GUI DELI NE Open AccessPain care for patients with epidermolysis bullosa:best care practice guidelinesKenneth R Goldschneider1*, Julie Good2, Emily Harrop3, Christina Liossi4,5, Anne Lynch-Jordan6, Anna E Martinez7,Lynne G Maxwell8and Danette Stanko-Lopp9AbstractBackground: Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effectsand patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial.Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care forthese patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge andpractice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB.Methods: The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International(DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge forEB patients worldwide. An international panel of experts in pain and palliative care who have extensive experiencecaring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of carewithout direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted.The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as wellas the panel of clinical experts. During development, EB family input was obtained and the document was reviewed bya wide variety of experts representing several disciplines related to the care of patients with EB.Results: The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinicallyrelevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care ofpatients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs betweenadults and children, it will be so noted.Conclusions: Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease isoften times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guidelinedevelopment process also highlighted areas for research in order to improve further the evidence base for future care.Keywords: Epidermolysis bullosa, Pain, Practice guidelines, RDEB, DEBRA, Acute pain, Chronic pain, Recessive dystrophicepidermolysis bullosa, Dystrophic Epidermolysis Bullosa Research Association InternationalBackgroundInherited epidermolysis bullosa (EB) comprises a group ofrare disorders, generally thought of as skin diseases. How-ever, EB has multi-system effects and patients present withanumberofboth acuteandchronicpaincare needs[1].Effectsonqualityof lifearesubstantial [2,3]. Duetoitslow prevalence, expertise in pain care for patients with thisdisease is often restricted to a few specialized care centers.Eventhen, evidence-basedpaincareislimitedbyanearabsenceof scientificliteraturespecifictoEB. Thissetofguidelines was requested by Dystrophic EpidermolysisBullosa Research Association International (DEBRA Inter-national) to help standardize the approach to pain care forbothadultandpediatricpatientswithEBinall partsofthe world. Consequently, a group of clinical pain care ex-perts fromafewcountries havecometogether tolendtheirexperienceto thelimited scientificliteratureto cre-ate these guidelines.Thepresent guidelinesonpaincareforpatientswithEBarebasedonareviewandsynthesisof theavailable* Correspondence: Kenneth.goldschneider@cchmc.org1Pain Management Center, Department of Anesthesiology, Cincinnati ChildrensHospital Medical Center, Cincinnati, Ohio, USAFull list of author information is available at the end of the article 2014 Goldschneider et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.Goldschneider et al. BMC Medicine 2014, 12:178http://www.biomedcentral.com/1741-7015/12/178literature, guided by expert consensus and thoughtfulapplicationof theory. The guidelines are divided intofour topics: psychological treatment of pain and pruritus,acute pain, chronic and recurrent pain, and specialtopics. The Psychological andIntegrativeTreatmentssectionleads off because the informationit containsapplies toall the topics that follow. The Acute Painsection focuses on postoperative pain. The ChronicandRecurrentPainsectionincludesdressingchanges,baths, skinpainandjoint andother bodypains. TheSpecial Topics section includes pain care in infantswith EB and pain care at the end of life. While not painperse, itchingisamajorsourceofdiscomfort[4]andis also discussed.Theaimof theguidelinesistoprovidetheuserwithinformationonpaincarefor childrenandadults withEB. Theseguidelinescanbeappliedtoallpatientsdiag-nosed with hereditary forms of EB. Patients with ac-quired forms are not included inthe guidelines. Theguidelinescontaintwotypesofguidance. Recommenda-tions are graded and highlighted in text boxes at the endof themanuscript. GoodPracticePointsarelocatedattheendofeachtopicalsectionandsummarizeconceptsandbest practices, basedontheclinical experienceofthe guidelines development group.Thedailyroutineof manypatientswithsevereformsof EBwill have a number of painful events, each ofwhichmaysuggest theneedforintervention. However,addressing each one pharmacologically may lead to alevel of sedation that prevents a meaningful level ofproductivity. Itisimportanttodiscusstheneedsof thepatientandtheoptionsforcaringforthoseneedswiththepatientandfamily. Together, thepatient, familyandpractitioner can transform the guidelines into an individ-ualizedcareplan. It is tobeexpectedthateachpatientsneedswillbedynamic; periodicreviewoftheneedsandgoals will optimize care at each step of the patients life.Of note, the termEB will be usedthroughout thetext. However, four major types of EBareknownandarecategorizedasSimplex(EBS), Junctional (JEB), dys-trophic types (DEB) and Kindler Syndrome. Arecentconsensus statement was releasedthat reclassifiedthesubtypesfurther basedonanatomiclocationwithintheskin and pattern of involvement, and discouraged the useof eponyms (withthe exceptionof Kindler Syndrome).EBSissub-typedasEBSsuprabasalandEBSbasal, JEBasJEBgeneralizedandJEBlocalized, DEBasRecessiveDEBand Dominant DEB(RDEBand DDEB, respec-tively) [5]. Additionally, there are at least 18 genes asso-ciatedwiththedifferenttypesofEB[5]. Theproposednew classification does not address the relation to pain-ful conditions, and, thus, thefour major typeswill bereferencedthroughout theguidelines. Thereis awiderange of severity within the types. EBS is usually due toautosomaldominantmutationsinkeratin5or14orinplectinandis oftenof milder severity. JEBcanresultfrommutationsinanyofsixdifferentbasementmem-branecomponents, isinheritedasanautosomal reces-sivedisorder, andcanrangefrommildtofatal earlyinlife. DEBcanbeinamilddominantform(DDEB)oramoresevererecessiveone(RDEB), bothduetomuta-tions incollagen7. Therecommendations that followareintendedtobegenerallyapplicabletoall patientswith EBwho experiencepain. The pain conditionsvaryinprevalenceamongthetypesof EB, andreaderswillfind relevant guidelines to apply in the care of the parti-cularpainproblemstheyandtheirpatientsface. Resour-ces (for example, particular medications and formulations,trainedmedical, nursingandtherapy personnel) willvary by location, andpractitioners andfamilies will,therefore, needtoadapt therecommendations basedon what is available in their locale. DEBRA International[6] is anoptimal facilitatingorganizationthat canaidimplementationof theguidelines bywayof providinginformation, support andmeans of contactingexpertcareproviders.MethodsIn2011, a multidisciplinary working groupformedtodevelopbestcarepracticeguidelinesforpainassociatedwith EB. The group comprised representatives fromnursing, medicineandpsychology whowereexpert intheclinical careof patients withEB. Guidelines topicsand subtopics were chosen by the multidisciplinarygroup with input from outside clinicians, based on issuespresentedintheliterature, seenclinicallyandraisedfordiscussionat DEBRAInternational Congress meetings.Individuals or small groupswere assigned to thevarioussubtopics. After relevant literature was reviewed, prelim-inaryrecommendationsforeachsubsectionweremade.Recommendationswerecirculatedbyemail amongtheentire panel of experts for reviewandinput/feedbackwas incorporated. Initial citations were added or re-moved as required for accuracy and appropriateness,and criticismmade of areas of weakness. Thus, thegroup formed the first iteration of expert consensus. Therevised recommendations were recirculated to the groupforreview, toestablishconsensusmorefirmly. Apanelofoutsidereviewers, comprisingbothcliniciansandpa-tients/families, then reviewed the document for compre-hensibility, omissions and applicability.Followingexternal review(seeAcknowledgementsforreviewers), fundingbecameavailableandasubsequentsystematicevidencereviewwasconductedbyatrainedmethodologist (authorDSL). Clinical questionsandthesystematicsearchstrategyweredeveloped, basedontheguidelinetopicsandsubtopicsfromtheworkinggroup.ThepopulationofinterestcomprisespatientswithpainGoldschneider et al. BMC Medicine 2014, 12:178 Page 2 of 23http://www.biomedcentral.com/1741-7015/12/178who have any variant of EB. Theinterventionsincluded,but werenot limitedto, pharmacological, holistic, psy-chological, psychical therapy and/or environmental in-terventions. Outcomesof interestwereimprovementinsymptomcontrol (for example, pain, itch) andlevel offunction.Systematic literature searches were conducted usingMedLine, CINAHL, PsycInfo and The Cochrane Library.Searchterms for epidermolysis bullosa andpain,re-gionalanesthesia, ornerveblock wereusedasmedicalsubject headingsand/orkeywordsinall databases. ThesearchwasonlylimitedtoarticlespublishedinEnglish.No other restrictions, limits or filters were used. Publica-tiondateswerenotrestrictedforanytopicorsubtopic,as thediagnosis is rareandthere werefewstudies ofhigher level, directly-related evidence (that is, systematicreviews, meta-analyses, randomized controlled trials).Referencelistsweresearchedtoidentifystudies. Studiessubmittedbytheworkinggroupandusedintheinitialconsensus processes werealsoreviewed. Themost re-cent systematic search for pediatric acute, chronic, or re-currentpainmanagementinEBpatientswasconductedin December 2011.Citations from the evidence searches were reviewed bytitle andabstract for potential inclusion, regardless ofstudydesign(n = 1,061). Evidencerelatedtotheclinicalquestions fromsystematic reviews, meta-analyses andRCTsaswell asobservational studies, casereportsandexpert opinionarticleswerereviewed(seeFigure1). Atotal of 57 references were found and evaluated thatwere specific tothe cross matchof EBandthe pain-relatedkeywords(seeabove), of whichonly8werein-cludedintospecificrecommendations. Therationaleforincluding and excluding these references is found inTable 1 and in Additional file 1.All included articles were critically appraised using evi-denceappraisal formsfromtheLEGEND(LetEvidenceGuideEveryNewDecision) evidenceevaluationsystem[7,8]. Themethodologistassessedriskof biasinthein-cluded studies by evaluating quality for all individualstudiesbydomainandstudydesign. Thequalitylevelsfor includedstudies were recorded(seeTable 2). Thereaderwill findtheevidencelevel