Effect of cholesterol-lowering treatment with a 585 on plasma membrane function and liver electron microscope appearence in rats.

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The

long

and

winding

road

of

non

steroidal

antinflammatory

drugs

and

paracetamol

in

cancer

pain

management:

A

critical

review

Sebastiano

Mercadante

a,b,∗

,

Antonino

Giarratano

a,b

a_La_Maddalena_Cancer_Center,_Palermo,_Italy b_University_of_Palermo,_Italy

Accepted4January2013 Contents 1. Introduction... 141 2. Methods... 141 3. Results... 141 4. Discussion ... 141 4.1. Paracetamol... 142 4.2. NSAIDs ... 143 5. Conclusion... 144

Conflictofintereststatement... 144

Reviewers... 144

References... 144

Biographies ... 145

Abstract

TheaimofthisreviewwastoassessthevalueofNSAIDsandparacetamolinpatientswithcancerpainto updateapreviousreview

performedtenyearsagoonthistopic.Theapproachwasanalyticandbasedonclinicalconsiderations,ratherthanonrawevidence,which

oftendoesnotprovideusefulinformationinclinicalpractice.Bothpublishedreportsfromanextensivesearchofelectronicdatabaseswere

collectedfromJanuary2001toDecember2011.Afree-textsearchmethodwasusedincludingthefollowingwordsandtheircombination:

“Anti-inflammatorydrugsORparacetamolORacetaminophen”AND/OR“cancerpain”.Anyrandomized-controlledtrialwasconsidered.

Thirteenreportsfulfittedinclusioncriteriainthissystematicreview.Randomizedtrialshavebeenperformedbyusingdifferentmodalities

ofintervention.Singledrugsaddedonopioidtherapyorduringopioidsubstitutionwithopioidsasrescuedrugsthroughapatientcontrolled

analgesia,werecomparedwithplaceboorbetweenthem.Fivestudiesregardedparacetamol.Otherfourstudiesassessedtheefficacydipyrone,

ketorolac,dexketoprofen,andsubcutaneousketoprofenincancerpainmanagement,mainlyontopofanopioidregimen.Theroleofparacetamol

andNSAIDsinthemanagementofcancerpainstillremainscontroversial.Thepaperspublishedinthislastdecadewereunabletoanswer

themainquestions.Thereisnoproofthattheyshouldbeusedtostartthetreatmentandhowlongtheyshouldbeadministeredwhenopioid

treatmentisaddedontop.Whileparacetamolseemstobedevoidofanybenefit,particularlyifgivenatusualclinicaldoseswhichshould

belessthan4g/day,ketorolacseemstoprovideanadditiveanalgesiceffecteveninpatientsreceivingdifferentdosesofopioids.Themain

indicationfromtheanalysisofthesedataisthatNSAIDscouldbegiveninpatientsreceivingopioids,evaluatingtheirbenefitandweighton

opioidtherapyinindividualpatientswhohaveafavorableresponsetojustifyaprolongeduse.

Keywords:Cancerpain;Anti-inflammatorydrugs;Paracetamol

∗_{Corresponding}_author_at:_La_Maddalena_Cancer_Center,_Via_San_Lorenzo_312,₉₀₁₄₆_Palermo,_Italy._Tel.:₊₃₉_0916806521;_fax:₊₃₉₀₉₁_6806110.

