SUMMARY ARTICLE

A Review of Adjunctive Therapies for Burn Injury Pain

During the Opioid Crisis

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Daniel E. Kim, MD,*,† Kaitlin A. Pruskowski, PharmD,*,† Craig R. Ainsworth, MD,*,†
Hans R. Linsenbardt, PhD,* Julie A. Rizzo, MD,*,† and Leopoldo C. Cancio, MD*

Opioids are the mainstay of pain management after burn injury. The United States currently faces an epidemic
of opioid overuse and abuse, while simultaneously experiencing a nationwide shortage of intravenous narcotics.
Adjunctive pain management therapies must be sought and utilized to reduce the use of opioids in burn care
to prevent the long-term negative effects of these medications and to minimize the dependence on opioids for
analgesia. The purpose of this review was to identify literature on adjunctive pain management therapies that have
been demonstrated to reduce pain severity or opioid consumption in adult burn patients. Three databases were
searched for prospective studies, randomized controlled trials, and systematic reviews that evaluated adjunctive
pain management strategies published between 2008 and 2019 in adult burn patients. Forty-six studies were
analyzed, including 24 randomized controlled trials, six crossover trials, and 10 systematic reviews. Various
adjunctive pain management therapies showed statistically significant reduction in pain severity. Only one
randomized controlled trial on music therapy for acute background pain showed a reduction in opioid use. One
cohort study on hypnosis demonstrated reduced opioid use compared with historical controls. We recommend
the development of individualized analgesic regimens with the incorporation of adjunctive therapies in order to
improve burn pain management in the midst of an abuse crisis and concomitant national opioid shortage.

Burn injury may be the most painful trauma that a patient
can sustain. The management of postburn pain is exceed-
ingly complex, as it is variable in quality and intensity among
individuals throughout the healing process.1,2 Untreated or
inadequately treated pain can lead to posttraumatic stress
disorder. Thus, a robust, multimodal analgesic regimen is a
necessity.3
Opioids are the analgesics of choice for burn pain.4,5 These
medications activate µ-opioid receptors in the central nervous
system to cause analgesia, sedation, and euphoria. Opioids
carry their own risks, to include dependence, tolerance, and
hyperalgesia in addition to inherent side effects.6 Additionally,
opioids are not effective at treating neuropathic burn pain.7,8
Tolerance to opioids leads to escalating doses that provide
little added benefit while increasing the incidence of side
effects, such as constipation.9
The overuse and abuse of prescription opioid medications
has become epidemic in the United States.10 The U.S.
Department of Health and Human Services stated that the
likelihood of chronic opioid use increases with each additional
day of medication given.11 In an effort to discourage the use
of opioids, physicians now are required by state governments
to screen prescription monitoring databases before prescribing
these drugs.
In the midst of this opioid epidemic, there is a simulta-
neous national shortage of parenteral narcotics.12 This
drug shortage has been caused by a reduction in opioid
manufacturing by several companies as was suggested by the
Drug Enforcement Agency, as well as suspension of produc-
tion due to manufacturing violations found by the Food and
Drug Administration (FDA).12 This has led to critical na-
tionwide shortages of intravenous preparations of morphine,
hydromorphone, and fentanyl.12
In order to combat the current crisis of opioid overuse
and abuse, to address national shortages, and to battle the
frequent reports that burn pain is frequently undertreated,4
adjunctive pain management modalities for burn pain con-
trol must be implemented into a multimodal pain manage-
ment strategy. The purpose of this review was to evaluate
the literature on adjunctive therapies for pain management
in adult burn patients.

From the *U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston,
Texas; †Uniformed Services University of the Health Sciences, Bethesda,
Maryland
Conflict of interest statement: None.
Funding: None.
Disclaimer: The opinions or assertations expressed herein are the private views of
the authors, and are not to be construed as official or as reflecting the views of
the Department of the Army or the Department of Defense.
Address correspondence to Julie A. Rizzo, MD, 3698 Chambers Pass, JBSA Fort
Sam Houston, TX 78234. Email: julie.a.rizzo.mil@mail.mil
Published by Oxford University Press on behalf of the American Burn Association
2019. This work is written by (a) US Government employee(s) and is in the
public domain in the US.
doi:10.1093/jbcr/irz111
METHODS
Three online databases, PubMed, Ovid, and ClinicalKey, were
searched for the keywords “burn” and “pain,” limited to the
year 2008 to the current date. The last search was performed
in February 2019. The PubMed search was filtered for clin-
ical study, comparative study, or review; humans; English; and
adult: 19+ years. The Ovid search was filtered for English
language, humans, all adult (19+), clinical study, clinical
trial, meta-analysis, randomized controlled trial (RCT), or
systematic review. The ClinicalKey search was filtered for
1
 Journal of Burn Care & Research
2  Kim et al XXXX/XXXX 2019

meta-analysis, systematic reviews, or RCT, then manually
screened for adult, human studies.
Only thermal injuries to the skin from flame, scald, or con-
tact with a heated probe (thermode) were included. Acute and
chronic burn wounds and hypertrophic burn scars were in-
cluded. Relevant references cited from those articles were also
examined. Articles limited to only opioids or benzodiazepines
were excluded. Although anxiety, fear, depression,
studies was not performed due to the heterogeneity of the ad-
junctive therapies and due to the varying time frames of pain
score collection.
Burn pain consists of four components: background
pain, neuropathic pain, procedural pain, and breakthrough
pain.14 The studies were categorized based on whether they
addressed the management of background pain, neuropathic
pain, procedural pain, or breakthrough pain and our findings

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posttraumatic stress, and level of sedation are interrelated with are summarized below. Additionally, we present a brief dis-
pain, they were beyond the scope of this study. cussion of adjuncts well-utilized in the nonburned population
that have potential for use in the burn patient.