foreacharticleusedtodirectlysupporteachrecommendationnotedafteritscitation in the Reference section of the Summary of rec-ommendations(Table3). Agespecificityofeachrecom-mendation is also noted. Data were collected ondescriptivecharacteristics of patients, characteristics ofthepainmanagementinterventions, andassociatedout-comes of reported pain management interventions.Using the Grade for the Body of Evidence tool in the LE-GEND system [7] provided objective criteria for evaluat-ing evidence related to each recommendation (seeTable 4).Giventhe paucityof data for statistical analysis, it wasdeemedappropriate to conduct a face-to-faceconsensusmeetingon4, 5May2012inCincinnati, OH. TheLE-GENDtoolforJudgingtheStrengthofaRecommenda-tion (see Table 4) was used as a guide for finalizingrecommendationstatements bydiscussingthe body ofevidenceanddiscussingsafety/harmandother dimen-sions[7]. Theoverall GRADE(A, B, C, D)for eachrec-ommendationstatementwasthendetermined, basedonthis process and the established criteria for GRADE[9,10].Updating procedureTheguidelines will be updatedevery three years afterthe first version. If new relevant evidence is detected be-fore the update, the information will be published on the114 records identified from the working group253 records reviewedin full text for eligibility 1,040 records screened by title and abstract review 1,160 records identified 1,046 records identified through database searches 120 duplicates removed787 records excluded57 records excluded (not related to the clinical question, once reviewed in full text)196 records included in guideline body of evidence Figure 1 Flow of information through the evidence evaluation process.Goldschneider et al. BMC Medicine 2014, 12:178 Page 3 of 23http://www.biomedcentral.com/1741-7015/12/178webpageforDEBRAInternational that isdedicatedtoclinical the Pain guidelines [11].Results and discussionPsychological and integrative approachesIntroductionAbiopsychosocial approachemphasizingmedical, psy-chological andphysical therapies for painmanagementhasbeensuggestedtobethemostusefulforadultsandchildren with acute and chronic pain [12]. This approachhasalsobeenadvocatedforEBpatients[3]andshouldbeinitiatedfromearlyinyouthandmodifiedwithmat-uration. Itisrecommendedthatpsychological interven-tions be used in conjunction with physical andpharmacologic therapies.Types of therapiesPsychological therapiesforpainmanagementhavebeenshowntomodifypainintensity, reducerelateddistress,decrease pain-relatedfunctional disability andimprovepaincoping. Painful experiencesamenabletotreatmentincludeacutepainrelatedtoprocedures (for example,whirlpool treatments)ormedical routines(forexample,bandage changes, bathing), andchronicpainconditionssuch as headache, abdominal pain or other disease-relatedconditions. Psychological therapiesincludecognitivebe-havioraltherapy(CBT), hypnosis, biofeedbackandrelax-ationtraining, amongothers. CBTfocuses onchangingthe catastrophic thinking and negative emotions sur-roundingpainaswell asmodifyinglifestyletopromotewellness behavior despite chronic pain [13]. Hypnosis is aTable 1 EB-specific articles used in producing recommendationsStudy citation Study type Population (setting, patients) Intervention/Comparison groups OutcomesChiu 1999 [68] Case report Country: Canada Setting: ChildrensHospital Age: 11 years Gender:Male Patient with Severe JEBAmitryptiline (25 mg at night) wasprescribed and patient started on aprogram of cognitive behavioraltraining (hypnotic imagery, distraction).Oral midazolam (7.5 mg) was initiated20 minutes prior to bath or dressingchangePain managementGoldschneider2010 [41,42]Review articles Country: United States Setting:Childrens Hospital Patientswith EBPain management and prevention Pain managementHerod 2002 [44] Review article Country: England (London) Setting:Childrens Hospital Patients with EBGeneral pain management Pain managementMellerio 2007 [152] Review article Country: United States, England,Chile Setting: Hospital Patientswith EBMedical management General pain managementSaroyan 2009 [156] Case report Country: United States Setting:Hospital Female infant with EBS,severe, Dowling-Meara subtypeUse of IV ketamine given orally Oraladministration of IV ketamine (10 mgmL,Monarch Pharmaceuticals) at a startingdose of 0.5 mg (0.125 mgkg dose) Overfour days, the dose was titrated to 3 mg(0.75 mgkgdose) in response to observedeffectAchieve analgesia duringpainful dressing changesvan Scheppingen2008 [4]Qualitative study(Interviews)Country: Netherlands Setting:Center for Blistering DiseasesAge: 6 to 18 years Childrenwith different (sub)types of EB)Interviews conducted at homes or in hospitalQuestions explored were: (i) What problemsdo children with EB actually experience asbeing the most difficult? (ii) What is theimpact of these problems on their daily life?(iii) Are there differences in experiencesbetween mildly and severely affectedchildren?Themes of pain for severedisease (generalized blisteringwith motion impairment) andfor mild disease (localizedblistering or generalizedblistering without motionimpairment).Watterson 2004 [74] Case report Country: United States Setting:Hospital Children with EB usingperipheral opioidsTopical morphine gel applied to the mostpainful areas of skin at that time for eachchildPain scoresEB, epidermolysis bullosa, EBS, epidermolysis bullosa simples; JEB, junctional epidermolysis bullosa.Table 2 Evidence levels [8]Quality level Definition1aaor 1baSystematic review, meta-analysis,or meta-synthesis of multiple studies2a or 2b Best study design for domain3a or 3b Fair study design for domain4a or 4b Weak study design for domain5a or 5b General review, expert opinion,case report, consensus report,or guideline5 Local Consensusaa = good quality study; b = lesser quality study.Goldschneider et al. BMC Medicine 2014, 12:178 Page 4 of 23http://www.biomedcentral.com/1741-7015/12/178Table 3 Summary of recommendationsApplication Level ofrecommendationTarget agegroupKey references (evidence grade)A. Psychological therapies offer effective approaches to management of chronic and acute pain as well as itching.For chronic pain management use cognitive behavioraltherapy (CBT).B All Gerik 2005 [13] (5a), Palermo 2005 [17] (5a)For acute pain management, offer the patient distraction,hypnosis, visualization, relaxation or other forms of CBTB All Green 2005 [14] (5a), Uman 2006 [21]Consider habit reversal training, and other psychologicaltechniques for management of pruritusC All Chida 2007 [29] (1a), Ehlers 1995 [32] (2b), Azrin 1973 [30](4b), Hagermark 1995 [28] (5a), Rosenbaum 1981 [31] (5a)B. Postoperative pain can be handled as for other patients in the same setting, with modifications.Basic perioperative assessment and pain treatmentsshould be used as for non-EB patients, with modificationA All Goldschneider 2010 [41] (5a), Goldschneider 2010b [42] (5a)Transmucosal (including intranasal fentanyl andtransbuccal opioids) should be considered for shortprocedures and pain of brief duration when intravenousand enteral routes are unavailableB All Manjushree et al., 2002 [45] (2b); Borland et al., 2007 [46](2b); Desjardins et al., 2000 [47] (2a)Perioperative opioid use must account for preoperativeexposure, with appropriate dose increases to account fortoleranceB All Hartrick 2008 [56] (1a), Mhuircheartaigh 2009 [55] (1a),Viscusi 2005 [54] (2a)Regional anesthesia is appropriate for pain resulting froma number of major surgeries. Dressing of catheters mustbe non-adhesive and monitored carefullyC All Diwan 2001 [51] (5a), Doi 2006 [53] (5b), Englbrecht2010 [52] (5a), Kelly 1988 [48] (5b), Sopchak 1993 [49] (5a),Yee 1989 [50] (5a)C. Skin wounds and related pain are the hallmark of EB of most subtypes. Prevention and rapid healing of wounds through activitypacing, optimal nutrition and infection control are important. A number of pharmacologic treatments are availableMaintain optimal nutrition and mobility and treatinfections as indicatedD All Denyer 2010 [57] (5a)Consider topical therapies for pain C All Cepeda 2010 [77] (1a), Lander 2006 [76] (1a), LeBon 2009[73] (1a), Twillman 1999 [72] (5a), Watterson 2004 [74](5a)Systemic pharmacologic therapy should be adapted totreat both acute and chronic forms of skin painB All Noble 2010 [59] (1a), Moore, 2011 [ 67] (1a), Nicholson2009 [65] (1a)Monitor potential long-term complications of chronicallyadministered medicationsC Pediatric Huh 2010 [62] (4a), Camilleri 2011 [66] (5a), Chiu 1999 [68](5a), Cruciani 2008 [63] (5a), Gray 2008 [69] (5a)D. Baths and dressing changes require attention to both pain and anxietyAnxiolytics and analgesics should be used for proceduralpain and fear. Care must be taken when combining suchmedications due to cumulative sedative effectsB All Bell 2009 [85] (1a), Blonk 2010 [84] (1b), Ezike 2011 [82](2a), Desjardins 2000 [47] (2a), Borland 2007 [46] (2b),Manjushree 2002 [45] (2b), Humphries 1997 [83] (2b),Wolfe 2010 [81] (5a), Ugur 2009 [86] (5a)Cognitive behavioral techniques should be implementedas the child becomes old enough to use themeffectively. Specifically, distraction should be used foryounger childrenB All Green 2005 [14] (5a); Gerik 2005 [13] (5a), Palermo 2005[17] (5a)Environmental measures such as adding salt to the waterto make it isotonic and keeping the room warm arerecommendedB All Arbuckle 2010 [78] (5a), Cerio 2010 [79] (5a), Peterson(Poster) 2011 [80] (5b)E. EB affects the gastrointestinal tract in its entirety. Pain from ulcerative lesions responds to topical therapy. GERD and esophagealstrictures have nutritional as well as comfort implications and should be addressed promptly when found. Maintaining good bowel habitsand reducing iatrogenic causes of constipation are crucial.Topical treatments are recommended for oral andperianal painC All Ergun 1992 [98] (4a), Travis 1992 [97] (4b), Marini 2001[99] (5a), Buchsel 2008 [100] (5a), Buchsel 2003 [101] (5b),Cingi 2010 [102] (2a)Therapy should be directed to manage gastroesophagealreflux and esophageal strictures using standardtreatmentsC All Freeman 2008 [95] (4a)Constipation should be addressed nutritionally, withhydration and addition of fiber in the diet to keep stoolsoft, by minimizing medication-induced dysmotility andwith stool softenersC All Belsey 2010 [112] (1a), Freeman 2008 [98] (4a), Hanson2006 [113] (4a)Goldschneider et al. BMC Medicine 2014, 12:178 Page 5 of 23http://www.biomedcentral.com/1741-7015/12/178psychological stateof heightenedawarenessandfocusedattention, inwhichcriticalfacultiesarereducedandsus-ceptibility and receptiveness to ideas are greatly enhanced[14]. Relaxation training usually includes techniques,suchas diaphragmaticbreathing, musclerelaxationandvisualization/imagery, that assist inadaptive coping viadistraction, reducedemotional arousal andactivationofthe parasympathetic nervous