Mechanism, assessment and management of pain in chronic pancreatitis

12 Pages·2016·0.48 MB·English

by  Michelle A. Anderson

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Pancreatology
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Original article
Mechanism, assessment and management of pain in chronic
pancreatitis: Recommendations of a multidisciplinary study group
Michelle A. Anderson a, Venkata Akshintala b, Kathryn M. Albers c, Stephen T. Amann d,
InnaBelfer e, Randall Brand b,Suresh Chari f, Greg Cote g, Brian M. Davis c, Luca Frulloni h,
Andres Gelrud i, Nalini Gudaj, Abhinav Humark, Rodger A. Liddle l, Adam Slivka b,
Rachelle Stopczynski Gupta b, Eva Szigethy m, Jyothsna Talluri b, Wahid Wassef n,
C. Mel Wilcoxo, John Windsor p, Dhiraj Yadav b, David C. Whitcomb b,q,r,*
aDepartmentofMedicine,UniversityofMichigan,AnnArbor,MI,USA
bDepartmentofMedicine,UniversityofPittsburgh,Pittsburgh,PA,USA
cDepartmentofNeurobiology,UniversityofPittsburgh,Pittsburgh,PA,USA
dNorthMississippiMedicalCenter,Tupelo,MS,USA
eDepartmentofAnesthesiology,UniversityofPittsburgh,Pittsburgh,PA,USA
fDepartmentofMedicine,MayoClinic,Rochester,MN,USA
gDepartmentofMedicine,MedicalUniversityofSouthCarolina,Charleston,SC,USA
hDepartmentofMedicine,UniversityofVerona,Verona,Italy
iDepartmentofMedicine,UniversityofChicago,Chicago,IL,USA
jDepartmentofGastroenterology,AuroraSt.Luke'sMedicalCenter,Milwaukee,WI,USA
kDepartmentofSurgery,UniversityofPittsburgh,Pittsburgh,PA,USA
lDepartmentofMedicine,DukeUniversity,Durham,NC,USA
mDepartmentofPsychiatry,UniversityofPittsburgh,Pittsburgh,PA,USA
nDepartmentofMedicine,UniversityofMassachusetts,Worcester,MA,USA
oDepartmentofMedicine,UniversityofAlabamaatBirmingham,Birmingham,AL,USA
pDepartmentofSurgery,UniversityofAuckland,Auckland,NewZealand
qDepartmentofCellBiology&MolecularPhysiology,UniversityofPittsburgh,Pittsburgh,PA,USA
rDepartmentofHumanGenetics,UniversityofPittsburgh,Pittsburgh,PA,USA
a r t i c l e i n f o a b s t r a c t
Articlehistory: Description: Paininpatientswithchronicpancreatitis(CP)remainstheprimaryclinicalcomplaintand
Availableonline11November2015 sourceofpoorqualityoflife.However,clearguidanceonevaluationandtreatmentislacking.
Methods: Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain
Keywords: assessmentandpaintreatmentinCP.LevelsofevidencewereassignedusingtheOxfordsystem,and
Chronicpancreatitis consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with sub-
Therapeuticendoscopy stantialpost-meetingdiscussion,debate,andmanuscriptrefinement.
Pancreaticsurgery
Results: Twelve discussion questions and proposed guidance statements were presented. Conference
Chronicpain
participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to
Qualityoflife
Inflammation effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain
shouldbeassessedateachclinicalvisit,butevidencetosupportanoptimalapproachtoassessingpain
character,frequencyandseverityislacking.Management:Therewasgeneralagreementontherolesfor
endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psy-
chological,endoscopic,surgicalandothertherapies.
Conclusions: Progressisoccurringinpainbiologyandtreatmentoptions,butpaininpatientswithCP
remainsamajorproblemthatisinadequatelyunderstood,measuredandmanaged.Thegrowingbodyof
informationneedstobetranslatedintomoreeffectiveclinicalcare.
Copyright©2015,IAPandEPC.PublishedbyElsevierIndia,adivisionofReedElsevierIndiaPvt.Ltd.This
isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/
4.0/).
* Correspondingauthor.GIAdministration,UniversityofPittsburgh/UPMC,Room401.4,3708FifthAve,Pittsburgh,PA15213,USA.Tel.:þ14125789515;fax:þ1412578
9537.
E-mailaddress:[email protected](D.C.Whitcomb).
http://dx.doi.org/10.1016/j.pan.2015.10.015
1424-3903/Copyright©2015,IAPandEPC.PublishedbyElsevierIndia,adivisionofReedElsevierIndiaPvt.Ltd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
84 M.A.Andersonetal./Pancreatology16(2016)83e94
Introduction Evidenceanddiscussion
Chronicpancreatitis(CP)isachronicinflammatorydisorderof The working group included physicians and scientists who
the pancreas that is complicated by severe, constant and regularly attend PancreasFest, expressed a primary interest in
disablingpaininnearlyhalfofallpatients[1]andleadstosome pancreatic pain, and met as a group during break-out sessions.
of the worst quality of life (QOL) scores for any chronic disease Primary areas of interest and need were identified by discussion
[1e3]. Chronic pancreatitis was considered a disease of alco- andpresentationsinyearone.Theadhocgroupwasencouragedto
holismuntilthediscoverythatsmoking,complexgenotypes,and invitetheparticipationofotherexperts,andtoorganizeandpri-
otherfactorsaccountedfortheunderlyingetiologyinoverhalfof oritize the state-of-the-art and state-of-the-science, and present
all cases of this disease [4e6]. Studies of patients with CP and theirprioritiestothelargergroupatthesubsequentPancreasFest
painindicatethattherearemultiplepainpatterns,characteristics meeting.Dr.AndersonorganizedthePancreasFestworkinggroups,
and severity levels, and that morphology on abdominal imaging andtheprocessofdevelopingdiscussionquestionswasinitiated,
maynotcorrelatewithpainfeatures[7].Thestrongestpredictor withrefinementandfocusduringthethirdyear.
