1. health and fitness
2. disease
3. chronic pain

The Journal of Pain, Vol 8, No 7 (July), 2007: pp 533-548
Available online at www.sciencedirect.com
C RITICAL 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; and
‡
Division 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 injury
is 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 management guidelines and protocols have been developed and implemented, unrelieved moderate-tosevere 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 examines
burn 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 and
chronic pain mechanisms, science.
Received August 7, 2006; Revised January 22, 2007; Accepted February 8,
2007.
Address reprint requests to Dr. Gretchen J. Summer, C-522/Box 0440, 521
Parnassus 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
A
lthough burn injury pain was well-described as a
major clinical problem over 2 decades ago,154,157
researchers continue to report that burn pain remains undertreated.23,24,26,30,121,129,161,196,207 This is of
concern because unrelieved pain is thought to contribute
to long-term sensory problems, including chronic pain, paresthesias, and dyesthesias,18,44,84,99,134,212 a common occurrence after burn injury,28,109,110,176 as well as debilitating psychological conditions.21,41,58,161,172,177,197,215 This
533
534
review examines burn injury pain and its management
across 3 phases of burn recovery (ie, acute, healing, and
rehabilitation), emphasizing 3 types of pain that require
separate assessment, management, and frequent evaluation. Although the review addresses patients of all
ages, from critical care to outpatients, the primary focus
is on pharmacologic management of the adult hospitalized patient who is awake and not supported by mechanical ventilation. The review concludes with a discussion, suggestions for improvement, and a call for
critically needed science to guide the standard of care as
well as the development of new therapeutic approaches.
Significance
Unrelieved burn injury pain is a significant public
health problem.
In the United States, an estimated 1.25 million individuals sustain a burn injury each year.19 Of these, between
700,000 and 827,000182 seek care at an emergency department, and between 51,000 and 71,000 require hospitalization.104 Although these figures reflect decreased
prevalence as the result of successful burn prevention
strategies,81 they do not reflect the significant increase
in patients surviving major burns.46,85,152 Nor do they
reveal that the number of patients admitted to burn
centers has increased significantly due to the recognition
that even smaller burns require specialized care.104 Yet,
burns are one of the most resource-intensive of all health
care conditions.25,42,61,130,166 Thus, there has been a
widespread trend to treat patients with larger and more
complex burns on an outpatient basis and to discharge
inpatients sooner. Over the past 10 years, the average
length of an inpatient stay declined from 13 days to 8
days.3 This approach means that outpatients experience
more severe pain and have pain management needs
across all the phases of burn recovery.
Phases of Burn Recovery
Important to a discussion of burn injury pain is an understanding of burn recovery. Burn recovery is frequently divided into 3 phases, based on local and systemic, pathophysiologic responses. The acute phase, also
referred to as the emergency or resuscitative phase (due
to the need for massive fluid replacement often required
to maintain circulating volume), is when initial wound
debridement is performed after the patient has been
stabilized. The healing phase is characterized by the goal
to accomplish healing, which requires a clean wound
bed, achieved through frequent dressing changes or surgical intervention. The rehabilitation, or remodeling
phase, is the time during which the intense inflammatory
response associated with raised, erythematous (reddened) scar tissue subsides and tissue collagenases cease
remodeling, resulting in a softer, less erythematous and
sometimes flatter scar. The acute phase may be completely bypassed in smaller injuries and typically lasts 2 to
3 days.122,165 The length of the healing phase may be
weeks or more, and the rehabilitation phase most often
Burn Injury Pain: The Continuing Challenge
takes at least 1 year but sometimes much longer, depending on patient participation in the treatment plan;
patient age; location, size, and depth of burn; as well as
comorbid or preexisting conditions.106
Pain is the most frequent complaint of burn-injured
patients.116 Burns induce mechanical and thermal hyperalgesia in human skin.150,163 However, primary mechanical hyperalgesia, induced by mechanical stimulation
of the injured site, is the major source of severe pain
after a burn injury. In this review, the terms “pain” and
“hyperalgesia” refer to primary mechanical hyperalgesia.
Clinical observations suggest that hyperalgesia is likely
to be most severe and variable in intensity during the
healing phase. The intensity of hyperalgesia cannot be
predicted based on factors such as patient age, sex, ethnicity, education, occupation, or socioeconomic status7,26,154 and does not always correlate with the size of
the burn.26,41,154
Burn Injury Pain Assessment
Assessment tools are essential to the diagnosis of underlying burn pain syndromes and the effectiveness of
their treatment. In the burn patient population, the
most common pain assessment tools are verbal self-report instruments that measure pain intensity, such as the
“0 to 10” numeric rating scale. However, visual analog,
descriptor (eg, adjective), face, and color scales, are also
used. In 1 of the few studies that examined patient preference, burn-injured patients preferred faces209 and
color scales to the more commonly used visual analogue
and adjective scales.60
Osgood et al191 introduced the first pediatric burn pain
assessment tool: A large thermometer-like numeric rating scale designed with white numbers (0 to 10) on a
crimson background. Whereas this and other pediatric
pain assessment tools can be used in adults and elderly
patients (eg, faces72), no pain assessment tool has been
validated for use among elderly burn-injured patients.