system. While these interven-tions are frequently patient-focused, CBT can also includeparent/familytrainingrelatedtobehavioral management,reducingcaregiverdistressandenhancingenvironmentalfactors necessary for positive coping [15].Table 3 Summary of recommendations (Continued)F. Bone pain treatment must account for factors that include nutrition, mobility, potential occult fractures and is treated by combinations ofnutritional, physical, pharmacologic and psychological interventions.Joint pain should be treated with mechanical interventions,physical therapy, CBT and surgical correctionC All Bruckner 2011 [126] (4b), Gandrud 2003 [131] (4b), Martinez2010 [125] (5a), Lacativa 2010 [127] (5a), Tilg 2008 [128] (5a),Noguera 2003 [130] (5a), Falcini 1996 [132] (5a)Osteoporosis should be treated to reduce pain in EB D All Levis 2012 [129] (1a), Martinez 2010 [125] (5a)Back pain should be addressed with standardmulti-disciplinary careC All Chou, et al., 2007 [133] (5a)G. Corneal abrasions are common in EB, prevention and supportive care are appropriateCare should include general supportive and analgesic care,protecting the eye from further damage, and topicaltherapiesC All Watson, 2012 [136] (1a), Calder 2005 [138] (1a)H. Pain in infants is as widespread as in any other age, but unique pharmacologic, developmental and physiologic issues must be accounted forin infants with all types of EBAssess patients as needed and prior to and afterinterventions; health care workers should use validatedmeasures. (Grade: A)A Infants Gibbins 2014 [139] (2a) Stevens 2014 [140] (2a), Hummel2008 [141] (2a), Krechel 1995 [142] (2b), Lawrence 1993[143] (2b), Manworren 2002 [144] (2a)Sucrose solutions should be administered for mild tomoderate pain alone or as an adjunctB YounginfantsHarrison 2010 [150] (1a), Yamada 2008 [149] (1a) Cignacco2012 [151] (2a)Standard analgesics should be used in infants as in olderpatients with careful attention to dosing and monitoringB Infants Tremlett 2010 [153] (5a), MacDonald 2010 [154] (5b)I. End of Life pain care is an expected part of care for EB, which in many cases is life-limiting in nature. All basic principles of palliative care applyas they do for other terminal disease states.Assess and manage physical, emotional and spiritualsuffering of the patient, while providing support for thewhole familyA All Craig 2007 [165] (5a), AAP 2000 [166] (5b), WHO [167] (5b)Opioids are the cornerstone of good analgesia in thissetting. Opioid rotation may need to be considered toimprove analgesia and reduce side effects, and adjunctsmay need to be addedB All Eisenberg 2009 [174] (1a), Quigley 2010 [172] (1a), Davies2008 [61] (4a), Bruera 1996 [171] (4b), Watterson 2005 (5b)Consider targeted medication for neuropathic pain whenpain proves refractory to conventional therapiesD All Allegaert 2010 (5a), Saroyan 2009 (5a). Clements 1982 (5a),Watterson 2005 [87] (5b)Continuous subcutaneous infusion of combinations ofmedication is an option when parenteral therapy isneeded in the terminal phaseC All Reymond 2003 [178] (2b), ONeil 2001 [176] (5a), Watterson2005 [87] (5b)Where needed, breakthrough medication can be giventransmucosally (oral or nasal) for rapid onset and avoidanceof the enteral routeB All Zeppetella 2009 [182] (1a)J. A combination of environmental, cognitive-behavioral and pharmacologic therapies are available for use for EB-related pruritus, which can be asevere symptom of the disease.Use environmental and behavioral interventions for itchcontrolC All Nischler 2008 [183] (5b), EB Nurse Website [187] (5b)Antihistamines are recommended and can be chosendepending upon desirability of sedating effectsD All Ahuja 2011 [188] (2b), Goutos 2010 [186] (3a)Gabapentin, pregabalin, TCA, SNRIs and othernon-traditional antipruritics agents should be stronglyconsidered for itch treatmentC All Goutos 2010 [186] (3a), Ahuja 2013 [189] (2a), Murphy 2003[197] (2a)EB, epidermolysis bullosa; GERD, gastroesophageal reflux disease; SNRI, serotonin norepinephrine reuptake inhibitors; TCA, tricyclic antidepressant.Goldschneider et al. BMC Medicine 2014, 12:178 Page 6 of 23http://www.biomedcentral.com/1741-7015/12/178As an adjunct to relaxation training, biofeedback mon-itors physiological functions (for example, heart rate,muscletension, temperature) inordertoimprovecon-trol of bodily processes that might ease chronic pain.Frequently, sensors areattached totheskinby adhesive,whichisrelativelycontraindicatedinEB. CliponpulseoximeterprobescanbesafelyusedinpatientswithEBto track heart rate, and provide an alternative method ofbiofeedback.Efficacy of psychological interventions in chronic and acutepain managementPsychological therapieshavebeenshowntobeeffect-iveindecreasingpainintensityandfrequencyinotherpediatric chronic painconditions [16,17] withemer-ging evidence showing improvement in pain-relatedfunctional disability as well [17,18]. The addition ofbiofeedbacktorelaxationtrainingdoesnotnecessarilyresult in superior pain outcomes [17]. Modest datasupport the use of CBTinadults withchronic painand disability [19] (see Box 1).Psychological interventionsareuseful forthemanage-ment of acute pediatric pain (see Box 1) although evidencefortheirefficacyvariesdependingonthetypeofpain.Forprocedurerelatedpain, particularlyneedleproce-dures, distraction, hypnosisandCBT areeffective, evi-dence based interventions [20-24].Inareviewof non-pharmacological treatmentstore-ducethedistressduetoacutewoundcareinburnpa-tients, some evidence has beenshownthat healthcareproviderinterventions(massageandmaximizingpatientcontrol andpredictability), childinterventions (for ex-ample, virtual reality gaming [25] and therapist coachingof stress management techniques [26]) are beneficial.For postoperative pain, there is insufficient evidence forthe efficacy of most psychological interventions, but prep-aration, guided imagery and CBTare promising [27].Psychological interventions for itchPatientswithEBmayexperiencesevereitch, whichnotonlyintensifiestheirsufferingbut canalsobeasourceofsocialembarrassmentsecondarytotheappearanceoftheexcoriatedskinandthepreoccupationwithscratch-inginsocial situations. Beyondthis, damageof thein-tegrity of the skin can create a portal of entry forsystemicinfections. Regardlessof theunderlyingcause,itchevokesthebehaviorofscratchingthatincreasesin-flammationandstimulatesnervefibers, leadingtomoreitching and scratching [28]. Perpetuation of the itch-scratch cycle alters the integrity of skin leading to barrierdamage. Scratchingalsocauses undesirable changes inskin, suchaslichenificationandprurigonoduleforma-tion. Successful treatment of itchrequires interruptionof this cycle. Non-pharmacological treatments, suchasCBT, hypnosis, meditation, prayer, biofeedbackandeyemovement desensitization and reprocessing (EMDR),havebeenusedwithsomesuccessinbothadultsandchildren with conditions such as atopic dermatitis[29]. Habit reversal isaspecificbehavioral interven-tion whereby habitual behaviors are brought into con-scious awareness and specific behavioral techniquesaredevelopedasacompetingresponsetotheurgetoitch[30,31](seeBox1). Inpractice, thistechniqueisfrequentlycombinedwithCBT andrelaxationaspartof a treatment package applicable to patients of allages [29,32].Integrative medicine therapiesComplementary andalternative medicine (CAM) prac-tices constitute therapies that are oftenrequestedbypatientsandfamiliesforavarietyofchronicpaincon-ditions. This class of treatments includes, but is notlimited to: acupuncture, meditation, massage, herbalpreparations, yoga and chiropractic work. The evi-dence for therapies suchas acupuncture [33], musicTable 4 Table for judging the strength of arecommendation [8]Dimension DefinitionGrade of the body of evidence High, Moderate, Low, Not AssignableSafety/harm (side effects andrisks)Minimal, Moderate, SeriousHealth benefit to patient Significant, Moderate, MinimalBurden on patient to adhere torecommendationLow, Unable to determine, HighCost-effectiveness to healthcaresystemCost-effective, Inconclusive, Notcost-effectiveDirectness of the evidence forthis target populationDirectly relates, Some concern ofdirectness, Indirectly relatesImpact on morbidity/mortalityor quality of lifeHigh, Medium, LowBox 1. Recommendations for use of cognitivebehavioral therapies in EB1. For chronic pain management use cognitive behavioraltherapy (CBT). (Grade: B)2. For acute pain management, offer the patient distraction,hypnosis, visualization, relaxation or other forms of CBT.(Grade: B)3. Consider habit reversal training, and other psychologicaltechniques for management of pruritus. (Grade: C)Goldschneider et al. BMC Medicine 2014, 12:178 Page 7 of 23http://www.biomedcentral.com/1741-7015/12/178therapy[34], chiropracticcare, oryoga[35]ismodestinthe pediatric andadult painpopulations, withnospecific studies in EB. Prima facie evidence would sug-gest thatmassage and chiropractic interventions mightbeharmful giventheskinfragilityandtheosteopeniathatisoftenseeninEB. Withregardtoherbalsupple-mentation, oneof thechief sideeffectsforanumberof these preparations is bleeding, although the evi-denceisnot clear [36]. Thus, thistreatment maybecontraindicated in patients having surgery, openwoundsorahistoryofgastrointestinaltractbleeding.Theactiveingredientsintheherbalpreparationsmayalso have interactions with any other prescribedmedication; attentiontopotential drug-druginterac-tions should be considered.Goodpracticepoints Assessment of thesuitabilityofpsychological therapies for EB patients experiencingchronic and acute pain should always take into accountdevelopmental issues including age, cognitive level andpsychopathology [37]. Include parents in behavioralpainmanagement interventions [38] for childrenandadolescents.Acute pain care: postoperative pain managementIntroductionAsamultisystemdisorder, EBcausesavarietyof dis-ruptionsto bodysystemsthatareamenabletosurgicalintervention. While there are no controlled trials ofpostoperativepaintherapies inEB, general principlesof pain care apply.AssessmentAs for all patients, painshould be regularly assessed,andthenreassessedafterinterventiontoevaluateanal-gesic efficacy and detect side effects. Numeric ratingscaleshavebeenshowntobeeffectiveforchildrenofadevelopmentallevelaboveeightyearswhocanverbalizetheirpainscoresaswellasforadults. Painassessmentin younger or nonverbal patients can be completedusingtheFaceLegsArmsCryConsolability(FLACC)andChildrensHospital of EasternOntarioPainScale(CHEOPS)[39,40]augmentedbyreportsofparentsorother close family care-givers.Systemic therapiesAnalgesic treatment starts before andduringsurgeryand includes the use of opioids, non-steroidal anti-inflammatorydrugs, acetaminophenand, whenappro-priatefor the type of surgery, regional anesthesia [41,42].Patient controlledanalgesia (PCA) technology