White Paper

PHARMACEUTICAL

Analgesic Agents and Strategies in

Pain Research

CROMSOURCE is an international provider of outsourced services to the

pharmaceutical, biotechnology and medical device industries, specialized

in clinical development and staffing solutions.

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Table of Contents

1. Introduction.................................................................................3

2. ChallengesofClinicalTrialDesign................................................................3

3. DentalImpactionPainModel(DIPM).............................................................4

4. ToolsforAssessingPainIntensity.................................................................5

5. ToolsforPainReliefAssessment.................................................................6

6. DurationofAnalgesicEffect(Timetofirstrescuemedication)..........................................6

7. TheCentroRicercheClinichediVerona............................................................7

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

9. References..................................................................................8

10. AboutTheAuthors............................................................................9

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1. Introduction Painisamajorprimaryhealthcareproblemwithanenormousimpactonpublichealth.Painisthemostcommonsymptomforwhichpatientsseekmedicalattention(1,2)andisamajorcauseofsickleave(3). It is estimatedthata thirdof thepopulation liveswithchronicpain,definedaspain lasting longer thansixmonths,includingabout100millionAmericans(4).

Althoughthere isnoexactdefinitionofpain itcanbedefinedasanunpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissuedamage,ordescribed in termsof suchdamage(5). Despiteintenseresearchtherehasbeenalackofrealbreakthroughsinnovelanalgesicdrugdevelopmentover the past fifty years. Current drug treatments for pain either work poorly or are associated withdose-limiting adverse effects which severely curtail their use, including gastrointestinal bleeding withnonsteroidalanti-inflammatories(NSAIDs)(6);drugdependency,toleranceandrespiratorydepressionwithopioids(7);andurinaryretention,blurredvision,drymouthwithtricyclicantidepressants(8).

Thecombinationofhighprevalenceandalackofsatisfactorytreatmentsmeansthatthereissignificantunmetmedicalneedfornewmedicinesforthetreatmentofpain.Thisisreflectedbythefactthat,atthetimeofwriting,therearemorethan3432on-goingtrialsandamongthem416are industry-sponsoredinterventional clinical trials related to the pharmacological treatment of pain(9). Regulatory authoritiesin Europe and North America have responded by recently issuing updated draft guidance on clinicaldevelopmentofproductsforthetreatmentofpain(10,11).

2. Challenges of Clinical Trial Design Designing clinical trials for the testing newmedicines for thetreatmentofpainisaverychallengingarea.Painisasubjectivephenomenonandtypicallyacutepaininthepostoperativeperioddecreasesoverdays,whilethechronicpainofosteoarthritiscanwaxandwaneoverweeks.Tofurthercomplicatemattersahighandvariableplaceboresponserateiscommon.

IntheUnitedStatestheFDAtypicallyexpectssponsorstoconducttwoseparateplacebo-controlledtrials,whileinEuropetheEMAwill not accept two-arm placebo-controlled trials if a provenintervention is available. In addition, in dose-response studiesatleastthreefixeddosesofactivetreatmentplusaplaceboarmarenormallyrequired.ThesechallengescanbeaddressedbytheDentalImpactionPainModel.

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3. Dental Impaction Pain Model (DIPM) Painfollowingremovalofimpactedthirdmolartoothisausefulclinicalmodelforevaluatingpharmacologicaltreatmentsforpain,particularlythosetargetedatacutepain.ThemodernversionoftheDentalImpactionPainModel (DIPM)wasdeveloped in themid-1970s(12) and today it is arguably themostutilisedof allthe acute painmodels. It is particularly useful for proof-of-concept studies that require dose-rangingandprofilingofthetime-effectcurveforefficacyincludingonset,peakeffect,anddurationofanalgesicactivity(13). In addition the DIPM can test analgesics across a range of modes of action, differentiatebetweennumerous treatmentsarms (ofcomparatordrugsordose levels),demonstrateshigh levelsofreproducibility,andgiveresultsthatcanbegeneralisedtootherpainstates.ForthisreasontheDIPMhasbeenincludedintheregulatorysubmissionofmanyanalgesicproductswhichhavebeenapprovedbytheFDA,EMAandotherauthoritiesinternationally.

SensitivityoftheDIPMManystudieshavedefinedtheexceptionalsensitivity,reproducibility,andversatilityoftheDIPM.TheassaysensitivityofDIPMissuchthatclear-cutseparationofactivedrugsfromplacebohasbeendemonstratedwithasamplesizeofjusttenpergroup(14).

Suchexquisite sensitivity isdue to thehomogeneityof thestudypopulation, thepredictable levelandappropriateintensityofthepostsurgicalpain,andtheminimisationofvariabilitybyusingasinglestudycentre(13).