ofpoorqualityoflifeanddisabilityamongcomplicationsofCPis The final discussion questions presented to attendees of Pan-
constant pain [1]. Recent studies have addressed the quality of creasFest2012werefollowedbyoneormoreguidancestatements
life [2,8], and comparative effectiveness of treatment for neuro- intendedtoprovideaconcisesummaryand,ifindicated,aclinical
pathicpain[9,10]andoutcomesofbothendoscopicandsurgical recommendation or guidance. The initial recommendations were
treatments [11,12]. Finally, there is growing use of total pancre- presented to the audience and projected onto a screen on a
atectomy with islet autotransplantation (TPIAT) for control of statement-by-statement basis. The audience, which was approxi-
pain [13e15]. mately90%MDorMD-PhD,4%PhDand6%others,suchasstudy
Severalrecentguidelinesforthegeneralmanagementofpainin nurses(Appendix),respondedtothedraftguidancestatementsfor
CPhavebeenpublished[15e18].Inaddition,specificguidelinesfor specificclinicalquestionsandthenindicatedtheirlevelofagree-
theendoscopictreatmentofpainwerepublishedbyconsensusofa mentbasedona5-pointscale(strongpositive,weakpositive,un-
working group supported by the European Society of Gastroin- certainorequivocal,weaknegative,strongnegative)usingdigital
testinal Endoscopy (ESGE) [19]. These documents carefully votingdevices.Conferenceattendeesdiscussedtheinitialquestions
addressedseveralclinicalquestionsfromexistingliteratureandby andguidancestatementsoftheworkinggroup.Theresponseswere
discussion.Theevolvingliteratureonpancreatitis-associatedpain, tabulated and projected for the entire conference to discuss and
advances in the neuroscience of pain [3], various methods for reviseinreal-time.Theconferenceparticipantsthenvotedagainon
assessing pain and new treatment options, including total thelevelofagreementwitheachstatementthat,afterdiscussion,
pancreatectomywithTPIATjustifyacomprehensivereview,iden- required more information or clarification. The participants sent
tification of knowledge gaps and recommendations for future additional comments to the study members by email to be
research. consideredinthefinaldiscussion.
The working groups revised and extended the evidence and
discussionsectionsforeachquestionoveratwo-yearperiodwith
Guidelinefocus
updatedreferences.Thefocuswastoimproveaccuracyandspeci-
ficityineachstatement,improveclarity,andre-reviewcontrover-
The clinical recommendations guide the evaluation and man-
sialareas.Inaddition,commongroundandagreementofexperts
agementofpaininadultpatientswithrecurrentacutepancreatitis
from different disciplines with different approaches was sought
(AP)andchronicpancreatitis.Inadequatedataonpediatricgroups
throughoutthemanuscriptwriting,reviewandrewritingprocess.
precluded inclusion of this important population in the current
All working group members reviewed each major version of the
review.
document,andallparticipantswhoparticipatedinthediscussion
TheproblemofpaininCPiswellrecognized,andrepresentsa
andreviewedandapprovedthefinaldocumentareincludedasco-
major area of emphasis by the clinicaletranslational working
authors.
groups meeting at PancreasFest. In addition to regular working
groupmeetings,acomprehensive,multidisciplinaryreviewofthe
Results
problemofpaininCPwasundertakenoverathree-yearperiodat
theannualPancreasFestmeeting,aspreviouslydescribed[15,20].
Part1.Mechanismsofpaininchronicpancreatitis
The PancreasFest working groups wereorganized byacademic
physicians and scientists associated with the North American
Three broad discussion questions were developed. Question 2
Pancreatitis StudyGroup(seeNAPS2[4]) andthe Center forPain
wassubdividedtoaddressspecificissues.
Research,UniversityofPittsburgh(www.paincenter.pitt.edu)who
Discussion Question 1: What causes pain in chronic
had an interest in pancreatic pain. The Pain Working Group was
pancreatitis?
furtherdevelopedbyinvitingcontentexpertstoparticipateinthe
GuidanceStatement1:PaininCPmayarisefrommechanical
process.AdHocsub-groupswereorganizedtodevelopandframe
(intraductalpressure/obstruction),inflammatory,malabsorptiveor
discussion questions and guiding statements in three areas: 1)
neurogenic/neuropathic changes in the pancreas and/or sur-
mechanismsof painin CP; 2) the assessmentof pain;and 3) the
roundingorgans.
treatmentofpain,includingTPIAT.
EvidenceLevel:2b
Evidencereviewandgrading Gradeofrecommendation:B
LevelofAgreement:A89%;B9%;C0%;D0%;E2%.
LevelsofevidencewererankedbasedontheOxfordCenterfor
Evidence-Based Medicine's system [21]. Consensus was assessed Evidence and Discussion: Pancreatic duct obstruction, stric-
usingtheGradingofRecommendationsAssessment,Development tures, and/or peri-pancreatic fibrosis may cause ductal hyperten-
andEvaluation(GRADE)gridfortheclinicalguidelinestatements sion or ischemia from a stricture or a compartment syndrome
[22]. leadingtopain[23e26].However,whenmeasured,pancreaticduct
M.A.Andersonetal./Pancreatology16(2016)83e94 85
pressuresdonotcorrelatewellwithpancreatitispainseverityand Evidence and Discussion: Pancreatic nerve hypertrophy and
arenotpredictiveofpainreliefinpatientsundergoingsurgicalor intra/perineural inflammation have been described in human CP
endoscopic stone removal or stenting [27]. The most convincing andcorrelatewithpancreaticpainseverity[39].Theincreasedsize
data that pancreatic duct abnormalities cause pain are studies andexcitabilityofpancreaticnervesappearstobeduetothehighly
demonstrating pain relief in patients undergoing decompressive neurotrophic environment produced by the inflamed pancreas.
surgery (e.g. pancreaticojejunostomy) or endoscopic sphincter- There is elevation in growth factors and cytokines that promote
otomy,pancreaticstoneextraction,and/orpancreaticductstenting growth and/or sensitization of sympathetic and parasympathetic
[28,29].Amongstudypatients,34%hadsustainedpainrelief5years efferents and sensory fibers [3,30,39]. This environment also in-
after surgery, whereas only 15% of patients were pain-free creases neuronal expression of genes that cause sensitization
following endotherapy [29]. Neither technique, using the re- includingTRPV1,TRPA1,TRPV4andPAR2[34,42e44].
portedpatientselectioncriteria,providesoptimallong-termpain InexperimentalmodelstheapplicationofantagonistsforTRPV1
relief. Sham-controlled studies of endoscopic or surgical decom- andTRPA1,channelsrequiredforinflammatoryhyperalgesia,block
pressivetherapiesarelacking. pain and prevent recurrent acute pancreatitis (RAP) from devel-
Alterations in nociception have been associated with both oping the hallmarks of CP, including fibrosis and sustained
experimental and human CP [3]. Sensory nerve excitability is inflammation[45].
increasedinanimalswithCPandisaccompaniedbyupregulation Pain associated with CP may result from negative synergistic
ofcalcitoningene-relatedpeptide(CGRP),substancePandbrain- interactions between the pancreatic parenchyma, immune cells
derived neurotrophic factor (BDNF) [30e32], which also signal and the PNS. Activated sympathetic fibers can release molecules
pain. Pharmacological blockade of these transmitters improves (e.g. ATP) that sensitize sensory fibers, as well as molecules (e.g.