RESULTS Management of Background Pain

The study selection process is shown in Figure 1. The database
searches initially produced 630 total citations. Study titles and
abstracts were reviewed and the list was narrowed to 56 ar-
ticles that specifically dealt with therapies other than opioids
for patients with burn injury. Articles that examined various
topical therapies for skin graft donor sites and subcutaneous
anesthetic injections were already systematically reviewed by
Sinha and excluded from our review.13 Full texts of the 56
studies were examined, further eliminating 15 studies for the
reasons listed in Figure 1. Cited references were screened and
five pertinent studies were also included.
Forty-six studies are presented in our review. The details
of each study are shown in Table 1. Statistical analysis of the
Background pain is constant pain due to direct injury to or
inflammation of skin tissue.7 Because of the hypermetabolic
state that develops after burn injury, burn patients often have
increased blood flow to the kidneys and liver, which results in
augmented renal clearance and accelerated hepatic biotrans-
formation of opioids resulting in increased analgesic clearance
and increased pain.15–17
Ketamine. Ketamine is a dissociative anesthetic that is prima-
rily an N-methyl-D-aspartate receptor antagonist and is also
believed to be an agonist of the µ-, δ-, and κ-opioid receptors.
Ketamine blocks pain transmission by inhibiting central sensi-
tization.18 Although it is associated with side effects of nausea,

Studies identified in Studies identified in Studies identified in

PubMed Ovid ClinicalKey
n = 378 n = 147 n = 317

Studies after duplicates removed

n = 630

Studies screened Studies excluded

n = 630 n = 574

Full text articles

Full text articles
examined
excluded with reasons
n = 56 n = 15
Examined by other
Review articles 6
General summary 4
Additional studies from No pain analysis 3
cited references Full text in Chinese 1
n=5 Trial not complete 1

Studies included in
systematic review
n = 46

Figure 1. Flow chart of study selection process.

Journal of Burn Care & Research
Volume XX, Number XX Kim et al  3

Table 1.  Studies from 2008 to 2019 examining the use of adjunctive therapies to treat burn pain
Number of
Adjunct Studied Year Author Study Type Subjects Findings

Management for Background Pain

Ketamine 2011 McGuiness19 SR 106 Hyperalgesia was reduced in the ketamine
group. Clinical relevance was question-
able since subjects were voluntary and

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thermode burns were small.
Methadone 2013 Jones15 Retrospective CCS 70 Methadone group had more ventilator-free
days. No difference was observed in
opioid or benzodiazepine consump-
tion.
Ibuprofen 2011 Promes22 RCT 61 Pain scores did not differ between treat-
ment and placebo groups. Use of other
analgesics was not restricted.
Propranolol 2015 Orrey23 RCT 43 Propranolol was associated with worse pain
scores on days 5–19.
Cooling 2016 Bitter24 CR 1 Burn pain was controlled with cool water
and NSAIDs.
2017 Cho27 RCT 94 Tap water had better pain reduction
than water + tea tree oil or spray. No
analgesics were given.
Low-frequency 2015 Prather28 RCT 27 The ultrasound group had a nonsignificant
ultrasound trend toward reduced pain.
Music 2016 Najafi Ghezeljeh29 RCT 100 The music group had significantly reduced
pain. The music group had significantly
less opioid use.
Massage 2014 Cho32 RCT 146 The massage group had a greater reduc-
tion in scar pain. Analgesic consump-
tion was not mentioned.
2018 Ault33 SR 166 Massage significantly decreased pain. Anal-
gesic use was not mentioned.
Music + massage 2017 Najafi Ghezeljeh31 RCT 240 Music, massage, and music plus massage
all significantly lowered pain scores.
Opioid use was not measured.
Aromatherapy 2016 Seyyed-Rasooli34 RCT 90 Massage aromatherapy and inhalation
aromatherapy both significantly
reduced pain during dressing changes.
Analgesics were not available.
2016 Bikmoradi35 RCT 50 Inhaled damask rose essence decreased
pain during dressing application. Both
aromatherapy and control groups re-
ceived identical morphine and diaz-
epam doses prior to procedure.
2018 Choi36 SR 248 There was no evidence to support routine
use of aromatherapy for pain treatment.
Extracorporeal shock 2016 Cho37 RCT 40 The treatment group had greater reduction
wave therapy in scar pain than the placebo group.
Analgesic use was not mentioned.
Hypnosis 2008 Shakibaei41 RCT 44 Reduction in pain intensity was observed
in dose-responsive manner with hyp-
nosis. Analgesic consumption for
hypnosis and control groups was not
altered.
2018 Jafarizadeh42 RCT 60 Hypnosis decreased pain quality but not
pain intensity after multiple sessions.
Morphine dosage was not recorded.
 Journal of Burn Care & Research
4  Kim et al XXXX/XXXX 2019

Table 1. Continued

Number of
Adjunct Studied Year Author Study Type Subjects Findings

Management for Neuropathic Pain

Gabapentin 2008 Gray7 CS 6 All patients reported improvement in their
neuropathic pain.
2014 Wibbenmeyer46 RCT 53 There were no differences in acute and