VersatilityoftheDIPMTheDIPMissignificantlymoreversatilethanotherpainmodels.Themodelcanbeeasilyadaptedtoperformmultiple-dose studiesand tocorrelatepharmacodynamics topharmacokinetics (PK/PDmodelling). Themodelcanalsobeusedtoinvestigatepre-emptiveinterventionswheretheinvestigationaldrugisgivenpre-operatively.Inaddition,thepossibilityofasinglesitebeingabletoenrolallrequiredsubjectsinanacceptabletimeframeensuresvariabilitybetweencentresiseliminated.

TheDIPMhasbeenusedtoevaluateNSAIDs(bothselectiveandnonselectiveCOXinhibitors),opioidsandcombinationanalgesics,aswellasinvestigationaldrugswithuniquemechanismsofaction.AstheunderlyingpathophysiologyofpainbecomeselucidatedtheDIPMwillcontinuetoserveasatoolformonitoringtherelativecontributionsofdifferentpainevents,includingperipheralandcentralsensitization(12).

LogisticalFactorsLogisticalanddemographic factorsalso favourtheuseof theDIPMinpainstudies.Forexample,studysubjects are usually young and otherwise healthy, without pre-existing pain or complicating medicalillnesses.Inadditionthenumberofavailablesubjectsislarge.

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Potentialsubjectsaretypicallypresentonanelectivewaitinglistandscheduling canbe somewhatflexible toallowtime forwell-plannedscreening and pre-operative procedures. The surgical procedureis short, well standardised and typically completed without use ofsedationandusingonly local anaesthesia. Thisensures subjects arealert and ambulatory immediately after surgery, without memoryimpairmentordrug-inducednausea.Thesefactors,coupledwiththeoverallintensityandtemporaldistributionofpain(onsettwotofourhourspost-operatively,remainingrelativelyconstantfortwelvehoursbeforediminishinggraduallyoverthenextonetotwodays)haveleddirectlytothepopularityandwidespreadacceptanceoftheDIPM.

Figure 1 - Visual Analogue Scale

No Pain Worst Pain Imaginable

VerbalRatingScale(VRS)Participantsusea4-pointcategoricalverbalratingscalefor the subjective assessment of post-operative pain.TheVRSiscollectedasanindependentmeasureofthepatient’spain,separatetothatrecordedontheVAS.

ParticipantsareprovidedwithaworksheetandareaskedtoselectthewordthatbestdescribestheirlevelofpainbycheckingtheappropriateboxfromNone(0)toMild(1),Moderate(2),orSevere(3).Thenumberassociatedwiththeadjectivechosenbytheparticipantconstitutesthepainintensity.

4. Tools for Assessing Pain Intensity Pain intensity is the fundamental measure that defines the efficacy of an analgesic drug. As patient-reportedoutcomes,painintensitycanbemeasuredbynumericalratingscales,visualanaloguescales,orcategorical scales.

VisualAnalogueScale(VAS)The VAS is a continuous variable and uses a 10 cm line to register a score from “no pain” to “Worstpain imaginable” (Figure1). Patients areasked to indicatebydrawinga single vertical lineonapaperthe point along the line that best represents their pain intensity at the time of the assessment. Thedistanceofthelinealongthescaleconstitutesthepainintensity.

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5. Tools for Pain Relief Assessment

VerbalRatingScale(VRS)Participantsusea5-pointcategoricalverbalratingscaleforthesubjectiveassessmentofpost-operativepainrelief.ParticipantsareprovidedwithaworksheetandareaskedtochecktheappropriateboxthatbestdescribestheirlevelofpainrelieffromNone(0),Slight(1),Moderate(2),Lots(3),orComplete(4).Thenumberassociatedwiththeadjectivechosenbythepatientconstitutesthepainrelief.

GlobalEvaluationGlobalassessmentsaimtoelucidatethesubject’sintegrated,overallexperiencewiththeanalgesic,ratherthananadditionalassessmentofefficacyorsafety.Theyaresometimesusedasexploratoryendpointstousewheninterpretingchangeusingothermeasures.Ateitherthecompletionoftheevaluationperiodoratthetimethesubjecttakesarescueanalgesic,whichevercomesfirst,participantsareprovidedwithaworksheetandareaskedtochecktheappropriateboxthatbestdescribeshowtheywouldratethestudymedicationtheyreceivedfromPoor(0)toFair(1),Good(2),VeryGood(3),orExcellent(4).Thenumberassociatedwiththeadjectivechosenbythepatientconstitutestheglobalevaluation.

6. Duration of Analgesic Effect (Time to first rescue medication) Forthismeasure,VASandVRSscoresarecompletedimmediatelypriortodosingwithrescuemedicationandthetimeatwhichrescuemedicationisadministeredisrecorded.