pain. Additionally, release of neuropeptides such as CGRP and epinephrine) that can activate immune cells. Release of NGF by
substance P, produce classic features of inflammation, including immune and acinar cells sensitizes sensory fibers and induces
edema, necrosis and neutrophil infiltration [33]. Nerve growth sprouting [37]. Sensitized primary afferents release CGRP and
factor(NGF),whichplaysakeyroleinregulatingneuronalactiva- glutamate,contributingto“neurogenic”inflammation.
tion and receptor expression (e.g., transient receptor potential DiscussionQuestion2.B:Aretherespecificpathologicfeatures
cation channel subfamily V member 1 [TRPV1]), is ectopically in the pancreas or the central nervous system of patients with
expressed in acinar and ductal tissues in CP [30,34]. Anti-NGF chronicpancreatitisthatareassociatedwithpain?
therapysuppressessubstancePandCGRPexpressionandreduces Guidance Statement: Some patients with CP and pain have
pancreaticpain[32]. changesinthecentralnervoussystem.Thesechangesmayindicate
Inflammationisamajorsourceofpancreaticpain.Immunecells alterationsincentralpainprocessing.
infiltratingthepancreaswithreleaseofcytokinesandchemokines,
such as IL-8 and fractalkine, have also been linked to pancreatic EvidenceLevel:3b
pain [35,36]. Pain in CP has been associated with increased Gradeofrecommendation:C
numbers of mast cells in the pancreas [37]. Mast cells produce LevelofAgreement:A57%;B29%;C5%;D0%;E9%
tryptase, whichcan activateprotease-activatedreceptor2 (PAR2)
onsensoryfibersofthepancreas[37]andincreasepainsignaling. Evidence and Discussion: Some patients with CP have evi-
PAR2 expression is elevated in human CP specimens [38]. Tissue denceofalterationsincentralpainprocessing.Patientsmayhave
resected from patients with severe pancreatitis pain may exhibit hypersensitivity in unaffected organs and an increased incidence
leukocytes infiltration of nerves, nerve hypertrophy and areas of in referred pain. For example, CP patients are more sensitive to
neuritis suggesting both inflammatory and neuropathic changes painful abdominal and rectal stimuli [36]. This increased sensi-
underliepainassociatedwithCP[35,39]. tivity may reflect changes in central neuronal pathways of the
Abdominal pain related to pancreatic disease may originate spinalcordandbrain[46,47].BrainMRIstudiesshowalterationin
fromoutsidethepancreas.Forexample,ina6-monthopenlabel brain thickness and microstructure in cingulate and prefrontal
study, patients with proven pancreatic insufficiency taking pan- cortices correlating to CP patients' clinical pain scores [48,49],
crelipase at an average dose of 187K ± 75K lipase units/day, had reminiscent of changes seen in patients that suffer from other
decreased pain severity, with the percent reporting no pain chronic painstates (e.g.lowerbackpain)[50].PainfromCP may
increasingfrom37.3%to66.0%[40].Amongallpatients,44%hadan also lead to changes in cortical projections of the nociceptive
improvementinpainscorewhile10.6%reportedworsepain[40].A system[51].
reduction in flatulence was also reported, raising the possibility Inanimalmodels,changesintheCNShavebeenreportedatthe
that the pain was linked with maldigestion. An older study sug- spinalcordlevelwherenon-neuronalcells,includingmicrogliaand
gestedthatPERTreducespancreaticpaindirectlyinthecontextof astrocytes, are activated [46,47]. These cells playa pivotalrole in
minimal change diseases, but replication studies are needed to central sensitization in a number of models of persistent neuro-
confirmorrefutethesedata[41]. pathicpain.
DiscussionQuestion2.A:Aretherepathologicfeaturesinthe Discussion Question 3: Are there genetic, environmental,
pancreasortheperipheralnervoussystemofpatientswithchronic emotionalorotherfactorsthatcontributetothevariabilityofpain
pancreatitisthatareassociatedwithcontinuous,neuropathic-type inpatientswithchronicpancreatitis?
pain? Guidance Statement: Genetic, environmental, including early
Guidance Statement: Some patients with CP and constant childhoodevents[52]andemotionalfactors[53]havebeenshown
neuropathic-type pain have changes in peripheral nerve fiber tocontributetothevariabilityofpaininavarietyofdiseasesys-
anatomyandphysiology.Insome patientspainmaynotbe asso- tems. Currently there are insufficient data in humans with CP to
ciatedwithchangesintheperipheralnervoussystem. definethemechanismsorrelativecontributionsofthesefactors.
EvidenceLevel:5 EvidenceLevel:5
Gradeofrecommendation:D Gradeofrecommendation:D
LevelofAgreement:A28%;B26%;C33%;D5%;E8% LevelofAgreement:A82%;B16%;C2%;D0%E0%
86 M.A.Andersonetal./Pancreatology16(2016)83e94
Evidence and Discussion: CP-related pain may have unique scale (11 sensory, 4 affective) whose score is translated into a
mechanismsthatarerelatedtogeneticbackground[50].Studiesof sensoryscore,anaffectivescoreandatotalscore.Inadditiontothe
CP-relatedpainshownoassociationofpainwithgeneticmarkers 15itemscale,italsoincludesaPresentPainIntensity(PPI)scaleand
linked to postsurgical chronic pain [35,39,42]. However, animal a VAS. The NIH Patient-Reported Outcome Measurement Infor-
studiesaswellashumantwinandfamilystudiesrevealthatupto mationSystem(PROMIS)instrumentsarewellvalidatedandcanbe
50%ofvariouschronicpainsyndromescanbeattributedtoheri- measuredreliablyacrossdifferentconditions[72].
tablefactors[35,55,56]. Discussion Question 5: How should the impact of pain be
Some gene products may predispose an individual to more evaluatedinpatientswithchronicpancreatitis?
intenseorpersistentpainorprovideprotectionfromsuchapain GuidanceStatement:Validatedinstrumentsshouldbeusedto
[55].Having“painriskalleles”mayincreasevulnerabilitytopain evaluate quality of life (QOL). This may include evaluation of
(including CP-related pain), through individual and combined ef- physical,social,andemotionalfunctions.
fectsandinteractionwithenvironmentalfactors[55].