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1. Introduction

AccordingtotheWorldHealthOrganization(WHO),non steroidal anti-inflammatorydrugs (NSAIDs) and paraceta-mol(PAR)areprescribedaloneasfirststep,orinassociation toopioidsforthesubsequentanalgesicladdersteps[1].The rationale for adding this class of drugs to an opioid regi-menistoimprovethebalancebetweenanalgesiaandadverse effectsbyeitherincreasinganalgesiawithoutaddingadverse effectsorbymaintaininganalgesiawithlessadverseeffects, providinganopioid-sparingeffect.ConcernsaboutNSAIDs arerelatedtotheiradverseeffectsandtheuseofthisclass ofdrugsremainsdebatable,particularlywhentheyareused first,andthencontinuedwithopioidsintheotherstepsinthe long-termtreatment,whentheirefficacycannotbeevaluated duetotheanalgesiccoveringofferedbyopioids,orinelderly

[2].Evidence-basedreviewsoftenproviderawdatawhichdo notseemalwaysapplicableintheclinicalsettingduetothe rigidcriteriaofselection.Forexample,conclusions suggest-ingtoincreasethedoseofNSAIDstoamaximumacceptable dose[3]maybenotadvisablefromaclinicalpointofview. Moreover,thesereviewsfocused onthelevel of methodol-ogy[4],ratherthantheclinicalrationaleofthestudy,which isfundamentalforaconsequentclinicalapplicationindaily practice.Finally,manystudiesreviewedwere reallyoldin termsofmethodology,questionsposed,anddrugsused.The aimof thisreviewwastoassessthe valueofNSAIDs and paracetamolinpatientswithcancerpaintoupdatea previ-ousreviewperformed tenyearsagoonthistopic [5].The approachwasanalyticandbasedonclinicalconsiderations, ratherthanonraw evidence,whichoftendoes notprovide usefulinformationinclinicalpractice(Tables1and2).

2. Methods

Both published reports from an extensive search of

electronic data bases, including MEDLINE, PUBMED,

CANCERLIT, andEMBASEwere collectedfromJanuary

2001toDecember2011.Afree-textsearchmethodwasused includingthefollowingwordsandtheircombination:

“Anti-inflammatory drugs OR paracetamol OR acetaminophen”

AND/OR“cancerpain”.Handsearchingofrelevantjournals, andEuropeanconferenceproceedingswerealsoconsidered. The references of all relevant reports and review articles weresearchedforadditionaltrials.Theinclusioncriteriawas randomized-controlledtrialperformedincancerpatients.

3. Results

Theliteraturesearchretrieved3703papers.Allabstracts werereadbytheauthorsandthirteenreportsfulfitted inclu-sion criteria in this systematic review. Four papers were not considered, as paracetamol was used in combination

with hydrocodone and compared with tramadol [6], in

combinationwithcodeineandcomparedwith hydrocodone-paracetamol [7], andin combination with oxycodoneand comparedwithplaceboinpatientswhowerereceiving dis-crete doses of transdermal fentanyl or morphine [8], and

in another study ibuprofen was included in a compound

containingcobrotoxinandtramadol[9].Randomizedtrials havebeenperformedbyusingdifferentmodalitiesof inter-vention. Single drugs added on opioid therapy or during opioid substitutionwithopioidsas rescue drugsthrough a patientcontrolledanalgesia,werecomparedwithplaceboor betweenthem.Fivestudiesregardedparacetamol.Otherfour studiesassessedtheefficacydipyrone,ketorolac, dexketopro-fen,subcutaneousketoprofen,incancerpainmanagement, mainlyontopofanopioidregimen.

4. Discussion

Inapreviousreviewupdatedto2001,theevidencefrom clinicaltrialsavailableatthattimewasoflimitedamountand

Table1

Studiesofparacetamol.R(randomized),DB(doubleblind),CO(crossover),P(parallel).

