Core Outcome Domains and Measures for Pediatric Acute and Chronic/Recurrent Pain Clinical Trials: PedIMMPACT Recommendations

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The Journal of Pain, Vol 9, No 9 (September), 2008: pp 771-783Available online at www.sciencedirect.com

onsensus Statement

ore Outcome Domains and Measures for Pediatric Acute andhronic/Recurrent Pain Clinical Trials: PedIMMPACTecommendations

atrick J. McGrath,* Gary A. Walco,† Dennis C. Turk,‡ Robert H. Dworkin,§

ark T. Brown,� Karina Davidson,¶ Christopher Eccleston,** G. Allen Finley,*enneth Goldschneider,†† Lynne Haverkos,‡‡ Sharon H. Hertz,§§ Gustaf Ljungman,��

onya Palermo,¶¶ Bob A. Rappaport,§§ Thomas Rhodes,*** Neil Schechter,†††

ane Scott,§§ Navil Sethna,‡‡‡ Ola K. Svensson,§§§ Jennifer Stinson,���

arl L. von Baeyer,¶¶¶ Lynn Walker,**** Steven Weisman,†††† Richard E. White,‡‡‡‡

nne Zajicek,‡‡ and Lonnie Zeltzer§§§§

Dalhousie University and IWK Health Center, Halifax, Canada;Hackensack University Medical Center, Hackensack, New Jersey;University of Washington, Seattle, Washington;University of Rochester Medical Center, Rochester, New York;Pfizer Inc., Ann Arbor, Michigan;Columbia University, New York, New York;*University of Bath, Bath, United Kingdom;†Children’s Hospital Medical Center, Cincinnati, Ohio;‡NIH/NICHD, Bethesda, Maryland;§Food and Drug Administration, Rockville, Maryland;�University of Uppsala, Children’s Hospital, Uppsala, Sweden;¶Oregon Health and Science University, Portland, Oregon;**Merck and Company, Blue Bell, Pennsylvania;††St. Francis Hospital and Medical Center, Hartford, Connecticut;‡‡Harvard Medical School, Children’s Hospital, Boston, Massachusetts;§§AstraZeneca, Stockholm, Sweden;��University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada;¶¶University of Saskatchewan, Saskatoon, Canada;***Vanderbilt University Medical Center, Nashville, Tennessee;†††Children’s Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin;‡‡‡Endo Pharmaceuticals, Chadds Ford, Pennsylvania; and§§§David Geffen School of Medicine at UCLA, Los Angeles, California.

Abstract: Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment inClinical Trials (IMMPACT), 26 professionals from academia, governmental agencies, and the pharma-ceutical industry participated in a 2-stage Delphi poll and a consensus meeting that identified coreoutcome domains and measures that should be considered in clinical trials of treatments for acute andchronic pain in children and adolescents. Consensus was refined by consultation with the interna-tional pediatric pain community through announcement of our recommendations on the PediatricPain List and inviting and incorporating comments from external sources. There was consensus thatinvestigators conducting pediatric acute pain clinical trials should consider assessing outcomes in painintensity; global judgment of satisfaction with treatment; symptoms and adverse events; physicalrecovery; emotional response; and economic factors. There was also agreement that investigators

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pain intensity; physical functioning; emotional functioning; role functioning; symptoms and adverseevents; global judgment of satisfaction with treatment; sleep; and economic factors. Specific mea-sures or measurement strategies were recommended for different age groups for each domain.Perspective: Based on systematic review and consensus of experts, core domains and measures forclinical trials to treat pain in children and adolescents were defined. This will assist in comparison andpooling of data and promote evidence-based treatment, encourage complete reporting of outcomes,simplify the review of proposals and manuscripts, and facilitate clinicians making informed decisionsregarding treatment.

© 2008 by the American Pain SocietyKey words: Acute pain, chronic pain, children, adolescents, pediatric, clinical trials, randomized con-trolled trials, assessment, outcomes, health-related quality of life, physical functioning, emotional

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he need for careful attention to pain in childrenand adolescents has been highlighted ever sinceEland and Anderson23 reported that children were

ot receiving analgesics for major surgery. Measuresave been developed, treatments have been evaluated,nd practice has changed. However, many children anddolescents continue to suffer from inadequatelyreated pain of all types.17,60

Randomized, clinical trials (RCTs) are the gold standardethod of evaluating interventions. They are also im-ortant in knowledge transfer, as a well-designed andell-publicized trial can promote changes in clinicalractice.Standardization of outcome domains and measures inediatric pain RCTs would streamline designing and re-iewing research protocols and articles, simplify andtrengthen systematic reviews, and help clinicians makereatment decisions. However, any standardization isrovisional, as the process of outcome measures devel-pment is dynamic and subject to frequent updates.The Initiative on Methods, Measurement, and Pain As-

essment in Clinical Trials (IMMPACT) has recently recom-ended 6 core domains be considered in clinical trials of

hronic pain in adults72 and specific measures to assess eachf these domains.20 To encourage clinical trials in the pedi-tric population and to improve the interpretability andggregation of data across pediatric pain trials, the Pediat-ic Initiative on Methods, Measurement, and Pain Assess-ent in Clinical Trials (PedIMMPACT) was developed. Ad-itional information concerning IMMPACT can be found atww.immpact.org.