This may be, in part, because pain in older burn-injured
patients is only beginning to be described.65,79,184 Research in other patient populations has demonstrated
that the verbal descriptor scale is best for measuring pain
in older adults, including those with mild to moderate
cognitive impairment.73
When patients are unable to provide a self-report, behavioral observations may be a valid approach.71 An observational pain scale has been developed for use in
burn-injured children.11 A cautionary note is warranted,
however, because significant discordance has been demonstrated between burn nurses’ and burn-injured patients’ pain assessments.27,57,82 For this reason, individuals who are unable to communicate their pain are at
greater risk for undertreatment of their pain—an important clinical problem for which excellent clinical practice
recommendations have recently been published.71
As in other patient populations, the manually marked
visual analog scale is preferred for research purposes because its continuous range makes it a sensitive measure-
REVIEW/Summer et al
ment method. However, burn-injured patients are often
unable to manually mark a scale due to the extent and/or
severity of their injuries. Choinière29 solved this problem
by introducing a visual analog scale designed to elicit a
verbal self-report. Similar to the instrument introduced
by Osgood et al,135 the visual analog thermometer is
based on a thermometer-like design.191 However, it is a
hand-held, washable instrument with a sliding red panel.
A pediatric verbal self-report visual analog scale45 has
been adapted for use in burn-injured children.164
Although limited due to small sample size, a strong
correlation was found between manual and verbal burn
pain assessment scales, indicating good concurrent validity189 consistent with research in other patient populations.62 Thus, educating the patient as to the purpose
and importance of multiple pain assessments and offering them a choice as to which method they prefer may
provide them with some control over communication
methods as well as improve the capacity of more patients
to participate in research. Assessing pain in the burninjured patient is complex because it requires the separate assessment and management of multiple types of
pain.30,165
Types of Burn Injury Pain
Procedural Pain
Procedural pain (eg, primary mechanical hyperalgesia)
is the most intense and most likely type of burn injury
pain to be undertreated.6,20,26 Patients describe procedural pain as having an intense burning and stinging
quality that may continue to a lesser degree but may be
accompanied by intermittent sharp pain for minutes to
hours after dressing changes and physiotherapy have
ended.122 Wound debridement, dressing changes, and
strenuous physical and occupational therapy that require manipulation of already inflamed tissue may contribute to increased pain and inflammation in burn
wounds. In addition, dependent positioning of injured
extremities (ie, below the level of the heart) can induce
excruciating, throbbing pain, thought to be caused by
pressure associated with venous distention in inflamed,
edematous tissue. These observations are based on clinical experience, however, and require study. Procedural
pain is a multidimensional experience that frequently
induces significant anxiety and distress.24,80,164 These
multidimensional manifestations of the procedural pain
experience are critical aspects of this important clinical
problem as emphasized in the following section.
Procedural Pain and Associated Anxiety
and Distress
New burn care providers sometimes ask if patients “get
used to” or habituate to procedural pain. However, clinical observations and research suggests that procedural
pain–associated anxiety may increase over time in burninjured patients.5,59,208 This finding has important implications for clinical care because strong correlations were
found between pain, psychological distress,41 and phys-
535
ical as well as psychological outcomes in burn-injured
children186 and adults.48 Anxiety and distress, as measured by tension during burn dressing changes, was significantly related to overall and worst pain, whereas
amount of analgesics and anxiolytics given, postburn
day, and total body surface area were not.57
Anxiolytic agents, such as the benzodiazepines (eg, diazepam, lorazepam, and midazolam) are known to reduce pain and anxiety associated with burn dressing
changes in burn-injured adults141 and children.178 Lorazepam was found to reduce procedural pain ratings in
patients who had “high pain” defined as a baseline of 50
or greater on a 0 to 100 mm visual analog scale.141 However, benzodiazepines have been found to antagonize
opioid analgesia in postoperative patients.56 Moreover,
similar to opioids, patients’ responses to benzodiazepines are highly variable. Although some patients may
have development of respiratory depression, others, particularly those with a history of alcohol or chemical dependence, may not respond to doses within the recommended safety and efficacy range. Therefore, the
administration of benzodiazepines requires increased
staffing to provide close monitoring for untoward effects, a standard of care commonly referred to as “conscious sedation.” Because burn care is resource-intensive
and insurance and government reimbursements have
declined, the use of benzodiazepines that require a conscious sedation protocol has declined in the acute care
setting in some burn centers24 and is impractical in the
outpatient setting. Other classes of sedative hypnotics
such as ketamine80 and propofol31,180 significantly reduce pain and associated anxiety and distress during
burn 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, hyperarousal and intrusive reexperiencing), including imipramine,167 chloral hydrate,167 morphine,172 and respiridone.183 However, lack of a clearly defined standardized
diagnostic criterion for study entry and use of an unvalidated clinical interview to determine improvement or
methodological flaws make the results difficult to interpret.46 Whether decreasing acute stress symptoms in
burn-injured patients with pharmacologic agents translates into a decreased prevalence of traumatic stress disorders is unknown and requires further study. One reason for this may be the difficulty to accurately diagnose
traumatic stress disorders in patients with burn injuries.133
Prevalence rates for traumatic stress disorders associated with burn injury vary substantially across studies,
ranging between 11% and 50%.12,46 In addition to painassociated anxiety and distress, factors that contribute to
acute and post-traumatic stress disorders after burn injury include female sex,197 avoidant coping style, location of burn, preburn depression, type and severity of
baseline symptoms, personality disorder, history of alcohol and/or chemical dependency, and poor social support.46 Findings are inconsistent regarding body image
after burn injury.198 Overall, the data suggest that severe
536
burns do not necessarily induce physical impairment or
poor psychosocial adjustment, particularly in burned
children,17 but size of burn and in-hospital ratings of
stress may predict rate and degree of physical and psychological recovery.48 These results suggest that in addition to aggressive wound closure, interventions that reduce in-hospital distress may accelerate and improve
both physical and psychosocial recovery.