is a safeanduseful waytodeliver opioids topatentsof all ageswith EB, as it is for non-EB patients (see Box 2).In the postoperative period, EB patients may be slow toresumeoral intake, especiallyafteroropharyngeal proce-dures, suchasesophageal dilatationordental rehabilita-tion. Forpatientslackinggastrostomytubes, intravenousanalgesia may be required. Intravenous analgesia should bemultimodal andmayincludeopioids(forexample, mor-phine or hydromorphone), nonsteroidal anti-inflammatorydrugs(NSAIDS; whenpostoperativebleedingisnot arisk and renal function is normal (for example, ketorolac))andacetaminophen(enteral or intravenous). Giventhehigh rate of superficial bleeding fromskin wounds,cyclooxygenase-2 inhibitors may have a role to play, giventheyhave prothrombotic features insome studies [43].Due to the risk of blister formation with rectal manipula-tion, there is controversy regarding whether the rectalrouteofadministrationmaybeusedinEBpatients[44].Intranasal opioids canbeeffectivefor short-termtreat-ment, if other routes are not available [45-47], and may beparticularly helpful for procedures of short durationwhenrapid-actinganalgesiais desiredintheabsenceof intravenous access. Oral disintegrating and trans-buccal formulations maybehelpful as well, althoughtheypresumeintactmucosa, whichmaynot beapplic-able (see Box 2).Patientswithprolongedpostoperativepainbecauseofextensivesurgery may benefit fromthe use of opioid-based PCA with dose adjustments that take into consid-eration prior opioid use. While no EB-specific literatureexists, thismodalityisstandardtreatmentinmanycen-tersforpatientsoldenoughtounderstandtheconcept(typicallysevenyearsofageorolder). Activationof thedosingbuttonmaybelimitedbypseudosyndactyly, souse should be determined on a case-by-case basis. PCA-by-proxy (dose administeredby a nurse or designatedfamily member) is practicedinsome pediatric centersBox 2. Recommendations for acute pain care in EB1. Basic perioperative pain assessment and treatments should beused as for non-EB patients, with modification. (Grade: A)2. Transmucosal (including intranasal fentanyl and trans buccalopioids) should be considered for short procedures and painof brief duration when intravenous and enteral routes areunavailable. (Grade: B)3. Perioperative opioid use must take preoperative exposureinto consideration, with appropriate dose increases toaccount for tolerance. (Grade: B)4. Regional anesthesia is appropriate for pain resulting from anumber of major surgeries. Dressing of catheters must benon-adhesive and monitored carefully. (Grade: C)Goldschneider et al. BMC Medicine 2014, 12:178 Page 8 of 23http://www.biomedcentral.com/1741-7015/12/178andmaybeanalternativeapproachtoPCAdosingforchildren.Preoperative toleranceThe preoperative painstatus of the patient shouldbetaken into consideration when choosing opioid dose,bothintra-andpost-operatively. ManyEBpatientshaverecurringacuteand/orchronicpainandmaybetakingopioids daily, either prior to bathing/dressing changes orfor ongoing pain. These patients require increased doses ofopioidsforadequateanalgesiceffect, duetothedevelop-mentoftolerance. Theirusual dailyopioidintakeshouldbe considered the baseline opioid dose to which the post-operative analgesia shouldbe added(see Box 2). Drugpharmacokinetics may be alteredinpatients chronicallyexposedtosedativesandopioids. Flexibilityindosing, re-viewof prioranestheticrecordsanddiscussionwiththepatient or family can aid appropriate dosing.Regional anesthesiaSome common procedures (and the corresponding regionalanesthesia technique used) in EB patients include: fundopli-cation (epidural) [48-50], hand and foot surgery (peripheralnerve block, either single shot or continuous peripheralnerve catheter infusion following bolus injection) and handsurgery(bothaxillaryandinfraclavicularapproacheshavebeen used for brachial plexus block) [51,52].Regional anesthesiatechniquesshouldbemodifiedinpatientswithEBtominimizedamagetotheskin. Skinpreparationmaybeperformedbypouringprepsolution(povidone-iodineor chlorhexidine) onthesitewithoutrubbing, thenblottingandallowingthesolutiontodry.Ultrasoundguidance canbeusedfor peripheral nerveblockswithgeneroususeof gel tominimizeskinabra-sionwhenmovingtheprobe. Whenacatheter isplaced(epidural orperipheral nerve), itmaybetunnelledsub-cutaneously if desired [53] then secured to the skinusing silicone-based tapes and dressings (MepitacW,MepitelW, MepilexW)orothersoftnon-adhesivedress-ings. Adhesivedressingsandadhesiveadjunctsshouldbeavoided. If thereis any doubt about the safetyofusingadressing, itshouldbetestedonasmallareaofskinwithpatientorparentalconsent. Withlocalinfectionbeing a relative contraindication to regional anesthesia,examinationof the skinoverlying the point of entry ismandatory prior to attempting a catheter placement. If leav-ingacatheterintheepidural spaceisundesirable, thenasingle injection of a long-acting form of opioid (DepoDurW)maybeagoodoptionwhenavailable[54,55], althoughmonitoringisimportantduetoriskofhypoventilation[56]. Lidocaine infiltrationmay be used by dentists/oralsurgeonswhenextractionsarenecessary, butcaremustbetakenwheninjectingtoavoidmucosal blisterformation (see Box 2).Non-pharmacologic therapiesNon-pharmacologictechniquesshouldalsobeemployedincombinationwiththepharmacologictechniqueslistedabove. Theseinclude, but arenot limitedto, distraction(music, reading, videogamesandmovies), visualization,imagery/virtual reality and breathing techniques (see Effi-cacy of Psychological Interventions in Chronic andAcute Pain Management, above andBox 1). Effectiveapproaches used in the past should be discussed with thepatient or parents and their use supported wheneverpossible.Goodpracticepoints Postoperativepaincanbeman-aged as for other patients in the same setting, with mod-ifications to account for the ability to self-administermedications, priordrugexposure, andtheconditionofthe skin at potential regional anesthesia injection/cathetersites.Chronic and recurrent pain careEBhas alargenumber of painful complications, somechronicandothersacutebut repetitive. Careof EBin-volves painful interventions on a daily basis. Almostevery organ system can be affected, but the following arethe major sources of pain: skin, gastrointestinal tract,musculoskeletal system, eyes.Skin and wound painIntroductionTheclassicpresentationof EBisthede-velopmentofskinwoundsthatarepainful intheirownright, butwhichoftenbecomeinfected, heal poorlyandfrequently lead to scarring. This combination makes skinand wound pain a prominentcomplaintof patients withEB.Environmental andbehavioral approaches Dressingsthat are non-adhesive uponremoval, suchas silicone-based products, are helpful in reducing skin-traumapain. Different subtypesof EBanddifferent individualsseemtohavevaryingdressingrequirements[57]. Nu-tritionisimportant inpromotingwoundhealing, andanecdotally, patientswithpoornutritional statushavemore wounds and slower healing, whichleadto in-creased pain. Experience suggests that attention togood nutrition, surveillance for superficial infectionandaggressivetreatment of infectionreducepain. Asdiscussed in the section on psychological interven-tions, CBTis helpful for anumber of painful condi-tions and should be applied in EB.Systemic approachesThe pharmacological treatment ofskin and wound pain is non-specific, with no evidence intheEBpopulationtopromoteonetreatment over an-other. NSAIDs, acetaminophen, tramadol and opioidsGoldschneider et al. BMC Medicine 2014, 12:178 Page 9 of 23http://www.biomedcentral.com/1741-7015/12/178are usedwithsuccess. Cannabinoids have some anec-dotal support. Itchisamajorproblem(seebelow) thatcanleadtoincreasedscratchingandsubsequent devel-opmentofpainfulwounds. Hence, managingpruritusisimportant to prevent wound-related pain.Many patients with severe types of EB use long-actingopioidpreparationstoprovideabasal comfortlevel. Ofnote, therearenoclearguidelinesthatlong-acting opioids are preferable to use of intermittentopioids for non-cancer pain [58], although there ismodest evidence for opioiduse, ingeneral, for non-cancer pain in adults [58,59]. Individualization of ther-apy is recommended.Regularandfrequent dosingof opioidsiscommonandmeritsspecial attention. Regardlessoftheopioidchosen, chronicuseof opioids mayhaveendocrino-logiceffects, suchashypogonadism[60]. Monitoringshouldbeconsidered, especiallygiventhepropensityfor osteopenia and delayed puberty in adolescentsandyoungadultswithEB. Intheabsenceofdata, theuseofopioidsisrecommendedasclinicallyindicated(see Box 3).Methadone merits particular consideration. Dose titra-tioncanbeunpredictableduetolongandvariablehalf-lifeaswell astosaturableplasmaproteinbinding[61].The long andvariable half-life, as well as the risk ofmethadone-induced prolonged QTsyndrome [62,63],mandates care in its use alone and with other drugs thatmay also prolong the QT interval. Guidelines on electro-cardiographic screeningare limited[64] (especiallyforadult patients of smaller stature and children). Given therisk of prolonged QT and methadones complex and vari-able pharmacokinetics, it is recommendedthat metha-doneonlybeprescribedbypractitionerswithexperienceevaluating and monitoring its use [65]. Methadone use is,therefore, bestdone with input from apainmanagementand/or palliative care specialist.Amongthecommonsideeffectsofopioids, constipa-tion[66] andpruritus areparticularlysignificant. Bothare significant baseline problems in EBand the reader isreferred to the sections on gastrointestinal pain andpruritus.Thepainofextensivewoundshasaqualitysuggestiveof neuropathicpain; bothareoftendescribedasburn-ing inquality. Thereisevidencesupportingtheuseofgabapentin for neuropathic pain in other conditions[67]. Medications suchas tricyclic antidepressants andgabapentin have shown anecdotal success in EB skinpaininachild[68], as well as for adult patients withacuteskinpainduetoburns[69]. Thepotentialfortri-cyclicantidepressantstoprolongtheQTintervalmeansthatcautionshouldbetakenusingthisclassofmedica-tionsinRDEBpatients, whoareat riskfor developingcardiomyopathy[70], asalethal outcomeinthissettinghas been reported [71].TopicalapproachesForlocalizedwounds, topical lido-caine jelly (2% concentration) has been used anecdotally.Morphine mixed in hydrogel formulations has been usedin different types of localized painful wounds [72,73] buthas only limited anecdotal experience in EB wounds [74](see Box 3). Use of these medication vehicles raisesquestions of absorption and systemic effects that requirefurtherinvestigationbeforefullrecommendationscanbemade. Limited anecdotal evidence supports the use ofkeratinocyte hydrogel dressings for poorly healing woundsand RDEB [75].Blood draws and intravenous access as well as theneedfor skinbiopsies are minor technical proceduresthat can be very