Althoughthegeneticstudiesofpancreaticpainarestillintheir EvidenceLevel:2b
infancycomparedtostudiesonsomaticpainormigraine,several Gradeofrecommendation:C
publishedreportshaveshownthatcertaingeneticmechanismsof LevelofAgreement:A56%;B28%;C9%;D0%;E7%
paindevelopmentand/orpersistencemaybesharedbetweenso-
matic and visceral pain disorders; these include adrenergic and Evidence and Discussion: Chronic pancreatitis strongly im-
serotoninergic pathways. For example, the serotonin-transporter- pactsanumberoffunctionseachofwhichcanreduceapatient's
linked polymorphic region (5HTTLPR) correlated with pain QOL. In a cohort study of 265 CP patients, physical function was
severity in patients with irritable bowel syndrome [57,58], and impaired in 25% of patients, emotional function in 15%, and the
variation in beta-2 adrenergic receptor predicted pain-related perceptionofdiminishedoverallhealthfunctionwaspresentin19%
quality of life in patients with functional gastrointestinal di- [73].IntheNAPS2study443well-phenotypedCPsubjectsand611
agnoses[58]. control subjects were assessed for QOL using the Short Form 12
Onereasonforslowprogressinunderstandingthegeneticas- (SF12) questionnaire [4]. The QOL in CP subjects was similar or
pects of pancreatic pain is lack of comprehensive visceral pain worse than the QOL of many other chronic conditions [2]. In
phenotypicassessmentinCPpatients.Within-casedesignandas- anotherrecentstudyat4USpancreaticdiseasecenters,74%of111
sociation analysis of genetic polymorphisms with specific pain patientsreportedthatworkliveswerealteredbytheirdisease,60%
phenotypes(suchasconstantvs.intermittentpain,painseverity/ reported an effect on social lives and 46% reported an effect on
intensity,etc)maybemoresensitive forCP-relatedpaingenetics spouse/significantotherrelationship[74].Thisstudyalsoreported
studies and reveal genetic factors that explain inter-individual that 80% of CP patients reported that they had not been treated
variability in perception of this pain. Genome-wide association withrespectanddignityonatleastonevisittotheERbeinglabeled
studies in large cohorts of CP patients with pain phenotypes are alcoholic or a drug seeker suggesting that self-esteem maybe
anticipatedtofurtheradvancethefield[62]. another domain with an impact on CP patients [74]. In a recent
smallerstudy,inadditiontopainintensity,BMIanddiseasedura-
Part2:assessmentofpainandqualityoflife(QOL)inCP tionsignificantlyimpactedqualityoflife[8].Thus,multiplefactors
associatedwithCPaffectQOL.
Fourdiscussionquestionsweredeveloped. Until recently, only generic instruments for the evaluation of
Discussion Question 4: What is the minimum assessment of QOL have been available to evaluate these patients [75]. These
painthatshouldbeperformedinpatientswithchronicpancreatitis include Short-Form 36 (SF-36) and European Organization of
atbaselineandatfollow-up? ResearchfortheTreatmentofCancer(EORTC)questionnaires.Both
GuidanceStatement:Painshouldbeevaluatedateachvisitto instruments have undergone extensive psychometric evaluation
assesscharacter,frequencyandintensity.Whenpossible,validated [73,76].TheSF-12hasbeenthoroughlystudiedinCP[2,77,78].Inan
instrumentsshouldbeused. evaluationof163consecutivepatientswithCP,theSF-12appeared
tooutperformtheEORTCinclinicalpractice[77].Thegenericin-
EvidenceLevel:2b strumentsappeartoberobustinevaluatingCPQOLandtheSF12
Gradeofrecommendation:B hasbeenfollowedsequentiallyovertimeinCP[79].
LevelofAgreement:A80%;B17%;C2%;D0%;E0% Recently,anewdisease-specificinstrumentwasdevelopedfor
the evaluation of quality of life in this group of patients:
EvidenceandDiscussion:Thedescriptionofpaininpatients Pancreatitis Qualityof Life Instrument (PanQOLI)[80]. This is an
with CP should include its character, frequency and intensity. 18 item questionnaire designed to be the first disease-specific
Frequencymaybeoneofthemostunder-appreciatedparameters instrument to evaluate QOL in CP [80]. It includes unique fea-
in this field. In a prospective cohort study, 186 patients had turesnotfoundingenericinstruments(economicfactors,stigma)
constant pain patterns compared to 228 with intermittent pain and consists of 4 domains: physical function (5 items), social
[1]. Regardless of the intensity of the pain, those with constant function(5 items), emotionalfunction(4 items)and self-esteem
pain patterns had higher rates of disability (OR 3.2 (95% CI (4-items) [81]. The presence of a self-esteem component is
2.0e5.1)), hospitalizations (X2 ¼ 8.8, p ¼ 0.00001), pain medi- uniquetothisdisease-specificinstrumentandisbelievedbythe
cations (OR 4.4 (95% CI 2.8e6.8)), and lower QOL evaluations studygroup to make it more sensitive for the evaluation of this
(MentalComponentScore;MCS39.9vs.47.6,p<0.001)(Physical groupofpatients.
Component Score;PCS 33.3 vs. 42.2, p < 0.001) thanthosewith Given that pain significantly affects QOL, the use of these in-
intermittentpain[1]. strumentsprovidesanimportantmeasureofpainimpact.Atleast
Anumberofinstrumentsarecurrentlyavailabletoevaluatepain one of the QOL measures should therefore be used in measuring
severity.Thevisualanalogscale(VAS)ispresentedasa10cmline diseaseprogression,impactandtreatmentsuccessinconjunction
anchoredbyverbaldescriptors(nopain-worstpain)[70].Although withpainmeasures.
it is easy to use, it does not measure pain character, frequency, Discussion Question 6: In patients with chronic pancreatitis,
patternorpaininterference.TheMcGillquestionnaireisa15-item shouldpsychosocialassessmentbedone?
M.A.Andersonetal./Pancreatology16(2016)83e94 87
Guidance Statement: Patients should be assessed for psycho- pancreatic duct stones and strictures [102] which can be treated
logicalco-morbidities(e.g.anxiety,depression,opiateabuse)and with a reasonable expectation of relieving the pain. Therefore,
functionalpainusingvalidatedinstruments. abdominal imaging studies are very important in identifying
structural abnormalities that maycontribute topain in some pa-
EvidenceLevel:5 tients,eventhoughimagesthemselvescannotpredictthepresence,
Gradeofrecommendation:D typeorpatternofpain[7].
LevelofAgreement:A48%;B38%;C8%;D2%;E4% Anumberofpotentiallyusefulimagingmodalitiesarecurrently
available[103].AbdominalimagingwitheitherCTorMRIiswidely
Evidence and Discussion: Pain behavior is a well-studied available and sensitive to detect complications of CP linked to
phenomenon and is described in patients suffering from chronic structuralordensitychanges.EUSisalsoanestablishedmodality
pain[82].Thisbehaviorcanbeadaptiveandhelpfulormaladaptive forevaluation of CP [104]. These modalities should be used judi-
and interfere with coping mechanisms. Examples of maladaptive ciouslyandonlywhentheresultsareexpectedtochangeorguide
behaviors include the development of drug abuse/addiction furtherinterventions.
behavior, the development of distress and anxiety disorders that
interferewithcopingmechanisms,andthedevelopmentofclinical Part3.ManagementandtreatmentofpaininCP
depression that impairs the ability to deal with pain [83]. In a
structured, evidence-based review of the literature, 3.27% of Fivediscussionquestionsweredeveloped.