Authors No. Design Drug-doses Results Comments

Axelsson(2003) 30 DBCO 7days

Paracetamol4gversusPlacebo Nodifferencesinpain intensity

Painleveltoolow Highdosesofparacetamol Stockler(2004) 30 DBCO

2days

Paracetamol5gversusPlacebo Significantdifferencesinpain intensity

Highdosesofparacetamol Differencesclinicallynot significant

Tasmacouglu(2009) 43 DBP 24h

Paracetamol4g

MorphinePCAversusPlacebo MorphinePCA

Nodifferencesinopioid consumptionorpainintensity

Highdosesofparacetamol

Israel(2010) 22 DBCO 4days

Paracetamol2gversusPlacebo Nodifferencesinpain intensity

Painwasalreadycontrolledwith meandosesof255mgoforal morphine

Cubero(2010) 50 DBP 7days

Paracetamol1.5gversusPlacebo Nobenefitinanalgesiaor timetostabilization

Add-onopioidswitchingto methadone.Nodataonfinal dosesofmethadone

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Table2

StudiesofNSAIds.R(randomized),DB(doubleblind),CO(crossover),P(parallel).

Authors No. Design Drug-doses Results Comments

Duarte(2007) 34 RDBCO 2days

Dipyrone2gversusPlacebo Betterpaincontrolwith dipyrone

Patientsreceiving60mgoforal morphine

Painremaineduncontrolledand placebophaseaftercrossing-over wasbetter

Mercadante(2002) 47 RP 4weeks

Ketorolac60mgversus Non-ketorolac

Betteranalgesiaand opioid-sparingeffect

Patientsreceivingmorphinein escalatingdoses Rodriguez(2003) 115 RDBP 7days Dexketoprofen25mgversus Ketorolac40mg Dexketoprofenatleast similartoketorolac

Ptswithbonepain

Unclearopioidconsumption(useof anintegratedscore) Moselli(2010) 172 SemiC 4weeks Ketoprofen700–1400mgadded toSCmorphineversusSC morphineonly

Betterpaincontroland lessopioidconsumption

Doseincrementsproportionaltopain intensity.Controlgroupwaschosen basedoncontraindicationsto NSAIDs.

quality.NSAIDscouldnotbeconsideredanalgesicsfora spe-cifictypeorcauseofpain,butmayprovideadditiveanalgesia inpatientsreceivingopioids.Thesimplefindingofanopioid sparingeffectmaybequestionedincancerpaintreatmentand shouldnotmerelybeanindicationtoaddNSAIDstoan opi-oidregimen,asthesamelevelofanalgesiacanbeachieved increasingopioid dose.Itcouldbequestionedwhetherthe addictionofNSAIDstoatherapeuticregimeisworth expos-ing the patients tothe side effects of anothermedication, althoughtheuseofNSAIDsmaybeusefulwhentheincreases inopioiddosagedeterminetheoccurrenceofopioidtoxicity inindividualspresentingasignificantanalgesicresponse[5]. From the analytical revision of the selected papers in the last ten years, many flaws were noticed regarding the methodologyanddesignchosenbyauthorstodemonstrate aconstructtotransferinclinicalpractice.Therefore,limited informationwasaddedtoliteraturetoprovidespecific guide-lines.

4.1. Paracetamol

Paracetamolis considered asafer non opioid analgesic in comparison with NSAIDs, and is considered the first choiceinmanyguidelinesforthemanagementofnoncancer pain[10,11].However,itsefficacyincancerpatients often receiving oioids for their background analgesia shouldbe demonstratedand hasbeen the subject of researchin this lastdecadeonlyinafewstudies.Arandomizeddouble-blind cross-overplacebo-controlledtrialwasperformedto ascer-tainwhetherparacetamolhasaclinicallysignificantadditive analgesiceffecttomorphinein30advancedcancerpatients withwell-controlledpain[12].Patientsreceivedparacetamol 1000mgorplacebofourtimesadayforaweek.The follow-ingweekpatientscrossedovertoreceivetheothertreatment. Thirtypatientsreceivingamediandoseoforalmorphineof 70mg completed boththe study weeks. No differences in painlevelbetweentheweekwithparacetamolandtheweek withplacebocouldbedetected.However,patientsincluded

inthestudyhadamedianpainlevelof2/10onanumerical scaleof0–10.Withthislevelofpainitisquitedifficultto observeanydifferencesbecauseofaflooreffect.Dataremain inconclusive,astheanalgesiceffectofparacetamolwasnot exploredinpatientswithpain,becausepatientsalreadyhad anoptimalpaincontrol,andopioidconsumption,for exam-ple areduction indoses, during the study weeks was not reported.Finallyparacetamoldosesproposedseemtobe rel-atively high,particularlyfor patients athighrisks andthis usecannotadvisedinclinicalpractice.

