8/13/2019 1-s2.0-S1526590007005123-main

1/16

CRITICAL R EVIEW

Burn Injury Pain: The Continuing Challenge

Gretchen J. Summer,*, Kathleen A. Puntillo,* Christine Miaskowski,* Paul G. Green,,

and Jon D. Levine*,,

*Department of Physiological Nursing, School of Nursing;Department of Oral and Maxillofacial Surgery, School of Dentistry; andDivision of Neuroscience, Biomedical Sciences Program, University of California-San Francisco, San Francisco,California.

Abstract: The development of more effective methods of relieving pain associated with burn injuryis a major unmet medical need. Not only is acute burn injury pain a source of immense suffering, but

it has been linked to debilitating chronic pain and stress-related disorders. Although pain manage-

ment guidelines and protocols have been developed and implemented, unrelieved moderate-to-

severe pain continues to be reported after burn injury. One reason for this is that the intensity of pain

associated with wound care and rehabilitation therapy, the major source of severe pain in this patient

population, varies widely over the 3 phases of burn recovery, making it difficult to estimate analgesic

requirements. The effects of opioids, the most commonly administered analgesics for burn injury

procedural pain, are difficult to gauge over the course of burn recovery because the need for an

opioid may change rapidly, resulting in the overmedication or undermedication of burn-injured

patients. Understanding the mechanisms that contribute to the intensity and variability of burn injury

pain over time is crucial to its proper management. We provide an overview of the types of pain

associated with a burn injury, describe how these different types of pain interfere with the phases of

burn recovery, and summarize pharmacologic pain management strategies across the continuum of

burn care. We conclude with a discussion and suggestions for improvement. Rational management,

based on the underlying mechanisms that contribute to the intensity and variability of burn injury

pain, is in its infancy. The paucity of information highlights the need for research that explores and

advances the identification of mechanisms of acute and chronic burn injury pain.

Perspective:Researchers continue to report that burn pain is undertreated. This review examinesburn injury pain management across the phases of burn recovery, emphasizing 3 types of pain that

require separate assessment and management. It provides insights and suggestions for future research

directions to address this significant clinical problem.

2007 by the American Pain Society

Key words: Thermal burn, pain management, phases of burn recovery, inflammation, acute andchronic pain mechanisms, science.

Although burn injury pain was well-described as amajor clinical problem over 2 decades ago,154,157

researchers continue to report that burn pain re-mains undertreated.23,24,26,30,121,129,161,196,207 This is of

concern because unrelieved pain is thought to contributeto long-term sensory problems, including chronic pain, par-esthesias, and dyesthesias,18,44,84,99,134,212 a common oc-currence after burn injury,28,109,110,176 as well as debilitat-

ing psychological conditions.21,41,58,161,172,177,197,215 This

Received August 7, 2006; Revised January 22, 2007; Accepted February 8,2007.

Address reprint requests to Dr. Gretchen J. Summer, C-522/Box 0440, 521Parnassus Avenue, San Francisco, CA 94143. E-mail: gretchen.summer@ucsf.edu

1526-5900/$32.00

2007 by the American Pain Society

doi:10.1016/j.jpain.2007.02.426

The Journal of Pain, Vol 8, No 7 (July), 2007: pp 533-548Available online at www.sciencedirect.com

533

8/13/2019 1-s2.0-S1526590007005123-main

2/16

review examines burn injury pain and its managementacross 3 phases of burn recovery (ie, acute, healing, andrehabilitation), emphasizing 3 types of pain that requireseparate assessment, management, and frequent evalu-ation. Although the review addresses patients of allages, from critical care to outpatients, the primary focusis on pharmacologic management of the adult hospital-

ized patient who is awake and not supported by me-chanical ventilation. The review concludes with a discus-sion, suggestions for improvement, and a call forcritically needed science to guide the standard of care aswell as the development of new therapeutic approaches.

Significance

Unrelieved burn injury pain is a significant publichealth problem.

In the United States, an estimated 1.25 million individ-uals sustain a burn injury each year.19 Of these, between700,000 and 827,000182 seek care at an emergency de-

partment, and between 51,000 and 71,000 require hos-pitalization.104 Although these figures reflect decreasedprevalence as the result of successful burn preventionstrategies,81 they do not reflect the significant increasein patients surviving major burns.46,85,152 Nor do theyreveal that the number of patients admitted to burncenters has increased significantly due to the recognitionthat even smaller burns require specialized care.104 Yet,burns are one of the most resource-intensive of all healthcare conditions.25,42,61,130,166 Thus, there has been awidespread trend to treat patients with larger and morecomplex burns on an outpatient basis and to dischargeinpatients sooner. Over the past 10 years, the average

length of an inpatient stay declined from 13 days to 8days.3 This approach means that outpatients experiencemore severe pain and have pain management needsacross all the phases of burn recovery.

Phases of Burn Recovery

Important to a discussion of burn injury pain is an un-derstanding of burn recovery. Burn recovery is fre-quently divided into 3 phases, based on local and sys-temic, pathophysiologic responses. The acute phase, alsoreferred to as the emergency or resuscitative phase (dueto the need for massive fluid replacement often required

to maintain circulating volume), is when initial wounddebridement is performed after the patient has beenstabilized. The healing phase is characterized by the goalto accomplish healing, which requires a clean woundbed, achieved through frequent dressing changes or sur-gical intervention. The rehabilitation, or remodelingphase, is the time during which the intense inflammatoryresponse associated with raised, erythematous (red-dened) scar tissue subsides and tissue collagenases ceaseremodeling, resulting in a softer, less erythematous andsometimes flatter scar. The acute phase may be com-pletely bypassed in smaller injuries and typically lasts 2 to3 days.122,165 The length of the healing phase may be

weeks or more, and the rehabilitation phase most often

takes at least 1 year but sometimes much longer, de-pending on patient participation in the treatment plan;patient age; location, size, and depth of burn; as well ascomorbid or preexisting conditions.106

Pain is the most frequent complaint of burn-injuredpatients.116 Burns induce mechanical and thermal hyper-algesia in human skin.150,163 However, primary mechan-

ical hyperalgesia, induced by mechanical stimulationof the injured site, is the major source of severe painafter a burn injury. In this review, the terms pain andhyperalgesia refer to primary mechanical hyperal-gesia.

Clinical observations suggest that hyperalgesia is likelyto be most severe and variable in intensity during thehealing phase. The intensity of hyperalgesia cannot bepredicted based on factors such as patient age, sex, eth-nicity, education, occupation, or socioeconomic sta-tus7,26,154 and does not always correlate with the size ofthe burn.26,41,154

Burn Injury Pain Assessment

Assessment tools are essential to the diagnosis of un-derlying burn pain syndromes and the effectiveness oftheir treatment. In the burn patient population, themost common pain assessment tools are verbal self-re-port instruments that measure pain intensity, such as the0 to 10 numeric rating scale. However, visual analog,descriptor (eg, adjective), face, and color scales, are alsoused. In 1 of the few studies that examined patient pref-erence, burn-injured patients preferred faces209 andcolor scales to the more commonly used visual analogueand adjective scales.60

Osgood et al191 introduced the first pediatric burn painassessment tool: A large thermometer-like numeric rat-ing scale designed with white numbers (0 to 10) on acrimson background. Whereas this and other pediatricpain assessment tools can be used in adults and elderlypatients (eg, faces72), no pain assessment tool has beenvalidated for use among elderly burn-injured patients.This may be, in part, because pain in older burn-injuredpatients is only beginning to be described.65,79,184 Re-search in other patient populations has demonstratedthat the verbal descriptor scale is best for measuring painin older adults, including those with mild to moderatecognitive impairment.73

When patients are unable to provide a self-report, be-havioral observations may be a valid approach.71 An ob-servational pain scale has been developed for use inburn-injured children.11 A cautionary note is warranted,however, because significant discordance has been dem-onstrated between burn nurses and burn-injured pa-tients pain assessments.27,57,82 For this reason, individu-als who are unable to communicate their pain are atgreater risk for undertreatment of their painan impor-tant clinical problem for which excellent clinical practicerecommendations have recently been published.71

As in other patient populations, the manually markedvisual analog scale is preferred for research purposes be-

cause its continuous range makes it a sensitive measure-

534 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

3/16

ment method. However, burn-injured patients are oftenunable to manually mark a scale due to the extent and/orseverity of their injuries. Choinire29 solved this problemby introducing a visual analog scale designed to elicit averbal self-report. Similar to the instrument introducedby Osgood et al,135 the visual analog thermometer isbased on a thermometer-like design.191 However, it is a

hand-held, washable instrument with a sliding redpanel.A pediatric verbal self-report visual analog scale45 hasbeen adapted for use in burn-injured children.164

Although limited due to small sample size, a strongcorrelation was found between manual and verbal burnpain assessment scales, indicating good concurrent valid-ity189 consistent with research in other patient popula-tions.62 Thus, educating the patient as to the purposeand importance of multiple pain assessments and offer-ing them a choice as to which method they prefer mayprovide them with some control over communicationmethods as well as improve the capacity of more patientsto participate in research. Assessing pain in the burn-

injured patient is complex because it requires the sepa-rate assessment and management of multiple types ofpain.30,165

Types of Burn Injury Pain

Procedural PainProcedural pain (eg, primary mechanical hyperalgesia)

is the most intense and most likely type of burn injurypain to be undertreated.6,20,26 Patients describe proce-dural pain as having an intense burning and stingingquality that may continue to a lesser degree but may be

accompanied by intermittent sharp pain for minutes tohours after dressing changes and physiotherapy haveended.122 Wound debridement, dressing changes, andstrenuous physical and occupational therapy that re-quire manipulation of already inflamed tissue may con-tribute to increased pain and inflammation in burnwounds. In addition, dependent positioning of injuredextremities (ie, below the level of the heart) can induceexcruciating, throbbing pain, thought to be caused bypressure associated with venous distention in inflamed,edematous tissue. These observations are based on clin-ical experience, however, and require study. Proceduralpain is a multidimensional experience that frequently

induces significant anxiety and distress.24,80,164

Thesemultidimensional manifestations of the procedural painexperience are critical aspects of this important clinicalproblem as emphasized in the following section.

