruriticconditions. tor isresponsibleforallpruritus,nosingletherapeuticap- kines andothers.Becausenosinglemechanismormedia- tified, includinghistamine,neuropeptides,opioids,cyto- select pruriticcondition.Manymediatorshavebeeniden- may beresponsibleforcontributingtothepathogenesisof nea. CNScontrolcentresmodulatepruritussensations,and oftheskin,mucousmembraneandcor- nerve endingswithextensivearborizationoccurringinthe evolving fields. severity andtheimpactofpruritusonqualitylifeare ogy. Objectivemeasuresofpruritusseverity, scratching ation ofpatientsmayleadclinicianstoaspecificaetiol- thorough physicalexaminationandlaboratorystudyevalu- temic diseasescanleadtothisnon-specificsymptom,and symptom indermatology. Dermatologicdiseasesandsys- ognized sinceantiquity;itisthemostfrequentlydescribed Pruritus isaprimarysensorymodalitythathasbeenrec- SUMMARYCONCLUSIONS AND of life(1,28,46). biofeedback helptostopscratchingandimprovequality therapy, controlledphysicalexercise,supportgroupsand ing (1). response, alterationsincutaneousbloodflowandscratch- which pruritusmaybegeneratedorexacerbated,e.g.sweat a numberofsecondarypsychosomaticmechanismsthrough and neuropeptides.Ithastobeborneinmindthatthereare by anumberofstress-relatedmediatorssuchashistamine (1). Pruritusmaybeprecipitated,prolongedorenhanced tors canaffect thecourseofanyphysicaldiseaseprocess It hasbecomeincreasinglyclearthatpsychologicalfac- approaches Psychological .ZirwasMJ,SeralyMP. 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