chronic pain patients (n ¼ 2507) were found to develop abuse/ DiscussionQuestion8:Whatshouldtheinitialmanagementbe
addiction behavior and 11.5% of patients (n ¼ 2466) developed forpaininpatientswithuncomplicatedchronicpancreatitis?
aberrantdrug-relatedbehaviors[84]. GuidanceStatement:Medicalmanagementshouldbethefirst
Thereisnosingleinstrumentthatiscurrentlyavailabletoassess lineoftherapyforpaininuncomplicatedCP.Ifpresent,psychiatric
thesevariouspsychosocialbehaviors[66].Itisnecessarytochoose disordersandmaladaptivecopingstrategiesshouldbeaddressedin
an instrument that is considered to best evaluate the suspected conjunctionwithpaintherapy.
abnormalbehaviors[85,86].Giventhecomplexityoftheassessment
process,theworkinggroupmembersbelievethatreferraltoapain EvidenceLevel:1b
specialistwithskillsinbehavioralpsychologyisreasonable,partic- Gradeofrecommendation:B
ularlyifaberrantpainbehaviorissuspectedandresponsetotherapy LevelofAgreement:A65%;B18%;C8%;D3%;E6%
hasbeensuboptimal.Inadditiontoadministeringtheseassessment
instruments to determine the potential presence of aberrant Evidence and Discussion: All patients with established CP
behavior,itishelpfulforpsychologiststoofferinterventionsinthis should be offered medical management for pain, when present.
difficult subset of patients, including the Interdisciplinary Pain Patients who have an inflammatory mass, pancreatic duct
RehabilitationProgram(IPRP)[96].Suchanapproachappearstobe obstructionsecondarytoastrictureand/ormainductstone(s),or
cost-effectiveinthissub-groupofpatients,asstudiesdemonstrate peripancreatic complications (e.g., pseudocyst) might require
thatapproximately49%ofpatientscanreturntoworkwithsignifi- additionaltreatment(s).Eveninpatientswhoappearappropriate
cantlyreducedlevelsofdepression,pain-relatedcatastrophizingand forendoscopicorsurgicaltherapy,initialmedicalmanagementof
pain intensity, but no change in anxiety levels [97]. Furthermore, painisrecommendedtogiverelief,tobetterunderstandthepain
studiesinpatientswithchronicbackpainhavedemonstratedthatan mechanism, responsiveness to treatment and whether there is a
IPRPis10.6 times more cost-effective thanthe use ofSpinal Cord significantsensitization.
Stimulators(SCS),12timesmorethanstandardmedicalcareand26 Astepwiseapproachshouldbeusedforanalgesicmedications
timesmorethansurgery[98,99]. [17,106]. Non-narcotic analgesic medications (e.g. nonsteroidal
Therefore, it is crucial to evaluate the psychosocial impact of anti-inflammatorydrugs[NSAIDS])aretheinitialchoice.Narcotic
chronic pancreatitis in addition to the pain and quality of life medications should be considered in a patient who has constant
evaluationpreviouslydiscussed.Thesuggestedinstrumentsforthis and/orseverepainnotcontrolledwithnon-narcoticanalgesics.The
evaluationwould include the Pain-Anxiety Scale (PASS) [87], the initial choice of narcotic should be a weaker, mixed ago-
PainCatastrophizingScale(PCS)[88,89],theDrugAbuseScreening nisteantagonist or partial agonist (e.g. tramadol) before using
Test (DAST) [90], the brief Michigan Alcohol Screening Test stronger narcotics (e.g. morphine, hydrocodone and hydro-
(bMAST)[86],and/ortheCurrentOpioidMisuseMeasure(COMM). morphone). Patients who are expected to require long-term
If patients are found to have psychosocial dysfunction based on narcotic analgesia for pancreatic pain are most appropriately
thesescales,thereisagrowingbodyofliteraturethatisdeveloping evaluatedandmanagedinaPainClinic.Aneuromodulatingagent
tosupporttheuseofnon-opioidpharmacotherapy[100]andthe (e.g. pregabalin) should be considered in a patient who requires
psychosocial interventions [101], such as cognitive behavioral narcoticanalgesicsonaregularbasis[10].
therapy,mindfulnessmeditationandhypnotherapytohelpaddress There is no definitive evidence that pancreatic enzyme
theseissues. replacementtherapy(PERT)providegeneralpainreliefinCP[107].
DiscussionQuestion7:Areabdominalimagingstudiesusefulin However,forinitialmedicalmanagement,oralpancreaticenzyme
assessingpaininpatientswithchronicpancreatitis? supplementsinadequatedosesandwithrapidreleasehavebeen
Statement: Abdominal imaging may be useful in identifying showntoprovidesomepainrelief,possiblybyprovidingnegative
pancreaticorbiliaryductobstruction,inflammation,pseudocystsor feedbackinhibitionofpancreaticsecretioninearlydisease[41].In
extrapancreaticcomplicationsthatmaydirectspecifictreatments. advanced CP with pancreatic exocrine insufficiency, PERT may
provide relief from symptoms of maldigestion [40]. Pancreatic
EvidenceLevel:2b enzyme replacement therapy in patients with CP can reduce the
Gradeofrecommendation:C extentofsteatorrheaandpossiblypain,butalsoothersymptoms
LevelofAgreement:A80%;B18%;C2%;D0%;E0% thatimpactapatient'sQoL[18,108e110].
TheroleofantioxidantsinmanagementofpaininCPisdebatable
Evidence and Discussion: A number of CP complications can [111,112];thereissomeevidenceofabenefitinasubsetofpatients
developthatcauseorexacerbatepain.Theseincludepseudocysts, withidiopathicCP,butnotinpatientswithalcoholicCP[113].Some
88 M.A.Andersonetal./Pancreatology16(2016)83e94
studiesshowatrendtowardssomepainrelief,andmoresowitha ESWLhasanimportantroleinmanagementofpaininpatients
combination ofantioxidants rather thanwith singleagents [114]. withCP.Atselectedcenterswithalargeexperience,ESWLoflarge
Recent meta-analyses also suggest that antioxidants can provide (5 mm or greater) pancreatic stones can achieve clearance in
marginalpainrelief[115,116].Thechallengewiththemeta-analysis approximately 75% of patients undergoingmultiple sessions, and
is that the studies were from different populations, different treatment was associated with significant pain relief [124]. In a
etiologies,differentformulations,andmayhaveothermajorcon- randomized trial, ESWL without ERCP for ductal clearance was
foundingvariables.Thus,antioxidanttherapyisnotroutinelyrec- found to be as effective and more cost effective than the routine
ommendedinthemanagementofpainassociatedwithCP,butthere combinationofESWLwithERCPandductalclearanceofstonesand
maybearoleinsomecases,suchasidiopathicCP[113]. debris[125].