distressing, especially for children. Top-ical anesthetics arecommonlyusedinnon-EBpopula-tionswithgood effect. Amethocaine appears to be moreeffective than a eutectic mixture of local anesthetics(EMLAW)[76]. Thesemayhavearolewhenappliedtointact skin, but cannot be recommendedfor use onwoundsduetounknownrateandextentofabsorptionof lidocaine. Blisteringas alocalizedallergicreactiontoEMLAW(oritscontents) hasbeenrarelyobserved,indicatingcautioninitsuseevenonintactskin. Lido-caineinjectedwithasmall gaugeneedleisastandardapproach to superficial analgesia in all age groups.Additionally, it is recommended that bicarbonate beaddedtobufferthepHof thelidocainetoreducethepainof injection[77]. As notedabove, CBT(for ex-ample, distraction and relaxation) is effective in theacutepainsetting[21]andshouldbeemployedwhen-everpossibleinconjunctionwithmedicationmanage-ment (see Box 1).Goodpracticepoints Preventionandrapidhealingofwoundsthroughnon-adherentdressings, optimal nutri-tion and infection control are priorities.Box 3. Recommendations for wound pain treatment1. Maintain optimal nutrition and mobility and treat infectionsas indicated (Grade: D)2. Consider topical therapies for pain (Grade: C)3. Systemic pharmacologic therapy should be adapted to treatboth acute and chronic forms of skin pain. (Grade: B)4. Monitor potential long-term complications of chronicallyadministered medications. (Grade: C)Goldschneider et al. BMC Medicine 2014, 12:178 Page 10 of 23http://www.biomedcentral.com/1741-7015/12/178Bathing and dressing changesIntroductionBathing and bandage changes are a source ofsignificant recurrent pain and anxiety for patients with EB.Environmental treatment Oatmeal andsalt havebeenaddedtobathwater toreducethe painof immersion[78]. Theformer mayhaveanti-pruritic, cleansingandprotective properties for dermatologic conditions in gen-eral [79] that may be similarly effective inEB. Salt isaddedtomakethewaterisotonic, whichhasanecdotalsupportfrommanyfamiliesof patientswithEBinclud-ingpreliminarysurveydatafromEBfamilies[80]. Iso-tonic saline (0.9%NaCl) is 9 grams of salt/1 liter ofwater; total amount of salt varying according to the desiredwatervolume. Bleachandvinegarareanecdotallyhelpfulin drying the skin and reducing bacterial colonization,whichsomepatientsfindcomfortingwhileothersreportincreased pain at the wound sites. The salt water does notrequire plain water rinse, whereas vinegar and bleach bathsrequirerinsingtoreducetheriskof itch. Manypatientselect to reduce the frequency of bathing as a simple meas-ure tominimize bath-relatedpain. Anecdotally, startingthe bath by immersing the patient still in his/her bandagescan ease the transition into the water and help reduce thepainofremovingthedressings. Otherpatientsfinddraftsfromheatingandcoolingsystemstobepainful onopenwounds, soattentiontogeneral environmental factorsisrecommended (see Box 4).AnalgesicsAnalgesics used by patients with EB have in-cluded enteral opioids, NSAIDs and acetaminophen.Thenasal routemaypermit administrationof medica-tions whenintravenous access is absent [81]. Fentanylworks well by this route for non-EBpatients intheperioperativesetting[45], forbreakthroughcancerpain(seesection onBreakthrough painmedicationat theendoflife)andhasbeenusedforacutepainmanagementinthe emergency department with success [46]. Butorphanolis a mixed agonistantagonist that can be used via the in-tranasal route and is effective both for pain (for example,dental postoperative pain [47]) as well as for opioid-inducedpruritus. Fixeddosesprayis availablefor out-patient use in the United States, which limits the ability toadjustforpatientsize. Timingofmedicationadministra-tion should be adjusted to match expected peak analgesiawith anticipated peak pain (see Box 4).Ketamine can be administered enterally for wound carepain, for whichtherearedatafromadult andpediatricburn populations[82,83]but notforEB patients. The IVform of ketamine given orally has been used with variablesuccess for other chronic pain conditions [84] as well as incancer patients [85] and in pediatric palliative care [86].Inhalednitrousoxidehasbeensuggestedforpediatricwound care in EB in some texts and reviewarticles[44,87], butitsuseinEBpatientshasnotbeenstudiedor reported. Nitrous oxide has been used for painful pro-cedures inother settings [88] andis available inbothfixed50:50andvariablecombinationswithoxygen. De-pending on the delivery system (mouth piece, face mask,ornasal mask)concernsariseaboutenvironmental pol-lution and exposure of health care personnel [89]. In theabsenceof evidenceof efficacy, concernmustberaisedaboutrepeateduseforwoundcareordressingchangesbecauseof longstandingevidenceofmegaloblasticbonemarrow changes and neurologic abnormalities due to in-hibitionof methioninesynthaseandcobalaminactivitywith repeated exposure to nitrous oxide [90,91].Anxiolysis The pain caused by baths and dressing changesis commonly cited by families as generating anxiety in thepatient, which in turn is stressful for the caregiver. Medica-tionsusedforacuteanxiolysisinthispopulationincludemidazolam, diazepamandlorazepamandareconsideredgood treatment for acute anxiety in other populations (forexample, childrenfordental procedures, [92,93]; priortoadultburnprocedures[94]). Inadditiontoanxiolysis, thepre-procedural use of benzodiazepines offers the possibilityof anterogradeamnesiawhichmayprevent thedevelop-ment of increased anxiety with repeated procedures. Whenusingbenzodiazepinesincombinationwithopioids, caremustbetakentoavoidoversedation(seeBox4). Asre-sponsetoeachmedicationwill haveindividual variation,doseadjustmentsshouldbemadecarefullyandprefer-ablyonedrugatatime, whenmorethanoneisbeingadministered.Other behavioral comfort measures In addition tomedication management, recommendations from caregiversBox 4. Recommendations for bathing and dressingchange pain treatment1. Anxiolytics and analgesics should be used for procedural painand fear. Care must be taken when combining suchmedications due to cumulative sedative effects (Grade: B).2. Cognitive behavioral techniques should be implemented asthe child becomes old enough to use them effectively.Specifically, distraction should be used for younger children(Grade: B).3. Environmental comfort measures are recommended; theseinclude adding salt to the water to make it isotonic andkeeping the room warm (Grade: B).Goldschneider et al. BMC Medicine 2014, 12:178 Page 11 of 23http://www.biomedcentral.com/1741-7015/12/178include preparing all materials aheadof bandage re-moval toreducetheamount of timewounds areex-posedtoair. Involving childreninthe process at asearlyanageaspossiblehelpsthemtodevelopasenseofcontrol. Maintainingroomtemperatureatamoder-ately warm level has also been recommended. CBT canbeappliedtotreatingtheanxietyandpainassociatedwith bathing and bandagechanges (see section on psy-chological approaches, above).Good practice pointsBathing and dressing changes arerecurrent sources of both pain and anxiety. Therapyshouldfocus onbothsymptoms, usingenvironmental,psychological and pharmacologic approaches.Pain related to the gastrointestinal tractIntroduction Gastrointestinal complications are com-moninchildrenandadultswithEBwithspecificcom-plications linked to different subtypes [95-97].Upper gastrointestinal tractTopicaltreatmentsOral ulceration, blisteringandmu-cositisarethemostfrequentgastrointestinal complica-tions inpatients withEB[98]. While oral ulcerationcanoccur inall types of EB, it is most commonandproblematic inpatients withthe severe types of thisdisease. Oral ulcerationcanbeextremelypainful andleadtodifficulties infeedingandmaintainingdentalhygiene. Apart from oral analgesics, topical preparationsare available. Sucralfate suspensionhas beenusedtopreventandmanageoral blistersinfivechildren, 6-to11-years-old, with RDEB when applied four times a dayfor six months [99]. The number of blisters reducedwithinthreeweeksandpainreducedwithinoneweek(see Box 5).Polyvinylpyrrolidone-sodium hyaluronate gel (GelclairW)either used as a mouth rinse or applied directly to amouth lesion in children, has been used anecdotally in EB.Secondary evidence comes from two recent reviews whichshowed that GelclairWmay be useful as an adjunctive ther-apyindecreasingthepainfullesionsoforalmucositisincancer patients [100,101]. Chlorhexidine gluconate andbenzydamine hydrochloride mouth spray is used regularlyin EB patients at the London centers with reported benefitbut has not beenevaluatedsystematically. Secondaryevidenceforthepotential efficacyof thisinterventionexistsfortreatingthepainofacuteviralpharyngitisinadults [102].Gastroesophageal reflux Patients withEBareat highrisk for gastroesophageal reflux disease (GERD) - especiallyinfants with generalized EBS, JEB and patients with severegeneralized RDEB who can develop esophagitis [95]. Whilechildren with GERD may not complain of dyspeptic symp-toms until they are older, crying and sleep disturbance arecommonlyassociatedwiththissymptom. Managementisguidedbystandardtreatmentinnon-EBpatients, andmay involve treating the reflux with antacids, hista-mine H2-blockers and proton pump inhibitors and,rarely, surgery [103,104] (see Box 5).Esophageal strictures Esophageal stricture formationand dysphagia are most common in patients with severegeneralizedRDEBwithacumulativeriskof developingstrictures or stenosis risingsteadilyfrom6.73%at age1 year to 94.72% at age 45 years [105]. However, stricturescan also be seen in other subtypes of EB including Kindlersyndrome [106]. Dysphagia anddelayedprogressionoffoodthroughthestricturecanpresent withretrosternalchestpain. Esophageal strictures, ifsymptomatic, requiretreatment with a fluoroscopically guided balloon dilatationwith peri- and post-operative steroids administered to re-ducethe recurrent stenosis rate[107-109] (seeBox5).Acutesymptomscanrespondtemporarilytooral dexa-methasoneornebulizedbudesonide, basedonanecdotalevidence. Arecentcasereportexaminedtheuseofdailyoral viscous budesonide therapy (0.5 mg/2 mL budesonidenebulizer solution mixed with 5 g of sucralose and malto-dextrin) intwochildrenwithRDEBwhohadrecurrentproximal esophageal strictures [110]. Both children had areduction in the rate of stricture formation and symptomsof dysphagia.Lower gastrointestinal tractConstipationConstipation has been shown to be presentin 35% of children with all types of EB [95] and can causeabdominal pain and pain on defecation as well aslead toperianal trauma. Acaseof colonicperforationandearlyBox 5. Recommendations for gastrointestinal paintreatment1. Topical treatments are recommended for oral and perianalpain. (Grade: C)2. Therapy should be directed to manage gastroesophagealreflux and esophageal strictures using standard treatments.