eceived February 7, 2008; Revised April 9, 2008; Accepted April 15, 2008.he views expressed in this article are those of the authors. No officialndorsement by the US Food and Drug Administration, US National In-titutes of Health, or the pharmaceutical companies that provided unre-tricted grants to the University of Rochester, Office of Professional Edu-ation should be inferred.upported by unrestricted grants from AstraZeneca, Endo Pharmaceuti-als Inc., Merck and Co, and Pfizer to the University of Rochester Office ofontinuing Professional Education to support the IMMPACT Delphi poll,ackground literature reviews, and consensus meeting described in thisrticle.ddress reprint requests to Dr. Gary A. Walco, Joseph M. Sanzari Chil-ren’s Hospital at Hackensack University Medical Center, 30 Prospectvenue, Hackensack, NJ 07601. E-mail: [email protected]/$34.002008 by the American Pain Society

boi:10.1016/j.jpain.2008.04.007

The PedIMMPACT group first obtained consensus on do-ains to be used for acute and chronic pain using the ageroups of 3 to 6 years and 7 years and up. Next, the avail-bility and adequacy of measures within each domain wereonsidered. When there was insufficient empirical datavailable to make an evidence-based recommendation,onsensus was sought among the participants.PedIMMPACT recommends core outcome domains

hat should be considered in the design of all clinicalfficacy or effectiveness trials of pharmacologic, behav-oral, or environmental interventions. Our recommenda-ions are presented to promote standardization of do-ains and measures for clinical trials in pediatric pain.ne or more of these domains might, in any given trial,e justifiably excluded. We do not intend to imply thatssessment of core domains be considered a requirementor regulatory approval of a product or for publication of clinical trial. Furthermore, a researcher need not beimited by the domains of focus offered here. For exam-le, targeted drug development for chronic pain condi-ions in children and adolescents may require assessmenttrategies that go beyond parameters discussed. A re-iew of these factors exceeded the scope of thisedIMMPACT consensus meeting.We endorse conducting trials according to Good Clini-

al Practice73 and registration and publication of all tri-ls, including trials that fail to show the hypothesizedffect. We also support the CONSORT Statement16 touide planning and publication of clinical trials. Behav-

oral trials should consider additions to the CONSORTtatement that are specifically applicable to pediatric be-avioral trials.48

Pain in neonates and infants was not considered be-ause of the significant developmental differences be-ween infants and neonates, on one hand, and childrennd adolescents on the other. PedIMMPACT also did notonsider pain in cognitively impaired children because ofifferences in assessing these children. Efforts to developtandards for these populations will be the focus of fu-ure PedIMMPACT meetings.

ethodsThe consensus group was constructed to represent the

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eeping the group small enough to accomplish the goalsnd to permit free-ranging discussion and debate. Wesed a consensus strategy that consisted of a 2-stageelphi poll18 that helped the group focus attention on

elevant domains and measures during a 2-day consen-us meeting (March 17–19, 2005). The consensus was re-ned using commissioned systematic reviews of self-re-ort and observational measures of pain intensity. Wenalized consensus through post-meeting consultationmong the group using e-mail. Finally, we subjected ourajor findings to public review by the international pe-iatric pain community by means of disseminationn the Pediatric Pain Listserv (http://pediatric-pain.ca/pml/), which is subscribed to by more than 450 research-rs and clinicians who are working in pediatric pain inore than 45 countries. Suggestions obtained from thisrocess were incorporated within our recommendations.

articipantsThere were 3 groups of stakeholders represented: Ac-

demic research, government funding and regulatorygencies, and the pharmaceutical industry. The academicarticipants were selected by the organizers to representhe interdisciplinary international pediatric pain clinicalesearch community and included representation fromnesthesiology, clinical trials methods, epidemiology,eurology, nursing, pediatrics, pediatric oncology, psy-hology, and rehabilitation medicine. The meeting washaired by the senior author (McGrath), who was assistedy the 2 coleaders of previous IMMPACT meetings (Turknd Dworkin) and was attended by a total of 26 profes-ionals, all of whom are coauthors of this report. Theepresentatives from industry were all scientists and notirectly involved in marketing. Each company was al-

owed 1 participant in the consensus process. The repre-entatives from the United States Food and Drug Admin-stration and the National Institutes of Health werenvolved in assessment of interventions used in childrennd adolescents for pain. Each participant was instructedo speak for himself or herself as an individual and not as

representative of any organization. All participantsere involved in the Delphi poll, the consensus meeting,ost-consensus consultations, and approved the manu-cript and all revisions. Because this was a professionalonsensus meeting with voluntary participation, it waseemed that there were no human subjects concerns,nd institutional review board approval was not sought.

evelopmental IssuesWe believe that consideration of developmental pro-

esses is critical for understanding children’s pain. Devel-pment includes biological, psychological, and socialrocesses that all must be considered when designing aediatric pain trial. Children change in their cognitive,motional, and physical capabilities during the entire pe-iatric age range. Age is only a rough approximation ofevelopment but is often the most appropriate proxy.There are differences across the age span in type and

ncidence of pain, abilities to provide self-reports, as well t

s the role of child and family factors. For example, chil-ren of different ages tend to vary in the nature andrequency of different procedures and surgeries, andhere is evidence that most children below 4 years of agere unable to use standard self-report scales of pain in-ensity. There are other clear developmental features ofain. Pain, as measured by self-report and by behavioruring blood draws, for example, decreases with agerom 6 years through the teenage years, with girls re-orting more pain than boys over the age range.27,28,74

he role of parents in pain management also changesith development.7 In addition, the incidence of recur-

ent pain follows a clear developmental sequence. Head-che, for example, increases dramatically with age. Be-ore puberty, recurrent headache occurs at a low rate,nd there is a slightly greater incidence of headache inoys than girls.66,74 With the onset of puberty, the inci-ence of both migraine and tension type headaches in-reases dramatically, and females assume the muchigher incidence of headache that is shown in adult stud-

es.66 For these reasons, we made each of our decisionsith developmental issues clearly in mind. We consid-red evidence of developmental change in the relevancef specific outcome domains and the appropriateness ofpecific measures and generally preferred measures thatave been shown to be valid across a broad age range. Inertain circumstances, however, different measures areore appropriate for different ages.