Nonpharmacologic adjuncts to reduce pain and associated anxiety and distress include cognitive techniques
(eg, distraction and focusing attention), behavioral techniques (eg, classic conditioning, including pairing relaxation with previously conditioned autonomic responses),
education and/or preparatory information (eg, enhancing predictability of sensory and procedural components of
aversive procedures91,92), hypnotherapeutic techniques
(eg, incorporates behavioral and cognitive techniques with
introduction of posthypnotic cues for relaxation),1 and alternative 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 demonstrated to significantly reduce pain and/or associated
anxiety and distress when used as an adjunct to opioid
analgesics during burn dressing changes.46,55 Patterson
et al140 suggested that hypnosis, which appears to be
more effective in patients with severe pain caused by
motivational factors, and virtual reality may be combined to optimize their beneficial effects.143 Preliminary
findings support this suggestion as well as the increased
efficiency with which hypnosis can be administered by
eliminating the need for the presence of a trained clinician,144 an advantage that may help to offset the cost of
expensive equipment required to administer “virtual reality hypnosis.”
Nonpharmacologic interventions can also cause harm.
Single-session psychological debriefing was found to increase symptoms of post-traumatic stress disorder in
burn-injured patients,10,15,168 similar to other patient
populations.14 In addition, combining attention focusing
(ie, attending to procedural sensations) with ignoring
has been shown to increase symptoms of traumatic stress
(eg, intrusion) in burn-injured patients.47 A group that
was taught to use 2 behavioral coping techniques (eg, as
opposed 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 of
ignoring and focusing attention during burn dressing
changes is not empirically justified and may potentially
cause harm.46 Although the theoretical basis and application of nonpharmacologic adjuncts are not within the
scope of this review, they are well described by Patterson
et al.1,138,139,143
Background Pain
Burn-injured patients with high anxiety also tend to
report more background pain.26 Similar to procedural
pain, wide variability has been documented in the intensity of background pain after burn injury.96,162 Back-
Burn Injury Pain: The Continuing Challenge
ground pain is characterized by its prolonged duration,
relatively constant nature, and mild to moderate intensity.96 Burn background pain is typically described as a
continuous “burning” or “throbbing” pain that is
present when the patient is relatively immobile. Therefore, it is usually best treated with regularly scheduled
analgesics that provide a continuous serum therapeutic
blood level.142,100
Breakthrough Pain
Similar to postoperative patients, patients with burns
experience transient worsening of pain most frequently
associated with movement that is referred to as breakthrough pain.33 Burn-injured patients also describe
spontaneous components of breakthrough pain. Spontaneous breakthrough pain may be due to changing
mechanisms of pain over time as well as inadequate dosing, which occurs when serum blood levels of analgesics
drop below what is needed to control background
pain.159 Spontaneous breakthrough pain is commonly
reported by patients in qualitative terms such as “stinging,” “pricking,” “shooting,” and “pounding” (unpublished data). Although pain associated with primary mechanical hyperalgesia caused by movement may also be
called procedural pain, most burn care providers consider this pain to be a type of breakthrough pain. Mechanical hyperalgesia of this nature is particularly severe
after extended periods of immobility in those patients
with injuries over joints and/or in whom the extremities
are affected.
For optimal analgesia after burn injury, a guiding
principle is that each patient requires a separate assessment of procedural, background, and breakthrough pain throughout the rapidly changing course
of burn recovery.30 The next section describes the pain
associated with the 3 phases of burn recovery and how
these different types of pain may occur in and interfere with each phase.
Phases of Burn Recovery and
Pain Management
Acute Phase
Stabilization of the patient and preservation of function are the primary goals of treatment during the acute
phase. Large thermal injuries (⬎15% total body surface
area) evoke profound systemic fluid shifts and physiologic stress responses.213 This phase may be completely
bypassed in the case of smaller burns122 and varies in
length but typically lasts no longer than 3 days.165 Acute
intoxication with alcohol or chemical substances, which
may be a precipitant to the burn injury,93 may initially
complicate care of the burn-injured patient and can adversely interact with analgesic and anxiolytic medications.165
Procedural Pain During the
Acute Phase
Procedural pain during the acute phase may range
from mild to excruciating. It is critical to aggressively
REVIEW/Summer et al
manage pain and anxiety for the first dressing change. If
the first dressing change evokes extreme anxiety and
emotional distress, clinical experience suggests that
these responses are likely to increase over time and may
lead to long-term pain management problems.105 Thus,
some burn centers provide anxiolytic medication as an
adjunct to opioids as a standard of care during this phase
unless otherwise contraindicated.137
Of note, patients may have progressed to the rehabilitation phase and then return to the healing phase after
required surgical procedures. Thus, the phases of burn
recovery do not always occur in a stepwise monotonic
progression.