(Grade: C)3. Constipation should be addressed nutritionally, withhydration and addition of fiber in the diet to keep stool soft,with stool softeners and by minimizing medication-induceddysmotility. (Grade: C)Goldschneider et al. BMC Medicine 2014, 12:178 Page 12 of 23http://www.biomedcentral.com/1741-7015/12/178death resulting from severe constipation in DEB has beendescribed[111]. Chronicperianal painduringdefecationcan produce stool withholding behavior which exacerbatesconstipation. Chronic opioid use may contribute to poorbowel motility. First line management is preventionwith dietary manipulation; however, patients with severetypesof EBoftenrequiretheregularuseof alaxative(seeBox5). Polyethyleneglycoliseffectiveclinicallyintreating constipationinchildrenandadults withEB,with empiric evidence of efficacy in adult [112] andpediatric [113] non-EB cohorts.ColitisAsubgroupof children withRDEBmaydevelopcolitis, presentingwithabdominalpainandothersymp-toms[95,114]. Dietaryrestrictionandanti-inflammatorydrugs, suchas sulfasalazine, have beenusedbut withvariable effects on controlling the colitis [95].Perianal painPerianal blisteringandulcerationiscom-monanddebilitatinginchildrenandadultswithseveretypes of EB. Topically, sucralfate has been shown to be su-perior topetroleumjellyinfacilitatinganal fistulotomyhealingandlesseningwoundpain[115]. Sucralfatesus-pension has also been used to lessen the pain of oral andgenital ulcerationinpatientswithBehcetsdisease[116].Anecdotally, topical sucralfate combined withCavilon(analcohol-freeliquidbarrier filmthat dries quicklytoformabreathable, transparentcoatingontheskin, con-taininghexamethyldisiloxane, isooctane, acrylateterpoly-mer, polyphenylmethylsiloxane) appearstoimprovepainin perianal lesions of some patients with EB. Non-surgicaltreatment is of small benefit for both pain and healing ofchronic anal fissures [117], with recommendations of top-ical diltiazem and glyceryl trinitrate followed by surgery ifneeded in adults [118]. No data on anal fissure treatmentin EB patients exist (see Box 5).Good practice points EB affects the gastrointestinaltractinitsentirety. Painthatoriginatesfromulcerativelesions may respond to topical therapy. GERD andesophagealstrictureshavenutritionalaswellascomfortimplications and should be addressed promptly whenfound. Maintaininggoodbowelhabitsandreducingiat-rogenic causes of constipation are crucial.Musculoskeletal painIntroductionMusculoskeletal complications arecom-monandfrequentlypainfulforpatientswithEB. Theseconditions include pseudosyndactyly, osteopenia, backpain, fractures and occasional co-morbid rheumatologicdisorders.Joint pain Pseudosyndactyly affects hands, feet, anklesandwrists. Painful hyperkeratoticlesionsdeveloponthesoles of patients with EBS. Occupational therapy ap-proachescanimprovefunctionanddecreasepainviauseof adaptive equipment and specially designed orthotics andclothing. Physical andoccupational therapy play crucialrolesinencouragingpatient mobility. Forweight-bearingpatients, carefulattentiontofootwear, nails, orthoticsandhyperkeratosis management areimportantaspects ofpaincare[119]. Referringpatientstoprogramstomaintainorregain strength, to prevent or minimize joint contractures,and to optimize mobility is recommended based on anec-dotal evidence (see Box 6). Coping skills training and activ-ity pacing can enhance effectiveness of therapy [120].Surgical interventionhashadsomesuccessinincreasingmobility and reducing pain [121]. EB patients can also haveinflammatoryarthritis[122,123]; appropriateimagingcanbe helpful indetermining inflammatory causes of pain.Giventhat inflammatorymarkersareusuallyelevatedinEB patients, these markers alone are not likely to be usefulto diagnose joint pathology.Bone pain Osteopenia, osteoporosis and fractures arenow well recognized and commonly seen in patients withthe severest types of EB [124-126], as a cause of bone andjoint pain. Thecausesaremultifactorial andincludere-ducedmobility, delayedpuberty, limitedexposureof theskintosunlight, inadequatenutritional intakeformeta-bolic requirements and chronic inflammation. Chronic in-flammation causes increased osteoclast activity [127,128].As a consequence of the osteoporosis, a significantproportionof patientsdevelopfractures. Theincidenceof vertebral fractures in patients with RDEB is unknown,but may be underestimated due to the fact that fracturesof the lumbar and thoracic spine may be clinically silent,or present without overt or localized back pain on palpa-tion [125]. Anecdotally, however, some patients canpresent withbackpain, inwhichcaseahighindexofsuspicionshouldbemaintained. Treatmentofosteopor-osis andderivative painis baseduponstandardtreat-ment of osteoporosis in non-EB patients, which relies onvitaminDandcalciumsupplementation, exercise andbisphosphonate treatment [129] (see Box 6).Box 6. Recommendations for musculoskeletal paintreatment1. Joint pain should be treated with mechanical interventions,physical therapy, cognitive behavioral therapy and surgicalcorrection (Grade: C).2. Osteoporosis should be treated to reduce pain in EB (Grade: D).3. Back pain should be addressed with standard multi-disciplinarycare (Grade: C).Goldschneider et al. BMC Medicine 2014, 12:178 Page 13 of 23http://www.biomedcentral.com/1741-7015/12/178Anecdotally, bisphosphonateshavebeenfoundusefulintreatingpatientswithevidenceof osteoporosiswith-out fracture. Bisphosphonates appear to improve fractureson annual X-rays and lead to a noticeable improvement inpain. Indirect support for the use of bisphosphonatescomesfromitsuseinrheumatologicandotherpediatricconditions, associated with osteopenia [130,131] and reso-lutionof backpain[131,132], but efficacyspecificallyinpatients with EB has not been formally studied.BackpainOlderpatientswithEBcanhavebackpain.Beyondosteopenia-relatedissues, biomechanical causescanbeinvolved. Foot blistersandpainfulhyperkeratosiscan cause abnormal gait and compensatory postures.Further, impairedmobilitycanaddamyofascialcompo-nent to pain. Management of back pain includes optimalfoot care, assessment of primary and secondary mechan-ical factors, evaluationandtreatmentof osteopeniaandfractures, physicaltherapy, standardanalgesicsandCBTinterventions. BackpaintreatmentintheEBpopulationis extrapolatedfrombasicprinciples recommendedforthe general population[133], for lack of EB-specificevidence (see Box 6).NSAIDsareroutinelyusedforboneandjointpainofavarietyoftypesandareappropriateforthesetypesofpain in EB. Care should be taken to monitor for side ef-fects, andthecyclooxygenase-2inhibitors maybe usefulinthosepatientswhoexperienceimprovedpaincontrolbut note increasing blood loss fromwounds, or whohave gastrointestinal upsetwith standard NSAIDs. Acet-aminophendoesnot affect bleedingandcanbeuseful.Tramadol andopioids are alsouseful for more severepain. Some prefer use of long-acting opioid preparations,withmethadonebeingtheonlyoneavailableinliquidform. Limitations in methadone use are discussed insub-section on systemic approaches under Skin andWound Pain.Goodpracticepoints Bonehealthshouldbeoptimizedwith calciumand vitamin Dsupplements as needed,maintenance of maximum mobility, minimization of jointdeformity and monitoring for/treatment of pubertal delay.Routine screening for bone mineral density may be usefultoascertaincasesof osteopeniabeforetheyprogresstoosteoporosis andfractures. Care must be takennot tooverlookinflammatoryjointdisease, aspainsecondarytothiswillrespondtodiseasemodifyingtherapy. Mul-tidisciplinary treatment modalities are helpful in ad-dressingbackpainandapplytosuchpainintheEBpopulation as well.Eye painOphthalmologic involvement is pervasive in EB [134,135].Eyepainisoftencausedbycorneal abrasions. Comfortmeasures such as avoiding bright light (a natural reactionto the photophobia that results from the trauma), lubricat-ingeyedrops, NSAIDs andantibioticdrops havebeenused. Evidenceforthesetreatmentsforrecurrent cornealabrasionsofotheretiologiesismodest[136]. Theuseofeyepatches innon-EBpatients doesnot aidpainreliefand, therefore, is not recommended for use in EB patientseither [137]. There is some evidence that topical NSAIDsprovideanalgesiafor acute, traumaticcorneal abrasions[138] (see Box 7).Good practice pointsCorneal abrasions are painful andcommon in EB; prevention and supportive care areappropriate.Special TopicsPain care in infants with EBIntroductionInthesevereformsofEB, painstartsim-mediately, andgreat care needs tobe takeninmostof theactivitiesof dailyliving. InfantswithEBrequirecareful attentiontoenvironmental factors at ahigherlevel than for older children but otherwise can re-ceivepaincareusingguidelines for specifictypes ofdiscomfort.Painassessment Painassessmentshouldbecompletedon all neonates with EB at regular intervals and asneeded(seeBox8). Avalidneonatal painscaleshouldbe used, considering both physiologic and behavioralmeasures. Someexamplesinclude: thePrematureInfantPainProfile(PIPP) [139,140], theNeonatal PainAgita-tionandSedationScale(N-PASS) [141], theCrying, Re-quires oxygen, Increased vital signs, Expression and Sleeplesspain scale (CRIES) [142], and the Neonatal Infant Pain Scale(NIPS) [143]. The Face Legs Arms Cry Consolability(FLACC)scaleisrecommendedforinfantsbetween1to12months[144]. Thesepainscaleshavebeenvalidatedforusebynurses, althoughtrainingcouldbegeneralizedto non-nurse care givers and family members. Pain shouldbe reassessedfrequently during andafter interventionsanduntilcomfortisachievedbasedonacombinationofoneof theabovescalesandclinical judgment. Analgesicinterventions shouldmatchdegreeor level of pain. Ofnote, infants, especially neonates, seem to be a higher riskBox 7. Recommendations for eye pain treatment1. Care should include general supportive and analgesic care,protecting the eye from further damage and topical therapies(Grade: C).Goldschneider et al. BMC Medicine 2014, 12:178 Page 14 of 23http://www.biomedcentral.com/1741-7015/12/178for respiratory compromise [145,146] due to reducedclearanceofopioidsininfantsyoungerthantwomonths[147,148]. Therefore, careful clinical and cardiopulmonarymonitoring is crucial when providing opioids to this popu-lation (see Box 8).Procedural pain As for older patients, procedures areone of the major sources of painfor infants withEB.Wound care specifically requires a multidisciplinary teamapproach to ensure consistent and optimized pain control.There is evidence that a variety of pharmacologic andnon-pharmacologic interventions are helpful in bothtermandpre-terminfants[149]. Therefore, painman-agement interventions should precede all scheduledpainful procedures, suchasdressingchanges, bathingand venipuncture. The range of analgesics and the routesbywhichtheycanbeadministeredarethesameasforolder patients. Oral sucrose is an analgesic unique toyoung infants and can be used alone for mild pain (for ex-ample, immunizationpain[150]) orinconjunctionwithother