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neuropathic pain nor in opioid con-
sumption between the gabapentin and
placebo groups.
Pregabalin 2011 Gray14 RCT 90 Pregabalin significantly reduced neuro-
pathic and procedural pain. There was
no significant difference in opioid con-
sumption.
Transcranial direct cur- 2013 Portilla47 CS, randomized 3 One patient had improvement in pain from
rent stimulation crossover trial 2 to 0. The other two patients had no
pain improvement.
Electroacupuncture 2015 Cuignet49 CS 32 Acupuncture reduced pain in the sub-
group of responders. All patients had
decreased pruritis and increased periph-
eral sensory thresholds. Opioid con-
sumption was not measured.
Laser 2017 Ebid50 RCT 49 Laser therapy decreased pain for 12 weeks
after 6 weeks of therapy. There was no
mention of pain medication use.
2017 Zuccaro51 SR 468 There was insufficient evidence to draw
conclusions due to decreased quality
and high bias in multiple studies.
2016 Levi52 Retrospective co- 93 Laser therapy reduced pain, but question-
hort naire utilized was not validated for
burn patients.
Management for Procedural Pain
Dexmedetomidine 2013 Asmussen9 MA/SR 266 There were no difference in pain scores be-
tween treatment and control groups.
Ketamine 2013 Kundra53 Randomized cross- 60 Pain score reduction was significantly
over trial greater for the ketamine group than
the control (dexmedetomidine) group.
Opioid consumption was not studied.
2010 Zor17 RCT 24 Combining ketamine with other analgesics
or sedatives had significantly lower pain
scores than ketamine alone and less side
effects. Opioid consumption was not
examined.
Intravenous lidocaine 2012 Wasiak2 SR 45 The lidocaine group had significantly lower
pain ratings but no difference in opioid
demand or consumption.
Nitrous oxide 2016 do Vale56 Randomized cross- 15 There was no difference in pain scores
over trial or opioid consumption between the
inhaled nitrous oxide and control (ox-
ygen) groups.
Methoxyflurane 2016 Gaskell57 Randomized cross- 8 Pain score analysis was not performed.
over trial Use of additional analgesics was not
reported.
Music 2016 Hsu30 RCT 70 Music significantly reduced pain scores
during dressing changes. There was no
difference in morphine use between
music and control groups.
Journal of Burn Care & Research
Volume XX, Number XX Kim et al  5

Table 1. Continued

Number of
Adjunct Studied Year Author Study Type Subjects Findings

2010 Tan58 Randomized cross- 29 Music therapy decreased pain levels be-
over trial fore, during, and after dressing changes
compared to standard care. There was
no difference in the amount of opioids

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and sedatives given.
2017 Li59 MA/SR 260 Music interventions had a positive effect
on burn pain relief. No data on anal-
gesic use were extractable.
Whole-body vibration 2017 Ray60 RCT 31 The vibration group had significant de-
crease in mid- and post-session pain
compared to the control group. There
was no difference in pain medication
use.
Jaw relaxation 2013 Mohammadi RCT 100 The relaxation group had significantly
Fakhar61 reduced pain before and after dressing
change. Effect on analgesic consump-
tion was not reported.
Hypnosis 2010 Berger62 Cohort with 46 Daily pain scores were significantly reduced
matched his- in the hypnosis group. Daily opioid
torical controls requirements were significantly reduced
after introduction of hypnosis.
2018 Provencal63 MA/SR 234 Hypnosis had a 9% decrease in pain inten-
sity, but no decrease in opioid require-
ment.
Virtual reality 2018 Scapin66 SR Not pooled Majority of studies showed signifi-
cant reduction in pain scores during
procedures.
2009 Carrougher67 Randomized cross- 39 The VR session had significant reduc-
over trial tion in pain scores but average opioid
equivalents administered were not dif-
ferent.
2009 Konstantatos68 RCT 86 VR reduced pain intensity during and after
dressing changes. Amount of morphine
received did not differ between VR and
control groups.
Relaxation + hypnosis 2018 Scheffler69 MA/SR 516 Nonpharmacological interventions are
+ virtual reality favored to provide improvement in
procedural pain. Analgesic use was not
mentioned.
Interactive gaming 2012 Yohannan72 RCT 23 The Wii group had greater pain reduction
console but not statistically significant. Use of
analgesics was not mentioned.
2016 Parker71 RCT 22 The Wii group had a greater reduction in
post-rehabilitation session pain scores.
Analgesia use was not assessed.
2016 Voon70 RCT 30 Pain scores were not different before and
after exercise nor between the Xbox
and control groups.
Transcranial direct cur- 2016 Hosseini Amiri48 RCT 60 Stimulation group had lower pain anx-
rent stimulation iety score after stimulation and after
dressing. There was no difference in
opioid consumption.

CCS = case control study; CR = case report; CS = case series; MA = meta-analysis; NSAIDs = nonsteroidal anti-inflammatory drugs; RCT = randomized controlled
trial; SR = scientific review; VR = virtual reality.