Background Pain During the
Acute Phase
The severity of background pain during the acute
phase may also range widely from none to severe. It is
often markedly decreased by covering the wound securely with a moist or occlusive dressing, which suggests
a contribution from exposure of the wound to air. Because this type of pain is continuous, controlled release
or long half-life opioids such as methadone are particularly effective for the management of background
pain.23 Moreover, methadone is a ␮-receptor agonist
and an excitatory amino acid N-methyl-D-aspartate
(NMDA) receptor antagonist. Thus, it may be of particular benefit to decrease morphine tolerance, which is often associated with enhanced hyperalgesia in the burninjured patient.181,211
Breakthrough Pain During the
Acute Phase
During the acute phase, it is not unusual for the burninjured patient who appears to have good pain control
on a stable analgesic regimen to suddenly experience an
increase in the severity of their pain, referred to as breakthrough pain. A subtype of breakthrough pain called
end-of-dose breakthrough pain may occur toward the
end of a dosing interval presumably because opioid levels have declined below a therapeutic level. Shortening
the dosing interval is usually recommended under these
circumstances.159 Increasing the dose without shortening the dosing interval may also be effective, but this
approach can result in higher than desirable peak serum
levels, producing or increasing undesirable side effects.4
Healing Phase
During the healing stage, the goal is to promote healing, either by removing devitalized tissue from the injured area, using topical enzymatic preparations and frequent dressing changes or by surgical excision and
grafting.8,98 During the transition from the acute to the
healing phase, a determination is made as to whether the
patient will require surgery to accomplish wound closure or
“to let the wounds heal on their own” with daily wound
care. If wounds cannot contract and approximate their
edges together, they will form extremely painful, nonhealing ulcers. However, if wounds heal over a joint, since they
will shrink by contraction, they may leave the patient with
537
a contracture, limiting range of motion. Thus, stretching
injured tissue during physiotherapy, a major source of primary mechanical hyperalgesia, is vital immediately after
and over the long course of burn recovery to prevent contractures and to optimize function.
Because of the time it takes to prepare a clean wound
bed necessary for epidermal migration to occur deep
dermal burns take longer to heal, which extends the period of time the patient endures severe pain. Moreover,
wounds that heal slowly are more likely to scar significantly, a phenomenon associated with prolonged inflammation.213 Since early excision and grafting significantly
reduce mortality and morbidity in the burn-injured patient
population,130 the goal is to establish a wound closure
treatment plan as soon as possible. That being said, a
determination of the depth of tissue damage is difficult,
even for the most experienced clinicians.67 Moreover,
inflammatory responses induce changes in the local microcirculation that contribute to further ischemia.213
Thus, the extent of tissue damage does not evolve completely for several days (eg, 3 days or longer) after burn
injury.67 During this “wait and watch” period, the burn
patient often experiences severe pain and anxiety.
Procedural Pain During the
Healing Phase
Unlike most acute injuries, procedural burn pain may
worsen unpredictably over the course of healing, an
event that adds to emotional distress in this patient population.13,26,30,58,171 This problem is not limited to a particular phase of burn recovery but is a frequent clinical
observation during the healing phase. Moreover, the
healing phase can last weeks, months, and sometimes
even years, during which time the patient must endure
repetitive, exquisitely painful, wound care and/or surgical procedures.
Short-acting, potent opioid analgesics timed to act
during peak procedure-induced primary mechanical hyperalgesia are most often indicated. In more severe
cases, local nerve blocks or general anesthesia may be an
option. Local anesthetic blocks have been used surprisingly sparsely in this patient population. One reason may
be that as previously mentioned, invasive lines provide a
portal of entry for infection in immunocompromised
burn-injured patients. In addition, for regional nerve
blocks, an acute pain service is usually required to provide the expertise and oversight necessary for this mode
of analgesia.
A common clinical observation in patients experiencing postoperative pain after skin grafting procedures is
that the split-skin donor site is substantially more painful
than the grafted site. Two studies suggest that local anesthetics can be used to decrease donor site pain in the
immediate postoperative period. Bupivacaine at a dose
of slightly less than 1.9 mg/kg added to intraoperative
donor site infiltration solution was found to be safe, as
demonstrated by low blood levels and the absence of
clinical signs of toxicity, and effective.53 In contrast, the
topical aerosol application of 0.5% bupivacaine was not
as effective as 2% lidocaine when applied intraopera-
538
tively to donor sites before application of an occlusive
dressing.88 In this study, lidocaine produced an analgesic
effect 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 vitro studies show that C-fiber nociceptors require a significantly
higher dose of lidocaine (0.8 mmol/L) than A-delta fiber
nociceptors, 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 stimulation (ie, pressurized spray of water, wet to dry dressings,
and so forth). These wounds fill in with vascular granulation tissue, which can be exquisitely sensitive to pressure. 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 seizures associated with systemic absorption.32,120,206 One
study suggested that clean vascular wounds with a minimal amount of associated inflammation may be more
responsive to the analgesic effects of topical local anesthetics.88 Of note, a recent study that compared infected
and noninfected burn-injured patients showed a significant increase in pain intensity in patients with infection.193 Burns induce profound inflammation.151 It is
possible that inflammation induces plastic changes in peripheral C-fiber nociceptors,2 making them less responsive to local anesthetics, but this 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 compartment block at the thigh donor site.34 Prolonged, preemptive nerve block reduced primary and secondary hyperalgesia over a period of 12 hours after a thermal burn
in human volunteers, whereas erythema and blister formation were not significantly affected.147
The analgesic effect of topically applied ketamine148
and the nonsteroidal anti-inflammatory drug ketorolac126 have also been evaluated in the burn-injured patient population without success. In addition, morphine
has been applied topically (eg, formulated with the antimicrobial cream sulfadiazine), resulting in a slight analgesic effect in the experimental group compared with
placebo, but the difference was not statistically significant.108 Subcutaneous local administration of morphine
was effective in attenuating pain after an experimental
thermal 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 the
clinical setting, the topical administration of opioids such
as loperamide warrant further study.