Procedural Pain and Associated Anxietyand Distress

New burn care providers sometimes ask if patients getused to or habituate to procedural pain. However, clin-ical observations and research suggests that proceduralpainassociated anxiety may increase over time in burn-injured patients.5,59,208 This finding has important impli-cations for clinical care because strong correlations were

found between pain, psychological distress,41 and phys-

ical as well as psychological outcomes in burn-injuredchildren186 and adults.48 Anxiety and distress, as mea-sured by tension during burn dressing changes, was sig-nificantly related to overall and worst pain, whereasamount of analgesics and anxiolytics given, postburnday, and total body surface area were not.57

Anxiolytic agents, such as the benzodiazepines (eg, di-

azepam, lorazepam, and midazolam) are known to re-duce pain and anxiety associated with burn dressingchanges in burn-injured adults141 and children.178 Loraz-epam was found to reduce procedural pain ratings inpatients who had high pain defined as a baseline of 50or greater on a 0 to 100 mm visual analog scale.141 How-ever, benzodiazepines have been found to antagonizeopioid analgesia in postoperative patients.56 Moreover,similar to opioids, patients responses to benzodiaz-epines are highly variable. Although some patients mayhave development of respiratory depression, others, par-ticularly those with a history of alcohol or chemical de-pendence, may not respond to doses within the recom-

mended safety and efficacy range. Therefore, theadministration of benzodiazepines requires increasedstaffing to provide close monitoring for untoward ef-fects, a standard of care commonly referred to as con-scious sedation. Because burn care is resource-intensiveand insurance and government reimbursements havedeclined, the use of benzodiazepines that require a con-scious sedation protocol has declined in the acute caresetting in some burn centers24 and is impractical in theoutpatient setting. Other classes of sedative hypnoticssuch as ketamine80 and propofol31,180 significantly re-duce pain and associated anxiety and distress duringburn dressing change procedures, but their use is usually

limited to the critical care setting for the same reason.Pharmacologic agents have also been used to reduce

acute stress symptoms in burn-injured children (eg, hy-perarousal and intrusive reexperiencing), including imip-ramine,167 chloral hydrate,167 morphine,172 and respiri-done.183 However, lack of a clearly defined standardizeddiagnostic criterion for study entry and use of an unvali-dated clinical interview to determine improvement ormethodological flaws make the results difficult to inter-pret.46 Whether decreasing acute stress symptoms inburn-injured patients with pharmacologic agents trans-lates into a decreased prevalence of traumatic stress dis-orders is unknown and requires further study. One rea-

son for this may be the difficulty to accurately diagnosetraumatic stress disorders in patients with burn inju-ries.133

Prevalence rates for traumatic stress disorders associ-ated with burn injury vary substantially across studies,ranging between 11% and 50%.12,46 In addition to pain-associated anxiety and distress, factors that contribute toacute and post-traumatic stress disorders after burn in-jury include female sex,197 avoidant coping style, loca-tion of burn, preburn depression, type and severity ofbaseline symptoms, personality disorder, history of alco-hol and/or chemical dependency, and poor social sup-port.46 Findings are inconsistent regarding body image

after burn injury.198 Overall, the data suggest that severe

535REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

4/16

burns do not necessarily induce physical impairment orpoor psychosocial adjustment, particularly in burnedchildren,17 but size of burn and in-hospital ratings ofstress may predict rate and degree of physical and psy-chological recovery.48 These results suggest that in addi-tion to aggressive wound closure, interventions that re-duce in-hospital distress may accelerate and improve

both physical and psychosocial recovery.Nonpharmacologic adjuncts to reduce pain and associ-

ated anxiety and distress include cognitive techniques(eg, distraction and focusing attention), behavioral tech-niques (eg, classic conditioning, including pairing relax-ation with previously conditioned autonomic responses),education and/or preparatory information (eg, enhanc-ing predictability of sensory and procedural components ofaversive procedures91,92), hypnotherapeutic techniques(eg, incorporates behavioral and cognitivetechniques withintroduction of posthypnotic cues for relaxation),1 and al-ternative medicine (eg, massage, acupressure).46 Of these,hypnosis,46,90 music,47,54,90,160 and virtual reality75-77 (ie,

technologically driven distraction) have been demon-strated to significantly reduce pain and/or associatedanxiety and distress when used as an adjunct to opioidanalgesics during burn dressing changes.46,55 Pattersonet al140 suggested that hypnosis, which appears to bemore effective in patients with severe pain caused bymotivational factors, and virtual reality may be com-bined to optimize their beneficial effects.143 Preliminaryfindings support this suggestion as well as the increasedefficiency with which hypnosis can be administered byeliminating the need for the presence of a trained clini-cian,144 an advantage that may help to offset the cost ofexpensive equipment required to administer virtual re-

ality hypnosis.Nonpharmacologic interventions can also cause harm.

Single-session psychological debriefing was found to in-crease symptoms of post-traumatic stress disorder inburn-injured patients,10,15,168 similar to other patientpopulations.14 In addition, combining attention focusing(ie, attending to procedural sensations) with ignoringhas been shown to increase symptoms of traumatic stress(eg, intrusion) in burn-injured patients.47 A group thatwas taught to use 2 behavioral coping techniques (eg, asopposed to using 1 or the other), including avoidance(eg, ignoring) and approach (eg, focusing attention),during burn dressing changes reported more traumatic

stress symptoms than untreated control subjects.47 Thus,the use of single-session debriefing and combined use ofignoring and focusing attention during burn dressingchanges is not empirically justified and may potentiallycause harm.46 Although the theoretical basis and appli-cation of nonpharmacologic adjuncts are not within thescope of this review, they are well described by Pattersonet al.1,138,139,143

Background PainBurn-injured patients with high anxiety also tend to

report more background pain.26 Similar to proceduralpain, wide variability has been documented in the inten-

sity of background pain after burn injury.96,162 Back-

ground pain is characterized by its prolonged duration,relatively constant nature, and mild to moderate inten-sity.96 Burn background pain is typically described as acontinuous burning or throbbing pain that ispresent when the patient is relatively immobile. There-fore, it is usually best treated with regularly scheduledanalgesics that provide a continuous serum therapeutic

blood level.142,100

Breakthrough PainSimilar to postoperative patients, patients with burns

experience transient worsening of pain most frequentlyassociated with movement that is referred to as break-through pain.33 Burn-injured patients also describespontaneous components of breakthrough pain. Spon-taneous breakthrough pain may be due to changingmechanisms of pain over time as well as inadequate dos-ing, which occurs when serum blood levels of analgesicsdrop below what is needed to control backgroundpain.159 Spontaneous breakthrough pain is commonly

reported by patients in qualitative terms such as sting-ing, pricking, shooting, and pounding (unpub-lished data). Although pain associated with primary me-chanical hyperalgesia caused by movement may also becalled procedural pain, most burn care providers con-sider this pain to be a type of breakthrough pain. Me-chanical hyperalgesia of this nature is particularly severeafter extended periods of immobility in those patientswith injuries over joints and/or in whom the extremitiesare affected.

For optimal analgesia after burn injury, a guidingprinciple is that each patient requires a separate as-sessment of procedural, background, and break-

through pain throughout the rapidly changing courseof burn recovery.30 The next section describes the painassociated with the 3 phases of burn recovery and howthese different types of pain may occur in and inter-fere with each phase.

Phases of Burn Recovery andPain Management

Acute PhaseStabilization of the patient and preservation of func-

tion are the primary goals of treatment during the acutephase. Large thermal injuries (15% total body surfacearea) evoke profound systemic fluid shifts and physio-logic stress responses.213 This phase may be completelybypassed in the case of smaller burns122 and varies inlength but typically lasts no longer than 3 days.165 Acuteintoxication with alcohol or chemical substances, whichmay be a precipitant to the burn injury,93 may initiallycomplicate care of the burn-injured patient and can ad-versely interact with analgesic and anxiolytic medica-tions.165

Procedural Pain During theAcute Phase

Procedural pain during the acute phase may range

from mild to excruciating. It is critical to aggressively

536 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

5/16

manage pain and anxiety for the first dressing change. Ifthe first dressing change evokes extreme anxiety andemotional distress, clinical experience suggests thatthese responses are likely to increase over time and maylead to long-term pain management problems.105 Thus,some burn centers provide anxiolytic medication as anadjunct to opioids as a standard of care during this phase

unless otherwise contraindicated.137

Of note, patients may have progressed to the rehabil-itation phase and then return to the healing phase afterrequired surgical procedures. Thus, the phases of burnrecovery do not always occur in a stepwise monotonicprogression.

Background Pain During theAcute Phase

The severity of background pain during the acutephase may also range widely from none to severe. It isoften markedly decreased by covering the wound se-curely with a moist or occlusive dressing, which suggests

a contribution from exposure of the wound to air. Be-cause this type of pain is continuous, controlled releaseor long half-life opioids such as methadone are particu-larly effective for the management of backgroundpain.23 Moreover, methadone is a -receptor agonistand an excitatory amino acid N-methyl-D-aspartate(NMDA) receptor antagonist. Thus, it may be of particu-lar benefit to decrease morphine tolerance, which is of-ten associated with enhanced hyperalgesia in the burn-injured patient.181,211

Breakthrough Pain During theAcute Phase

During the acute phase, it is not unusual for the burn-injured patient who appears to have good pain controlon a stable analgesic regimen to suddenly experience anincrease in the severity of their pain, referred to as break-through pain. A subtype of breakthrough pain calledend-of-dose breakthrough pain may occur toward theend of a dosing interval presumably because opioid lev-els have declined below a therapeutic level. Shorteningthe dosing interval is usually recommended under thesecircumstances.159 Increasing the dose without shorten-ing the dosing interval may also be effective, but thisapproach can result in higher than desirable peak serumlevels, producing or increasing undesirable side effects.4

Healing PhaseDuring the healing stage, the goal is to promote heal-

ing, either by removing devitalized tissue from the in-jured area, using topical enzymatic preparations and fre-quent dressing changes or by surgical excision andgrafting.8,98 During the transition from the acute to thehealing phase, a determination is made as to whether thepatient willrequiresurgery to accomplish wound closure orto let the wounds heal on their own with daily woundcare. If wounds cannot contract and approximate theiredges together, they will form extremely painful, nonheal-ing ulcers. However, if wounds heal over a joint, since they

will shrink by contraction, they may leave the patient with

a contracture, limiting range of motion. Thus, stretchinginjured tissue during physiotherapy, a major source of pri-mary mechanical hyperalgesia, is vital immediately afterand over the long course of burn recovery to prevent con-tractures and to optimize function.