6  Kim et al XXXX/XXXX 2019
vomiting, hallucinations, mood alteration, bizarre dreams,
and emergence delirium, ketamine causes less respiratory de-
pression and tends to preserve hemodynamic stability.19 A sys-
tematic review was performed of four RCTs on burn patients
that received either intravenous ketamine or placebo as part
of their regimen for acute background pain.19 All studies
utilized a standard thermode on healthy volunteers to create
a controlled, superficial to superficial partial thickness injury.
Ketamine doses varied from 9 µg/kg/min up to 0.8 mg every
15 minutes in conjunction with morphine. Patients who re-
ceived ketamine showed significant reduction in hyperalgesia.
Side effects were not demonstrated at subanesthetic doses of
ketamine. All of the four studies were performed on volun-
tary participants with very small burns; therefore, the authors
cautioned the clinical relevance of their review.
Methadone.  As a µ-opioid receptor agonist, methadone is
commonly used to treat acute and chronic background pain
due to its long (8–59 hours) half-life. As an N-methyl-D-
aspartate receptor antagonist, methadone also inhibits opioid
tolerance and reduces central sensitization.15 A  retrospec-
tive study showed that mechanically ventilated burn patients
who received a median daily dose of 15  mg of methadone
had five additional ventilator-free days compared with those
who received placebo.15 However, the amounts of opioids and
benzodiazepines received were not significantly different be-
tween the two groups.
Nonsteroidal Anti-inflammatory Drugs. Nonsteroidal anti-in-
flammatory drugs (NSAIDs) are often used for their antipy-
retic, anti-inflammatory, and analgesic effects, but their use
in burn patients is limited due to side effects, such as gas-
trointestinal bleeding, decreased platelet activity, and acute
kidney injury. For most critically ill burn patients, these risks
outweigh the benefits of using NSAIDs.20 In a retrospective
case-control study conducted in nonburn patients within the
Veterans’ Affairs system, new use of any NSAID increased the
risk of acute kidney injury development.21 In a multicenter
RCT, patients with >10% TBSA burns received 800  mg of
intravenous ibuprofen every 6 hours for 5 days or placebo.22
The ibuprofen group had a significant reduction in temper-
ature for the first 24 hours. However, pain scores did not
differ from those who received placebo. The pain endpoint
was difficult to assess since patients in both groups were often
too sedated to report pain scores. No serious safety concerns
were reported after administering 5 days of high-dose NSAID
therapy.
Propranolol. Postburn activation of β-adrenoreceptors releases
catecholamines, which may contribute to hyperalgesia; ac-
cordingly, β-adrenergic antagonists may have an analgesic ef-
fect.23 A multicenter RCT was performed on acutely burned
patients comparing propranolol to placebo.23 The interven-
tion group received 120 mg of extended-release propranolol
twice daily until 3 weeks after hospital discharge. The propran-
olol group had higher pain scores than the placebo group on
study days 5 through 19, demonstrating the lack of efficacy of
this medication for managing acute burn pain. Theoretically,
due to its ability to blunt the hypermetabolic effects seen after
burn injury, propranolol may attenuate the hypermetabolism
Journal of Burn Care & Research
and potentially decrease the degree of augmented renal clear-
ance observed after burn injury which would permit pain
medications administered to have a longer beneficial effect.
Cooling. Cold running water or cold compresses are common
burn first-aid treatments and an important adjunct for initial
pain control.24 Cool water lavage may limit burn depth by
halting further thermal injury and by decreasing inflammation
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and edema.25 Cooling therapy should be limited in extent and
duration, due to the potential risk of hypothermia. In a re-
spective study of 929 burn patients, only 1.6% had a tempera-
ture less than 35°C, none of which were related to prehospital
cooling.26
A three-arm RCT was conducted on 94 patients with 1%
TBSA thermal injury comparing cool tap water, a commercial
foam dressing containing water and tea tree oil, and a similar
spray formulation.27 All three groups had reduced pain scores
after 20 minutes of treatment, with tap water having a sig-
nificantly greater reduction in pain. Additionally, there was a
significant difference in pain score reduction between groups
cooled by tap water below versus above 24°C. No analgesics
were given during any procedures.
Noncontact Low-Frequency Ultrasound.  Noncontact low-
frequency ultrasound (NLFU) is purported to improve wound
healing by destroying bacteria, reducing biofilm, down-
regulating inflammatory cytokines, and up-regulating vascular
endothelial growth factor.28 NLFU at 40 kHz delivers energy
into and below the wound bed to create changes in the micro-
environment. In a multicenter RCT, donor sites of burn and
cutaneous ulcer patients were treated for 5  days with either
standard care utilizing a hydrocolloid border and transparent
dressing or standard care plus NLFU.28 The pain scores for
the NLFU group were lower at 2 weeks but did not reach
statistical significance. The amount of analgesic consumption
was not studied.
Music.  Music carries the benefits of being portable and ad-
justable to patient preferences.29 Music alleviates pain via
“gate-control”: inhibitory impulses from the cerebral cortex
and thalamus block sensory fibers at the spinal cord from
transmitting pain information to the brain.30 Music also
stimulates the midbrain and higher centers to activate endor-
phin secretion. A RCT on burn patients who listened to self-
selected music for 20 minutes daily for 3 days had significantly
less pain than the control group.29 In addition, the music
group also consumed significantly less opioids over the 3-day
period (mean opioid intake was 9.32 mg for the music group
versus 13.7 mg for the control group).
Massage.  Massaging of the skin may inhibit transmission of
pain signals and produce endorphins.31 Cho investigated
the effects of massage on chronic background pain in addi-
tion to standard rehabilitation for hypertrophic scars.32 The
randomized intervention group received 30 minutes of mas-
sage three times a week and had significantly greater reduc-
tion in scar pain. However, the study did not report whether