rocessA 2-stage Delphi poll18 was conducted before a 2-day

onsensus meeting that discussed the results of the pollnd made final recommendations.The Delphi poll was conducted by e-mail and askedarticipants to rate the outcome domains that had beenuggested in the original IMMPACT recommendations72

nd to recommend others. This information was solicitedor acute pain and for chronic pain in 2 age groups (3–6ears and 7–16 years). The participants were also askedo suggest possible measures for each domain. The re-ults from the first poll were summarized and were sup-lied to the participants for the repeat poll. The Delphioll results were used as a guide to structure the discus-ion at the consensus meeting.The meeting reviewed the results of the Delphi poll

nd discussed acute pain domains and measures andhen went on to examine domains and measures forhronic and recurrent pain. Because of the wealth ofesearch on measures of pain intensity and the need toarefully consider the extensive data available, system-tic reviews were commissioned that reviewed scales foreasurement of pain by self-report and by observation

f behavior. The self-report review67 was performed by aeam headed by Jennifer Stinson and the behavioraleasures review79 was conducted by a team headed byarl von Baeyer. The team leaders were chosen for theirxpertise in pain measurement and because they hadot been involved in the development of any measureshat their group reviewed and they were present at

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eviews67,79 are available on the PedIMMPACT page atww.immpact.org/meetings.html. On the other hand,

onsensus group members who had developed particu-ar measures were allowed full participation in all discus-ions during the meeting or consultations. During oureliberations, we considered but were not constrainedy the work of previous IMMPACT consensus articles onomains and measures in chronic pain in adults.20,72

A consultation was held with the wider pediatric painommunity. Two announcements with a summary of ouronsensus were placed on the Pediatric Pain listservhttp://pediatricpain.ca/ppml/ppmlist.html), and recipi-nts who requested a full copy were sent a copy of theraft consensus document. The comments were re-iewed by the senior author, and suggestions were in-orporated. Consensus was refined by e-mail exchangesith the other authors after the meeting.

esultsThe domains to be used in a clinical trial should corre-

pond to the objectives of the study, include the fullange of outcomes of interest, and be appropriate forhe problem and for the populations studied.72 We se-ected domains to recommend for consideration in pedi-tric clinical trials that would meet these criteria, woulde clinically meaningful, developmentally appropriate,nd responsive to intervention.Criteria for selection of measures were based on thosesed by Dworkin et al20 and on previous work.26,64 Theseriteria include (1) appropriateness of the measure’s con-ent and conceptual model; (2) reliability; (3) validity;4) responsiveness; (5) interpretability; (6) precision ofcores; (7) respondent and administrator acceptability;8) respondent and administrator burden and feasibility;9) availability and equivalence of alternate forms andethods of administration (eg, self-report, interviewer);

nd (10) availability and equivalence of versions for dif-erent cultures and languages. In addition, we empha-

able 1. Core Outcome Domainsecommended for Consideration in Clinicalrials of Pediatric Acute Painain intensitylobal judgment of satisfaction with treatmentymptoms and adverse eventshysical recoverymotional responseconomic factors

able 2. Evidence-Based Recommendations forlinical Trials in Children and Adolescents

AGE TYPE of PAIN

to 4 years Procedure-related and postoperativto 12 years Procedure-related, postoperative, a

ized the developmental appropriateness of each mea-ure.We recommend that the domains and measures de-

cribed below be considered for use in all clinical trials ofhe efficacy or effectiveness of pain interventions in chil-ren and adolescents. We present evidence-based rec-mmendations for specific domains and measures whenhe research data support specific approaches and con-ensus recommendations when the evidence was insuf-cient to make evidence-based recommendations. Wenticipate that as research progresses, our recommenda-ions will need to be updated.

cute Pain Domains and MeasuresAcute pain can arise from (1) medical procedures rang-

ng from immunization and simple venipuncture to de-ridement of skin in severe burns, (2) postoperative painnd other medical interventions, (3) injury, and (4) acutexacerbation of disease pain. These types of acute painre quite different from one another in terms of timeourse and some of our recommendations vary, based onhe particular features or nature of the acute pain.PedIMMPACT recommends that the domains in Table 1e considered as core outcome domains in acute painlinical trials in children and adolescents. We recognizehat any one trial may not include all domains. Moreover,e wish to emphasize that we are not recommending thatultiple domains necessarily be primary outcomes for

ndividual trials. Measures of different domains are of-en not highly correlated,80 and the specific researchuestion should dictate which domains are measurednd what domain(s) and measure(s) are selected as therimary outcome. However, the appropriateness of eachomain should be considered during the design of alllinical trials with children and adolescents.

ain IntensityPain intensity is an obvious core outcome domain for

cute pain clinical trials. In pediatric pain, both self-re-ort and behavioral measures of pain have been devel-ped, validated, and widely used. Behavioral measuresf pain were developed because children below the agef about 3 to 4 years cannot provide valid self-reports.35

The PedIMMPACT group reviewed and accepted theecommendations in the commissioned literature reportn self-report measures of pain intensity (Table 2). Exten-ive details on the justification for the selection of theseeasures are available in Stinson et al.67

The Poker Chip Tool consists of a set of 4 red plasticoker chips, each used to denote a “piece of hurt.” The

f-Report Measures of Acute Pain Intensity in

MEASURE CITATION

Poker Chip Tool Hester et al35

sease-related Faces Pain Scale-Revised Hicks et al36

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hild is asked to choose “how many pieces of hurt” theyave right now. Children without pain would say they doot have any pieces of hurt. The first chip corresponds toa little hurt,” the second chip indicates “a little moreurt,” the third chip means “more hurt,” and the fourthhip equals the “most hurt you could ever have.” Theoker Chip Tool is scored from 0 to 4.35 The Poker Chipool has undergone extensive psychometric testing byarious teams of investigators.30,32,69

There are many different “faces” scales for the mea-urement of pain intensity. The Faces Pain Scale – RevisedFPS-R)37 is a revised version of a scale originally devel-ped by Bieri et al.6 It consists of 6 gender-neutral linerawings of faces that are scored from 0 to 10. It haseen shown to have adequate psychometric proper-ies.9,10,32