Inasmalldouble-blindrandomizedcrossoverstudy, para-cetamolwasadministeredindosesof1gevery4hfivetimes perday(5g/day),fortwodaysin30patientsreceivingmean dosesoforalmorphineequivalentsof200mg/dayandhaving moderatepain(4/10onanumericalscale0–10)[13].While significant, thedifferencesinpainintensity werevery low (0.4forthenumericalscale0–10),inpatientsreceiving para-cetamol, although authors reportthat somepatients could benefit a lot. No differences in preference, breakthrough doses or adverse effects werereported.The positive inter-pretationisagainstclinicalobservationswhichhaveshown that, on average, areduction of approximately two points or a reduction of approximately30% inthe pain intensity represent a clinicallyimportant difference [14]. Also, the modalitiesanddosesofparacetamolwereofconcern(every fourhoursfivetimesperday),thenightlydosebeingskipped, leavingthepatientdevoidofthepotentialanalgesiceffectof paracetamolforsleepinghours.Atwodaysstudyisprobably insufficienttotestananalgesiceffectinchronicpain.Finally, paracetamoldosesexceeding4g/dayareproblematicforthe riskofhepaticdamageinapopulationatrisksuchaselderly cancerpatients.

Forinstance,thesedatawerecontradictedbyotherstudies. Inapainclinic,43patientswithnon-neuropathicpainwho werereceivingstep2treatmentandhavingapainintensity of≥4/10wereselectedforarandomizeddouble-blind con-trolledstudy.Theyreceived1gofparacetamolintravenously or saline every 6h. A patient-controlled analgesia with

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intravenousmorphinewasofferedwithabolusdoseof1mg andalockingtimeof5min [15].Pain intensitydecreased in bothgroups, but no significant differences were found betweenthe groups.Similarly, no differencesinmorphine consumption were observed. It is likely that this use of morphine would have flattened any possible influence of paracetamol.Thus,despiteitsfavorablesafety,intravenous administrationofparacetamol(4g/day)didnotaddany ben-efitover thecontrol of cancerpain intermsof increate in analgesicefficacyordecreaseinmorphineconsumption.

Inarandomizeddouble-blind,placebo-controlled, cross-overtrialtheadjuntiveuseofparacetamolwithstrongopioids wasassessed.Patientsreceivingamediandoseof255mgof oralmorphineequivalents,weretreatedwith500mgof para-cetamol four times daily for five days andfive days with placebo in arandomized order. 22 patients concluded the study.Nostatisticallydifferencesinpainintensity(mean dif-ference0.16onanumericalscale0–10)andbreakthrough analgesics,aswellintensityofadverseeffects,wereobserved

[16].However,patientshadarelativelywellcontrolledpain, andaflooreffectcouldhaveminimizedtheadditiveanalgesic effect.

Finally,paracetamolwasusedtoassistopioidswitching

from morphine to methadone in a randomized,

double-blind,placebo-controlledstudy[17].Whateverthereasonfor switching,possiblyuncontrolledpainand/oradverseeffects, 50 patients having unfavorable balance between pain and adverseeffects,didnotchangedtheiranalgesicregimenfor oneweek.Observingapatientinacriticalsituationofpoor analgesiaandadverseeffects,withoutanytherapeutic inter-ventionfor one weekis unrealistic inthe real world The additionofparacetamol,750mgevery6hforasevendays period,didnotprovideanybenefitinpaincontrolortimeof stabilizationofanalgesiaoncemethadonewasintroduced.It wouldhavebeeninterestingtoknowthedosesofmethadone achievedinthetwogroupsattimeofstabilization,andhow thedoseswerechangedduringthestudyperiodafterstarting withaninverselyproportionalratiosusedforswitchingfrom morphinetomethadone.