the pain reduction led to lower analgesic consumption. A sys-
tematic review by Ault investigated eight trials that utilized
burn scar massage.33 Two of the trials assessed pain scores
Journal of Burn Care & Research
Volume XX, Number XX Kim et al  7
and showed significant improvement with massage, thereby
favoring the intervention over standard rehabilitation therapy.
The effect on analgesic use was not mentioned.
Music and Massage. The combination of music and massage
was evaluated in a RCT that compared the effects of only self-
selected music, only massage, or music plus massage for 20
minutes daily for 3 days on acute background pain.31 All three
intervention groups had significantly lower pain scores both
before and after each session compared to controls. However,
there was no significant difference in pain reduction among
the three intervention groups. The use of opioids was not
measured. The study concluded that music and massage both
reduced pain but did not work synergistically.
Aromatherapy.  A 3-arm RCT compared aromatherapy mas-
sage with lavender and almond oil, to inhalation aromatherapy
with rose and lavender oil, and to routine ward care.34 After 30
minutes of intervention, pain and anxiety scores significantly
decreased for subjects who received aromatherapy massage
and inhalation aromatherapy. Analgesics were not available for
the patients and the amount of tranquilizers given were not
reported. An additional RCT compared inhaled damask rose
essence to placebo and demonstrated a significant reduction
in pain during dressing application.35 However, a systematic
review of aromatherapy as a complementary therapy to facil-
itate pain relief in burn patients was performed and did not
find convincing clinical evidence from four RCTs to support
routine use of this intervention.36
Extracorporeal Shock Wave Therapy.  Since the 1980s, extra-
corporeal shock wave therapy (ESWT) has been used for the
regenerative treatment of musculoskeletal diseases and non-
invasive pain management.37 In a RCT, patients with chronic
burn scar pain received three sessions of ESWT or sham
procedures.37 The ESWT group had significantly greater re-
duction in pain scores. Additionally, immediate pain reduction
was observed in a quarter of the ESWT patients. The authors
proposed that ESWT increases blood flow to facilitate tissue
regeneration and inhibit nociceptors in the burn scar which
blocks central sensitization and decreases substance P syn-
thesis in the dorsal root ganglion. The study did not mention
the use of analgesics.
Hypnosis.  Medical hypnosis provides analgesia by helping
patients accept clinicians’ suggestions to change their pain
perceptions.38 Hypnosis includes establishing rapport and
creating a positive setting, breathing and relaxation, absorp-
tion into the hypnotic state, inducing analgesia, and bringing
the patient out of hypnosis. A  mechanism by which hyp-
nosis reduces pain is by activation of the anterior cingulate
cortex.39,40 The limitations of this therapy include failure of
hypnosis, delirium, and improper patient expectations. Two
RCTs examined the ability of hypnosis to reduce burn-related
background pain. The first demonstrated a significant re-
duction in pain intensity after multiple sessions, revealing a
dose-responsive effect of hypnosis.41 The second trial did not
demonstrate the same reduction in pain intensity; however,
it showed a significant reduction in pain quality in a dose-
responsive manner.42 This was thought to be due to the
nature of the therapeutic suggestions used during the hypno-
therapy sessions, influencing the areas of the brain related to
the emotional aspects of pain. Neither trial examined analgesic
consumption.
SUMMARY FOR THE MANAGEMENT OF
BACKGROUND PAIN
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A number of pharmacologic and nonpharmacologic strategies
have been studied for the management of acute and chronic
background pain in burn patients. Ketamine, cooling, music,
massage, aromatherapy, and ESWT have been shown to de-
crease pain severity, with variable effects on opioid consump-
tion. All of these options can be considered as adjuncts for
background pain. Hypnosis demonstrated mixed results
with respect to background pain reduction and requires
further study.
Management of Neuropathic Pain
Neuropathic pain is caused by the direct injury or inflamma-
tion to neural tissue in the peripheral or central nervous system
and often persists after burn wounds have healed. Neuropathic
pain is frequently a component of chronic background pain.
As neurons “heal” and regenerate, abnormal excitability at or
near the site of nerve injury can occur. Burn survivors may
experience numbness and tingling in the burned areas, which
may progress to painful paresthesias.43,44
Gabapentinoids.  Gabapentin inhibits the sensitization of
the central nervous system to noxious stimuli by binding to
the voltage-gated calcium channels in the dorsal horn and
dorsal root ganglia, subsequently reducing neurotransmitter
release.7,45 A  case series of six burn patients that received
300 to 600  mg three times per day of gabapentin showed
improvements in burning, knife-like, stinging, and throbbing
qualities of pain.7 In a double-blind RCT, patients with at
least 5% TBSA burns received either gabapentin or placebo
throughout their hospitalization.46 The gabapentin group
had no improvement in acute pain or in neuropathic pain.
Furthermore, opioid consumption did not differ between the
groups.
Pregabalin is a gabapentin analogue with greater potency
and earlier onset of clinical effect, and is commonly used to
treat neuropathic pain.14 In a RCT comparing 4 weeks of
pregabalin 75 mg twice per day versus placebo, burn patients
on pregabalin reported significant improvement in the hot
and sharp qualities of neuropathic pain as well as a reduction
in procedural pain.14 Reduction in the amounts of opioids
consumed was not observed in either group.
Transcranial Direct Current Stimulation.  Transcranial di-
rect current stimulation (tDCS) applies a weak, constant,
direct current that flows between the electrodes to stimu-
late the cortex of interest.47 tDCS is thought to relieve acute
pain by changing the excitability and the concentrations of
γ-aminobutyric acid and glutamate in the sensory cortex.48
Portilla studied the utility of tDCS for treating chronic neuro-
pathic pain.47 In the crossover study, three patients with pain
over prior burn areas received either tDCS or sham therapy.