analgesics as well as physical and environmental in-terventions for more severe acute pain [40,151].Bathing and dressing changes To maintain appropriatemoisture levels and facilitate the healing of wounds,dressings shouldbenon-adherent as for older patientsandappropriateinsize. Infectedwounds will requiremore frequent dressing changes [57,152]. Changingdressingsonelimbatatimeisadvocatedininfants, toreducethelikelihoodofhavingtheskinrubbedofftheopposite limb by feet kicking together, causing new,painful lesions(seeBox8). Thisapproachalsodecreasesthe chance of bacterial spread from a colonized wound toan uncontaminated area [57,78]. For baths, adding salt tothe water is recommended asfor older patients (see sub-sectiononenvironmental treatment under BathingandDressing Changes).In addition to environmental adjustments, many infantswill require analgesics withbathanddressingchanges.NSAIDs, acetaminophenandopioidsareall used, asforolder patients (see Section Bathing and Dressing Changes)(see Box8). Codeine isnotrecommended, when alterna-tives are available, as neonates lack the capacity tometabolizethedrugintoactivemetabolites, andclinicalresponsesarehighlyvariableat allages, duetopolymor-phisms in codeines metabolic pathway [153,154].Severely affected hospitalized infantsSeverely affectednewbornswithdeeptissuedamagemayrequireexten-sive pharmacologic support to achieve a level of comfort(seeBox8). These infants mayrequire aroundtheclockor continuous infusionof opioids andanadjuvant. Atransition to methadone for better steady state levelsshouldbeconsidered(refer tosub-sectiononsystemicapproaches under Skin and Wound Pain) for caveatsaboutmethadone use). A case study has shown effectivepaincontrol inaninfantwithseverechronicpain(andpossibly pruritus) whentreatedwithgabapentin[155].Patients receiving frequent opioid treatment may requireextracareinavoidingopioid-inducedconstipationandin maintaining adequate caloric intake.Oral ketaminehas beenusedtosupplement opioidswhen pain associated with dressing changes is severe[156]. Use of ketamine raises concerns due to findings ofadverse neurodevelopmental effects in young animalswhoreceivedprolongedintravenous infusions of keta-mine [157]. However, these effects are not known tooccurinhumaninfantsandareunlikelytooccurwithsmall doses administered at intervals.Good practice points Infants benefit fromthe samerangeofanalgesicsasolderpatients. Theycanuniquelybenefit fromoral sucrose for brief painful episodes.Careful monitoringiscrucial ininfantsreceivingsedat-ing medications. Babies withEBandtheirparentsbene-fit fromclose physical contact like any other families.Holdingandcuddlingcanbedonesafely, withscrupu-lous attention to lifting and handling in order to preventnew lesions and pain.End of life pain careIntroductionThe epidemiology of death in EB varies bytype [158], but is not limited to dermatologic causes. Pa-tients withJEB, generalizedseveretypeareat greatestrisk of fatality early in life froma range of causes[159,160]. PersonswithRDEBmaysuccumbinearlytomid-adulthoodfrommultiplecauses[161-163] whereaspatientswithgeneralizedtypesofEBsimplexareatriskof laryngotracheal complications [164].The palliative approach to pain experienced by individ-ualswhoarefacinglife-threateningillnessaddressesthephysical, emotional andspiritual sufferingof thepatientBox 8. Recommendations for infant pain care1. Assess patients as needed and prior to and afterinterventions; health care workers should use validatedmeasures. (Grade: A)2. Sucrose solutions should be administered for mild tomoderate pain alone or as an adjunct. (Grade: B)3. Standard analgesics should be used in infants as in olderpatients with careful attention to dosing and monitoring.(Grade: B)Goldschneider et al. BMC Medicine 2014, 12:178 Page 15 of 23http://www.biomedcentral.com/1741-7015/12/178andincludes support for the whole family [165-167](seeBox9). Squamouscellcarcinomaisfrequentlydi-agnosed in patients with severe subtypes [168] and canpresentchallengestypical of cancer-relatedpainwhenitmetastasizes. TheWorldHealthOrganizationladderapproachtopaincarefor thosepatients withcancerandotherpersistent illnessesrecommendsatwo-stepladder as a framework for pain care [169].OpioidsOpioids have a role in EB pain management, aspreviouslyindicatedintheseguidelines(seeBox9). Pa-tients in the palliative phase of their illness may be givenanoral opioidsustainedreleasemedication[170]. Opi-oids should be titrated against pain and side effects, withdifferences in approach needed depending on issuessuch as opioid tolerance and rate of development of newpainproblems[170]. However, if appropriateopioidin-creases are not effective, it is important to considerpharmacologic tolerance, poor absorption and neuro-pathicpain. Tolerancecanbeaddressedbyrotatingtheopioid to capitalize upon incomplete cross-tolerance[171,172]. In the face of poor absorption, parenteraltherapymaybeneeded(seebelow). Ifneuropathicpainissuspected, methadonemaybeanoptiontoconsider.IthasN-methyl-D-aspartate(NMDA)antagonist actioninadditiontomu-agonistpropertiescommontostand-ardopioids, andcanbebeneficial forneuropathicpain[173] anddoesnot relyonrenal excretion[61], whichmay be reduced in the palliative phase of EB [87].Althougharecentmeta-analysiscouldnotestablishdif-ferences inefficacyamongtypes of opioids for neuro-pathic pain, it was determinedthat intermediate term(weekstomonths) useof opioidsforneuropathicpainmaybehelpful[174]. Cautionsintheuseofmethadonearediscussedinthesub-sectiononsystemicapproachesunder Skin and Wound Pain.Adjunctivemeasures forneuropathicpainManyEBpatients will have beentreatedwithadjunctive agentssuchas amitriptylineor gabapentinearlier intheir ill-ness, oftenwithgoodeffect [87,155]. These bothmaytakeaperiodoftimetoachievefullanalgesiceffectandusually need to be given by the enteral route. Ketamine ismore rapidly effective and can be given orally [84-86,175]orusedsubcutaneously(seebelow). It shouldbenotedthat whenketamineby-passeshepaticfirstpassmetabol-ism, the relative proportion of norketamine is reduced andthepatientmayexperiencemoresedationandhallucina-tionsandless analgesiafor agivendose[175]. Otheroptionsforaddressingneuropathicpain(seeBox9)interminal care include opioid rotation to methadone(see above), which can also be included in a subcutane-ous infusion (see below).Infusions andissues of drugdelivery Parenteral ad-ministration of analgesiamay be needed in the palliativephase, when ability to take enteral medications is no lon-ger an option or if rapid escalation of therapy is needed.There has been an historicreluctanceto usecontinuoussubcutaneousinfusions, duetothefearof precipitatingfurther blistering. However, subcutaneous infusions havebeenreportedtobetoleratedinthefinal daysoflifeinan adult EB patient [176] (see Box 9).In non-EB patients with cancer pain, the subcutaneousrouteofmorphineiseffectivetoasimilardegreeastheintravenous [177]. Other alternatives, suchas adherenttransdermal deliverysystems, needregularremoval andreplacement. Repeated subcutaneous/intramuscular in-jections are very frightening for children, as are attemptstoobtainIV access. Alternatively, sitesof subcutaneousneedle insertion last reasonably well [87,177]. If subcuta-neoussitesdobecomeinflamed, somebenefithasbeenshown from adding low dose dexamethasone to the infu-sion [178], although this has not been used to our know-ledge in children with EB.Breakthrough pain medication at the end of lifeEvenwhengoodbaselinepainrelief hasbeenachieved, mostpatients will requireoccasional breakthrough doses ofanalgesia. Uniformlyeffectivebreakthroughdosingpro-tocols have not been determined for children with EBatendoflife, althoughtherearegeneralrecommendationsBox 9. Recommendations for end of life paintreatment1. Assess and manage physical, emotional and spiritual sufferingof the patient, while providing support for the whole family.(Grade: A)2. Opioids are the cornerstone of good analgesia in this setting.Opioid rotation may need to be considered to improveanalgesia and reduce side effects, and adjuncts may need tobe added. (Grade: B)3. Consider targeted medication for neuropathic pain or whenpain proves refractory to convention therapies. (Grade: D)4. Continuous subcutaneous infusion of medication is an optionwhen parenteral therapy is needed in the terminal phase.(Grade: C)5. Where needed, breakthrough medication can be giventransmucosally (oral or nasal) for rapid onset and avoidanceof the enteral route. (Grade: B)Goldschneider et al. BMC Medicine 2014, 12:178 Page 16 of 23http://www.biomedcentral.com/1741-7015/12/178fromseveralinternationalsources[169,179]anddatatosupporttheuseof upto20%of total dailyopioidcon-sumption[180,181] inadultswithcancer. Ingeneral, ashort-acting, immediate release form of opioid should begivenat approximately 10%to15%of the total back-groundopioiddoseof theprevious24hours. If rescuedosing is used frequently and consistently, then thebaselineopioiddosingneedstobeincreased. Individualpatient factors shouldbetakenintoconsideration(in-cludingprior opioidexposure, renal andhepaticfunc-tion, other medication use) and consultation with anexpertin pain managementand/or palliativecare isrec-ommended. The same principle is recommended foropioids given via all routes of administration. When veryrapid onset is needed, transmucosal administrationofopioids may be preferable (see Box 9). Commerciallyavailable transmucosal preparations of fentanyl are avail-ableindoseslikelytobesuitableforolderchildrenandadults. Evidence supports the use of transbuccal fentanylforbreakthroughpainincancerpatients[182]. Anadd-itional benefitof fentanyl isthatitisnotdependentonrenalexcretion. Insomecenters, theinjectableformula-tionsof morphineordiamorphinehavebeenusedbuc-cally at around a third of the standard enteral dose(equivalent to the intravenous dose), allowing moreflexibility of dosing. It is alsoimportant torememberthat extremeanxietymayconfoundpainperceptionorexpression and that there may be benefit in offering add-itional doses of buccal midazolam where this is felt to beasignificant factor. Therapyshouldbetargetedat spe-cific symptoms whenever possible, although combin-ation therapy is not unusual. Breakthrough analgesiashould be offered in the face of unexplained agitation incase of undiagnosed pain, after which medicationforprimary agitation/anxietymaybeconsidered. Whileitislikelythat bothof thesewouldcauseadegreeof sed-ation at higher doses, this should not be the primary aimof treatment.Good practice pointsPalliative pain care is an expectedpartofcareforEB, whichinmanycasesislife-limitinginnature. All basicprinciplesofpalliativecareapplyasthey do for other terminal disease states.PruritusIntroductionItch is a prominent, debilitating and dam-aging symptomfor childrenwithEB, but