Because of the time it takes to prepare a clean woundbed necessary for epidermal migration to occur deep

dermal burns take longer to heal, which extends the pe-riod of time the patient endures severe pain. Moreover,wounds that heal slowly are more likely to scar signifi-cantly, a phenomenon associated with prolonged inflam-mation.213 Since early excision and grafting significantlyreduce mortality and morbidity in the burn-injured patientpopulation,130 the goal is to establish a wound closuretreatment plan as soon as possible. That being said, adetermination of the depth of tissue damage is difficult,even for the most experienced clinicians.67 Moreover,inflammatory responses induce changes in the local mi-crocirculation that contribute to further ischemia.213

Thus, the extent of tissue damage does not evolve com-

pletely for several days (eg, 3 days or longer) after burninjury.67 During this wait and watch period, the burnpatient often experiences severe pain and anxiety.

Procedural Pain During theHealing Phase

Unlike most acute injuries, procedural burn pain mayworsen unpredictably over the course of healing, anevent that adds to emotional distress in this patient pop-ulation.13,26,30,58,171 This problem is not limited to a par-ticular phase of burn recovery but is a frequent clinicalobservation during the healing phase. Moreover, thehealing phase can last weeks, months, and sometimes

even years, during which time the patient must endurerepetitive, exquisitely painful, wound care and/or surgi-cal procedures.

Short-acting, potent opioid analgesics timed to actduring peak procedure-induced primary mechanical hy-peralgesia are most often indicated. In more severecases, local nerve blocks or general anesthesia may be anoption. Local anesthetic blocks have been used surpris-ingly sparsely in this patient population. One reason maybe that as previously mentioned, invasive lines provide aportal of entry for infection in immunocompromisedburn-injured patients. In addition, for regional nerveblocks, an acute pain service is usually required to pro-

vide the expertise and oversight necessary for this modeof analgesia.

A common clinical observation in patients experienc-ing postoperative pain after skin grafting procedures isthat the split-skin donor site is substantially more painfulthan the grafted site. Two studies suggest that local an-esthetics can be used to decrease donor site pain in theimmediate postoperative period. Bupivacaine at a doseof slightly less than 1.9 mg/kg added to intraoperativedonor site infiltration solution was found to be safe, asdemonstrated by low blood levels and the absence ofclinical signs of toxicity, and effective.53 In contrast, thetopical aerosol application of 0.5% bupivacaine was not

as effective as 2% lidocaine when applied intraopera-

537REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

6/16

tively to donor sites before application of an occlusive

dressing.88 In this study, lidocaine produced an analgesiceffect that reduced opioid requirements compared with

patients who received 0.5% bupivacaine or placebo.

Research has shown topical146 as well as preemptive

injections of lidocaine37 to be disappointingly ineffective

in healthy volunteers undergoing burn injury, consistent

with the poor response observed clinically.In vitrostud-ies show that C-fiber nociceptors require a significantly

higher dose of lidocaine (0.8 mmol/L) than A-delta fibernociceptors, which were blocked by as little as 0.2 mmol/L

lidocaine.51,52 These differential findings suggest that

the analgesic effect of lidocaine is dose-dependent, but

little is known about topical lidocaine and the peripheral

mechanisms of burn injury pain.

Deep wounds that must heal by contraction and then

primary closure if necessary require mechanical stimula-tion (ie, pressurized spray of water, wet to dry dressings,

and so forth). These wounds fill in with vascular granu-

lation tissue, which can be exquisitely sensitive to pres-

sure. Topical lidocaine has met with limited success in

these types of wounds. In addition, lidocaine requires

caution due to the risk of cardiac arrhythmias and sei-

zures associated with systemic absorption.32,120,206 One

study suggested that clean vascular wounds with a min-imal amount of associated inflammation may be more

responsive to the analgesic effects of topical local anes-

thetics.88 Of note, a recent study that compared infected

and noninfected burn-injured patients showed a signifi-

cant increase in pain intensity in patients with infec-tion.193 Burns induce profound inflammation.151 It is

possible that inflammation induces plastic changes in pe-

ripheralC-fiber nociceptors,2

making them less respon-sive to local anesthetics, butthis mechanism has not been

studied.Regional blocks have also been used to relieve donor

site pain. A recent randomized, double-blinded study

demonstrated efficacy of a continuous fascia iliac com-

partment block at the thigh donor site.34 Prolonged, pre-emptive nerve block reduced primary and secondary hy-

peralgesia over a period of 12 hours after a thermal burn

in human volunteers, whereas erythema and blister for-

mation were not significantly affected.147

The analgesic effect of topically applied ketamine148

and the nonsteroidal anti-inflammatory drug ketoro-

lac126 have also been evaluated in the burn-injured pa-tient population without success. In addition, morphine

has been applied topically (eg, formulated with the an-timicrobial cream sulfadiazine), resulting in a slight an-

algesic effect in the experimental group compared with

placebo, but the difference was not statistically signifi-

cant.108 Subcutaneous local administration of morphine

was effective in attenuating pain after an experimentalthermal injury,125 and topical loperamide, a -receptor

agonist, was effective after a deep burn in rats.97

Whereas local subcutaneous morphine sulfate injections

are not practical, nor would they be well tolerated, in theclinical setting, the topical administration of opioids such

as loperamide warrant further study.

Background Pain in the Healing Phase

Clinical experience suggests that background pain isless intense than either procedural pain or breakthroughpain,30 but research is needed to better characterize thistype of pain and its variability over the healing phase ofburn recovery. A common clinical observation during thehealing phase is that background pain may increase pre-

cipitously just before epithelialization is complete. Thisincrease in pain characteristically occurs with the appear-ance of epithelial skin buds, structures that heraldreepithelialization and subsequent wound closure. Thisperiod of healing is exquisitely painful, but the painceases rapidly as epithelial cells spread out to cover theburn wound. As noted above, regularly scheduled ad-ministration of medications that provides continuoustherapeutic serum blood levels is optimal for the man-agement of background pain. Several doses (eg, 5) ofsystemically administered medication are required be-fore a therapeutic serum level is achieved in burn-injuredpatients.100 Thus, a loading dose and short-acting opi-oids may be indicated when initiating background painmanagement with regularly scheduled medications thathave a long half-life (eg, MS Contin [Purdue Frederick,Norwalk, CT], Oxycontin [Purdue Pharma L.P., Stamford,CT], methadone, and so forth).

Breakthrough Pain in theHealing Phase

Breakthrough pain during the healing phase is oftenassociated with movement. Because of the critical needfor mobilization of the burn-injured patient, effectivemanagement of breakthrough pain is critical to mini-

mize the risk of complications (eg, respiratory infection,deconditioning, loss of function, and contractures). Thetime course of angiogenesis, neural regeneration, andreepithelialization during the healing phase of burn re-covery warrants investigation to correlate it withchanges in primary mechanical hyperalgesia, the majorsource of severe pain in burn-injured patients.

Rehabilitation PhaseThe rehabilitation phase is characterized by comple-

tion of wound closure, scar maturation, and aggressivephysical and occupational therapy to stretch healing tis-sues, prevent contractures, and optimize functional out-

comes. During the rehabilitation phase, complaints ofon-going, spontaneous pain and/or paresthesias, dyes-thesias, or allodynia in response to temperature changes,particularly cold, as well as neuropathic pain symptoms,may arise.28,39,109,185 Qualitative terms patients use todescribe these sensations include phasic burning, tin-gling, prickling, and shooting sensations.176

Procedural Pain During the RehabilitationPhase

The pain management needs of patients with burnsusually decline markedly once healing (ie, wound clo-sure) has occurred. In this case, opioids are usually not

indicated for procedural pain during the rehabilitation

538 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

7/16

phase. However, because of the increased treatment oflarger and more complex burns on an outpatient basis,and because patients frequently require multiple surgi-cal and other painful procedures involving, for example,the use of subcutaneous skin expanders as a source ofpainsometimes used to enlarge the surface area of po-tential donor skin in patients with large burnspotent,

short-acting opioids (eg, fentanyl, hydromorphone, mor-phine) may be indicated. For moderate pain, oxycodoneor a similar opioid preparation mixed with acetamino-phen is indicated. Opioid medications are usually discon-tinued by the beginning of, or early in this phase. Be-cause of the frequent need for large doses of opioidanalgesics up until wound closure is accomplished, taper-ing of opioids may be indicated to avoid symptoms ofwithdrawal. Clonidine can augment opioid analgesia aswell as diminish the hyperadrenergic symptoms of opioidabstinence and anxiety. Therefore, clonidine may beconsidered as an analgesic adjunct as well as an impor-tant adjuvant during opioid tapering. Benzodiazepine

tapering may also be indicated. Although this importantclinical issue is gaining attention, particularly in criticallyill burn-injured children,180 research is needed to en-hance the safe and effective management of opioid andbenzodiazepine withdrawal with tapering schedulesand adjuvants such as clonidine.

Background Pain During the RehabilitationPhase

If wound closure has occurred, background pain maynot be a problem during the rehabilitation phase of burnrecovery. However, if open wounds remain, and back-ground pain is an issue, the same principles suggested for

the treatment of background pain during the healingphase apply.

Breakthrough Pain During the RehabilitationPhase

Breakthrough pain associated with movement orstretching exercises may be significant, but this type ofpain can often be anticipated, planned for, and treatedas with a painful procedure.

Pharmacokinetics and PharmacodynamicsAfter Burn Injury

Burn injuries induce a profound inflammatory re-sponse that can affect changes in pharmacokinetics andpharmacodynamics, depending on the size of the injury(greater than 10% body surface area).122 Massive fluidresuscitation is necessary to maintain hemodynamic sta-bility and to avoid burn shock.203 Thus, the primaryroute of administration during the acute phase is intra-venous because of potential problems with enteral ab-sorption related to decreasedperfusion.122 Within days,a transition to a flow phase36 occurs that is character-ized by increased resting energy expenditure and hyper-metabolism that can last from several weeks to monthsto years after injury, depending on the size of the

burn.35,101,145

During the healing and rehabilitation phases, the met-abolic rate of burn-injured patients increased by 50%when burn size was greater than 20% to 30% surfacearea and even greater in larger burns or if burn woundsepsis was present.169 Increased circulating catecholaminesand adrenal steroid hormones are integral parts of thisphysiologic response thought to support recovery through

compensatory cardiovascular, metabolic, and immuno-logic changes.94 Thus, concern for changes in pharmaco-kinetics and pharmacodynamics after burn injury can bea barrier to pain management.