8  Kim et al XXXX/XXXX 2019
During tDCS, 2 mA was delivered for 20 minutes to the
motor cortex contralateral to the most painful burn site. Only
one patient reported a decrease in pain score from 2 to 0 while
the other two patients remained the same. The sample size
was too small for statistical analysis.
Acupuncture. A case series of 32 patients evaluated a combi-
nation of electroacupuncture and standard acupuncture as a
method to counteract the peripheral hyperalgesia associated
with pathological burn scars.49 The study demonstrated that
patients diverged into two distinct subgroups of responders
and nonresponders, with responders experiencing a signif-
icant reduction in pain. No demographic differences were
noted between the subgroups but the nonresponders were
found to have higher pain tolerance and perception prior
to treatment, limiting potential therapeutic benefit. All
patients benefited from decreased pruritus and increased no-
ciceptive thresholds for both pain perception and pain tol-
erance. Although opioid consumption was not a measured
outcome, no additional analgesics were initiated during the
study.
Laser Therapy.  In the past 20  years, laser therapy has
emerged as an effective tool for managing burn scar-related
complications. Laser inhibits the release of cyclooxygenase 2,
prostaglandins, and cytokines, accelerates collagen synthesis
and cell proliferation, and inhibits nerve fiber transmission.50
Each type of laser offers distinct advantages depending on
the patient’s primary scar-related complaint. A  double-blind
RCT demonstrated a significant decrease in scar pain after 6
weeks of treatment, which lasted for at least an additional 6
weeks after treatment was completed.50 However, a system-
atic review evaluating the effectiveness of laser therapy pro-
vided limited support.51 Studies that utilized a validated pain
assessment tool reported a decrease in pain which was not
statistically significant, whereas studies that assessed patients’
experience with unvalidated questionnaires demonstrated a
statistically significant pain reduction.52 The systematic re-
view concluded that there was insufficient scientific evidence
in the current literature to determine the role of laser therapy
in burn scar treatment.
SUMMARY FOR THE MANAGEMENT OF
NEUROPATHIC PAIN
The gabapentinoids, gabapentin and pregabalin, have been
studied for the treatment of postburn neuropathic pain, with
mixed results. Acupuncture may be of benefit in patients who
can be identified as responders before the initiation of treat-
ment. Since limited options are available for the management
of neuropathic pain, gabapentinoids and laser therapy should
be considered as potential treatment options.
Management of Procedural Pain
Procedural pain is increased hyperalgesia that occurs during
or immediately after a dressing change or rehabilitation
efforts. Burn patients must endure multiple procedures, fre-
quent dressing changes, and early mobilization. Wound care
Journal of Burn Care & Research
is often reported to be as painful or more painful as the initial
burn event.
Dexmedetomidine.  Dexmedetomidine is an α 2-adren-
ergic receptor agonist used to produce analgesia and
sedation. Dexmedetomidine has minimal to no risk of respi-
ratory depression, making it a safe option in this regard for
nonintubated patients.9 However, caution must be exercised
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when administering this drug in hemodynamically labile
patients, as bradycardia and hypotension have been observed.
A  meta-analysis of four RCTs found patients that received
dexmedetomidine showed no significant difference in pain
scores at 1 and 2 hours after either dressing changes or recon-
structive surgery.9
Ketamine. Ketamine is not FDA-approved for analgesia; how-
ever, several studies have investigated its pain-reducing effects
in burn patients. Kundra conducted a RCT comparing oral
ketamine to oral dexmedetomidine during dressing changes
on 20% to 50% TBSA burned patients.53 Oral dosages
administered were ketamine 5 mg/kg and dexmedetomidine
4 mcg/kg. Since both drugs have low bioavailability (approx-
imately 15% for both), doses administered enterally must be
higher than parenterally administered doses.54,55 The patients
also received morphine 0.1  mg/kg intramuscularly every 6
hours and oral diazepam 5 mg every 12 hours. Pain scores sig-
nificantly decreased in both groups. Ketamine demonstrated
a greater reduction in pain but was associated with delirium
in 60% of patients and excessive salivation in 43% of patients.
The study did not examine ketamine’s effect on opioid
consumption.
Zor studied combinations of intramuscular ketamine
with other intramuscular analgesics and sedatives for
burn dressing changes.18 Prior to daily dressing changes
for 10  days, 24 patients received (I) ketamine only; (II)
tramadol, dexmedetomidine, and ketamine; or (III) tramadol,
midazolam, and ketamine. Groups II and III had significantly
lower immediate postprocedural pain scores than Group
I. Group II had the lowest incidence of hallucinations or dizzi-
ness. The study did not report trends in pain severity over the
10-day period or examine the amount of opioids consumed.
Intravenous Lidocaine.  Lidocaine binds to voltage-gated so-
dium channels in the nerve membrane, inhibiting nerve con-
duction in afferent nerves that signal pain.2 While lidocaine
has FDA approval for local anesthesia, it does not have la-
beling for systemic analgesia. A randomized crossover trial in
which grafted burn patients received intravenous lidocaine or
saline during wound care showed that intravenous lidocaine
significantly lowered pain scores but did not lower opioid de-
mand or consumption.2
Nitrous Oxide.  Nitrous oxide exhibits an analgesic effect
through the release of endogenous opioids that activate spinal
γ-aminobutyric acid receptors, which block pain transmis-
sion, though it does not have FDA approval for the treat-
ment of pain.56 Do Vale conducted a randomized crossover
trial comparing inhaled nitrous oxide to oxygen during burn
Journal of Burn Care & Research
Volume XX, Number XX Kim et al  9
dressing changes.56 Fifteen burned patients on intravenous fen-
tanyl patient-controlled analgesia (PCA) underwent dressing
changes with 65% nitrous oxide or 10  L/min of oxygen via
face mask. No differences in pain scores or opioid consumption
were observed between the nitrous oxide and oxygen groups.