Burn Injury Pain: The Continuing Challenge
Background Pain in the Healing Phase
Clinical experience suggests that background pain is
less intense than either procedural pain or breakthrough
pain,30 but research is needed to better characterize this
type of pain and its variability over the healing phase of
burn recovery. A common clinical observation during the
healing phase is that background pain may increase precipitously just before epithelialization is complete. This
increase in pain characteristically occurs with the appearance of epithelial skin “buds,” structures that herald
reepithelialization and subsequent wound closure. This
period of healing is exquisitely painful, but the pain
ceases rapidly as epithelial cells spread out to cover the
burn wound. As noted above, regularly scheduled administration of medications that provides continuous
therapeutic serum blood levels is optimal for the management of background pain. Several doses (eg, 5) of
systemically administered medication are required before a therapeutic serum level is achieved in burn-injured
patients.100 Thus, a “loading dose” and short-acting opioids may be indicated when initiating background pain
management with regularly scheduled medications that
have 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 the
Healing Phase
Breakthrough pain during the healing phase is often
associated with movement. Because of the critical need
for mobilization of the burn-injured patient, effective
management of breakthrough pain is critical to minimize the risk of complications (eg, respiratory infection,
deconditioning, loss of function, and contractures). The
time course of angiogenesis, neural regeneration, and
reepithelialization during the healing phase of burn recovery warrants investigation to correlate it with
changes in primary mechanical hyperalgesia, the major
source of severe pain in burn-injured patients.
Rehabilitation Phase
The rehabilitation phase is characterized by completion of wound closure, scar maturation, and aggressive
physical and occupational therapy to stretch healing tissues, prevent contractures, and optimize functional outcomes. During the rehabilitation phase, complaints of
on-going, spontaneous pain and/or paresthesias, dyesthesias, 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 to
describe these sensations include phasic burning, tingling, prickling, and shooting sensations.176
Procedural Pain During the Rehabilitation
Phase
The pain management needs of patients with burns
usually decline markedly once healing (ie, wound closure) has occurred. In this case, opioids are usually not
indicated for procedural pain during the rehabilitation
REVIEW/Summer et al
phase. However, because of the increased treatment of
larger and more complex burns on an outpatient basis,
and because patients frequently require multiple surgical and other painful procedures involving, for example,
the use of subcutaneous skin expanders as a source of
pain—sometimes used to enlarge the surface area of potential donor skin in patients with large burns—potent,
short-acting opioids (eg, fentanyl, hydromorphone, morphine) may be indicated. For moderate pain, oxycodone
or a similar opioid preparation mixed with acetaminophen is indicated. Opioid medications are usually discontinued by the beginning of, or early in this phase. Because of the frequent need for large doses of opioid
analgesics up until wound closure is accomplished, tapering of opioids may be indicated to avoid symptoms of
withdrawal. Clonidine can augment opioid analgesia as
well as diminish the hyperadrenergic symptoms of opioid
abstinence and anxiety. Therefore, clonidine may be
considered as an analgesic adjunct as well as an important adjuvant during opioid tapering. Benzodiazepine
tapering may also be indicated. Although this important
clinical issue is gaining attention, particularly in critically
ill burn-injured children,180 research is needed to enhance the safe and effective management of opioid and
benzodiazepine withdrawal with tapering schedules
and adjuvants such as clonidine.
Background Pain During the Rehabilitation
Phase
If wound closure has occurred, background pain may
not be a problem during the rehabilitation phase of burn
recovery. However, if open wounds remain, and background pain is an issue, the same principles suggested for
the treatment of background pain during the healing
phase apply.
Breakthrough Pain During the Rehabilitation
Phase
Breakthrough pain associated with movement or
stretching exercises may be significant, but this type of
pain can often be anticipated, planned for, and treated
as with a painful procedure.
Pharmacokinetics and Pharmacodynamics
After Burn Injury
Burn injuries induce a profound inflammatory response that can affect changes in pharmacokinetics and
pharmacodynamics, depending on the size of the injury
(greater than 10% body surface area).122 Massive fluid
resuscitation is necessary to maintain hemodynamic stability and to avoid “burn shock.”203 Thus, the primary
route of administration during the acute phase is intravenous because of potential problems with enteral absorption related to decreased perfusion.122 Within days,
a transition to a “flow” phase36 occurs that is characterized by increased resting energy expenditure and hypermetabolism that can last from several weeks to months
to years after injury, depending on the size of the
burn.35,101,145
539
During the healing and rehabilitation phases, the metabolic rate of burn-injured patients increased by 50%
when burn size was greater than 20% to 30% surface
area and even greater in larger burns or if burn wound
sepsis was present.169 Increased circulating catecholamines
and adrenal steroid hormones are integral parts of this
physiologic response thought to support recovery through
compensatory cardiovascular, metabolic, and immunologic changes.94 Thus, concern for changes in pharmacokinetics and pharmacodynamics after burn injury can be
a barrier to pain management.