Alterations in the pharmacokinetics and pharmacody-namics of a variety of nonopioid medications113,114 havebeen observed in burn-injured patients, ranging fromserum protein shifts to target receptor desensitization orsupersensitization.66,83,115,187 However, research sug-gests that elimination kinetics of morphine68,153,156 andlorazepam112 are not impaired after burn injury and thatsystemic clearance may actually be enhanced in largerburns (eg, up to 80% body surface area), beyond which

clearance decreases toward control levels.135Kealey and colleagues100 investigated the pharmaco-

kinetics of morphine in patients with a mean body sur-face area burn of 21.5% in an attempt to ascertain arational dosage schedule for patients with burns. Treat-ments included a morphine constant rate infusion fol-lowed by immediate release oral morphine solution andsustained release MS Contin (Purdue Frederick). The half-life of morphine oral solution was 3 hours, whereas thehalf life of MS Contin (Purdue Frederick) was 14.7 hours.Time to peak levels with oral morphine solution was 30minutes and time to peak levels with MS Contin (PurdueFrederick) was 1.4 hours. These data indicate that proce-

dural, background, and breakthrough pain can betreated with the use of rapid-release oral morphinepreparations for the recommended doses and that mor-phine sulphate sustained-release formulations are agood choice in the management of background pain inpatients with burns given an 8- to 12-hour dosage sched-ule.

Choinire et al153 studied 5 patients with major first-,second-, or third-degree burn injuries that received along-term intravenous morphine infusion. No differ-ences were found in steady-state concentrations and sys-tem clearance of morphine, and its metabolites M3G andM6G among patients with burns, other patient popula-

tions, and healthy volunteers receiving intravenously ad-ministered morphine over a period of 3 weeks. Amongpatients with burn injuries, the severity of burns and theduration of administration were not a cause of nonlinearkinetic variability of morphine or of morphine resistance.Although the morphine infusion rate was substantiallyvariable, from 4 to 39.5 mg/hour, it was not directly re-lated to its systemic clearance. Thus, until more data areavailable to the contrary, the monitoring of morphineshould be focused on the clinical response and titrated toeffect.

Intravenous local anesthetics are gaining interest butare rarely administered in most burn centers. Jonsson et

al95 demonstrated that lignocaine infusion was safe and

539REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

8/16

strikingly reduced self-assessed pain scores in 7 patientsduring the first 3 days after second-degree burns, with-out need for supplementary opiate analgesia, but nopharmacokinetic data are available. The relatively shorthalf-life of lidocaine, however, is advantageous becauseit is rapidly cleared following burn dressing changes andphysiotherapy.181 In a study of healthy volunteers, small

burns were induced before and after intravenous lido-caine administration.78 Local anesthetics administered inconcentrations that did not block nerve conduction sub-stantially reduced pain (primary and secondary thermalhyperalgesia). However, a significant preemptive effectcould not be demonstrated. Although the antihyperal-gesic effect of lidocaine probably is based on action atcentral (spinal) sites, peripheral sites may also be in-volved and research is needed to answer this question.78

As previously mentioned, topical application of localanesthetics has met with disappointing results. However,topical lidocaine may be safe and effective for control ofpruritus, a major problem during the rehabilitation

phase that can impede burn recovery. EMLA (a eutecticmixture of local anestheticsprilocaine and lignocaine)was evaluated in a pilot study involving burned chil-dren.103 EMLA was used to ameliorate postburn pruritusafter application onto newly formed, intact skin. Serialblood samples were collected in 5 children after 15.7 2.54 g (mean SD) of EMLA was applied to a skin surfacearea of 93.0 37.0 cm2. Prilocaine and lidocaine concen-trations were below toxic levels ando-toluidine was notdetected. The mean number of pruritic episodes and an-tihistamine breakthrough doses were greater in the 2prestudy control days compared with study day 3 (P .01andP .03, respectively). Skin at the site of EMLA appli-

cation remained anesthetized for 12 to 13 hours. Thesedata suggest that EMLA may be a safe, novel treatmentfor postburn pruritus when applied to vulnerable newlyhealed skin.

Pruritus

Pruritus (eg, itch) commonly replaces pain as a sourceof significant anxiety and distress during the rehabilita-tion phase.49,87,111,118,210Common pharmacologic inter-ventions for pruritus include antihistamines (eg, H1 andH2 antagonists, including diphenhydramine, cyprohep-tadine, and hydroxyzine),9,164,199 and some burn centers

have developed standardized protocols for the manage-ment of burn associated pruritus.164 Although few as-sessment scales exist, a pediatric itch man scale wascreated by Pat Blakeney and Janet Marvin, as describedby Ratcliff et al.164 Not only is itching a source of anxietyand distress, but attempts to relieve the itch by scratch-ing or rubbing jeopardizes newly healed skin, which iseasily blistered and injured in response to mechanicalstimulation.

Prevalence of pruritus after burn injury is high. Reportssuggest that 60%210 to 87%199 of patients report eitherpersistent (15%) or intermittent (44%) pruritus.16,199,210

Although oral pharmacologic agents are probably the

most common method as described above, topical phar-

macologic 103 and nonpharmacologic agents,118,164 mas-sage,49,50,70 and transcutaneous electrical nerve stimula-tion74 have also been studied to manage pruritus.However, these studies lack the evidence to make treat-

ment recommendations.46

Chronic Burn Injury PainChronic pain has been identified as a significant prob-

lem many years after burn recovery. In a study thatsurveyed members of the Phoenix Society for Burn Sur-

vivors, 52% of respondents reported on-going burn-re-lated pain an average of 12 years after injury (n 348,24% response rate).39 Other studies indicate that on-going pain, years after burn injury, is a significant prob-

lem.28,39,109,110,131 Complaints of chronic pain may firstarise during the rehabilitation phase of burn recovery. Itmay initially present as hypersensitive or hyposensitiveareas that develop in healed sites. Although hypersensi-

tivity in newly healed skin is common, it often dependson the location, with the scalp, axilla, perineum, andthe hands and feet being particularly sensitive for up to1 year after injury at these sites.158,201

Loss of sensibility is more common after deep burnsand grafted injuries.69,202 In a study of 236 patients whoresponded to a survey (67% response rate) at least 1 year

after burn trauma, more than one third of participantscomplained of pain. A total of 71% of patients com-plained of noxious paresthetic sensations, and only28.4% of this sample reported no sensory problems.109 Inan effort to define the extent of cutaneous sensory dys-function after burn injury, subjective reports of abnor-

mal sensations were compared between patients withhealed burns and normal control subjects.110 Psycho-physical measures of tactile, thermal (nonnoxious), andpain thresholds were assessed in the upper extremities of121 patients with healed burns, more than 18 months

after injury, and compared with pair-matched controlsubjects. Whereas more patients with deep dermal burnsthat had required skin grafting reported significant sen-sory loss than patients with superficial dermal burns thathad healed spontaneously, some patients reported in-creased sensitivity in their healed burns. Of note, the

majority of patients who had decreased thresholds alsoreported painful or paresthetic sensations at the site.

Depth of burn was the only factor associated with theseverity of sensory deficit, explaining more than onethird of the observed variability. Patient age, sex, andmedical variables, such as size of burn or time elapsed

since the injury, did not explain a significant proportionof the variation in the sensibility thresholds in this study.Of note, sensory loss was observed in burn sites as well asuninjured areas, which suggested to these authors thatchanges may have occurred in the central nervous sys-

tem. However, in an animal model of full-thickness burninjury, receptive fields were found to usually extend intoboth adjacent and noncontiguous skin,97 which is consis-tent, as these authors point out, with the anatomy of

terminal fields of cutaneous nociceptors that can be

540 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

9/16

quite extensive, stretching over several millimeters107 or

centimeters.174,175,194

Although few studies have evaluated their effect on

chronic pain after burn injury, centrally acting agents

used to treat neuropathic pain, including antidepres-

sants (eg, amitriptyline), anticonvulsants (eg, gabap-

entin), and clonidine may prove useful in this patient

population. In addition, benzodiazepines are usefuladjuvants due to their anticonvulsant properties; and

NMDA antagonists, such as ketamine and dextro-methorphan, may be useful as NMDA receptors play a

role in central sensitization after experimental burn

injury.86,204,205

In deep partial-thickness burns, thermal injury causes

primary afferent axons to swell, degranulate, and demy-

elinate.40,64,128 Macrophages invade the degenerating

nerve stump, removing myelin and axonal debris butleaving the basal lamina intact through Wallerian de-

generation.63 In addition, excision of eschar, sharp de-

bridement of devitalized tissue, and further ischemia in

the zone of tissue surrounding the burn wound induce

peripheral nerve damage. Indeed, the term phantom

skin was introduced by Atchison et al7 in response to

their observation that the pain of burns is often resistant

to opioids, similar to neuropathic pain.The preferential loss of large fibers in burn scar43

and graft tissue131,202 may contribute to the incidence

of neuropathic pain, consistent with the gate control

theory.173 The rate of degeneration may also play a role

in chronic burn pain similar to isoniazid neuropathy, aspatients may initially complain of numbness and tingling

paresthesias that are later accompanied by pain.173,176 In

thermal burn sites, neurons were shown to be com-pletely absent in human tissue 2 days after injury and

remained undetectable for 10 days.202 As damaged neu-rons regenerate, abnormal ectopic excitability at or near

the site of nerve injury may develop due to unusual dis-

tributions of sodium (Na) channels and abnormal re-

sponses to endogenous pain producing substances, in-cluding cytokines such as tumor necrosis factor-.216

Persistent abnormal excitability of sensory nerve end-

ings in a traumatic neuroma, the mass of nonneoplastic

Schwann cells, and neurites that may develop at the

proximal end of a severed or injured nerve is considereda mechanism for amputation-induced pain, which may

also play a role in the development of burn-inducedchronic pain. Local nerve injury tends to spread to distant

parts of the peripheral and central nervous system. Forexample, damage to neurons in the periphery has been

found to contribute to changes in the spinal cord that

may in turn contribute to neuropathic pain.22 It follows

that damage to sensory neurons may be a mechanism for

burn injuryinduced neuropathic pain, but this questionhas not been studied.