4.2. NSAIDs

Despitethelargeavailabilityofthisclassofdrugsinthe market,includingthenewgenerationofCOXIBs,onlyfew studiesassessedtheefficacyofthesedrugsincancerpain. Thirty-four ambulatorypatients starting 60mg/day of oral morphinefor cancerpainwererandomizedtoreceiveina double-blind,cross-overstudydesign,dipyroneindosesof 500mgorallyevery6horplacebo.Aftertwodayspatients received the alternative treatment, while maintaining the samedose ofmorphine. Painwasstill uncontrolled(7 and 5.5onanumericalscale,respectively),despitepaincontrol wassignificantlybetterwithdipyrone[18].However,after crossing-overpatientsswitchedonplaceboseemedtohave abetterpain reliefinthesubsequent two days. Curiously, authorsevaluatedasaproofofefficacythatpainimproved

duringtheplacebophase,afterdiscontinuationofdipyrone, asitwouldprovideprolongedanalgesia.Acorrect interpre-tationshouldbethatinthesecondphaseplacebowasasleast aseffectiveastheactivedrug.

Ketorolac 60mg/day was given in addition to patients receivingdifferentdosesofmorphineinarandomized con-trolled study. 47patients were titrated withoral morphine untilachievingadequateanalgesia.Subsequently,theywere randomizedtoreceiveketorolacornotandtheycouldchange doses of morphine according to the clinical needs. After a weekpatients receiving ketorolac showed a better anal-gesia in comparison with the group of patients receiving oralmorphineonly.Morphinedoseescalationwaslowerin patientstreatedwithketorolacandanopioidsparingeffect wasobserved.Theuseofketorolacwasassociatedwithmore gastricdiscomfortbutlessconstipationandwasmore con-venientinapharmacologicanalysiswhen addedtohigher dosesofmorphine[19].Whilethisstudydemonstratedthat ketorolac produced asignificant analgesic effect indepen-dently fromthe doses of morphine,dataon long-termuse arelacking.

115patientswithbonecancerpainwererandomizedfora double-blindevaluationofshort-term(7days)analgesic effi-cacyofdexketoprofen25mgor ketorolac10mgevery6h. Thetreatmentswerecomparable[20].Apainratingindexof ≥10,calculatedfromintensityandfrequencyofpain, anal-gesictaken,incapacityduetopain,sleepdisturbances,and apainintensityof≥4/10onanumericalscale0to10,were usedasinclusioncriteria,sothatitwasimpossibletoknow therealopioidconsumption.

With regard to the route of administration, when the oral route isimpracticable, continuous subcutaneous infu-sion(CSI) isconsideredas an effective,simpleandcheap alternative.Inaprospectiveobservationalopen-labelstudy, patientswithseverepainreceivingmorethan240mgoforal morphineequivalents,orpatientswhofailedadequatetrials ofotherstrongopioidsweretreatedwithacontinuous infu-sionof CSIof ketoprofenaddedtoCSIof morphine[21]. Thisgroupofpatientswasalsocomparedwithaconcomitant groupofpatientstreatedwithaCSIofmorphineonly,because ofexistingcontraindicationstoNSAIDs.Patientswerefirst converted from oral opioids to CSI of morphine, eventu-allyincreasingthedosageby25–50%incaseofseverepain (7–8/10and9–10/10onanumericalscale,respectively).The doseofketoprofenwas700or1400mg/dayinpatientswith apainintensityof7–8/10or9–10/10,respectivelyanddose ofmorphinewasreducedby10%topotentially counterbal-ancetheketoprofenadditiveanalgesiceffect.Thus,authors assumedthatdosescouldbeproportionaltothehighlevelsof thenumericalscale,asitwouldbealinearrelationbetween anincreaseinopioiddoseandtheanalgesiceffectofthedrug. Subsequently the CSI morphine dose were proportionally changedweeklyaccordingtothepainseverityorthenumber ofbolusesofCSImorphineusedasbreakthroughpain medi-cation.FromalargenumberofpatientswhounderwentCSI, authorsanalyzeddataregardingpatientswithafollow-upof