Alterations in the pharmacokinetics and pharmacodynamics of a variety of nonopioid medications113,114 have
been observed in burn-injured patients, ranging from
serum protein shifts to target receptor desensitization or
supersensitization.66,83,115,187 However, research suggests that elimination kinetics of morphine68,153,156 and
lorazepam112 are not impaired after burn injury and that
systemic clearance may actually be enhanced in larger
burns (eg, up to 80% body surface area), beyond which
clearance decreases toward control levels.135
Kealey and colleagues100 investigated the pharmacokinetics of morphine in patients with a mean body surface area burn of 21.5% in an attempt to ascertain a
rational dosage schedule for patients with burns. Treatments included a morphine constant rate infusion followed by immediate release oral morphine solution and
sustained release MS Contin (Purdue Frederick). The halflife of morphine oral solution was 3 hours, whereas the
half life of MS Contin (Purdue Frederick) was 14.7 hours.
Time to peak levels with oral morphine solution was 30
minutes and time to peak levels with MS Contin (Purdue
Frederick) was 1.4 hours. These data indicate that procedural, background, and breakthrough pain can be
treated with the use of rapid-release oral morphine
preparations for the recommended doses and that morphine sulphate sustained-release formulations are a
good choice in the management of background pain in
patients with burns given an 8- to 12-hour dosage schedule.
Choinière et al153 studied 5 patients with major first-,
second-, or third-degree burn injuries that received a
long-term intravenous morphine infusion. No differences were found in steady-state concentrations and system clearance of morphine, and its metabolites M3G and
M6G among patients with burns, other patient populations, and healthy volunteers receiving intravenously administered morphine over a period of 3 weeks. Among
patients with burn injuries, the severity of burns and the
duration of administration were not a cause of nonlinear
kinetic variability of morphine or of morphine resistance.
Although the morphine infusion rate was substantially
variable, from 4 to 39.5 mg/hour, it was not directly related to its systemic clearance. Thus, until more data are
available to the contrary, the monitoring of morphine
should be focused on the clinical response and titrated to
effect.
Intravenous local anesthetics are gaining interest but
are rarely administered in most burn centers. Jonsson et
al95 demonstrated that lignocaine infusion was safe and
540
strikingly reduced self-assessed pain scores in 7 patients
during the first 3 days after second-degree burns, without need for supplementary opiate analgesia, but no
pharmacokinetic data are available. The relatively short
half-life of lidocaine, however, is advantageous because
it is rapidly cleared following burn dressing changes and
physiotherapy.181 In a study of healthy volunteers, small
burns were induced before and after intravenous lidocaine administration.78 Local anesthetics administered in
concentrations that did not block nerve conduction substantially reduced pain (primary and secondary thermal
hyperalgesia). However, a significant preemptive effect
could not be demonstrated. Although the antihyperalgesic effect of lidocaine probably is based on action at
central (spinal) sites, peripheral sites may also be involved and research is needed to answer this question.78
As previously mentioned, topical application of local
anesthetics has met with disappointing results. However,
topical lidocaine may be safe and effective for control of
pruritus, a major problem during the rehabilitation
phase that can impede burn recovery. EMLA (a eutectic
mixture of local anesthetics—prilocaine and lignocaine)
was evaluated in a pilot study involving burned children.103 EMLA was used to ameliorate postburn pruritus
after application onto newly formed, intact skin. Serial
blood samples were collected in 5 children after 15.7 ⫾
2.54 g (mean ⫾ SD) of EMLA was applied to a skin surface
area of 93.0 ⫾ 37.0 cm2. Prilocaine and lidocaine concentrations were below toxic levels and o-toluidine was not
detected. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2
prestudy control days compared with study day 3 (P ⫽ .01
and P ⫽ .03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. These
data suggest that EMLA may be a safe, novel treatment
for postburn pruritus when applied to vulnerable newly
healed skin.
Pruritus
Pruritus (eg, itch) commonly replaces pain as a source
of significant anxiety and distress during the rehabilitation phase.49,87,111,118,210 Common pharmacologic interventions for pruritus include antihistamines (eg, H1 and
H2 antagonists, including diphenhydramine, cyproheptadine, and hydroxyzine),9,164,199 and some burn centers
have developed standardized protocols for the management of burn associated pruritus.164 Although few assessment scales exist, a pediatric “itch man scale” was
created by Pat Blakeney and Janet Marvin, as described
by Ratcliff et al.164 Not only is itching a source of anxiety
and distress, but attempts to relieve the itch by scratching or rubbing jeopardizes newly healed skin, which is
easily blistered and injured in response to mechanical
stimulation.
Prevalence of pruritus after burn injury is high. Reports
suggest that 60%210 to 87%199 of patients report either
persistent (15%) or intermittent (44%) pruritus.16,199,210
Although oral pharmacologic agents are probably the
most common method as described above, topical phar-
Burn Injury Pain: The Continuing Challenge
103
macologic
and nonpharmacologic agents,118,164 mas49,50,70
sage,
and transcutaneous electrical nerve stimulation74 have also been studied to manage pruritus.