We concluded that self-report measures of pain inten-ity are not sufficiently valid for children below 3 years ofge. With children of 3 and 4 years of age, many will note able to accurately self-report their pain and as a re-ult, an observational measure should also be used. Con-equently, the use of self-report of pain as a primaryutcome in 3- to 4-year-old children may not be war-anted.The numerical rating scale (NRS), in which pain inten-

ity is reported, for example, on a 0 to 10 scale. (NRS-11)r 0 to 100 scale (NRS-101), was seriously considered be-ause of its ease of use and ease of charting. Despite theidespread use of the NRS in clinical practice, the lack of

esearch on the NRS, except in the context of the Oucher5

n children and adolescents in acute pain precluded aecommendation for its use.Readers will note the contradiction in recommending a

isual analog score (VAS) but not an NRS when the VASequires a higher degree of abstraction than the NRS andhe VAS cannot be used in telephone follow-up. Thisnomaly in our recommendations has occurred becausef the lack of psychometric studies with the NRS in chil-ren and adolescents. This is an area for further research.Table 3 contains PedIMMPACT recommendations for ob-

ervational pain scales that should be considered for acuteain trials. Different scales are recommended for differentituations because they were designed for and validated inifferent circumstances. So, for example, the only observa-ional measure recommended for use by parents is the Par-nts’ Postoperative Pain Measures12 and the only mea-ure recommended for consideration in children inritical care settings is the COMFORT scale.1 More exten-ive justification of the selection of observational mea-

able 3. Evidence-Based Recommendations forAGE TYPE of PAIN

year and above Procedural pain; postoperative pain in hospitalyear and above Procedural pain; postoperative pain

year and above Postoperative pain at homeyear and above On ventilator or in critical care

ures is available in the commissioned paper prepared byon Baeyer and Spagrud.79

The FLACC scale50 is a 5-item scale that raters use tocore each of 5 categories, namely, (F) Face; (L) Legs; (A)ctivity; (C) Cry; and (C) Consolability, which are scored

rom 0 to 2. There are extensive reliability and validityata on the FLACC.45,50

The Children’s Hospital of Eastern Ontario Pain ScaleCHEOPS)46 has raters assess 6 behaviors (crying, facialxpression, verbal expression, torso position, touch, andeg position). There are extensive reliability and validityata on the CHEOPS.46,70

The Parent’s Postoperative Pain Scale11 is a 15-itemcale in which parents are asked to report on changesrom children’s usual behavior. The scale has been wellalidated.8,11,25

The COMFORT Scale1 measures alertness, calmness/gitation, respiration, physical movement, blood pressurehange, heart rate change, muscle tone, and facial tension.xtensive validity data are available for the COMFORTcale.75

The Toddler-Preschooler Postoperative Pain Scale is anbservational scale for measuring postoperative painpecifically for children aged 1 to 5 years. There are rea-onable validity data for this scale70,71 Studies have beenimited to relatively short-term pain (mostly a few hours)rom common surgeries. Although we believe extrapola-ion to longer term studies is reasonable, there are as yeto data available.Two types of single-item observational scales, global

cales and behaviorally anchored scales, were consideredut not recommended. Global scales require a single rat-

ng of the amount of pain by an observer. There may benchors such as “no pain” and “severe pain.” Globalcales, such as a VAS used by adults (parent, nurse, oresearch assistant) to rate children’s pain, have the ad-antage of being very simple to use. However, they maye prone to bias and poor validity because of the absencef any criteria for scoring pain. Van Dijk et al76 reviewedhe data on the VAS as an observational measure andoncluded there were not sufficient data to recommendts use.

Behaviorally anchored pain intensity scales have beeness widely used. They have several anchors of specificehaviors within a single item.38,59 There is insufficientvidence for their validity to recommend their use.Often, measures of pain intensity are used in the con-

ext of the duration of the pain. So, for example, theverage of multiple measures may be taken, or time pe-

ervational Measures for Acute Pain IntensityMEASURE PRIMARY CITATION

FLACC: Face, Legs, Arms, Cry, Consolability Merkel et al50

CHEOPS: Children’s Hospital of EasternOntario Pain Scale

McGrath et al46

PPPM: Parents’ Postoperative Pain Measure Chambers et al12

COMFORT Scale Ambuel et al171

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iods with pain above or below some level may be exam-ned. The purposes of the study will likely dictate the wayhat duration of pain is assessed.

lobal Judgment of Improvement and ofatisfaction With TreatmentGlobal judgment of satisfaction with treatment allowsatients or patient surrogates to provide an aggregatef their perspective of all aspects of the treatment expe-ience. Patient global ratings of satisfaction have notften been used in pediatric pain trials and thus it is ahallenge to assess the value of this domain in pediatricain. However, patient global ratings are widely usednd perceived as very useful in adult pain trials20 and inlinical trials for other problems. Patient global judg-ents focus on the patients’ experience and thus are, by

heir nature, patient-oriented.Both global ratings of improvement from the begin-ing of the trial and global ratings of satisfaction withreatment have been used extensively in the adult liter-ture.20 A recent meta-analysis of adult pain trials15 sum-arized data from 150 randomized, double-blinded tri-

ls included in 11 systematic reviews of single-dose, oralnalgesics for postoperative pain and found that globalatisfaction measures were highly correlated with morene-grained measures. Different formulations of thelobal satisfaction question did not appear to be impor-ant.The major issue with global ratings of satisfaction with

reatment is the concern that the ratings will meanomething different from one patient or surrogate tonother. Some may focus exclusively on the relief ofain, whereas others may consider side effects of thereatment. There are no data on the relationship be-ween patient global satisfaction questions and proxyatings by parents. In the case of children below about 8ears of age, only proxy measures are available.PedIMMPACT recognized the lack of sufficient informa-

