A Review of Adjunctive Therapies For Burn Injury Pain During The Opioid Crisis

A Review of Adjunctive Therapies for Burn Injury Pain during the Opioid Crisis
Daniel E. Kim MD1,2, Kaitlin A. Pruskowski PharmD1,2, Craig R. Ainsworth MD1,2, Hans R.
Linsenbardt PhD1, Julie A. Rizzo MD1,2, Leopoldo C. Cancio MD1
1
U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, TX
Downloaded from https://academic.oup.com/jbcr/advance-article-abstract/doi/10.1093/jbcr/irz111/5525879 by guest on 17 July 2019

2
Uniformed Services University of the Health Sciences, Bethesda, MD
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Corresponding Author:
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Julie A. Rizzo MD
3698 Chambers Pass
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JBSA Fort Sam Houston, TX 78234
Phone: 210-916-1514
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Email: julie.a.rizzo.mil@mail.mil
Disclaimer: The opinions or assertations expressed herein are the private views of the authors,
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and are not to be construed as official or as reflecting the views of the Department of the Army
or the Department of Defense.
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Financial Disclosures: None
Conflicts of Interest: None

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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.
Abstract
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
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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
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demonstrated to reduce pain severity or opioid consumption in adult burn patients. Three
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databases were searched for prospective studies, randomized controlled trials, and systematic
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reviews that evaluated adjunctive pain management strategies published between 2008 and 2019
in adult burn patients. Forty-six studies were analyzed, including 24 randomized control trials,
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six crossover trials, and ten systematic reviews. Various adjunctive pain management therapies
showed statistically significant reduction in pain severity. Only one randomized control trial on
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music therapy for acute background pain showed a reduction in opioid use. One cohort study on
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hypnosis demonstrated reduced opioid use compared with historical controls. We recommend the
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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
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national opioid shortage.

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Keywords: Pain management, burns, systematic review, opioid tolerance, opioids abuse, non-
opioid treatment, non-pharmacologic therapy.
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Introduction
Burn injury may be the most painful trauma that a patient can sustain. The management
of post-burn pain is exceedingly 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

post-traumatic stress disorder. Thus, a robust, multi-modal analgesic regimen is a necessity.3
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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
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their own risks, to include dependence, tolerance, and hyperalgesia in addition to inherent side
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effects.6 Additionally, opioids are not effective at treating neuropathic burn pain.7,8 Tolerance to
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opioids leads to escalating doses that provide little added benefit while increasing the incidence
of side effects, such as constipation.9

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The overuse and abuse of prescription opioid medications has become epidemic in the
United States.10 The US Department of Health and Human Services stated that the likelihood of
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chronic opioid use increases with each additional day of medication given.11 In an effort to
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discourage the use of opioids, physicians now are required by state governments to screen
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prescription monitoring databases before prescribing these drugs.
In the midst of this opioid epidemic, there is a simultaneous national shortage of

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parenteral narcotics.12 This drug shortage has been caused by a reduction in opioid
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manufacturing by several companies as was suggested by the Drug Enforcement Agency, as well
as suspension of production due to manufacturing violations found by the Food and Drug
Administration (FDA).12 This has led to critical nationwide shortages of intravenous preparations
of morphine, hydromorphone, and fentanyl.12
In order to combat the current crisis of opioid overuse and abuse, national shortages, and
to battle the frequent reports that burn pain is frequently undertreated,4 adjunctive pain
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management modalities for burn pain control must be implemented into a multi-modal pain
management strategy. The purpose of this review was to evaluate the literature on adjunctive
therapies for pain management in adult burn patients.
Methods

Three online databases, PubMed, Ovid, and ClinicalKey, were searched for the keywords
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“burn” and “pain,” limited to the year 2008 to the current date. The last search was performed in
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February 2019. The PubMed search was filtered for clinical study, comparative study, or review,
humans, English, and adult: 19+ years. The Ovid search was filtered for English language,
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humans, all adult (19+), clinical study, clinical trial, meta-analysis, randomized control trial
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(RCT), or systematic review. The ClinicalKey search was filtered for meta-analysis, systematic
reviews, or RCT, then manually screened for adult, human studies.

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Only thermal injuries to the skin from flame, scald, or contact with a heated probe
(thermode) were included. Acute and chronic burn wounds and hypertrophic burn scars were
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included. Relevant references cited from those articles were also examined. Articles limited to
only opioids or benzodiazepines were excluded. Although anxiety, fear, depression, post-
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traumatic stress, and level of sedation are interrelated to pain, they were beyond the scope of this
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study.
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Results
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 articles 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
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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
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the reasons listed in Figure 1. Cited references were screened and five pertinent studies were also
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included.
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Forty-six studies are presented in our review. The details of each study are shown in
Table 1. Statistical analysis of the studies was not performed due to the heterogeneity of the
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adjunctive therapies and due to the varying timeframes of pain score collection.
Burn pain consists of four components: background pain, neuropathic pain, procedural
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pain, and breakthrough pain.14 The studies were categorized based on whether they addressed the
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management of background pain, procedural pain, or breakthrough pain and our findings are
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summarized below. Additionally, we present a brief discussion of adjuncts well-utilized in the
non-burned population that have potential for use in the burn patient.
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Management of Background Pain
Background pain is constant pain due to direct injury or inflammation to 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 biotransformation of opioids resulting in increased analgesic clearance and
increased pain.15,16,17
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Ketamine. Ketamine is a dissociative anesthetic that is primarily an N-methyl-D-aspartate
(NMDA) 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 sensitization.18 Although it is