Another cause of chronic pain after deep burns in-

volves the frequent practice of tangential and/or fascial

excision of eschar associated with these injuries. Thispractice may cause intact peripheral afferent nociceptors

to become injured.181 It also seems likely that regenera-

tion of neurons from wound margins may contribute toburn pain.

Few studies have examined neural regeneration in hu-man autograft131,202 and healing skin43,123 after burninjury. Of these, only 1 obtained comparison samplesfrom the same patients, making it possible to determinechanges with control skin in the same patient over

time.202

Sensory measures of pinprick, warming, touch,and vibration were all significantly decreased (all P.001) in burn-grafted skin, with thermal threshold show-ing the greatest degree of functional recovery. Thesefindings correlated with histologic analysis of skin biopsyspecimens from the same site that showed a significantreduction in the axons that innervated the dermis andthe epidermis in burn graft relative to control skin (54%decrease, P .0001). Of note, the number of neuronsthat expressed substance P was significantly elevated inthe autografted site and appeared to correlate with pa-tient reports of pain and pruritus (P .05). These authorsconcluded that sensory regeneration may be fiber size

dependent in burn-graft skin, withsubstance Pcontainingfibers predominating but total fiber count decreasing.These data support the hypothesis that unmyelinatedneurons have a greater ability to traverse scar tissue andreinnervate grafted skin after full-thickness burn injury.However, no correlation was reported between thesefindings and pain severity scores.

Basic Science Models of BurnInjury Pain

Few basic science models have been available to studyburn injury pain. Although human models have been

introduced,124,125,149 it is difficult to separate the mech-anisms of burn injury pain in humans. More recently,however, several animal models have been intro-duced132,190,200,214 that make it possible to begin totease apart the complex mechanisms that contribute tothe variability and intensity of burn injury pain over time.

In experimental animal models, second-messengerproteins, including protein kinase C-epsilon (PKC)190

and neurotrophins such as nerve growth factor(NGF)190,195 have been identified as significant media-tors of acute burn-induced hyperalgesia. These media-tors may also play a role in chronic burn pain. PKC hasbeen found to mediate priming, a predilection toward

the development of chronic hyperalgesia in a previouslyhealed site of inflammation,136 and NGF induces hyper-algesia in noncontiguous, uninjured skin after burn in-jury in rats.195 NGF is also found in newly formed epithe-lial cells at the edge of wounds.119 The study ofperipheral mechanisms in chronic pain after burn injuryis a high priority for future research.

Why is Burn Injury Pain Still a MajorProblem After 20 Years?

Although the problem of undertreated burn injurypain was well described more than 20 years ago154,155,157

and despite a call to make pain the highest research

541REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

10/16

priority in burn care due to its detrimental effects onpatients as well as those who care for them more than 15years ago,117 burn injury pain remains a continuing chal-lenge.27,30,58,79,82,105,127,143,192,196 Recent publicationsreport unacceptably high pain ratings (mean, 7/10)for procedural pain 24 and chronic pain 4 months afterinjury.176 Clinical observations confirm that these reports

are not unusual. This is disconcerting when one considersthe wide availability of pain management guide-lines16,18,32,42,43,50,67,75,99,103 and the promotion ofguideline-based treatment approaches.1,58,88,104

Unlike surgical pain that subsides gradually, burn in-jury pain is highly variable and may increase over time,much to the patients distress, before healing is accom-plished. This makes approaching burn injury pain withthe World Health Organizations analgesic ladder38 ortitrating to effect often impractical. In fact, the laddercould be applied in reverse to this patient population,with the use of the most potent analgesics, opioids, first.However, like other health care providers, those who

care for burn patients must balance the dichotomy ofknowing that opioids can be used for analgesia as well asfor abuse. Moreover, it is valid to question the safety ofthe administration of opioids in patients with majorburns. Because of their requirement for massive fluidresuscitation during the first few days after admissionand the potential for contributing to hemodynamic in-stability, it has been recommended that patients such asthese not be administered more than 10 mg of intrave-nous morphine sulfate in a 24-hour period.188 This is asmall amount compared with what is administered tomost burn-injured patients,23,68,96 although, as pointedout by Choinire,30 the opioid doses reported in some

studies to patients with much smaller injuries are barelywithin the range required to control much less intensetypes of pain.141,179 In addition, burns are profoundlyimmunosuppressive, and there is a large body of litera-ture that suggests opioids may contribute to immuno-suppression. High risk for mortality and morbidity fre-quently places their safety above their need for painmanagement.

Nonetheless, perhaps it is time to stop insisting that burnpain is a very difficult type of pain to treat and question ifwe are doing the very best to treat it. Are burn centersusing the principles of multimodal analgesia (eg, differentclasses of medications in combination with nonpharmaco-

logic methods) in a systematic manner? As previously men-tioned, nonsteroidal anti-inflammatory agents are usu-ally contraindicated in this patient population, but othermedications are rarely used even though they appear tobe very useful for pain management in the burn-injuredpatient. For example, clonidine, ketamine, lidocaine, andmethadone appear to be underused in this patient pop-ulation. However, their use may decrease the need forrapidly acting, potent opioids usually required for pain-ful procedures. Moreover, the use of mixed -receptorantagonists and/or agonist-antagonists may prevent orameliorate tolerance that is so commonly observed inpatients with major burns.

We also need to ask, are members of the multidisci-

plinary burn team aware of the most recent data on painand analgesia, and is this information being imple-mented by those who care for burn-injured patients?Those who specialize in the care of these patients maybecome accustomed to the expectation that pain will notbe controlled, particularly during procedures. One mayrationalize that it will only hurt for a brief period of time,

but research suggests that peak procedural pain andglobal recollection of procedural pain are correlated57

and that global recollection of procedural pain (ie, 4hours immediately after surgery) influences patient sat-isfaction.89

Fentanyl has been demonstrated to be the most effec-tive analgesic for burn procedural pain, but do patientsreceive a dose of this potent and short-acting opioid intime to meet their need for peak procedural pain reliefor are we prevented from helping some patients in thismanner due to the fear of overdosing others in the samemanner? Research is needed to expand our vision forassisting this vulnerable patient population. The judi-

cious use of diluted naloxone and flumazenil reversesthe effects of opioids and benzodiazepines, but they arerarely used to avoid oversedation and other side effectsthat frequently limit the use of opioids and benzodiaz-epines. As suggested by Silbert et al,181 although newtherapeutic approaches are desperately needed, we donot need to wait on basic science. Alternatives are readilyavailable at the bedside today. Are nonpharmacologic aswell as pharmacologic interventions systematically im-plemented? Are we using new materials, such as dissolv-able staples to minimize procedural pain, unless contra-indicated? Is the pain plan visible? That is to say, is thepain management plan systematically evaluated, to keep

pace with the patients rapidly changing needs andmade visible for the burn management team?

Importantly, we also need more research on burn in-jury pain. The American Burn Association Patient Regis-try Participant Group and The National Institute on Dis-ability and Rehabilitation Research Burn Model SystemDatabase102 developers may be well positioned to makerecommendations as to how information could betracked similar to their important work tracking out-comes in the treatment of burn trauma in the UnitedStates.170 Until we have the science, we will continue tolack a basis for rationale treatment recommendationsfor acute and chronic burn injury pain. In particular, re-

search is needed to identify the underlying mechanismsfor burn injury pain over time. Only with this knowledgewill burn care providers be able to target specific mech-anisms that contribute to the variable intensity26,96,162

that makes this type of pain such a difficult managementproblem.

Conclusion

Burn-injured patients of all ages have procedural,background, and breakthrough pain during the acute,healing, and rehabilitative phases over the long courseof burn recovery. The establishment of multidisciplinary

burn team and institutionally supported system changes

542 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

11/16

that will promote the recognition and implementationof changes necessary to accomplish safe and effectiveburn pain management are critically needed. Moreover,research that focuses on the continuing challenge of

burn injury pain is critically important. Only with thesevaluable data can the efficacy of acute and chronic burninjury pain be improved and the underlying mechanismsfinally understood and rationally treated.

References

1. Adcock RJ, Boeve SA, Patterson DR: Psychologic and emo-tional recovery, in Carrougher GJ (ed): Burn Care and Ther-apy. St. Louis, MO, Mosby, 1998, pp 329-357

2. Aley KO,Messing RO,Mochly-Rosen D, Levine JD: Chronichypersensitivity for inflammatory nociceptor sensitizationmediated by the epsilon isozyme of protein kinase C. J Neu-rosci 20:4680-4685, 2000

3. American Burn Association National Burn Repository Ad-visory Committee. National Burn Repository: 2005 Report,Dataset Version 2.0. Chicago, IL, American Burn Association,2006, pp 1-35

4. American Pain Society. Principles of Analgesic Use in theTreatment of Acute Pain and Cancer Pain. Glenview, Ill,American Pain Society, A National Chapter of the Interna-tional Association for the Study of Pain, 2003

5. Andreasen NJ, Noyes R Jr, Hartford CE, Brodland G, Proc-tor S: Management of emotional reactions in seriouslyburned adults. N Engl J Med 286:65-69, 1972

6. Ashburn MA: Burn pain: The management of procedure-related pain. J Burn Care Rehabil 16:365-371, 1995

7. Atchison NE, Osgood PF, Carr DB, Szyfelbein, SK: Pain dur-ing burn dressing change in children: Relationship to burnarea, depth and analgesic regimens. Pain 47:41-45, 1991

8. Atiyeh BS, Gunn SW, Hayek SN: State of the art in burn

treatment. World J Surg 29:131-148, 2005

9. Baker RA, Zeller RA, Klein RL, Thornton RJ, Shuber JH,Marshall RE, Leibfarth AG, Latko JA: Burn wound itch con-trol using H1 and H2 antagonists. J Burn Care Rehabil 22:263-268, 2001

10. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, MarshallRD, Nemeroff CB, Shalev AY, Yehuda R. Consensus state-ment update on posttraumatic stress disorder from the in-ternational consensus group on depression and anxiety.J Clin Psychiatry 65(Suppl 1):55-62, 2004

11. Barone M, McCall J, Jenkins M, Warden G: The develop-ment of an observational pain scale (OPAS) for pediatricburns. In: Proceedings of the American Burn Association,32nd Annual Meeting, Vol. January/February, S154. Chi-

cago, IL, American Burn Association, 2000

12. Bauer KM, Hardy PE, VanDorsten B: Posttraumatic stressdisorder in burn populations: A critical review of the litera-ture. J Burn Care Rehabil 19:230-240, 1998

13. Beales JG: Factors influencing the expectation of painamong patients in a childrens burns unit. Burns 9:187-192, 1983

14. Bisson JI, Jenkins PL, Alexander J, Bannister C: Random-ised controlled trial of psychological debriefing for victimsof acute burn trauma. Br J Psychiatry 171:78-81, 1997

15. Bisson JI. Single-session early psychological interven-tions following traumatic events. Clin Psychol Rev 23:481-499, 2003

16. Blades B, Mellis N, Munster AM: A burn specific healthscale. J Trauma 22:872-875, 1982

17. Blakeney PE, McCauley RL, Herndon DN: Prolonged hy-permetabolic response over time, the use of anabolic agentsand exercise, and longitudinal evaluation of the burnedchild, in Herndon D (ed): Total Burn Care. New York, NY,Elsevier Science, 2002, pp 611-619

18. Brenner GJ, Ji RR, Shaffer S, Woolf CJ: Peripheral noxiousstimulation induces phosphorylation of the NMDA receptorNR1 subunit at the PKC-dependent site, serine-896, in spinalcord dorsal horn neurons. Eur J Neurosci 20:375-384, 2004

19. Brigham PA: American Burn Association Fact Sheet:Burn incidence and treatment in the United States. Chicago,IL, American Burn Association, 2000

20. Byers JF, Bridges S, Kijek J, LaBorde P: Burn patients

pain and anxiety experiences. J Burn Care Rehabil 22:144-149, 2001

21. Caffo E, Belaise C: Psychological aspects of traumaticinjury in children and adolescents. Child Adolesc PsychiatrClin N Am 12:493-535, 2003

22. Carlton SM, Hargett GL, Coggeshall RE: Plasticity inalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptor subunits in the rat dorsal horn following deaffer-entation. Neurosci Lett 242:21-24, 1998

23. Carrougher GJ, Ptacek JT, Sharar SR, Wiechman S,Honari S, Patterson DR, Heimbach DM: Comparison of pa-tient satisfaction and self-reports of pain in adult burn-in-jured patients. J Burn Care Rehabil 24:1-8, 2003

24. Carrougher GJ, Ptacek JT, Honari S, Schmidt AE, Tini-nenko JR, Gibran NS, Patterson DR: Self-reports of anxiety inburn-injured hospitalized adults during routine woundcare. J Burn Care Res 27:676-681, 2006

25. Chakerian MU, Demarest GB, Paiz A: Burn DRGs: Effectsof recent changes and implications for the future. J Trauma30:964-971; discussion 971-963, 1990

26. Choinire M, Melzack R, Rondeau J, Girard N, PaquinMJ: The pain of burns: Characteristics and correlates.J Trauma 29:1531-1539, 1989

27. Choinire M, Melzack R, Girard N, Rondeau J, PaquinMJ: Comparisons between patients and nurses assessmentof pain and medication efficacy in severe burn injuries. Pain40:143-152, 1990

28. Choinire M, Melzack R, Papillon J: Pain and paresthesiain patients with healed burns: An exploratory study. J PainSymptom Manage 6:437-444, 1991

29. Choinire M, Auger FA, Latarjet J: Visual analogue ther-mometer: A valid and useful instrument for measuring painin burned patients. Burns 20:229-235, 1994

30. Choinire M: Burn pain: A unique challenge. PainClini-cal Updates, International Association for the Study of PainIX, 2001

31. Coimbra C, Choiniere M, Hemmerling TM: Patient-con-trolled sedation using propofol for dressing changes in burnpatients: A dose-finding study. Anesth Analg 97:839-842, 2003

32. Coleman LS: Bupivacaine and ventricular fibrillation.Anesth Analg 99:1269; author reply 1269, 2004

543REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

12/16

33. Cousins M, Power I: Acute and postoperative pain. In:Wall PD, Melzack R (eds): Textbook of Pain. New York,Churchill Livingstone, 1999, pp 447-491

34. Cuignet O, Pirson J, Boughrouph J, Duville D. The effi-cacy of continuous fascia iliaca compartment block for painmanagement in burn patients undergoing skin grafting pro-cedures. Anesth Analg 98:1077-1081, 2004

35. Cunningham JJ, Hegarty MT, Meara PA, Burke JF: Mea-sured and predicted calorie requirements of adults duringrecovery from severe burn trauma. Am J Clin Nutr 49:404-408, 1989

36. Cuthbertson DP, Angeles Valero Zanuy MA, Leon SanzML: Post-shock metabolic response, 1942. Nutr Hosp 16:176-182; discussion 175-176, 2001

37. Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, KehletH: The effect of pre- versus post-injury infiltration with lido-caine on thermal and mechanical hyperalgesia after heatinjury to the skin. Pain 53:43-51, 1993

38. Dalton JA, Youngblood R: Clinical application of theWorld Health Organization analgesic ladder. J Intraven Nurs23:118-124, 2000

39. Dauber A, Osgood PF, Breslau AJ, Vernon HL, Carr DB:Chronic persistent pain after severe burns: A survey of 358burn survivors. Pain Med 3:6-17, 2002

40. deCamara DL, Raine TJ, London MD, Robson MC, Heg-gers JP: Progression of thermal injury: A morphologic study.Plast Reconstr Surg 69:491-499, 1982

41. Difede J, Jaffe AB, Musngi G, Perry S, Yurt R: Determi-nants of pain expression in hospitalized burn patients. Pain72:245-251, 1997

42. Dimick AR, Potts LH, Charles ED Jr, Wayne J, Reed IM:The cost of burn care and implications for the future onquality of care. J Trauma 26:260-266, 1986

43. Dunnick CA, Gibran NS, Heimbach DM: Substance P hasa role in neurogenic mediation of human burn wound heal-ing. J Burn Care Rehabil 17:390-396, 1996

44. Dworkin RH: An overview of neuropathic pain: Syn-dromes, symptoms, signs, and several mechanisms. Clin JPain 18:343-349, 2002

45. Eland JM: Minimizing pain associated with prekinder-garten intramuscular injections. Issues Compr Pediatr Nurs5:361-372, 1981

46. Esselman PC, Thombs BD, Magyar-Russell G, FauerbachJA: Burn rehabilitation: State of the science. Am J PhysiolMed Rehabil 85:383-413, 2006

47. Fauerbach JA, Lawrence JW, Haythornthwaite JA, Rich-

ter L: Coping with the stress of a painful medical procedure.Behav Res Ther 40:1003-1015, 2002

48. Fauerbach JA, Lezotte D, Hills RA, Cromes GF, KowalskeK, de Lateur BJ, Goodwin CW, Blakeney P, Herndon DN,Wiechman SA, Engrav LH, Patterson DR: Burden of burn: Anorm-based inquiry into the influence of burn size and dis-tress on recovery of physical and psychosocial function.J Burn Care Rehabil 26:21-32, 2005

49. Field T, Peck M, Hernandez-Reif M, Krugman S, BurmanI, Ozment-Schenck L: Postburn itching, pain, and psycholog-ical symptoms are reduced with massage therapy. J BurnCare Rehabil 21:189-193, 2000

50. Field T: Massage therapy for skin conditions in children.Dermatol Clin 23:717-721, 2005

51. Fink BR, Cairns AM: Differential peripheral axon block

with lidocaine: Unit studies in the cervical vagus nerve.Anesthesiology 59:182-186, 1983

52. Fink BR, Cairns AM: Differential slowing and block ofconduction by lidocaine in individual afferent myelinatedand unmyelinated axons. Anesthesiology 60:111-120, 1984

53. Fischer CG, Lloyd S, Kopcha R, Warden GD, McCall JE:The safety of adding bupivacaine to the subcutaneous infil-

tration solution used for donor site harvest. J Burn CareRehabil 24:361-364, 2003

54. Fratianne RB, Prensner JD, Huston MJ, Super DM,Yowler CJ, Standley JM: The effect of music-based imageryand musical alternate engagement on the burn debride-ment process. J Burn Care Rehabil 22:47-53, 2001

55. Frenay MC, Faymonville ME, Devlieger S, Albert A,Vanderkelen A: Psychological approaches during dressingchanges of burned patients: A prospective randomisedstudy comparing hypnosis against stress reducing strategy.Burns 27:793-799, 2001

56. Gear RW, Miaskowski C, Heller PH, Paul SM, Gordon NC,Levine JD: Benzodiazepine mediated antagonism of opioidanalgesia. Pain 71:25-29, 1997

57. Geisser ME, Bingham HG, Robinson ME: Pain and anxi-ety during burn dressing changes: Concordance betweenpatients and nurses ratings and relation to medication ad-ministration and patient variables. J Burn Care Rehabil 16:165-171; discussion 164, 1995

58. Gilboa D, Friedman M, Tsur H: The burn as a continuoustraumatic stress: Implications for emotional treatment dur-ing hospitalization. J Burn Care Rehabil 15:86-91, 1994

59. Goodstein RK: Burns: An overview of clinical conse-quences affecting patient, staff, and family. Compr Psychia-try 26:43-57, 1985

60. Gordon M, Greenfield E, Marvin J, Hester C, Lauterbach

S: Use of pain assessment tools: Is there a preference? J BurnCare Rehabil 19:451-454, 1998

61. Gore DC: Outcome and cost analysis for outpatient skingrafting. J Trauma 43:597-600; discussion 600-592, 1997

62. Guyatt GH, Townsend M, Berman LB, Keller JL: A com-parison of Likert and visual analogue scales for measuringchange in function. J Chronic Dis 40:1129-1133, 1987