Double-stopwatchMethodTheonsetofactionofthetestmedicationisdeterminedbynotingthetimeofanypainreliefandthentimetomeaningfulpainrelief.

This is achieved using the double-stopwatchmethod as follows:when the local anaesthesia followingsurgeryhasdissipated,andthepatient’spainisofmoderateorsevereintensity,theappropriateratingisrecordedonthepatientself-evaluationquestionnaireasthebaselinepainintensityassessment.Atthattime,thepatientisgiventwostopwatchesandtoldtostopthefirstonewhentheystarttofeelanypainrelievingeffect,andtostopthesecondwatchwhenmeaningfulpainreliefisachieved.Measuresofpainintensityandpainreliefarerecordedateachtimepoint.

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7. The Centro Ricerche Cliniche di Verona The Centro Ricerche Cliniche di Verona (CRC), operated byCROMSOURCE,conductsacutedentalpainclinicaltrialsusingtheDIPM.

The versatility and sensitivity of the DIPM, coupled with themodern facilities at CRC, allows rapid assessment of potentialnewanalgesicdrugsinarangeofproof-of-conceptandefficacystudies. Our reputation for successful compound separationwith theDIPM iswell established and acknowledged bymajorpharmaceuticalcompanies.

TheCRCiscustomdesignedtoconducthigh-volumetrialsandcomplexprotocolswithequipmentattheclinicincludinganECG,-70°Cfreezerandrefrigeratedcentrifuges,secureinvestigationaldrugstorageandcustomermonitoring rooms. In addition, provenoperational andquality control systemsmaintain dataintegrityandqualityassurance.

TheCRCandtheDIPMTheseacutedentalpainstudiesareperformedinpatientspreviouslyscheduledforextractionofatleastonefullyorpartiallyimpacted,thirdmandibularmolartooth.SurgeryisperformedattheCRCunderlocalanaesthesiabyboard-certifiedmaxillofacialoralsurgeonsfromVeronaUniversity.Thesurgerywaitinglistisusedtomatchotherwisehealthyvolunteerstoastudyprotocol.PatientsenrolledintoastudyarerequiredtovisittheCRConatleastthreeseparateoccasions:screening,surgeryandstudytreatmentdayandforafollow-upvisit.InthismannerCRCcanrecruitmorethan20patientspermonthandmorethan420intotal,eitherasoutpatientsorasinpatients.

The CRC has proven expertise in simple(15) and complex studydesigns using the DIPM, including randomised, double-blind,double dummy, parallel group, placebo- and active-controlled,single-ormultiple-dosedesignclinicalstudies.

Asanexample,anacutepainstudymaycomparetheanalgesicefficacyof twodrugsgivenasfixedcombinations togetherwiththeanalgesicefficacyofeachsinglecomponentincomparison(16). Thiscanbeachievedinasinglestudyusingtentreatmentarms:four different fixed combinations of the two test drugs, fourcorresponding single treatments, placebo, and ibuprofen as anactivecontrol.TheexperienceofCRCincomplexdesignssuchasthisensuressuccessfulcompletionofsuchprojects.

Dosingmaybealsoperformedbeforeoraftersurgery.Withpost-operativedosing,patientswhocomplainofmoderatetoseverepain on the VRSwithin three hours of surgery are randomisedtotreatment.Alternatively,patientscanbedosedpreoperatively,

generallywithinonehourof surgery. In this scenario,patientsallocated toactivecomparator receiveaseconddoseofibuprofen(400mg),4hoursafterthefirst800mgdose,whilepatientsinthetestdrugandplacebogroupsreceiveplaceboatthistime.Painintensityandpainreliefassessments,safetyassessmentsandpharmacokineticsamplingcanallbeundertakenpre-doseandupto24hourspost-surgery.Again,CRChasexperienceofbothmodelsofdosing.

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8. ConclusionsPainisamajorprimaryhealthcareproblemandthereismajorunmetmedicalneedfornewmedicinesfor the treatment of pain. Designing clinical trials for the testing new medicines for the treatmentof pain is a very challenging area. The Dental Impaction Pain Model (DIPM) is widely utilised andis particularly useful for proof-of-concept, dose-ranging and efficacy studies for analgesic drugs.The Centro Ricerche Cliniche di Verona (CRC), with CROMSOURCE support, is very experienced atconductingtrialsusingtheDIPManduseofthecentreallowsrapidassessmentofpotentialnewdrugs.