Ifmedicaltreatmentisineffectivewithinagiven,limitedtime Pancreatic ductal strictures most amenable to endoscopic
period,orifendoscopicand/orsurgicaltherapyareindicated,these therapyarethoseinthepancreatichead,ratherthanthebodyand
moreinvasivetreatmentsshouldnotbeundulydelayedinhopesof tail.Thereisalargeliteraturegivingevidencethatpancreaticduct
“spontaneous”painreliefovertime[117].Patientswhohavefailed stenting is effective for symptomatic ductal obstruction in the
orrefusedendoscopicorsurgicaltherapyshouldbecontinuedon setting of CP [126e129], even though there are no randomized,
themosteffectivemedicalapproaches.Intheappropriatesetting blinded, sham-controlled studies in this setting. Sphincterotomy,
patientsshouldalsoundergoevaluationforTPIAT[15],asdiscussed stricture dilation, and large caliber plastic stenting with one or
below. more7e10Frenchgaugestentsforaprolongedperiodoftime(for
DiscussionQuestion9:Doesbehaviormodification(cessation 3e12 months) appears to be most beneficial [130]. The use of
ofalcoholconsumptionandsmoking)helpinprovidingpainrelief multiple large plastic stents and expandable metal mesh stents
inchronicpancreatitis? (SEMS)inthepancreaticductremainsexperimentalandcannotyet
Guidance Statement: Cessation of alcohol consumption and beconsideredstandardofcare.
smokingmayhelpinprovidingpainrelief. Theutilityofendoscopicvs.surgicalapproachesintreatingpain
continuestobedebated.Tworandomizedtrials[131,132],including
EvidenceLevel:2b one with long-term follow-up, have compared endoscopic and
Gradeofrecommendation:C surgical treatment. The evidence indicates that surgery provides
LevelofAgreement.A49%;B27%;C19%;D5%;E0% superiorpainrelief(80vs.38%)intheshort(2years)andlong(6
years)term.Patients assignedtoendoscopictreatmenthadmore
Evidence and Discussion: Thereare no data specificallyeval- proceduresandapproximatelyhalfoftheseeventuallyhadsurgical
uating the role of alcohol abstinence and smoking cessation in treatment. However, concern has been expressed that this study
improving the severity of CP related pain. However, continued did not compare ‘like-with-like’. A highly selected group under-
alcohol consumptionand smokingincreases the riskof recurrent goingsurgerywascomparedtopatientswerelikelytohaveapoor
attacks of pancreatitis and disease progression [118e120]. A ran- outcomefromendotherapy(e.g.thosewithdiseaseinthebodyand
domized trial in patients with alcoholic acute pancreatitis tailandthosewithaheavyductalstoneburden)[133].Thus,the
demonstratedbenefitofrepeatedcounselingagainstalcoholcon- working group believes that additional studies are needed to
sumption in reducing the risk ofrecurrentattacks of pancreatitis determineoptimalutilityofendoscopicandsurgicalapproachesto
and hospitalizations [121]. It is recommended in several review treatingpaininpatientswithCP.
articles that counseling by certified therapists is indicated for AnalysisofNAPS2patientswhohadlong-termfollow-upatthe
alcohol abstinence and smoking cessation in all patients with CP UniversityofPittsburghprovidesaperspectiveoncurrentclinical
andirrespectiveofthepresenceorseverityofpain[122,123]. practice in an expert center [11]. Patients who were selected for
Discussion Question 10: What are the indications for endo- endoscopictherapyifitwasconsideredthattheetiologyofpainor
scopictherapyforpaininchronicpancreatitis? RAP was obstructive in nature. Endoscopic therapy was clinically
GuidanceStatement:Patientswhohavesymptomaticpancre- successful for 50% of patients with symptomatic CP, defined by
atic ductal dilatation and/or stricture(s) with/without intraductal cessation of narcotic therapyand resolution of RAP. When endo-
stone(s), pseudocysts or leaks are candidates for endoscopic scopicwasnotsuccessful,anadditional50%oftheremainingpa-
therapy. tientshadlong-termreliefwithsurgery[11].
Endoscopictreatmentisstillusedasafirstlinetherapyinmany
EvidenceLevel:2b centersandcontinuestoberecommendedbyendoscopysocieties
Gradeofrecommendation:B [19].Justificationforprimaryendoscopictreatmentismadeonthe
LevelofAgreement:A86%;B7%;C3%;D2%;E2% basis of it being less invasive, less expensive and more readily
available.Inselectpatients,surgeryshouldbeconsideredthefirst
EvidenceandDiscussion:Endoscopictherapyplaysanimpor- approach.Theseincludepatientswhohaveaheavystoneburden
tantroleinthetreatmentofCPassociatedpain[19].Becausethe especially in the body/tail of the pancreas with pancreatic ductal
cause of pain is multifactorial not all patients will respond to dilatation and/or strictures [131,132], and those with an inflam-
endoscopictreatment,evenwhentechnicallysuccessful.Itwasthe matorymass(wheretheprimaryetiologyofpainisnotlikelytobe
opinion of members of theworking groupthatendoscopic treat- ductobstruction).However,somepatientsmaydeclinesurgery,are
mentshouldbeperformedbyindividualswithspecificinterestand too high risk for surgery or may improve sufficiently following
expertiseinthisarea. initial endoscopic therapy to not require a definitive surgical
The working group believes that the best candidates for approach [11]. If patients do not significantly improve following
endoscopictreatmentarethosewithsignificantpainfromductal endoscopictherapyandtheyaresurgicalcandidates,thensurgical
obstruction identified by cross-sectional abdominal imaging, treatmentshouldnotbedelayed[117].
especiallydominantstricturesintheheadofthepancreas.Endo- Most symptomatic pancreatic pseudocysts can be treated
scopic therapymayalso be useful for some patients with biliary endoscopically.Transmuralendoscopicdrainageunderendoscopic
obstruction,pancreaticpseudocysts,pancreaticfistula,pancreatic ultrasoundguidancewithDopplersignalcanbeattemptedwhere
ductstricturesandthosewithpancreaticductcalculiwhomight expertiseisavailable.Whilenotmoreeffectivethansurgery,itis
respondtoextracorporealshockwavelithotripsy(ESWL). lessinvasiveandexpensive[134].Pancreatographyatthetimeof
M.A.Andersonetal./Pancreatology16(2016)83e94 89
endoscopic cyst drainage may help clarify ductal anatomy, duct [146]. Surgery, rather than endoscopic therapy should be
includingthelocationofstricturesandleaks[135].Inpatientswith consideredinpatientswhohaveaheavystoneburden,especiallyin
a disconnected duct syndrome, a pseudocyst and proximal duct thebody/tailofthepancreaswithpancreaticductaldilatationand/
dilatation, especially when there are intraductal calculi and/or or strictures. Endotherapy may be useful as a bridge to surgical
strictures, surgical decompression of the pseudocyst with duct treatment for those patients who are candidates for surgery, but
clearancemaybeindicatedtoaddresspain.Pancreaticductalleaks whoareinitiallyunfit[147].