63. Hallin RG, Wu G: Fitting the pieces in the peripheralnerve puzzle. Exp Neurol 172:482-492, 2001

64. Ham AW: Experimental study of the histopathology ofburns: With particular reference to sites of fluid loss in burnsof different depths. Ann Surg 120:689-697, 1944

65. Hammond J, Ward CG: Burns in octogenarians. SouthMed J 84:1316-1319, 1991

66. Han T, Kim H, Bae J, Kim K, Martyn JA: Neuromuscularpharmacodynamics of rocuronium in patients with majorburns. Anesth Analg 99:386-392, 2004

67. Heimbach D, Engrav L, Grube B, Marvin J: Burn depth: Areview. World J Surg 16:10-15, 1992

68. Herman RA, Veng-Pedersen P, Miotto J, Komorowski J,KealeyGP: Pharmacokinetics of morphine sulfate in patientswith burns. J Burn Care Rehabil 15:95-103, 1994

69. HermansonA, Jonsson CE,Lindbloom U: Sensibility afterburn injury. Clin Physiol 6:507-521, 1986

70. Hernandez-Reif M, Field T, Largie S, Hart S, Redzepi M,Nierenberg B, Peck TM: Childrens distress during burn treat-

544 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

13/16

ment is reduced by massage therapy. J Burn Care Rehabil22:191-195; discussion 190, 2001

71. Herr K, Coyne PJ, Key T, Manworren R, McCaffery M,Merkel S, Pelosi-Kelly J, Wild L: Pain assessment in the non-verbal patient: Position statement with clinical practice rec-ommendations. Pain Manag Nurs 7:44-52, 2006

72. Herr KA, Mobily PR, Kohout FJ, Wagenaar D. Evaluation

of the Faces Pain Scale for use with the elderly. Clin J Pain14:29-38, 1998

73. Herr KA, Spratt K, Mobily PR, Richardson G: Pain inten-sity assessment in older adults: Use of experimental pain tocompare psychometric properties and usability of selectedpain scales with younger adults. Clin J Pain 20:207-219, 2004

74. Hettrick HH, OBrien K, Laznick H, Sanchez J, Gorga D,Nagler W, Yurt R: Effect of transcutaneous electrical nervestimulation for the management of burn pruritus: A pilotstudy. J Burn Care Rehabil 25:236-240, 2004

75. Hoffman HG, Patterson DR, Carrougher GJ, Sharar SR:Effectiveness of virtual reality-based pain control with mul-tiple treatments. Clin J Pain 17:229-235, 2001

76. Hoffman HG: Virtual-reality therapy. Sci Am 291:58-65,2004

77. Hoffman HG, Patterson DR, Magula J, Carrougher GJ,Zeltzer K, Dagadakis S, Sharar SR: Water-friendly virtual re-ality pain control during wound care. J Clin Psychol 60:189-195, 2004

78. Holthusen H, Irsfeld S, Lipfert P: Effect of pre- or post-traumatically applied intravenous (IV) lidocaine on primaryand secondary hyperalgesia after experimental heat traumain humans. Pain 88:295-302, 2000

79. Honari S, Patterson DR, Gibbons J, Martin-Herz SP,Mann R, Gibran NS, Heimbach DM: Comparison of pain con-trol medication in three age groups of elderly patients.J Burn Care Rehabil 18:500-504, 1997

80. Humphries Y, Melson M, Gore D: Superiority of oral ket-amine as an analgesic and sedative for wound care proce-dures in the pediatric patient with burns. J Burn Care Reha-bil 18:34-36, 1997

81. Hunt JL: The 2000 presidential address back to the fu-ture: The American Burn Association and burn prevention.J Burn Care Rehabil 21:474-483, 2000

82. Iafrati NS: Pain on the burn unit: Patient vs nurse per-ceptions. J Burn Care Rehabil 7:413-416, 1986

83. Ibebunjo C, Martyn JA: Thermal injury induces greaterresistance to d-tubocurarine in local rather than in distantmuscles in the rat. Anesth Analg 91:1243-1249, 2000

84. Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T,Sandkuhler J: Synaptic amplifier of inflammatory pain in thespinal dorsal horn. Science 312:1659-1662, 2006

85. Ilechukwu ST: Psychiatry of the medically ill in the burnunit. Psychiatr Clin North Am 25:129-147, 2002

86. Ilkjaer S, Dirks J, Brennum J, Wernberg M, Dahl JB: Effectof systemic N-methyl-D-aspartate receptor antagonist (dex-tromethorphan) on primary and secondary hyperalgesia inhumans. Br J Anaesth 79:600-605, 1997

87. Jaffe SE, Patterson DR: Treating sleep problems in pa-tients with burn injuries: Practical considerations. J BurnCare Rehabil 25:294-305, 2004

88. Jellish WS, Gamelli RL, Furry PA, McGill VL, Fluder EM:Effect of topical local anesthetic application to skin harvest

sites for pain management in burn patients undergoingskin-grafting procedures. Ann Surg 229:115-120, 1999

89. Jensen MP, Martin SA, Cheung R: The meaning of painrelief in a clinical trial. J Pain 6:400-406, 2005

90. Jensen MP, McArthur KD, Barber J, Hanley MA, EngelJM, Romano JM, Cardenas DD, Kraft GH, Hoffman AJ,Patterson DR: Satisfaction with, and the beneficial side ef-

fects of, hypnotic analgesia. Int J Clin Exp Hypn 54:432-447,2006

91. Johnson JE, Fuller SS, Endress MP, Rice VH: Altering pa-tients responses to surgery: An extension and replication.Res Nurs Health 1:111-121, 1978

92. Johnson JE, Rice VH, Fuller SS, Endress MP: Sensory in-formation, instruction in a coping strategy, and recoveryfrom surgery. Res Nurs Health 1:4-17, 1978

93. Jones JD, Barber B, Engrav L, Heimbach D: Alcohol useand burn injury. J Burn Care Rehabil 12:148-152, 1991

94. Jones SB, de Silva KI, Shankar R, Gamelli RL: Significanceof the adrenal and sympathetic response to burn injury. In:Herndon D (ed): Total Burn Care. New York, WB Saunders,

2002, pp 347-36295. Jonsson A, Cassuto J, Hanson B: Inhibition of burn pain byintravenous lignocaine infusion. Lancet 338:151-152, 1990

96. Jonsson CE, Holmsten A, Dahlstrom L, Jonsson K. Back-ground pain in burn patients: Routine measurement andrecording of pain intensity in a burn unit. Burns 24:448-454,1998

97. Junger H, Moore AC, Sorkin LS: Effects of full-thicknessburns on nociceptor sensitization in anesthetized rats. Burns28:772-777, 2002

98. Kavanagh S, de Jong A: Care of burn patients in thehospital. Burns 30:A2-6, 2004

99. Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang H,

Van Der Meer C, Befort K, Woolf CJ, Ji RR: Ionotropic andmetabotropic receptors, protein kinase A, protein kinase C,and Src contribute to C-fiber-induced ERK activation andcAMP response element-binding protein phosphorylation indorsal horn neurons, leading to central sensitization. J Neu-rosci 24:8310-8321, 2004

100. Kealey GP: Pharmacologic management of back-ground pain in burn victims. J Burn Care Rehabil 16:358-362,1995

101. Khorram-Sefat R, Behrendt W, Heiden A, Hettich R:Long-term measurements of energy expenditure in severeburn injury. World J Surg 23:115-122, 1999

102. Klein MB, Lezotte DL, Fauerbach JA, Herndon DN,

Kowalske KJ, Carrougher GJ, Delateur BJ, Holavanahalli R,Esselman PC, Agustin TB, Engrav LH: The National Instituteon Disability and Rehabilitation Research Burn Model Sys-tem Database: A Tool for the Multicenter Study of the Out-come of Burn Injury. J Burn Care Res 28:84-96, 2007

103. Kopecky EA, Jacobson S, Hubley P, Palozzi L, ClarkeHM, Koren G: Safety and pharmacokinetics of EMLA in thetreatment of postburn pruritus in pediatric patients: A pilotstudy. J Burn Care Rehabil 22:235-242, 2001

104. LaBorde P: Burn epidemiology: The patient, the na-tion, the statistics, andthe data resources. Crit Care Nurs ClinNorth Am 16:13-25, 2004

105. Latarjet J, Choinire M: Pain in burn patients. Burns21:344-348, 1995

106. Lauterbach S, George R: Burn Pain, in McCaffrey M,

545REVIEW/Summer et al

8/13/2019 1-s2.0-S1526590007005123-main

14/16

Pasero C (eds): Pain: Clinical Manual. St. Louis, MO, Mosby,1999, pp 527-531

107. Leem JW, Willis WD, Chung JM: Cutaneous sensory re-ceptors in the rat foot. J Neurophysiol 69:1684-1699, 1993

108. Long TD, Cathers TA, Twillman R, ODonnell T, Garri-gues N, Jones T: Morphine-infused silver sulfadiazine (MISS)cream for burn analgesia: A pilot study. J Burn Care Rehabil

22:118-123, 2001109. Malenfant A, Forget R, Papillon J, Amsel R, Frigon JY,Choiniere M: Prevalence and characteristics of chronic sen-sory problems in burn patients. Pain 67:493-500, 1996

110. Malenfant A, Forget R, Amsel R, Papillon J, Frigon JY,Choiniere M: Tactile, thermal and pain sensibility in burnedpatients with and without chronic pain and paresthesiaproblems. Pain 77:241-251, 1998

111. Martin-Herz SP, PattersonDR, Honari S, GibbonsJ, GibranN, Heimbach DM: Pediatric pain control practices of NorthAmerican Burn Centers. J Burn Care Rehabil 24:26-36, 2003

112. Martyn J, Greenblatt DJ: Lorazepam conjugation is un-impaired in burn trauma. Clin Pharmacol Ther 43:250-255,

1988

113. Martyn JA, Greenblatt DJ, Hagen J, Hoaglin DC: Alter-ation by burn injury of the pharmacokinetics and pharma-codynamics of cimetidine in children. Eur J Clin Pharmacol36:361-367, 1989

114. Martyn JA, Bishop AL, Oliveri MF: Pharmacokineticsand pharmacodynamics of ranitidine after burn injury. ClinPharmacol Ther 51:408-414, 1992