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atleastonemonth,172receivingmorphineketoprofenCSI and48patientsreceivingmorphineCSIonly.Intheefficacy analysisauthorsincludedpatientswithwellcontrolledpain whentheyhadapainintensityof 0–2/10. Thisincontrast withdatawhichindicatedadifferentcut-offtodefinemild pain, whichisacceptable, generallynotrequiringchanges inopioiddoses[22].Theopioidconsumptionseemedtobe superiorinpatientstreatedwithoutketoprofenincomparison withpatientsreceivingtheCSIwiththedrug-combination. Onlyaminorityofpatients(2.3%)discontinuedketoprofen duetoadverseeffects.Thiswasanonrandomizedcontrolled studywithcleardifferencesofgroupsamples.Datawerealso difficulttointerpretgiventherationaleofthestudyprotocol whichsuggestedtouseincrementsstrictlyrelatedto numer-icalscalenumbers.Also,oneshouldarguefromtheprotocol that alevel of 6/10of painintensity isconsideredtobe a reasonablegoal,asdoseincrementsareproposedonlywhen painintensitygetsevere(≥7/10).Howeverpainintensityof 5–6/10(moderate pain)is estimated to significantly inter-ferewiththequalityofpatients’life[22],andgenerallythe consequentactionistochangetheopioiddose.

5. Conclusion

TheroleofparacetamolandNSAIDsinthemanagement of cancerpainstillremains controversial.The questionon howandwhenusingthesedrugshasnotbeenresolved.The paperspublishedinthislastdecadewereunabletoanswerthe mainquestions.Thereisnoproofthattheyshouldbeusedto startthetreatmentandhowlongtheyshouldbeadministered whenopioidtreatmentisaddedontop.Paracetamolseemsto bedevoidofanybenefit,particularlyifgivenatusualclinical dosesoflessthan4g/day.Indeed,ketorolacseemstoprovide anadditiveanalgesiceffecteveninpatientsreceiving differ-entdosesofopioids.Themainsuggestionfromtheanalysis ofthesedataisthatNSAIDscouldbegiveninpatients receiv-ingopioidsandevaluatingtheirbenefitandweightonopioid therapyinindividualpatientswhohaveafavorableresponse tojustifyaprolongeduse.Noproofhasbeenprovidedabout the useof thisclass ofdrugs as first stepof the analgesic ladder.

Conﬂictofintereststatement

No financial andpersonalrelationships withother peo-ple or organizations that could inappropriately influence (bias) their work, including employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations,andgrantsorotherfunding.

Reviewers

GiampieroPorzio,M.D.,HospitalSanSalvatore,Medical OncologyDepartment,IT-67100,L’Aquila,Italy.

Alonso-Babarro,Ph.D.,M.D.,HospitalUniversitarioLa Paz,PalliativeCare,PaseoCastellana261,ES-28046Madrid, Spain.

References

[1]RipamontiC,BandieriE.Paintherapy.CriticalReviewsin Oncol-ogy/Hematology2009;70:145–59.

[2]UrbanD,ChernyN,CataneR.Themanagementofcancerpaininthe elderly.CriticalReviewsinOncology/Hematology2010;73:176–83. [3]McNicolE,StrasselsSA,GoudasL,etal.NSAIDsorparacetamol,

aloneorcombinedwithopioidsforcancerpain.CochraneDatabaseof SystematicReviews2005:CD005180.