ion regarding patient global satisfaction with treatmentatings in pediatric pain trials on which to base an evidence-ased recommendation and emphasizes the need for moreesearch in this area. However, PedIMMPACT supports these of patient global or proxy global satisfaction measureshat are standardized so as to maximize the chances thatll individuals are using the same components to deter-ine their responses.The consensus was that global satisfaction should be

scertained by posing a global question about satisfac-ion with treatment with indications of what should beonsidered in the answer, for example, “Consideringain relief, side effects, physical recovery, emotional re-overy, and economic considerations (if appropriate),ow satisfied were you with the intervention your childeceived?” A common metric such as an NRS-11 (rating of–10) could be used. Following this rating, the reason for

he rating should be ascertained. For adolescents, theuestions could be posed directly to them.Given the importance of patient and parent satisfac-

ion in the uptake of any treatment and the importance

hronic pain, we were surprised with the lack of researchn this area in pediatric clinical trials. Such research isreatly needed.

dverse Events and SymptomsAll clinical trials with pharmaceuticals are required to

nalyze and report adverse events. This is less common inehavioral clinical trials and precludes the understand-

ng of the harm-benefit balance of these trials.24 Weecommend that adverse events be routinely ascertainedn behavioral trials as well as those of biomedical treat-

ents.Treatment-emergent adverse events refer to newly

merging signs, symptoms, laboratory findings, or dis-ases that occur after treatment is initiated. All treat-ent emergent adverse events should be reported.Serious adverse events—including death, hospital-

zation, prolongation of hospitalization, disability, orvents requiring intervention to prevent these out-omes—are often quite apparent and require immedi-te reporting on appropriate forms to local ethicsoards and regulatory agencies. Less serious adversevents are typically ascertained only if they are spon-aneously reported by the patient or by the clinicianaring for the patient. Often there is no particulartrategy to measure either the occurrence or severityf the events. Measurement of both is important, as 2

nterventions with similar occurrence of adversevents but different severity of adverse events are

ikely to be differentially accepted by patients.The most typical method used for measuring adverse

vents can be characterized as passive, unstructuredapture of events. Passive capture will minimize re-orting of adverse events and may under representhe actual occurrence of adverse events.3 Standardizedtrategies to discern the occurrence and severity ofdverse events will lead to more accurate reporting.ne concern with using standard lists to enumeratedverse events is that they may prime affirmative re-ponses. Thus, it is important to carefully balance thedvantages and disadvantages of approaches that usepen-ended inquiry compared with extensive lists ofotential signs and symptoms.No studies have been undertaken on standardized ac-

ive capture of adverse events in the treatment of pain inhe pediatric age range. We emphasize the need for re-earch in this important area.PedIMMPACT recognized that there is a lack of re-

earch on the assessment of adverse events in clinicalrials with children and adolescents and that insufficientvidence exists for evidence-based recommendations.owever, PedIMMPACT recommends that consideratione given in pediatric clinical trials to the active capture ofymptoms and adverse events and that the severity andmportance of each event be ascertained. Children olderhan 10 years may be able to be the prime informants. Inounger children, parents or caregivers will have to besed to give proxy data. However, proxy data especiallyor nonobservable phenomena (eg, hot flashes, racing

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earchers to develop appropriate measures in this verymportant area.

hysical RecoveryThe domain of physical recovery includes those aspectsf physical functioning that are influenced by the proce-ure or injury causing acute pain.40 Physical recovery isot a relevant domain for short procedures, such as nee-le sticks. However, it is an appropriate domain thathould be included for postsurgical trials and trials ofain management in injuries. The specific measure used

n this domain in acute pain will depend on the study. Forxample, swallowing 50 mL of water might well be im-ortant in a study of pain management in tonsillectomyut not particularly relevant in a trial of pain in herniaepair. Possible measurements of the physical recoveryomain include time to ambulation, time to resumewallowing, time to normal spirometry, oral intake, andime out of bed. The measure should be taken in a stan-ardized way across all participants in a clinical trial. Forxample, assessment of swallowing should involve a spe-ific set of instructions, a specific type and amount ofuid, and specified criteria for success.Measures such as tolerance of physical therapy areroblematic unless careful attention is paid to standard-

zation. One child might be said to be intolerant of phys-cal therapy because he or she did not want to go whensked, whereas another might be said to be intolerant tohysiotherapy only if he or she cried and refused to con-inue with physical therapy. There is also a wide range ofpproaches to physical therapy. One center may have anggressive and intrusive therapy program whereas an-ther may have a less intense program.Currently, there are no well-validated measures for as-

essing physical recovery in acute pediatric pain. Validated,tandardized measures would simplify the job of the clini-al trial investigator and facilitate comparisons across stud-es. The PedIMMPACT recommendation is that existing

easures of physical recovery should be systematically as-essed and that additional efforts should be devoted toeveloping measures of physical recovery that are appro-riate for the purposes of evaluating interventions to con-rol pain following procedures and injuries that have spe-ific effects on physical functioning.

motional ResponseThe domain of emotional response includes all aspectsf negative affect or distress secondary to pain. Thesemotions may include the affective component of pains well anxiety, depression, fear, distress, dysphoria, ornhappiness. The behavioral equivalents may be avoid-nce, withdrawal, or resistance. The maintenance of pos-tive affect would also be considered as part of this do-

ain.If the affective component of pain is to be measured,n the basis of evidence, PedIMMPACT recommends usef the Adolescent Pediatric Pain Tool.63 It is conceptuallyased on the McGill Pain Questionnaire,49 uses a set of 56ords grouped according to sensory, affective, and eval-

sed for children 8 years of age and over. In terms ofingle-item scales of the affective component of pain, weake an evidence-based recommendation to use the Fa-

ial Affective Scale47 that consists of 9 faces that vary inhe level of overt distress. This measure has been usedith young children but it is not clear that the affectiveeasures of pain are differentiated from intensity be-

ore about 8 to 10 years of age.We recommend, on the basis of evidence, the follow-

ng observational measures for the assessment of behav-oral distress during procedures: Procedure Behaviorheck List (PBCL)44 and the Procedure Behavioral Ratingcale Revised (PBRS-R).39 Both can be used for patients 1ear of age and older.There are many measures of depression and anxiety in

hildren. However, almost all validated measures haveeen used in the context of mental health problems andometimes in the context of chronic illness or chronicain. We recognized that simple measures of negativeffect may be appropriate in the context of acute painnd that VAS or NRS measures have been used. However,e believed there was insufficient evidence to make a

ecommendation for the use in acute pain trials of VAS orRS measures of negative affect at this time.