may cause a pseudocyst and/or fistulae, and can sometimes be The timing of surgical intervention is an important factor in
treated with transpapillary pancreatic duct stenting [136e138]. If clinicaloutcomes;surgeryhasbeen showntobemostsuccessful
theleakisassociatedwithahigh-gradeproximalstricturesand/or when performed within three years of symptom onset but the
calculi then treatment of this obstruction with transpapillary developmentofcentralpainisaconcernwhensurgicalinterven-
stentingmayleadtoresolution. tion is deferred [11,146] The probability of long-term pain relief
Biliary obstruction from CP may result in abdominal pain but fromsurgerycanbeestimatedonthebasisofthedurationofpain,
more commonly jaundice or cholestasis. In the short-term, bile use of preoperative opioids, and the number of endoscopic in-
ductstentingshouldbeperformedparticularlytorelievejaundice, terventions[116].
cholangitisorseverepruritus.Recentstudiessuggestthatcovered There is a range of surgical options, including resection,
expandable metal stents (SEMS) may be a viable management decompressionandacombinationofthese[148],aswellasTPIAT
option, although multiple plastic stents can provide better long- as reviewed by Bellin et al. [15]. Among drainage procedures,
term relief [139]. However, longer term follow-up data is patients with a dilated main duct and without an inflammatory
required. Patients with significant calcifications of the pancreatic massintheheadofthepancreasarebestmanagedwithdecom-
headmaybethoselesslikelytobenefitfromstentinginthelong- pression of the duct (longitudinal pancreatico-jejunostomy) and
term.SurgicalbiliarybypassbyRouxenYhepaticojejunostomyisa witheithercoringofthehead(Freyprocedure)orresectionofthe
definitivetreatment,yieldsexcellentdurableresultsandshouldbe head (Beger procedure) [148]. Patients with an inflammatory
considered in the fit patient [140,141]. However, hep- massintheheadofthepancreas,especiallyifmalignancycannot
atojejunostomyisnotwithoutproblems,andrarelycanresultinan be excluded, will require pancreatic head resection (Whipple's
anastomoticstrictureandthispromotessecondarybiliarycirrhosis procedure), with or without pancreatic duct decompression. Pa-
[142]. This can be combined with decompressive pancreato- tients with obstructive jaundice secondary to a benign distal
jejunostomyifindicated. biliarystricturemay benefitfrom a Roux-en-Y hepatico-jejunos-
NeurolytictherapiestotreatCPcanbedoneusingavarietyof tomyat the same time. Patients with non-alcoholic etiologies of
techniques, including EUS-guided [143], radiology image guided CPmaydowellwithTPIAT,butpainreliefandoutcomesarenotas
and surgical treatments. At this time, the use of EUS-guided CPB good for patients with an alcohol etiology [15,149,150]. Recom-
(celiac plexus block) cannot be recommended as routine therapy mendations for the evaluation, treatment and follow-up of pa-
forpaininCPsinceonlyone-halfofthepatientsexperiencepain tientswhomaybecandidatesforTPIATwererecentlypublished
reductionandthebeneficialeffecttendstobeshortlived[143].A [15].
recentrandomizedcontrolledtrialshowedthataddingsteroidsto Therearedatasuggestingthatdrainageofadilatedpancreatic
bupivacaine in celiac plexus block was no more effective than duct delays functional deterioration and disease progression in
placeboplusbupivacaineandbothgroupshadanoverallverypoor patients with mild-moderateCPand minimal pain [117,151]. This
response [144]. Surgical division of the splanchnic nerves in the approachhasnotbeenwidelyimplementedandpatientselection
chest(thoracicsplanchnicectomy)yields similarshort-term, vari- musttakeintoaccountcomorbidities,ongoingsubstanceuseanda
ableresponsesandthuscannotberoutinelyrecommended[145]. discussionwiththepatientbyasurgeonabouttherisksandben-
DiscussionQuestion 11: Whatare theindications forsurgery efitsofsurgery.
(resectionordrainageprocedure)forpaininchronicpancreatitis? Prospective randomized trials of pancreatico-duodenectomy
Guidance Statement A: Surgery by resection or drainage is (Whipple procedure), the duodenum-preserving pancreatic head
indicatedinpatientswithpersistentchronicpancreatitispainthat resection (Beger procedure), and the local resection of the
failstorespondtomedicaland/orendoscopictherapy. pancreatic head with longitudinal pancreatico-jejunostomy (Frey
procedure)indicateequivalentdegreesofpainrelief(70e80%)in
EvidenceLevel:2b both the short and long term [28,152]. The Frey procedure has a
Gradeofrecommendation:C lowerriskofperi-operativeandpost-operativecomplicationsand
LevelofAgreement:A67%;B27%;C6%;D0%;E0% hasbecomethepreferredprocedurebymanypancreaticsurgeons.
Theprincipalshort-comingofthelateralpancreatico-jejunostomy
Guidance Statement B: Pancreatic resection or drainage pro- (Puestow) procedure is the risk of recurrent symptoms due to
cedures (e.g. lateral pancreatico-jejunostomy) should not be per- progressive inflammation localized to the pancreatic head [153].
formed in patients who are candidates for total pancreatectomy Justdrainingadilatedduct(lateralpancreatico-jejunostomy)isno
and islet autotransplantation (TPIAT) in settings where this is longer considered the standard of care for the treatment of pain
available,asthiscanresultinalowyieldofislets. associatedwithobstructivepancreatopathy.
TPIAT is a new, and debated approach to management of
EvidenceLevel:2b intractablepaininpatientswithimpairedqualityoflifeduetoCPor
Gradeofrecommendation:C RAPinwhommedical,endoscopic,orpriorsurgicaltherapyhave
LevelofAgreement:A100%;B0%;C0%;D0%;E0% failed[15].Becauseisletisolationrequiresaspecialfacilityandis
technically challenging, it is only offered at a limited number of
EvidenceandDiscussion:Multipleclinicalstudiesprovideev- centers,primarilyintheUnitedStates.Delayinreferralofpatients
idencethatsurgeryisamoreeffectivelong-termtherapyforpainin forTPIATthatresultsinprogressivefibrosisandlossofisletcells,
patients with CP than endoscopic or other treatments [131,132]. proceeding with pancreatic resections, or performing some
Amongpatientswithpancreaticpain,surgeryisthemosteffective drainageproceduresmarkedlyreduceisletyield[149,156].Onthe
whentheetiologyofpainisobstructive,typicallywithsignificant otherhand,manyCPpatients,especiallywithmoreadvanceddis-
post-prandial pain exacerbations and a dilated main pancreatic ease,maybebetterservedwithmoretraditionalapproaches.