[4]NabalM,LibradaS,RedondoMJ,PigniA,BrunelliC,CaraceniA. Theroleofparacetamolandnonsteroidalanti-inflammatorydrugsin additiontoWHOstepIIIopioidsinthecontrolofpaininadvanced cancer.mAsystematic reviewoftheliterature.PalliativeMedicine 2012;26:305–12.

[5]MercadanteS.Theuseofanti-inflammatory drugsincancerpain. CancerTreatmentReviews2001;27:51–61.

[6]Rodriguez RF, Castillo J, Castillo MP, et al. Hydrocodone/ acetaminophenandtramadolchlorhydratecombinationtabletsforthe managementofchroniccancerpain:adouble-blindcomparativetrial. ClinicalJournalofPain2008;24:1–4.

[7]RodriguezRF,CastilloJ,CastilloMP,etal.Codeine/acetaminophen and hydrocodone/acetaminophen combinationtablets for the man-agementofchroniccancer painin adults: a23 days,prospective, double-blind,randomized,parallel-groupstudy.ClinicalTherapeutics 2007;29:581–7.

[8]SimaL,FangWX,WuXM,LiF.Efficacyofoxycodone/paracetamol forpatientswithbonecancerpain:amulticenter,randomized, double-blind, placebo-controlled trial. Journal of Clinical Pharmacy and Therapeutics2011;37:27–31.

[9]XuJM,SongST,FengFY,etal.Cobrotoxin-containinganalgesic com-poundtotreatchronicmoderatetoseverecancerpain:resultsfroma randomized,double-blind,cross-overstudyand fromanopen-label study.OncologyReports2006;16:1077–84.

[10]ChouR,QaseemA,SnowV,etal.Clinicalefficacyassessment sub-committeeoftheAmericancollegeofphysicians;AmericanCollegeof Physicians;AmericanPainSocietyLowBackPainGuidelinesPanel. Diagnosisandtreatmentoflowbackpain:ajointclinicalpractice guide-linefromtheAmericanCollegeofPhysiciansandtheAmericanPain Society.AnnalsofInternalMedicine2007;147:478–91.

[11]DagenaisS,TriccoAC,HaldemanS.Synthesisofrecommendationsfor theassessmentandmanagementoflowbackpainfromrecentclinical practiceguidelines.SpineJournal2010;10:514–29.

[12]AxelssonB,BorupS.Isthereanadditiveanalgesiceffectof paraceta-molatstep3?Adouble-blindrandomizedcontrolledstudy.Palliative Medicine2003;17:724–5.

[13]StocklerM,VardyJ,Pillai A,WarrD.Acetaminophen (paraceta-mol)improvespainandwell-beinginpeoplewithadvancedcancer alreadyreceiving a strong opioidregimen: a randomized, double-blind,placebo-controlledcross-overtrail.JournalofClinicalOncology 2004;22:3389–94.

[14]FarrarJT,YoungJrJP,LaMoreauxL,WerthJL,PooleRM.Clinical importanceofchangesinchronicpainintensitymeasuredonan 11-pointnumericalpainratingscale.Pain2001;94:149–58.

[15]Tasmacouglu B, Aydinli I, Keskinbora K, Pekel A, Salihoglu T, SonsuzA.Effectofintravenousadministrationofparacetamolon mor-phineconsumptionincancerpaincontrol.SupportiveCareinCancer 2009;17:1475–81.

[16]IsraelF,CounsM,ParkerG,etal.Lackofbenefitfrom paraceta-mol(acetaminophen)forpalliativecancerpatientsrequiringhigh-dose strong opioids: a randomized, double-blind, placebo-controlled,

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crossovertrial.JournalofPainandSymptomManagement2010;39: 548–54.

[17]CuberoD,delGiglioA.Earlyswitchingfrommorphinetomethadoneis notimprovedbyacetaminophenintheanalgesiaofoncologicpatients:a prospective,randomized,double-blind,placebo-controlledstudy. Sup-portiveCareinCancer2010;18:235–42.