However, these studies lack the evidence to make treatment recommendations.46
Chronic Burn Injury Pain
Chronic pain has been identified as a significant problem many years after burn recovery. In a study that
surveyed members of the Phoenix Society for Burn Survivors, 52% of respondents reported on-going burn-related pain an average of 12 years after injury (n ⫽ 348,
24% response rate).39 Other studies indicate that ongoing pain, years after burn injury, is a significant problem.28,39,109,110,131 Complaints of chronic pain may first
arise during the rehabilitation phase of burn recovery. It
may initially present as hypersensitive or hyposensitive
areas that develop in healed sites. Although hypersensitivity in newly healed skin is common, it often depends
on the location, with the scalp, axilla, perineum, and
the hands and feet being particularly sensitive for up to
1 year after injury at these sites.158,201
Loss of sensibility is more common after deep burns
and grafted injuries.69,202 In a study of 236 patients who
responded to a survey (67% response rate) at least 1 year
after burn trauma, more than one third of participants
complained of pain. A total of 71% of patients complained of noxious paresthetic sensations, and only
28.4% of this sample reported no sensory problems.109 In
an effort to define the extent of cutaneous sensory dysfunction after burn injury, subjective reports of abnormal sensations were compared between patients with
healed burns and normal control subjects.110 Psychophysical measures of tactile, thermal (nonnoxious), and
pain thresholds were assessed in the upper extremities of
121 patients with healed burns, more than 18 months
after injury, and compared with pair-matched control
subjects. Whereas more patients with deep dermal burns
that had required skin grafting reported significant sensory loss than patients with superficial dermal burns that
had healed spontaneously, some patients reported increased sensitivity in their healed burns. Of note, the
majority of patients who had decreased thresholds also
reported painful or paresthetic sensations at the site.
Depth of burn was the only factor associated with the
severity of sensory deficit, explaining more than one
third of the observed variability. Patient age, sex, and
medical variables, such as size of burn or time elapsed
since the injury, did not explain a significant proportion
of the variation in the sensibility thresholds in this study.
Of note, sensory loss was observed in burn sites as well as
uninjured areas, which suggested to these authors that
changes may have occurred in the central nervous system. However, in an animal model of full-thickness burn
injury, receptive fields were found to usually extend into
both adjacent and noncontiguous skin,97 which is consistent, as these authors point out, with the anatomy of
terminal fields of cutaneous nociceptors that can be
REVIEW/Summer et al
541
107
quite extensive, stretching over several millimeters
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 antidepressants (eg, amitriptyline), anticonvulsants (eg, gabapentin), and clonidine may prove useful in this patient
population. In addition, benzodiazepines are useful
adjuvants due to their anticonvulsant properties; and
NMDA antagonists, such as ketamine and dextromethorphan, 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 demyelinate.40,64,128 Macrophages invade the degenerating
nerve stump, removing myelin and axonal debris but
leaving the basal lamina intact through Wallerian degeneration.63 In addition, excision of eschar, sharp debridement 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, as
patients 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 completely absent in human tissue 2 days after injury and
remained undetectable for 10 days.202 As damaged neurons regenerate, abnormal ectopic excitability at or near
the site of nerve injury may develop due to unusual distributions of sodium (Na⫹) channels and abnormal responses to endogenous pain producing substances, including cytokines such as tumor necrosis factor-␣.216
Persistent abnormal excitability of sensory nerve endings 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 considered
a mechanism for amputation-induced pain, which may
also play a role in the development of burn-induced
chronic pain. Local nerve injury tends to spread to distant
parts of the peripheral and central nervous system. For
example, 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 injury–induced neuropathic pain, but this question
has not been studied.
Another cause of chronic pain after deep burns involves the frequent practice of tangential and/or fascial
excision of eschar associated with these injuries. This
practice may cause intact peripheral afferent nociceptors
to become injured.181 It also seems likely that regenera-
tion of neurons from wound margins may contribute to
burn pain.
Few studies have examined neural regeneration in human autograft131,202 and healing skin43,123 after burn
injury. Of these, only 1 obtained comparison samples
from the same patients, making it possible to determine
changes 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 showing the greatest degree of functional recovery. These
findings correlated with histologic analysis of skin biopsy
specimens from the same site that showed a significant
reduction in the axons that innervated the dermis and
the epidermis in burn graft relative to control skin (54%
decrease, P ⬍ .0001). Of note, the number of neurons
that expressed substance P was significantly elevated in
the autografted site and appeared to correlate with patient reports of pain and pruritus (P ⬍ .05). These authors
concluded that sensory regeneration may be fiber size–
dependent in burn-graft skin, with substance P– containing
fibers predominating but total fiber count decreasing.
These data support the hypothesis that unmyelinated
neurons have a greater ability to traverse scar tissue and
reinnervate grafted skin after full-thickness burn injury.
However, no correlation was reported between these
findings and pain severity scores.
Basic Science Models of Burn
Injury Pain
Few basic science models have been available to study
burn injury pain. Although human models have been
introduced,124,125,149 it is difficult to separate the mechanisms of burn injury pain in humans. More recently,
however, several animal models have been introduced132,190,200,214 that make it possible to begin to
tease apart the complex mechanisms that contribute to
the variability and intensity of burn injury pain over time.
In experimental animal models, second-messenger
proteins, including protein kinase C-epsilon (PKC⑀)190
and neurotrophins such as nerve growth factor
(NGF)190,195 have been identified as significant mediators of acute burn-induced hyperalgesia. These mediators may also play a role in chronic burn pain. PKC⑀ has
been found to mediate priming, a predilection toward
the development of chronic hyperalgesia in a previously
healed site of inflammation,136 and NGF induces hyperalgesia in noncontiguous, uninjured skin after burn injury in rats.195 NGF is also found in newly formed epithelial cells at the edge of wounds.119 The study of
peripheral mechanisms in chronic pain after burn injury
is a high priority for future research.
Why is Burn Injury Pain Still a Major
Problem After 20 Years?