Methoxyflurane.  Methoxyflurane is a halogenated ether with
analgesic properties that is deliverable via a handheld in-
haler.57 A  randomized crossover pilot study compared self-
administered methoxyflurane to ketamine-midazolam PCA in
eight patients undergoing burn dressing changes. Pain scores
remained low before, during, and after the procedure in both
groups. However, due to the small size of the study, statistical
analysis of pain scores was not possible, and the study did not
report the use of additional analgesics.
Music. A RCT by Hsu on 70 burn patients showed that lis-
tening to music before, during, and after daily dressing
changes significantly improved pain scores by the fourth day
compared to the control group.30 However, there was no dif-
ference in the amount of morphine used between the groups.
A limitation of the study was that information on the use of
nonopioid analgesics was not collected.
Music-based imagery (MBI) and music alternate engagement
(MAE) are two interactive forms of music therapy utilized to al-
leviate psychological and physical symptoms in burn patients.58
MBI is a relaxation technique during which a music therapist
takes the patient’s description of a safe and relaxing place and
puts it into a song to sing for the patient. MAE consists of ac-
tive music listening, singing, song phrase fill-in, deep breathing,
and rhythmic instrument playing. MAE works by gate-control
theory; the patient is diverted away from the painful stimulus to
the external stimulus of music. In a randomized crossover trial
by Tan, acutely burned patients received MBI before and after,
and MAE during, dressing changes.58 The music therapies sig-
nificantly decreased pain levels before, during, and after dressing
changes compared to controls. However, there were no signif-
icant differences in the amounts of opioids and sedatives used
between the music and control groups.
A systematic review by Li looking at all types of music
therapy on burn patients showed that music had a significantly
positive effect on procedural pain alleviation. However, the
authors stated that no data could be extracted on its effect on
analgesic use.59
Whole-Body Vibration. Whole-body vibration has been effec-
tively used during rehabilitation for muscle strengthening,
mobility, and balance, as well as for treating chronic musculo-
skeletal pain.60 The pain reducing effect of whole-body vibra-
tion is hypothesized to be via gate-control theory. In a RCT,
31 patients with 48 extremity burns underwent three sessions
of physical therapy with or without whole-body vibration.60
The vibration group had a significant decrease in mid- and
post-session pain compared to the control group. There was
no significant difference in pain medication use.
Jaw Relaxation.  Jaw relaxation is simple self-care technique
that can be used anytime with minimal side effects. Jaw relaxa-
tion reduces pain and anxiety through gate-control theory.61 In
a RCT, patients were randomized to either instruction on jaw
relaxation for 20 minutes prior to dressing changes or control.61
The intervention group had significantly less pain and anxiety be-
fore and after dressing changes. However, the study did not ana-
lyze any effect that jaw relaxation had on analgesic consumption.
Hypnosis. Hypnosis has been studied as an adjunct for proce-
dural pain as well as background pain. At one institution, 23
acutely burned patients admitted to the intensive care unit
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underwent hypnosis and their daily pain scores and opioid
consumption were compared to historical controls.62 The
hypnosis group had a significant reduction in pain scores and
opioid requirements. However, a limitation to the study was
that 17 of the initial 40 patients screened were excluded due
to delirium or preexisting psychiatric conditions.
A meta-analysis examined six randomized trials on hypnosis
and determined that this modality holds promise as an adjunct to
a well-established opioid regimen as the studies within the review
demonstrated an overall reduction in pain intensity of approxi-
mately 9%.63 But this reduction did not correlate to a decreased
need for opioids. The authors encouraged further study utilizing
a greater array of burn centers to objectively evaluate hypnosis
and its role in the pain management of burn patients.
Virtual Reality. Virtual reality (VR) uses engaging visual and
auditory stimuli to distract the patient’s attention away from
painful stimuli.64 A major advantage of VR is that its efficacy
persists over multiple sessions.65 The level of sensory immer-
sion depends on the equipment utilized. Choices include free-
standing monitors or goggles, 2D or 3D displays, speakers or
headphones, and passive viewing or active physical participa-
tion. Scapin conducted a systematic review of 34 VR studies,
including 23 RCTs.66 All of the VR studies except for one
showed reduction in pain severity. The majority of the studies
demonstrated statistical significance; however, the data could
not be pooled due to the heterogeneity of pain scales utilized.
Two studies included in the meta-analysis examined VR’s
effect on opioid utilization. A randomized crossover trial by
Carrougher investigated the use of SnowWorld via VR helmet
on 39 patients receiving physical therapy.67 The VR session had
significant reduction in pain scores compared to the no VR
session. However, the average opioid equivalents administered
were not statistically different. In a RCT by Konstantatos, 86
patients undergoing dressing changes received either relaxing
visual scenery through VR goggles and earpiece plus mor-
phine PCA or PCA alone.68 The VR group had significantly
less pain intensity than the standard group during and after
the dressing change. However, VR did not reduce the amount
of patient-administered morphine received.
Relaxation, hypnosis, and virtual reality. A systematic review
by Scheffler investigated nonpharmacological interventions of
relaxation, hypnosis, and VR in treating procedural pain during
burn wound care.69 A meta-analysis of 18 RCTs that assessed
pain intensity outcomes showed that these interventions sig-
nificantly reduced procedural pain. However, the effect of
these interventions on analgesic use was not mentioned.
Interactive Gaming Console. Interactive gaming consoles (IGCs)
are a subset of VR technology that are becoming more afford-
able, easier to use, and promote rehabilitative exercises.70 The