[18]Duarte-SouzaJ,LajoloP,PinczowskiH,delGiglioA.Adjunctdipyrone inassociationwithoralmorphineforcancer-relatedpain:thesooner thebetter.SupportiveCareinCancer2007;15:1319–23.

[19]MercadanteS,FulfaroF,CasuccioA.Arandomizedcontrolledstudy ontheuseofanti-inflammatorydrugsinpatientswithcancerpainon morphinetherapy:effectsondose-escalationandapharmacoeconomic analysis.EuropeanJournalofCancer2002;38:1358–63.

[20]RodriguezM,ContrerasD,GalvezR,etal.Double-blindevaluation ofshorttermanalgesicefficacyoforallyadministered dexketopro-fentrometamoland ketorolacinbone cancerpain.Pain2003;104: 103–10.

[21]MoselliNM,CrutoM,NassuccoP,Savojardo,DebernardiF. Long-termcontinuoussubcutaneousinfusionofketoprofencombinedwith morphine:asafeandeffectiveapproachtocancerpain.ClinicalJournal ofPain2010;26:267–74.

[22]SerlinRC,MendozaTR,NakamuraY,EdwardsKR,CleelandCS. Wheniscancerpainmild,moderateorsevere?Gradingpainseverity byitsinterferencewithfunction.Pain1995;61:277–84.

Biographies

SebastianoMercadantewasbornon3rdDecember1955. He achievedhis Doctor’s degree withfullmarksin 1979. He specialized in anesthesiology (1980–1983), University of Palermo;andinscienceof nutrition (1984–1987), Uni-versityof Palermo.He isProfessorofPalliativeMedicine, PostgraduateMaster,UniversityofPalermo,andDirectorof theAnesthesiaandIntensiveCareUnit,PainReliefand Pal-liativeCareUnit,LaMaddalenaClinicforCancer,Palermo, Italy.Hehasgivenmorethan400hundredlecturesatnational

and internationalcongresses, and isAssociated Editor, on theeditorialBoardand/orrefereeofmorethan30 interna-tionalpeer-reviewedjournalsinthefieldofpainandsymptom

management andanaesthesiology. He has published more

than350papersinpeer-reviewedinternationaljournalsand isauthorofmorethan40chaptersandbooks.

HewontheUmbertoVeronesiawardin2003,theaward of excellenceinscientificresearch,AmericanAcademyof Hospiceandpalliativemedicine,Boston2010,theawardof theESMOdesignedcenterofintegratedoncologyand pallia-tivecare,Stockolm2011,JohnMendelsohnaward,Houston 2013.

AntoninoGiarratano,wasbornin1961.Heachievedhis Doctor’sdegreein1986andspecializedinAnesthesiologyin 1989atUniversityofPalermo.HewasAssistantProfessorof AnesthesiolgyandIntensivecare(2000–2005).Since2005 Associate Professor of Anesthesiology andchiefof Inten-sivecareatuniversitaryhospitalofPalermo.HeisChairman ofRegionalchapterofnationalsocietyofAnesthesiologists since2003,andsince2005Memberof the ItalianSociety of Anesthesiology and Critical Care Medicine and

Euro-pean Society (ESICM). Since 2004 he is Delegate Chief

fromPoliclinicoHealthManagementfor “TheQuality”of theDepartmentofAnesthesiology-University ofPalermo andAssociate Researcher atthe BiologicalandMolecular Departmentof National Council ResearchinPalermo. He has been the regional delegate for The Italian Society of AnesthesiaandIntensiveCareMedicine(2006–2009).Since 2011istheDirectorofSchoolofanesthesiologyand inten-sive caremedicineofUniversity ofPalermo.He published dozenofpapersinthefiledof intensivecare,immunology, andcoagularivedisordres.