Although the problem of undertreated burn injury
pain was well described more than 20 years ago154,155,157
and despite a call to make pain the highest research
542
priority in burn care due to its detrimental effects on
patients as well as those who care for them more than 15
years ago,117 burn injury pain remains a continuing challenge.27,30,58,79,82,105,127,143,192,196 Recent publications
report unacceptably high pain ratings (mean, 7/10)
for procedural pain 24 and chronic pain 4 months after
injury.176 Clinical observations confirm that these reports
are not unusual. This is disconcerting when one considers
the wide availability of pain management guidelines16,18,32,42,43,50,67,75,99,103 and the promotion of
guideline-based treatment approaches.1,58,88,104
Unlike surgical pain that subsides gradually, burn injury pain is highly variable and may increase over time,
much to the patient’s distress, before healing is accomplished. This makes approaching burn injury pain with
the World Health Organization’s analgesic ladder38 or
titrating to effect often impractical. In fact, the ladder
could 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 of
knowing that opioids can be used for analgesia as well as
for abuse. Moreover, it is valid to question the safety of
the administration of opioids in patients with major
burns. Because of their requirement for massive fluid
resuscitation during the first few days after admission
and the potential for contributing to hemodynamic instability, it has been recommended that patients such as
these not be administered more than 10 mg of intravenous morphine sulfate in a 24-hour period.188 This is a
small amount compared with what is administered to
most burn-injured patients,23,68,96 although, as pointed
out by Choinière,30 the opioid doses reported in some
studies to patients with much smaller injuries are barely
within the range required to control much less intense
types of pain.141,179 In addition, burns are profoundly
immunosuppressive, and there is a large body of literature that suggests opioids may contribute to immunosuppression. High risk for mortality and morbidity frequently places their safety above their need for pain
management.
Nonetheless, perhaps it is time to stop insisting that burn
pain is a very difficult type of pain to treat and question if
we are doing the very best to treat it. Are burn centers
using the principles of multimodal analgesia (eg, different
classes of medications in combination with nonpharmacologic methods) in a systematic manner? As previously mentioned, nonsteroidal anti-inflammatory agents are usually contraindicated in this patient population, but other
medications are rarely used even though they appear to
be very useful for pain management in the burn-injured
patient. For example, clonidine, ketamine, lidocaine, and
methadone appear to be underused in this patient population. However, their use may decrease the need for
rapidly acting, potent opioids usually required for painful procedures. Moreover, the use of mixed ␮-receptor
antagonists and/or agonist-antagonists may prevent or
ameliorate tolerance that is so commonly observed in
patients with major burns.
We also need to ask, are members of the multidisci-
Burn Injury Pain: The Continuing Challenge
plinary burn team aware of the most recent data on pain
and analgesia, and is this information being implemented by those who care for burn-injured patients?
Those who specialize in the care of these patients may
become accustomed to the expectation that pain will not
be controlled, particularly during procedures. One may
rationalize that it will only hurt for a brief period of time,
but research suggests that peak procedural pain and
global recollection of procedural pain are correlated57
and that global recollection of procedural pain (ie, 4
hours immediately after surgery) influences patient satisfaction.89
Fentanyl has been demonstrated to be the most effective analgesic for burn procedural pain, but do patients
receive a dose of this potent and short-acting opioid in
time to meet their need for peak procedural pain relief
or are we prevented from helping some patients in this
manner due to the fear of overdosing others in the same
manner? Research is needed to expand our vision for
assisting this vulnerable patient population. The judicious use of diluted naloxone and flumazenil reverses
the effects of opioids and benzodiazepines, but they are
rarely used to avoid oversedation and other side effects
that frequently limit the use of opioids and benzodiazepines. As suggested by Silbert et al,181 although new
therapeutic approaches are desperately needed, we do
not need to wait on basic science. Alternatives are readily
available at the bedside today. Are nonpharmacologic as
well as pharmacologic interventions systematically implemented? Are we using new materials, such as dissolvable staples to minimize procedural pain, unless contraindicated? Is the pain plan visible? That is to say, is the
pain management plan systematically evaluated, to keep
pace with the patients’ rapidly changing needs and
made visible for the burn management team?
Importantly, we also need more research on burn injury pain. The American Burn Association Patient Registry Participant Group and The National Institute on Disability and Rehabilitation Research Burn Model System
Database102 developers may be well positioned to make
recommendations as to how information could be
tracked similar to their important work tracking outcomes in the treatment of burn trauma in the United
States.170 Until we have the science, we will continue to
lack a basis for rationale treatment recommendations
for acute and chronic burn injury pain. In particular, research is needed to identify the underlying mechanisms
for burn injury pain over time. Only with this knowledge
will burn care providers be able to target specific mechanisms that contribute to the variable intensity26,96,162
that makes this type of pain such a difficult management
problem.
Conclusion
Burn-injured patients of all ages have procedural,
background, and breakthrough pain during the acute,
healing, and rehabilitative phases over the long course
of burn recovery. The establishment of multidisciplinary
burn team and institutionally supported system changes
REVIEW/Summer et al
543
that will promote the recognition and implementation
of changes necessary to accomplish safe and effective
burn pain management are critically needed. Moreover,
research that focuses on the continuing challenge of
burn injury pain is critically important. Only with these
valuable data can the efficacy of acute and chronic burn
injury pain be improved and the underlying mechanisms
finally understood and rationally treated.
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