conomic FactorsPedIMMPACT determined that little research on eco-omic factors has been undertaken in pediatric pain andhus no evidence-based recommendations were possi-le. However, as a consensus group, we recommend thatconomic factors should be considered for inclusion inlinical trials of interventions for acute pain. The exacteasure used will depend on the purposes of the study

ut most likely will include both direct costs and indirectosts of different interventions. Direct costs include med-cal costs such as hospitalization, doctor’s visits, and costsf drugs. Indirect costs include parental time off work,ransportation costs, childcare, and incidental costs.Measurement of these costs will vary from study to

tudy depending on the goals of the study. For example,arly discharge from hospital might be one of the pri-ary outcomes in a study that was designed to reduce

ospital time, whereas cost of medication might be anppropriate outcome in a comparison of an expensivend less expensive drug. However, it is important to en-ure that the complete range of appropriate economicosts is included.Rescue medication or remedication is an inherent partf many single dose trials but very variable. In addition,he handling of data when remedication occurs is incon-istent.4 PedIMMPACT made no recommendations onescue medication other than that the reporting shoulde clear.

hronic and Recurrent Pain: Domainsnd MeasuresThere are many definitions of chronic pain, but theest accepted is to consider it pain that has persisted formonths or more or beyond the expected period of

ealing.51 Chronic pain conditions that are found in chil-

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ren and adolescents include, for example, complex re-ional pain syndrome and chronic daily headache. Recur-ent pain is pain that is episodic but reoccurs. Typically, aime frame within which episodes of pain recur of ateast 3 months is used. Examples of recurrent pain in-lude migraine headache, episodic sickle cell pain, recur-ent abdominal pain, and recurrent limb pain. Chronicnd recurrent pain conditions can coexist, as in someorms of sickle cell disease pain, or can be independent.hronic and recurrent pain can occur for known or un-nown reasons.Virtually all intervention research in chronic and recur-

ent pain has been conducted with adolescents. This re-ects the increasing prevalence of chronic and recurrentain that occurs in that age group. Thus, our recommen-ations must be considered with caution as applied toesearch with younger age groups.Table 4 contains the domains that we recommend

hould be considered for measurement in clinical trials ofhronic or recurrent pain. These domains are very similaro those recommended for consideration in clinical trialsf acute pain. We used slightly different terms in 2 do-ains. We use the term physical functioning in chronic

nd recurrent pain versus physical recovery in acute pain.motional functioning was used in chronic and recurrentain versus emotional response in acute pain. These dif-erences reflect the longer time course in chronic andecurrent pain than in acute pain. We also recommendonsideration of 2 domains, role functioning and sleep,n clinical trials for chronic and recurrent pain that wereot recommended in acute pain.For many domains, the same or very similar measures

re recommended for use in acute and chronic pain clin-cal trials. In these cases, we refer the reader back to therevious discussion in the acute pain section of this arti-le. However, several aspects of measurement are differ-nt because of the differing time course of chronic andecurrent pain versus acute pain. The attendees at theonsensus meeting had available a prepublication ver-ion of a review of measures used to assess the impact ofhronic pain on adolescents.21

ain IntensityAspects of the pain experience are typically the pri-ary outcome domain in treatment of chronic and re-

able 4. Core Outcome Domainsecommended for Consideration in Clinicalrials of Pediatric Chronic and Recurrent Painain intensitylobal judgment of satisfaction with treatmentymptoms and adverse eventshysical functioningmotional functioningole functioningleepconomic factors

urrent pain. However, there may be occasions, such as in t

ultidisciplinary chronic pain treatment, when the mostmportant outcome domain is disability. Disability spanshe domains of physical, emotional, and role function-ng.

We recommend the same self-report measures for as-essing pain intensity in chronic and recurrent pain clin-cal trials as we have for acute pain (Table 2). However,he method of collection of pain measures may be dif-erent. In chronic and recurrent pain, investigators maye most interested in pain over a longer time span than

n acute pain. The number of pain-free days or days inhich pain does not reach a specific level (eg, 3 on a-point scale) may also be pain intensity end points.Pain diaries are commonly used to assess pain symp-

oms and response to treatment in children and adoles-ents with recurrent and chronic pain. Diary methodolo-ies have been shown feasible and valid with severalecurring pain conditions including pediatric headachend sickle cell disease.19,56,62 Most pain diaries use anRS-6, in which reports are made on a 0 to 5 scale. Vary-

ng anchors do not seem to make a difference in rat-ngs.62 Other diaries may use faces scales or a VAS. Pro-pective diary methodologies may increase the validityf children’s pain reports in comparison to retrospective

nterviews31 that depend on retrospective summarizingnd averaging of symptoms. However, retrospective re-orts more closely reflect the clinical situation in which alinician asks questions such as “How have you been do-ng?”