90 M.A.Andersonetal./Pancreatology16(2016)83e94
Discussion Question 12: How should response to therapy for Assessmentofpain
painbeassessed? Although multiple possible mechanisms of pain have been
Guidance Statement: A combination of objective findings described, there are few, if any, well-validated instruments that
shouldbeusedtoassesstreatmentresponseoftherapiesovertime discriminatebetweenpainfeaturesandmechanisms.Large,well-
including use of serial validated pain scores, quality of life (QOL) controlled, long-term trials are needed to define the natural his-
instruments, pain medication use, frequency of pain episodes, toryofpainandtoevaluatearangeofpainassessmentinstruments.
hospitalizationsandemergencyroomvisits. These studies should include comprehensive evaluation of each
patient to determine the relative contribution and potential syn-
EvidenceLevel:2b ergy of active inflammation, obstruction, tissue hypertension or
Gradeofrecommendation:B ischemia, neuropathy, centralization, mental health and comor-
LevelofAgreement:A93%;B5%;C:2%;D0%;E0% bidities.Specificcomorbiditiesincludeextra-pancreaticpain,gas-
troparesis,dysmotility,diabetesmellitus,broaderpainsyndromes
EvidenceandDiscussion:Currenttoolstopredicttheresponse andcomplicationsoftreatmentssuchasnarcoticbowelsyndrome.
toallformsoftherapies(medical,endoscopic,surgery)areinade- The role of emotional and mental health, including anxiety and
quateandnewonesneedtobedeveloped.Therearelimiteddata depression, must be included in pain evaluations. The effects of
correlating the response to therapies with different pain perceivedsymptomsandresponsestotherapyshouldbeappliedto
mechanisms. theseassessments.
Painwillnotconsistentlyimprovewithendoscopicorsurgical
drainageofadilatedpancreaticductorwithresectionofinflamed
Managementandtreatmentofpain
parenchyma. This reinforces that pain mechanisms in CP are Bettermethodsthatspecificallytargetpainmechanismsmust
complex and may be modulated by multiple and differing path-
bedevelopedalongwithguidanceonwhichpatienttypesarelikely
waysduringevolutionofthedisease.
to respond. The indications for the primary use of endoscopic or
Avarietyofmethodshavebeenusedtoassesstheoutcomeof surgicaltherapyforspecificpatientpopulationsmustberesolved.
intervention for pain and QOL in CP, as reviewed in Discussion
Guidanceontheindividualriskandtimewindowneededtopre-
Questions 4 to 6. Placebo controlled trials are rare in CP but do
vent pain sensitization is needed. Pain management should also
suggest a low rate of response of approximately 20% [64]. The
monitor each active pain mechanism so that the effectiveness of
expectation of spontaneous abatement of pain (burn out) in CP,
each treatment approach can be monitored, and new problems
suggested by some [157] and found to be uncommon by others
detected early. The responses to intervention, whether medical,
[100], has resulted in undue patient suffering and been a disin-
surgical or experimental, should be documented using validated
centive to long-term, non-placebo-controlled studies. It appears
tools in systematic ways for ongoing evaluation. Patients under-
thatthefrequencyandseverityofpaindoesnotcorrelatewiththe
goingTPIATshouldbestudiedinalongitudinalandsystematicway
duration of CP [1], but is affected by multiple disease-modifying
before and after surgery, and the tissue evaluated to better un-
factors.Somecentersareusingasystematicmechanism-oriented derstand local and central pain mechanisms in specific disease
approachtopaininCPbyapplyingtoolssuchasquantitativesen-
states.
sory testing, electroencephalography and functional magnetic
resonanceimagingtoaddresscentralpain,butthisapproachhas
Summary
notbeenproventobesuperiortocurrentapproachesandrequires
furtherstudy[18].Regardlessofmethod,systematicassessmentof
Pain is the foremost problem in CP, and a major source of
pain character, pattern and severity must be monitored for long
morbidityanddecreasedQOLforaffectedpatients.Futurestudies
periods of time so that the effectiveness of interventions can by
tofurtherelucidatethelinkbetweenclinicalsignsandsymptomsof
accuratelyassessed.
CP,patientpainphenotypes,neuropathologicfeaturesandgenetic
and environmental influences are critical for the development of
Researchrecommendations
new, more effective treatment strategies. New tools for ongoing
assessment of pain and pain mechanisms are necessary for un-
Diseasemechanisms
derstandingthenaturalhistoryandforeffectivenessoftreatments
A major research effort is needed to identify sensitive and
specific biomarkers that link pain mechanisms with clinical fea- infutureclinicaltrials.Thecomplexityofpancreaticpainisclearly
oneclinicalproblemthatwouldgreatlybenefitfromarobustdia-
tures. The relationship between local and central pain should be
clarified in terms of context, timing and clinical features. The loguebetweencliniciansandbasicsciencepainresearchers.Only
by understanding the mechanisms contributing to the various
developmentofbettertechniquestostudycentralpaininhumans
presentationsofpancreaticpainwillitbepossibletoidentifythe
and experimental models is critical for addressing this issue.
most efficacious treatments with the minimum of complications
Although neuropathology is often evident in human pancreatic
andimprovementofthequalityoflifeoftheaffectedpatients.
tissuesamples,theclinicalcontextandassociatedpainphenotypes
havenotyetbeenidentified.Thus,neuropathicbiology,theclinical
context and specific consequences are not easily identified and Authorcontributions
treated by clinicians. Further studies are needed to determine
whetherspecificneuropathologies,suchasneuroinflammationor Developedtheconceptandtheconsensusprocess:M.A.A.,K.M.A.,
direct nerve injury, are associated with distinct clinical conse- R.E.B.,L.F.,andD.C.W.
quences. The relationship between normal and abnormal re- PancreasPainworkinggroups:M.A.A.(chair),K.M.A.,S.T.A.,I.B.,
sponses to pancreatic stress or injury must also be clarified, S.C.,G.C.,B.M.D,A.G.,N.G.,A.H.,R.L.,A.S,R.S.G.,E.S.,W.W.,C.M.W,
especially in relation to genetic and environmental modifiers, J.W.,andD.Y.
includingmedications.Mechanisticpathways,specificriskfactors, Wrote the Manuscript: D.C.W. (senior author), M.A.A., V.A.,
other variables and better biomarker linking the syndrome of K.M.A.,S.T.A.,I.B.,B.M.D.,R.S.G.,E.S.,J.T.,W.W.,C.M.W.,J.W.,D.Y.
constantpaintotheunderlyingpathologicprocessesinindividual Participated in discussion of statements, reviewed and approved
patientsareneeded. manuscript.Allauthorsandparticipants.
M.A.Andersonetal./Pancreatology16(2016)83e94 91
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