the mecha-nisms whichleadtothe manifestationof pruritus arepoorly understood [183]. Promising newinsights intothe causes andpotential treatments of chronicitchinanimal models [184], inhumanchronic itchgenerally[185] andinrecovering burnpatients [186] may holdpotential for application in the EB population.Non-pharmacological approachesMultiple environmen-tal andbehavioral approachestoaddressitchhavebeensuggested[183,187] andinclude: preventionof dryskin(systemichydrationandemollients), gentledebridementof dry/dead/crusted skin, prevention and treatment of skinwound infection; maintaining/supporting the healingprocessbyattentiontoanemiaandnutritional status,limitingdamage totheskinbyavoidingshear forcesimposedbyscratching(short nails, occlusivebarriers,pattingratherthanpullingortearingatasite), avoid-ingoverheatingandusingmeasurestokeepthebodycool (see Box 10). CBTis useful to reduce habitualscratchingbehaviors(seesectiononpsychological ap-proaches). Itisimportanttoavoidandtreatsecondarycauseswhenpresent (suchasdrugs, environmental itchtriggers, underlyingco-morbidities). Opioid-induceditchinEBcanbeaproblemandadifficultside effecttobal-ance against the desired analgesia; opioid rotation may behelpful.Pharmacological therapies Pharmacological therapiesincludetraditional oral antihistaminicmedications (seeBox10). Somepatientsprefersedatingformulationsatbedtime (for example, diphenhydramine, hydroxyzine,chlorpheniramine) and othersnon-sedating preparationsduringthe day (for example, cetirizine, loratadine andfexofenadine). Efficacyisvariableandrecommendationsarebasedonanecdotal experienceforlackof goodevi-dence in EB and other dermatologic conditions. Centrallyactingmedications, suchas gabapentinandpregabalin,have evidence for efficacy fromthe burn literature[186,188,189] and may have application in EB. Many ofthesemedicationshavealsobeenusedsuccessfullyforneuropathicpain(seesub-sectiononadjunctivemea-sures for neuropathic painunder End of Life Pain).Antidepressants with nortriptyline re-uptake inhibitoryactions have beenusedfor various pruritic conditionswith some evidence for efficacy, with mirtazapine showingBox 10. Recommendations for itch treatment1. Use environmental and behavioral interventions for itchcontrol. (Grade: C)2. Antihistamines are recommended and can be chosendepending upon desirability of sedating effects. (Grade: D)3. Gabapentin, pregabalin, TCA, serotonin norepinephrinereuptake inhibitors (SNRIs) and other non-traditionalantipruritic agents should be strongly considered for itchtreatment. (Grade: C)Goldschneider et al. BMC Medicine 2014, 12:178 Page 17 of 23http://www.biomedcentral.com/1741-7015/12/178promise [190-193]. Low-dosecyclosporinehas beenusedin a single case of dominant dystrophic EB to reduce gen-eralized itching [185,194]. Anecdotal success has been re-portedwithondansetroninEB; however, thesamehadbeenreportedforpruritusfromcholestaticjaundice, al-thoughcontrolledtrials didnot confirmefficacy [195].Similarsuggestionsweremaderelatedtothepruritusof uremia[196,197], leadingtorecommendationsthatondansetron should be considered, although clinicaltrials are needed in EB.Other medications that haveshownsporadicclinicalsuccess intreatingitchinEBinclude: cyproheptadine;selectiveserotoninre-uptakeinhibitors (SSRIs; fluoxet-ine, paroxetine, sertraline, fluvoxamine) [193]; tricyclicantidepressants (doxepin, amitriptyline, nortriptyline) [192];opioidantagonists(naloxone, naltrexone); kappareceptoragonists (butorphanol, dextromethorphan, nalbuphine);other5-HT3receptor antagonists(granisetron, dolase-tron); antipsychotic agents (olanzapine, pimozide) andcannabinoids. These agents andthe NK-1receptor antag-onistaprepitantmayprove to beuseful incertainsubsetsofpatients, althoughevidencetoguidetherapyislacking[198] and practitioners are encouraged to pursue the afore-mentionedtherapies basedonpatient responsetopriormedications, potential interactions within the patientsmedication list and medication availability (see Box 10).It iscommonpracticeformedicationsfromdifferentdrugclassestobeusedconcurrentlyandforagentsinthesameclasstoberotatedduetotheobservationthata particular medication may have improved efficacy afterintermittent drug holiday.Goodpracticepoints Acombinationofenvironmental,cognitive-behavioral and pharmacologic therapies is avail-able for use for EB-related pruritus, which can be a severesymptom of the disease.ConclusionsThese guidelines represent the initial effort to organize painmanagement forpatientswithEBbasedonexistingevi-dence. Whiletheguidelinesweredevelopedusingcurrentevidence and a rigorous evaluation process, there are limi-tations in the clinical use of the recommendations. The twobroad areas of concern involve practical limitations of im-plementationandthelevel ofavailableevidence. Tables5and6identifyissuesforimplementationoftheguidelinesaswell asgeneral recommendationsareasforresearchtoenhance the level of evidence.Additional fileAdditional file 1: EB-specific articles that were excluded from use inmaking recommendations, with rationales.Table 5 Implementation barriers1. Availability of resources (for example, medications and equipment)2. Legal and social restrictions on the use of various medications andtherapies.3. Limited and uneven distribution of knowledge and expertise4. International dissemination of guidelines and EB-related informationto local care providers and families (includes translation and accessto electronic and print media)Table 6 Areas of researchPsychological and integrative approaches:1. Test the efficacy of well-established cognitive behavioralinterventions for acute and chronic pain management in EB.2. Develop EB-specific pain assessment measures for both acute andchronic pain.3. Evaluate the efficacy of cognitive behavioral therapy for EB-relatedpruritus4. Evaluate the role for Integrative Medicine techniques for the EBpopulation.Acute pain:1. Improve the balance between analgesia and side effects specific toEB (for example, itching).2. Establish optimal treatment of needle-related pain.3. Define the role for ketamine and other non-opioid agents.Chronic and recurrent pain:1. Evaluate topical therapies including opioids, local anesthetics andNSAIDs.2. Determine optimal environmental interventions for bath anddressing changes including bath additives (salt, bleach, oatmeal).3. Define optimal perianal pain therapies.4. Clarify the role of bone density screening in preventing bone painand fractures.5. Determine the role of topical NSAIDs in treatment of cornealabrasion pain.6. Explore the role for various physical and occupational therapyinterventions for joint, bone and back pain.Infants:1. Validate observational pain scales in the setting of bandaged infants.2. Determine the safety and dosing of adjunct medications, such asgabapentin and topical agents.Pruritus:1. Establish the mechanisms of pruritus in EB and effective treatmentthereof.2. Refine the management of opioid-exacerbated itch.End of life:1. Define how best to integrate palliative care into the overall care ofpatients with EB prior to end of life.2. Define optimal treatments for pain at the end of life.A focused list to represent the broad categories that would benefit fromstudies in patients with EB.Goldschneider et al. BMC Medicine 2014, 12:178 Page 18 of 23http://www.biomedcentral.com/1741-7015/12/178AbbreviationsCBT: cognitive behavioral therapy/techniques; CHEOPS: Childrens Hospital ofEastern Ontario Pain Scale; CRIES: Crying, requires oxygen, Increased vitalsigns, Expression and Sleepless Pain Scale; DDEB: dominant dystrophicepidermolysis bullosa; DEB: dystrophic epidermolysis bullosa (dominant andrecessive types); EB: epidermolysis bullosa; EBS: epidermolysis bullosa simplex(basal and suprabasal types); FLACC: Face Legs Arms Cry Consolability PainScale; GERD: gastroesophageal reflux disease; JEB: junctional epidermolysisbullosa (generalized and localized); NIPS: Neonatal Infant Pain Scale;NMDA: N-methyl-d-aspartate; NSAIDs: non-steroidal anti-inflammatory drugs;N-PASS: Neonatal Pain Agitation and Sedation Scale; PCA: patient controlledanalgesia; PIPP: Premature Infant Pain Profile; RDEB: recessive dystrophicepidermolysis bullosa.Competing interestsThe authors declare that they have no competing interests.Authors contributionsThis work was initiated and led by KRG with active input from all authors. JG,EH, CL, ALJ, AEM, LGM and DSL participated in the review process andrecommendation/guideline draft, see text for details. DSL led the systematicevidence analysis and provided methodological support and guidance.Multi-disciplinary clinician input was obtained as was input from patientsand families early in the process (see Acknowledgments,below).Theconsensus meeting (see text) was attended in person or via Skype byKRG,ALJ,EH,JG,CL,LGM and BK (see Acknowledgements).All authorsread and approved the final manuscript.AcknowledgmentsGuideline development was supported by a small grant from DEBRA USA todefray the costs of travel, accommodation and preparation related to theconsensus meeting, held on 4, 5 May 2012 in Cincinnati, Ohio, USA. Thefollowing members of the original guidelines development committeehelped with initial content development and recommendations: Beverly IngeWalti, Kara Malcolm, Teresa Mingrone, and Stacy Shipley.The following Clinician Reviewers are gratefully acknowledged: Anna L.Bruckner, MD, Elizabeth Ely, RN, PhD, Kim Hazelbaker, RN, Barbara Hoggart,MD, Richard F. Howard, BSc, FRCA, Anne Lucky, MD, Geraldine Mancuso-Kelly,RN, Elena Pope, MD, Susan Rowe, RN, Alexandra Szabova, MD, Jean Whalen, RN.Warm thanks to the following Family and Patient Reviewers: PatsyDiGiovanna, Michelle Starkey, Natasha Starkey and *Brett Kopelan(*participated in consensus meeting).Special thanks to Andrea Ayers (administrative assistant to KRG), BrettKopelin (DEBRA USA), Francis Palisson (DEBRA Chile) and Avril Keenan(DEBRA Ireland) for their support.Author details1Pain Management Center, Department of Anesthesiology, Cincinnati ChildrensHospital Medical Center, Cincinnati, Ohio, USA. 2Lucille Packard ChildrensHospital, Department of Anesthesia (by courtesy, Pediatrics), Stanford University,Stanford, California, USA. 3Helen and Douglas Hospices, Oxford and JohnRadcliffe Hospital, Oxford, USA. 4University of Southampton, Southampton, UK.5Great Ormond Street Hospital for Children NHS Trust, London, UK. 6PainManagement Center and Division of Behavioral Medicine and ClinicalPsychology, Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio, USA.7National Paediatric Epidermolysis Bullosa Centre, Great Ormond Street HospitalNHS Foundation Trust, London, UK. 8Department of Anesthesiology and CriticalCare, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 9JamesM. 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