115. Martyn JA, Chang Y, Goudsouzian NG, Patel SS: Phar-macodynamics of mivacurium chloride in 13- to 18-yr-oldadolescents with thermal injury. Br J Anaesth 89:580-585,2002

116. Marvin J: Management of pain and anxiety, in Car-

rougher GJ (ed): Burn Care and Therapy. St. Louis, MO,Mosby, 1998, pp 167-183

117. MarvinJA, Carrougher G, Bayley B, Weber, B, KnightonJ, Rutan R: Burn nursing Delphi study: Setting research pri-orities. J Burn Care Rehabil 12:190-197, 1991

118. Matheson JD, Clayton J, Muller MJ: The reduction ofitch during burn wound healing. J Burn Care Rehabil 22:76-81; discussion 75, 2001

119. Matsuda H, Koyama H, Sato H, Sawada J, Itakura A,Tanaka A, Matsumoto M, Konno K, Ushio H, Matsuda K.Role of nerve growth factor in cutaneous wound healing:Accelerating effects in normal and healing-impaired dia-betic mice. J Exp Med 187:297-306, 1998

120. McLure HA, Rubin AP: Review of local anaestheticagents. Minerva Anestesiol 71:59-74, 2005

121. Melzack R: The tragedy of needless pain. Sci Am 262:27-33, 1990

122. Meyer WJ, Marvin JA, Patterson DR, Thomas C, Blak-eney PE: Management of pain and other discomforts inburned patients, in Herndon D (ed): Total Burn Care. Phila-delphia, PA, WB Saunders, 2002, pp 747-765

123. Mihara M: Regenerated cutaneous nerves in humanepidermal and subepidermal regions: An electron micros-copy study. Arch Dermatol Res 276:115-122, 1984

124. Miniche S, Dahl JB, Kehlet H. Time course of primaryand secondary hyperalgesia after heat injury to the skin. Br JAnaesth 71:201-205, 1993

125. Miniche S, Dahl JB, Kehlet H: Peripheral antinocicep-tive effects of morphine after burn injury. Acta AnaesthesiolScand 37:710-712, 1993

126. Miniche S, Pedersen JL, Kehlet H. Topical ketorolachas no antinociceptive or anti-inflammatory effect in ther-mal injury. Burns 20:483-486, 1994

127. Montgomery RK: Pain management in burn injury. Crit

Care Nurs Clin North Am 16:39-49, 2004128. Moritz AR, Henriques FC: Studies of thermal injury, II:The relative importance of time and surface temperature inthe causation of cutaneous burns: An experimental study.Am J Pathol 23:695-720, 1947

129. Morse JM, Mitcham C: The experience of agonizingpain and signals of disembodiment. J Psychosom Res 44:667-680, 1998

130. Munster AM, Smith-Meek M, Sharkey P. The effect ofearly surgical intervention on mortality and cost-effective-ness in burn care, 1978-91. Burns 20:61-64, 1994

131. Nedelec B, Hou Q, Sohbi I, Choiniere M, Beauregard G,Dykes RW: Sensory perception and neuroanatomical struc-

tures in normal and grafted skin of burn survivors. Burns31:817-830, 2005

132. Nozaki-Taguchi N, Yaksh TL: A novel model of primaryand secondary hyperalgesia after mild thermal injury in therat. Neurosci Lett 254:25-28, 1998

133. ODonnell ML,CreamerM, BryantRA, Schnyder U, ShalevA: Posttraumatic disorders following injury: An empirical andmethodological review. Clin Psychol Rev 23:587-603, 2003

134. Olgart L: [Breakthrough in pain research. Charting ofthe synaptic network may lead to new analgesics]. NordMed 113:6-12, 1998

135. Osgood PF, Kazianis A, Kemp JW, Atchison NE, Carr DB,Szyfelbein SK: Morphine pharmacokinetics in children fol-

lowing acute burns and after recovery from burns, in BondME, Charlton JE, Woolf CJ (eds): VIth World Congress onPain. Amsterdam, The Netherlands, Elsevier Science, 1995,pp 175-180

136. Parada CA, Yeh JJ, Joseph EK, Levine JD: Tumor necro-sis factor receptor type-1 in sensory neurons contributes toinduction of chronic enhancement of inflammatory hyper-algesia in rat. Eur J Neurosci 17:1847-1852, 2003

137. Parkland Health & Hospital System. Parkland BurnAcute Care Unit Adult Pain Management Pathway, in Mc-Caffrey M, Pasero CP (eds): Pain: Clinical Manual. St. Louis,MO, Mosby, 1999, p 529

138. Patterson DR: Practical application of psychologicaltechniques in controlling burn pain. J Burn Care Rehabil

13:13-18, 1992139. Patterson DR: Non-opioid-based approaches to burnpain. J Burn Care Rehabil 16:372-376, 1995

140. Patterson DR, Ptacek JT: Baseline pain as a moderatorof hypnotic analgesia for burn injury treatment. J ConsultClin Psychol 65:60-67, 1997

141. Patterson DR, Ptacek JT, Carrougher GJ, Sharar SR:Lorazepam as an adjunct to opioid analgesics in the treat-ment of burn pain. Pain 72:367-374, 1997

142. Patterson DR, Ptacek JT, Carrougher G, Heimbach DM,Sharar SR, Honari S: The 2002 Lindberg Award: PRN vs reg-ularly scheduled opioid analgesics in pediatric burn patients.J Burn Care Rehabil 23:424-430, 2002

143. Patterson DR, Hoffman HG, Weichman SA, Jensen MP,

546 Burn Injury Pain: The Continuing Challenge

8/13/2019 1-s2.0-S1526590007005123-main

15/16

Sharar SR: Optimizing control of pain from severe burns: aliterature review. Am J Clin Hypn 47:43-54, 2004

144. Patterson DR, Wiechman SA, Jensen M, Sharar SR: Hyp-nosis delivered through immersive virtual reality for burnpain: A clinical case series. Int J Clin Exp Hypn 54:130-142,2006

145. Pearson E, Soroff HS, Arney GK, Artz CP: An estimation

of the potassium requirements for equilibrium in burnedpatients. Surg Gynecol Obstet 112:263-273, 1961

146. Pedersen JL, Callesen T, Moiniche S, Kehlet H: Analge-sic and anti-inflammatory effects of lignocaine-prilocaine(EMLA) cream in human burn injury. Br J Anaesth 76:806-810, 1996

147. Pedersen JL, Crawford ME, Dahl JB, Brennum J, KehletH: Effect of preemptive nerve block on inflammation andhyperalgesia after human thermal injury. Anesthesiology84:1020-1026, 1996

148. Pedersen JL, Galle TS, Kehlet H: Peripheral analgesiceffects of ketamine in acute inflammatory pain. Anesthesi-ology 89:58-66, 1998

149. Pedersen JL, Kehlet H. Hyperalgesia in a human modelof acute inflammatory pain: A methodological study. Pain74:139-151, 1998

150. Pedersen JL, Kehlet H: Secondary hyperalgesia to heatstimuli after burn injury in man. Pain 76:377-384, 1998

151. Pedersen JL: Inflammatory pain in experimental burnsin man. Dan Med Bull 47:168-195, 2000

152. Pereira C, Murphy K, Herndon D: Outcome measures inburn care: Is mortality dead? Burns 30:761-771, 2004

153. Perreault S, Choiniere M, du Souich PB, Bellavance F,Beauregard G: Pharmacokinetics of morphine and its glucu-ronidated metabolites in burn injuries. Ann Pharmacother35:1588-1592, 2001

154. Perry S, Heidrich G, Ramos E. Assessment of pain inburned patients. J Burn Care Rehabil 2:322-326, 1981

155. Perry S, Heidrich G: Management of pain during de-bridement: A survey of US pain units. Pain 13:267-280, 1982

156. Perry S, Inturrisi CE: Analgesia and morphine disposi-tion in burn patients. J Burn Care Rehabil 4:276-279, 1983

157. Perry S: Undermedication for pain on a burn unit. GenHosp Psychiatry 6:308-316, 1984

158. Pontn B: Grafted skin. Acta Chir Scand Suppl 257:1-78,1960

159. Portenoy RK, Hagen NA: Breakthrough pain: Defini-tion, prevalence and characteristics. Pain 41:273-281, 1990

160. Prensner JD, Yowler CJ, Smith LF, Steele AL, FratianneRB: Music therapy for assistance with pain and anxiety man-agement in burn treatment. J Burn Care Rehabil 22:83-88;discussion 82-83, 2001

161. Ptacek JT, Patterson DR, Montgomery BK, HeimbachDM: Pain, coping, and adjustment in patients with burns:Preliminary findings from a prospective study. J Pain Symp-tom Manage 10:446-455, 1995

162. Ptacek JT, Patterson DR, Doctor J: Describing and pre-dicting the nature of procedural pain after thermal injuries:Implications for research. J Burn Care Rehabil 21:318-326,2000

163. Raja SN, Campbell JN, Meyer RA: Evidence for differentmechanisms of primary and secondary hyperalgesia follow-

ing heat injury to the glabrous skin. Brain 107(Pt4):1179-1188, 1984

164. Ratcliff S, Brown A, Rosenberg L, Rosenberg M, RobertR, Cuervo L, Villarreal C, Thomas C, Meyer WI: The effective-ness of a pain and anxiety protocol to treat the acute pedi-atric burn patient. Burns 32:554-562, 2006

165. Ready LB, Edwards WT: Management of Acute Pain: A

Practical Guide. Seattle, WA, International Association forthe Study of Pain (IASP), 1992

166. Rees JM, Dimick AR: The cost of burn care and thefederal governments response in the 1990s. Clin Plast Surg19:561-568, 1992

167. Robert R, Blakeney PE, Villarreal C, Rosenberg L, MeyerWJ III: Imipramine treatment in pediatric burn patients withsymptoms of acute stress disorder: A pilot study. J Am AcadChild Adolesc Psychiatry 38:873-882, 1999

168. Rose S, Bisson J, Wessely S: A systematic review of sin-gle-session psychological interventions (debriefing) fol-lowing trauma. Psychother Psychosom 72:176-184, 2003

169. Rutan TC, Herndon DN, Van Osten T, Abston S: Meta-

bolic rate alterations in early excision and grafting versusconservative treatment. J Trauma 26:140-142, 1986