9. References1. HasselstromJ,Liu-PalmgrenJ,Rasjo-WraakG(2002)Prevalenceofpainingeneralpractice.EurJPain.6:375-

385

2. BertakisKD,AzariR,CallahanEJ(2003)Patientpain:itsinfluenceonprimarycarephysician-patientinteraction.FamMed.35:119-123

3. MantyselkaP,KumpusaloE,AhonenR,KumpusaloA,KauhanenJ,ViinamakiH,HalonenP,TakalaJ(2001)Painasareasontovisitthedoctor:astudyinFinnishprimaryhealthcare.Pain.89:175-180.

4. JohannesCB,LeTK,ZhouX,JohnstonJA,DworkinRH(2010)TheprevalenceofchronicpaininUnitedStatesadults:resultsofanInternet-basedsurvey.JPain.11:1230-1239.

5. Task Forceon Taxonomyof the InternationalAssociation for the Studyof PainClassificationof chronic pain:descriptionof chronic pain syndromes anddefinitionof pain terms, task forceon taxonomy, 2nd Edition.H.Merskey, N. Bogduk (ed). http://www.iasp-pain.org/files/Content/ContentFolders/Publications2/FreeBooks/Classification-of-Chronic-Pain.pdf

6. HenryD,McGettiganP(2003)EpidemiologyoverviewofgastrointestinalandrenaltoxicityofNSAIDs.IntJClinPractSuppl.43-49.

7. SavageS,CovingtonEC,GilsonAM,GourlayD,HeitHA,HuntJB(2004)PublicPolicyStatementontheRightsandResponsibilitiesofHealthcareProfessionals intheUseofOpioidsfortheTreatmentofPain.AconsensusdocumentfromtheAmericanAcademyofPainMedicine,theAmericanPainSociety,andtheAmericanSocietyofAddictionMedicine.https://www.naabt.org/documents/APS_consensus_document.pdf

8. McCleaneG(2003)Pharmacologicalmanagementofneuropathicpain.CNSDrugs.17:1031-1043

9. https://clinicaltrials.gov/Accessed:20October2017.

10. USFDACenterforDrugEvaluationandResearch(CDER)(February2014)GuidanceforIndustryAnalgesicIndications:DevelopingDrugandBiologicalProducts(DraftGuidance).http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdfAccessed26May2015

11. EMAGuidelineon the clinical developmentofmedicinalproducts intended for the treatmentofpain, EMA/CHMP/970057/2011. Adopted 15 December 2016, date of coming into effect 1 July 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/12/WC500219131.pdf

12. UrquhartE(1994)Analgesicagentsandstrategiesinthedentalpainmodel.JDent.22:336-341.

13. CooperSA,DesjardinsPJ(2010)Thevalueofthedentalimpactionpainmodelindrugdevelopment.MethodsMolBiol.617:175-190.

14. CooperSA,ReynoldsD,KrugerGO,GottliebS(1980)Ananalgesicrelativepotencyassaycomparingzomepiracsodiumandaspirin.JClinPharmacol.20:98–106.

15. OstenfeldT,etal.(2011)Arandomized,controlledstudytoinvestigatetheanalgesicefficacyofsingledosesofthecannabinoidreceptor-2agonistGW842166,ibuprofenorplaceboinpatientswithacutepainfollowingthirdmolartoothextraction.ClinJPain.27:668-676.

16. MooreRA,etal.(2015)Dexketoprofen/tramadol:randomiseddouble-blindtrialandconfirmationofempiricaltheoryofcombinationanalgesicsinacutepain.JHeadachePain.16:541.

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10. About The AuthorsStefano Milleri has over 25 years’ experience of senior level roles in clinicaldevelopment,experimentalmedicineandclinicalpharmacologyunitmanagement.Before joiningCentroRicercheClinichedi Verona (theCROMSOURCEEarly Phasefacility)in2006asScientificandMedicalDirector,StefanowasformanyyearstheDirectoroftheClinicalPharmacology&DiscoveryMedicine(CPDM)UnitforGSKinVerona.

Stefano received hisMD and specializations in Lung Disease and Geriatrics fromUniversita’CattolicadelSacroCuore inRome,andhisPhD inNeuroscience fromPaduaUniversityandisafellowoftheItalianSocietyofPharmacology.Heisalsoavisitingprofessor,teachingcoursesattheuniversitiesofVerona,Florence,MilanandPisaandisco-authorofmorethan20fullpaperspublishedinpeerreviewedjournalsand40conferenceabstracts/proceedings.

Crispin Bennett isamedicalwriterforCROMSOURCE,basedintheStirling(UK)office.With a PhD in biochemistry, Crispin has over twenty years of industry experienceworkingonnewdrugsinnoveltherapeuticareas,takingprojectsfromstudydesignandprotocolwritingthroughtothefinalstudyreports.

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