The developmental level at which a child is capable ofelf-report via a daily diary has not been adequatelytudied; however, children as young as 6 years have beenncluded in diary studies. Until recently, pain diary meth-dology in children relied exclusively on conventionalaper-and-pencil measures, which have been associatedith several limitations including poor compliance, miss-

ng data, hoarding of responses, and back and forwardlling.56,68 Recently, the electronic diary methodologyas evaluated in school-age children and adolescentsith chronic pain.57 Advantages were found for increas-

ng the accuracy of children’s diary responses as well as inompliance using the electronic format compared to theaper format. These advantages in compliance are simi-

ar to those found in adult pain patients.68 Electroniciaries have the disadvantage of being expensive, incor-orate a number of logistical issues that must be re-olved, and there is limited experience in their use. Tour knowledge, there have been no pediatric clinical tri-ls that have compared the responsiveness with treat-ent of paper-and-pencil versus electronic diary assess-ents. Therefore, PedIMMPACT did not have specific

ecommendation about the use of electronic diaries, buthis methodology shows promise for future study.

lobal Judgment of Satisfactionith Treatment

There is insufficient research to make an evidence-ased recommendation. We suggest the same approachor measuring global judgment of satisfaction with

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hat is, a global question with specifiers. The context wille different as chronic and recurrent pain conditionsave a much longer time course than acute pain. More-ver, since we recommend somewhat different domainsor chronic and recurrent pain, our recommended ques-ions are somewhat different. We suggest wording suchs “Considering pain relief, symptoms, adverse events,ow your child is doing physically, emotionally, and in hisr her roles as a student and family member, sleep andconomic factors (if appropriate), how satisfied were youith the treatment your child received?” A commonetric such as a rating of 0 to 10 (NRS-11) could be used.

or adolescents, the questions could be posed directly tohem.

ymptoms and Adverse EventsWe recommend the same approach for measuring

ymptoms and adverse events in chronic and recurrentain as in acute pain. The context will be different ashronic and recurrent pain conditions have a muchonger time course than acute pain.

hysical FunctioningPhysical functioning in chronic and recurrent pain isifferent than physical recovery in acute pain. The do-ain in chronic and recurrent pain is most likely to be

ocused on activities of everyday life. Children and ado-escents with pain may be impaired in normal activitiesuch as sitting or walking or in more vigorous activitiesuch as running and other sports.We recommend the use of the Functional Disability

nventory that was developed by Walker et al81 for mea-uring physical functioning in school age children anddolescents. This measure asks about being able to do aange of everyday physical activities. The psychometricroperties of the Functional Disability Inventory haveeen well established with different populations.14,61,78

We recommend use of the PedsQL (www.pedsql.org)eveloped by Varni et al77 for assessing the physical func-ioning domain in younger children (less than 7 years).he PedsQL is a multidimensional scale with both parentnd child report versions that measures (1) Physical Func-ioning, (2) Emotional Functioning, (3) Social Function-ng, and (4) School Functioning. It is suitable for childrennd adolescents from 2 to 18 years.

motional FunctioningThe emotional functioning domain in chronic and re-

urrent pain trials most often refers to depression andnxiety. These 2 components of negative affect are oftenelated. Both anxiety and depression are elevated in chil-ren with chronic and recurrent pain,54 but most chil-ren with chronic or recurrent pain do not have clinical

evels of anxiety or depression.43

There are several well-established measures for childnd adolescent depression. We recommend the Chil-ren’s Depression Inventory41 because of its psychomet-ic properties and widespread use in pediatric pain stud-es. It is applicable from ages 7 to 17 years. We also

cale (RCADS) developed by Chorpita13 as a measure ofnxiety and depression separately and of negative affecthen these 2 scales are combined. As noted above, welso recommend the PedsQL77 for assessment of emo-ional functioning in younger children.

ole FunctioningChronic and recurrent pain can significantly interfereith the roles that children and adolescents, like adults,erform. These roles include being a student, friend, em-loyee, and family member. The nature of these roleshanges with development. For example, absence from aob is typically not relevant in younger children but maye of more importance in some adolescents.We recommend the use of school attendance as a mea-

ure of role functioning in school-age children. Becausechool attendance is mandatory, absence from school isn important measure of fulfillment of the role of stu-ent. We also recommend the PedMIDAS,33,34 which haseen validated for measurement of role functioning inhildren ages 6 to 18 years with persistent headache. Weecommend the PedsQL77 for assessment of role func-ioning across the age span.

leepThe role of sleep in chronic and recurrent pain has noteen widely investigated in children and adolescents.owever, preliminary evidence with pediatric popula-

ions55 and studies from the adult literature42 suggesthat sleep disruption is common in chronic and recurrentain. Walters et al82 found that more than half of chil-ren with pain-related conditions report difficultiesleeping. Palermo and Kiska55 used self-report question-aires in samples of adolescents with headache, juvenile

diopathic arthritis, or sickle cell disease and found thatepressive mood was predictive of sleep problems.We recommend the inclusion of sleep as a core out-

ome domain to be considered in chronic and recurrentain clinical trials. However, it is not possible to recom-end a specific measure of this domain because few

linical trials have included this outcome.Most sleep researchers agree that the gold standard

or measurement of sleep is night time polysomnogra-hy. However, polysomnography is intrusive and unreal-

stically expensive for widespread use in clinical trials.ctigraphy is another validated strategy for measuring

leep that uses a movement sensor.2 Sleep diaries inhich the child (or parent) keeps a record of the time too to bed, fall asleep, and wake up are used but littlealidation work has been done. Recently, Gaina et al29

ave validated the sleep diary against actigraphy inealthy children aged 13 and 14 years. Finally, instru-ents such as the Sleep Habits Questionnaire,53 which

urvey school age children on their sleep, may be useful.

conomic FactorsAs in acute pain, economic evaluations have not beenidely used and typically have been simplistic, hypothet-

cal, or retrospective rather than comprehensive and pro-

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780 PedIMMPACT Recommendations

n improvement in relation to contact time with a healthare provider, that online treatment for headaches andecurrent abdominal pain was 5.5 times more cost-effi-ient than would be face-to-face treatment.The challenge of determining total costs and benefitsf treatments in children and adolescents is even greaterhan in adults. Many of the effects on productivity arendirect. For example, it is usually the parent or guardianho does the driving and misses work to take a childatient for treatment. The impact of prolonged absencesrom school may not be appreciated until the effects onollege or vocational training have been felt.Comprehensive examination of economic factors will

equire assistance of health system economists or otherpecialists. However, sophisticated cost analyses thatrospectively account for all costs are needed. It is notossible to recommend specific measures of this domaint this time.