10  Kim et al XXXX/XXXX 2019
proposed mechanism by which video gameplay decreases pain
sensation is due to the increase in dopamine release in the mid-
brain in addition to cognitive distraction from noxious stimuli.71
A RCT by Yohannan on 23 burn patients compared three ses-
sions of Nintendo Wii Sports or Fit versus therapist-chosen
interventions for the burned joint region.72 The intervention
group experienced less pain but the difference was not sta-
tistically significant. The use of analgesics was not mentioned.
Another RCT utilizing Nintendo Wii, by Parker, versus routine
rehabilitation for 5 days on 22 patients showed a significant 17%
greater pain reduction.71 This study did not assess analgesia uti-
lization either.
The Xbox Kinect features controller-free, full-body
3D-motion capture and voice recognition. A  RCT by Voon
used the Xbox Kinect Sports Pack for supplemental self-
performed exercises for upper extremity burn wounds.70 In
addition to standard self-performed exercises of 15 minutes
twice daily, patients performed 15 minutes of Xbox Kinect
or self exercises twice daily. The Xbox group reported signif-
icantly longer exercise time per day compared to the control
group. However, pain scores were not different before and
after exercise or between the Xbox and control groups.
Transcranial Direct Current Stimulation.  Hosseini Amiri
investigated the effects of tDCS on procedural pain and anx-
iety.48 Before a dressing change, patients received either 1.0
mA stimulation for 20 minutes over the sensory cortex or
sham stimulation. The tDCS group had significantly lower
pain and anxiety scores both after stimulation and after the
dressing change. During the study, 20% of the stimulation
group and 33.3% of the sham group received morphine 5 mg,
but this difference was not statistically significant.
SUMMARY FOR THE MANAGEMENT OF
PROCEDURAL PAIN
Ketamine and intravenous lidocaine have been shown to im-
prove pain scores and are pharmacologic options for the treat-
ment of procedural pain in burn patients, whereas nitrous
oxide failed to convey any benefit. Effective nonpharmacologic
adjuncts for procedural pain include music, whole-body vibra-
tion, jaw relaxation, hypnosis, VR, IGC, and tDCS.
Management of Breakthrough Pain
Breakthrough pain is a transient worsening of pain, not as-
sociated with any type of procedure. This may occur due to
inadequate doses of analgesics for background pain, or may
be due to changing mechanisms of pain over time.44 To date,
there are no nonopioid adjuncts that are suitable for the man-
agement of breakthrough pain.
Adjuncts Studied in Nonburned Populations
Due to the limited number of adult burn patient pain studies
as well as the lack of power in existing studies to detect clini-
cally relevant endpoints, such as opioid consumption, extrap-
olation of nonburn literature is essential.
Acetaminophen.  Guidelines analyzing published evidence
in the field of pain recommend the use of nonopioids, such
Journal of Burn Care & Research
as acetaminophen; however, the addition of acetaminophen
has not been studied in adult burn patients.73 In a study
conducted in pediatric burn patients, one third of patients
were able to achieve adequate background pain control with
acetaminophen alone.74 In other adult surgical populations,
the addition of scheduled acetaminophen (1 g every 6 hours)
has been shown to reduce the amount of opioids required in
the postoperative period.75–77 In a meta-analysis of 11 RCTs
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that studied preoperative adult patients, intravenous ace-
taminophen showed significant reduction in postoperative
pain after elective surgeries, as well as significant reduction
in opioid consumption.78 Whether these outcomes can trans-
late to the acutely burned patient is uncertain. Nevertheless,
acetaminophen has a synergistic effect with opioids and our
recommendation is to include it in the pain treatment strategy
for most burn patients.8 There is a need to formally study this
medication in a prospective trial.
Antidepressants.  Antidepressants, including tricyclic
antidepressants and serotonin-norepinephrine reuptake
inhibitors, have been shown to have beneficial effects on neu-
ropathic pain. Many patients will need the abovementioned
medications to manage the depression, anxiety, and insomnia
that frequently accompany severe burn injury. While not yet
studied in burn patients, these agents could be ideal adjuncts
to a burn patient’s analgesic regimen. Duloxetine has been
shown to improve pain scores in patients with diabetic and
chemotherapy-induced peripheral neuropathy, while ami-
triptyline has been shown to improve pain in patients with
chronic oral-facial pain.79–81
Cannabinoids.  While somewhat controversial, cannabinoids
may be considered as part of a patient’s analgesic regimen.
Currently, the synthetic cannabinoids agents dronabinol (syn-
thetic delta-9-tetrahydrocannabinol), tetrahydrocannabinol,
and cannabidiol sprays are not FDA-approved for analgesia,
but are available in the United States. The cannabidiol spray
formulation carries an indication for the management of pain
related to cancer or multiple sclerosis. Cannabinoids have
been studied in the management of chronic and neuropathic
pain in the nonburn population and have shown promise and
may be considered for burn patients in the future.82–84
DISCUSSION
Pain associated with the treatment of burns is multifactorial
and long-lasting; thus, pain management requires a multifac-
eted approach. The most recent Practice Guidelines for the
Management of Pain in the burned population, published
in 2006, recommends opioids as a cornerstone for pain
management, along with nonopioid adjuncts, anxiolytics,
and nonpharmacologic treatment strategies.1 This strategy
correlates with the most recent Clinical Practice Guidelines
for the Management of Pain in nonburned patients, which
highlights the need for multimodality therapy in order to
optimize patient outcomes.85 Individualized analgesic treat-
ment plans should include multiple modalities to address
background pain, breakthrough pain, and neuropathic
pain. Multiple nonopioid and nonpharmacologic options
have been studied in burn patients. Ketamine, gabapentin,
Journal of Burn Care & Research
Volume XX, Number XX Kim et al  11
pregabalin, music, ESWT, jaw relaxation, whole-body vibra-
tion, hypnosis, laser, tDCS, IGC, and VR offer promise and
can be considered when designing an analgesic regimen for a
burn patient. Despite the abovementioned meta-analysis on
dexmedetomidine showing no pain benefit, in a double-blind
RCT conducted in nonburned women, dexmedetomidine
was shown to have synergy with opioids, leading to a decrease
in postoperative opioid requirements,86 which has correlated
with the clinical experience at our institution. Similarly, meth-
adone lacks strong clinical evidence in the burned population;
however, it is recommended in the ABA 2006 guidelines1
and our institution routinely prescribes it for background
pain and notes a progressive decrease in opioid requirements.
Ibuprofen, propranolol, ultrasound, acupuncture, and nitrous
oxide cannot be recommended at this time based on the avail-
able evidence and will require further investigation of their
ability to help manage burn pain.
Despite many of the studies showing significant reduc-
tion in pain scores after the addition of adjunctive analgesics
and nonpharmacologic strategies, there were no significant
changes in the amount of opioids consumed. This may be due
to the common practice of premedicating patients in antici-
pation of procedural pain. Additionally, many of the studies
presented were not powered to detect a difference in opioid
consumption. Also, investigators may have maintained con-
stant opioid use so that any difference in pain severity could be
attributed solely to the intervention. Establishing an analgesic
reduction protocol is warranted to further examine analgesic
consumption as a meaningful clinical endpoint.
IMPLICATIONS FOR FUTURE
INVESTIGATIONS
In order to develop optimal adjunctive therapies, a bedside-
to-bench and back again cycle should be considered. A com-
plete characterization of pain should be performed on every
patient, including patient characteristics and clinical factors,
along with concomitant symptoms and drug side effects.87–90
The experience of concomitant symptoms, including depres-
sion and anxiety, as well as opioid side effects may lower the
patient’s quality of life.91 Therefore, through a thorough char-
acterization of pain, clinicians and researchers will be better
able to diagnosis and treat pain.
Along with the previously mentioned points of premedicating
patients, underpowered studies, and maintaining consistent
opioid consumption that we found during this review, sev-
eral additional factors should be considered in future research.
Given the dynamic nature of pain in a burn population, longi-
tudinal studies should investigate the long-term effect of ad-
junctive therapies on pain and quality of life. Future studies
should include individual factors that predict responses to
therapies. These factors will permit a better design of preclin-
ical models to correlate with clinical observations.
CONCLUSION
An effective pain management plan incorporates both phar-
macologic and nonpharmacologic modalities that must be
tailored to each patient.92 While opioids are essential for
burn pain control, adjunctive nonopioid pain treatments
show improvement in pain scores, and have the potential
to reduce opioid use in well-designed, adequately powered
studies. In light of the national opioid abuse crisis, as well
as widespread shortages of intravenous opioids, alternative
pain management strategies must be considered for burn
patients.
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