omposite Domains and MeasuresComposite domains, for instance, health-related qual-

ty of life, could include several domains, such as physicalunctioning, emotional functioning, and role function-ng. A disadvantage of composite domains is that it is

ore difficult to know the specific changes that haveontributed to a difference between groups.Composite measures, in which a single instrumenteasures several different domains, have the potential

o reduce the burden on patients and to make data col-ection simpler and easier for all. On the other hand, theontent of composite measures may not match the spe-ific needs of a given study. In some cases there is psy-hometric evaluation of each component, whereas forther measures there is no psychometric evaluation ofubscales (or there may not be subscales). The individualubscales will not be interpretable if they have not eacheen psychometrically evaluated.Our recommendations could be met using compositeomains or composite measures. However, the compos-

te domain should be relevant for the particular study.he composite measure should have appropriate psycho-etric validation to answer the questions posed in the

tudy.

eview by the International PainommunityA 2-page summary of the PedIMMPACT recommenda-

ions described above was distributed to the Pediatricain Listserv (http://pediatricpain.ca/ppml/). The postingo the listserv invited interested parties to comment.ight comments were received, reviewed by the first au-hor, and integrated into the text.

iscussionOur consensus group of individuals representing aca-emic research, government funding and regulatorygencies, and the pharmaceutical industry used a varietyf consensus strategies (Delphi poll, consensus meeting,

f core outcome domains and measures that should beonsidered when designing clinical trials for acute orhronic pain in children over the age of 3 years.We are not suggesting that each of these domains andeasures be required for submission to regulatory agen-

ies or for publication in a scientific journal. Moreover,e do not suggest that positive results must be found forll of the domains and measures for a treatment trial toe considered positive. Importantly, the use of multipleutcome measures does involve unique interpretationalnd statistical issues.52 Although discussion of these is-ues is beyond the scope of the present article, they werehe focus of a separate IMMPACT meeting and publica-ion of recommendations is forthcoming.It should be noted that the PedIMMPACT group fo-

used on acute as well as chronic and recurrent pain inhildren to recommend assessment approaches for theseroblems. Although there may be overlap in specific as-essment strategies, that should not be taken to meanhat the etiology of acute and chronic pain syndromesre thought to be the same. Clearly for the latter, con-extual factors often take on greater importance andhould be assessed. Furthermore, as we better under-tand mechanisms underlying the onset and mainte-ance of chronic pain, identification of more specific as-essment strategies will ensue. To date, however, suchondition-specific targeted assessment approaches haveot been developed and validated.There will be clinical trials for which 1 or more of our

uggested domains or outcomes are not appropriate.etter measures may also be developed. Additional do-ains and measures may also be used as process mea-

ures. However, the reasons for selecting each measuresed in a clinical trial should be detailed. We also urgehat the reasons for not selecting recommended do-ains and measures be explicated.Clinical trialists will choose to have different domains as

rimary, depending on the focus of the trial. For example,n a rehabilitation-oriented intervention for chronic pain indolescents, the domain of pain intensity would not be arimary outcome if the focus of the intervention was on

ncreasing function. However, pain intensity would likelye a secondary outcome domain.The major strengths of this PedIMMPACT consensusrocess were the breadth and knowledge of the consen-us group and the extensive efforts used to develophese recommendations. These efforts included Delphiolling, a consensus meeting, commissioned systematiceviews, and an international consultation.A limitation of the PedIMMPACT consensus effort thateeds to be acknowledged is that many areas lack keyesearch studies. This dearth was especially evident withespect to the selection of specific measures for several ofhe recommended core outcome domains. As a result,he pediatric clinical trialist is left in a serious quandary.hould measures of unknown reliability and validity besed which may thus risk the interpretability of the trial?r should important outcome domains be ignored be-

ause of the lack of reliable and valid measures, preclud-

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learly, this dilemma can only be solved by developmentnd testing of appropriate measures. In the meantime,e encourage pediatric pain investigators to consider

eriously the value of collecting and analyzing the datahat we recommend. In many instances, testing of reli-bility and validity can proceed hand in hand with these of data as outcomes. The use of a standard set ofomains and measures will permit the pooling of datand facilitate establishment of the adequacy of the psy-hometric properties of these instruments.We are confident that this process of identifying com-on domains and measures will strengthen the effort toevelop appropriate measures and increase the numbernd quality of clinical trials in pediatric pain. Becauselinical trials are keystone knowledge transfer vehicles,his probably will improve the care given to our youngatients.These recommendations will have a finite lifespan. Weope that our recommendations for specific measuresill lead to refinements and innovations as researchvaluates the application of well-established measures

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o fill the serious gaps in the literature we have identi-ed. For example, a new composite measure of chronicain in adolescents, the Bath Adolescent Pain Question-aire, has been developed by researchers in Bath, Unitedingdom,22 but there are insufficient data to recommendhis measure at this time. Similarly, Palermo et al58 devel-ped the Child Activity Limitations Interview, a measure ofain-related functional impairment in school-age childrennd adolescents that shows promise but requires furtheresearch before its use can be recommended.In summary, PedIMMPACT was an international con-

ensus process that recommended specific domains andeasures for clinical trials in acute and in chronic and

ecurrent pain. These recommendations are based onhe best available research and expert opinion and wereeveloped to improve the quality, interpretability, andggregation of clinical trials for the treatment of pediat-ic patient with pain.

cknowledgmentsThe authors appreciate the administrative support pro-

ided by Paul Lambiase and Mary Gleichauf.

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