associated with side effects of nausea, vomiting, hallucinations, mood alteration, bizarre dreams,
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and emergence delirium, ketamine causes less respiratory depression and tends to preserve
hemodynamic stability.19 A systematic review was performed on four RCTs on burn patients that
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received either intravenous ketamine or a placebo as part of their regimen for acute background
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pain.19 All studies utilized a standard thermode on healthy volunteers to create a controlled,
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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 received ketamine showed
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significant reduction in hyperalgesia. Side effects were not demonstrated at sub-anesthetic doses
of ketamine. All of the four studies were performed on voluntary participants with very small
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burns, therefore, the authors caution the clinical relevance of their review.
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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 NMDA receptor antagonist,
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methadone also inhibits opioid tolerance and reduces central sensitization.15 A retrospective
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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 between the two groups.
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Non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDS are often used for their anti-
pyretic, anti-inflammatory, and analgesic effects, but their use in burn patients is limited due to
side effects, such as gastrointestinal bleeding, decreased platelet activity, and acute kidney injury
(AKI). For most critically ill burn patients, these risks outweigh the benefits of using NSAIDS.20

In a retrospective case-control study conducted in non-burn patients within the Veterans’ Affairs
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system, new use of any NSAID increased the risk of AKI development.21 In a multicenter RCT,
patients with >10% total body surface area (TBSA) burns received 800 mg of intravenous
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ibuprofen every six hours for five days or a placebo.22 The ibuprofen group had a significant
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reduction in temperature for the first 24 hours. However, pain scores did not differ from those
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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
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administering five days of high-dose NSAID therapy.
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Propranolol. Post-burn activation of β-adrenoreceptors releases catecholamines, which may

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contribute to hyperalgesia; accordingly, β-adrenergic antagonists may have an analgesic effect.23

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A multicenter RCT was performed on acutely burned patients comparing propranolol to
placebo.23 The intervention group received 120 mg of extended-release propranolol twice daily
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until three weeks after hospital discharge. The propranolol group had higher pain scores than the
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placebo group on study days five through nineteen, 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
and potentially decrease the degree of augmented renal clearance observed after burn injury
which would permit pain medications administered to have a longer beneficial effect.
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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 and edema.25 Cooling therapy should be
limited in extent and duration, due to the potential risk of hypothermia. In a respective study of

929 burn patients, only 1.6% had a temperature less than 35⁰ C, none of which were related to
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prehospital cooling.26
A three-arm RCT was conducted on 94 patients with 1% TBSA thermal injury comparing
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cool tap water, a commercial foam dressing containing water and tea tree oil, and a similar spray
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formulation.27 All three groups had reduced pain scores after 20 minutes of treatment, with tap
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water having a significantly greater reduction in pain. Additionally, there was a significant
difference in pain score reduction between groups cooled by tap water below versus above 24⁰
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C. No analgesics were given during any procedures.
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Noncontact low-frequency ultrasound (NLFU). NLFU is purported to improve wound healing

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by destroying bacteria, reducing biofilm, down-regulating inflammatory cytokines, and up-

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regulating vascular endothelial growth factor.28 NLFU at 40 kHz delivers energy into and below
the wound bed to create changes to the microenvironment. In a multi-center RCT, donor sites of
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burn and cutaneous ulcer patients were treated for five days with either standard care utilizing a
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hydrocolloid border and transparent dressing or standard care plus NLFU.28 The pain scores for
the NLFU group were lower at two weeks but did not reach statistical significance. The amount
of analgesic consumption was not studied.
Music. Music carries the benefits of being portable and adjustable to patient preferences.29 Music
alleviates pain via “gate-control”: inhibitory impulses from the cerebral cortex and thalamus
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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 endorphin secretion. A RCT on burn
patients who listened to self-selected music for 20 minutes daily for three days had significantly
less pain than the control group.29 In addition, the music group also consumed significantly less

opioids over the three-day period (mean opioid intake was 9.32 mg for the music group versus
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13.7 mg for the control group).
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Massage. Massaging of the skin may inhibit transmission of pain signals and produce
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endorphins.31 Cho investigated the effects of massage on chronic background pain in addition to
standard rehabilitation for hypertrophic scars.32 The randomized intervention group received 30
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minutes of massage three times a week and had significantly greater reduction in scar pain.
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However, the study did not report whether the pain reduction led to lower analgesic
consumption. A systematic review by Ault investigated eight trials that utilized burn scar
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massage.33 Two of the trials assessed pain scores and showed significant improvement with
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massage, thereby favoring the intervention over standard rehabilitation therapy. The effect on
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analgesic use was not mentioned.

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Music and Massage. The combination of music and massage was evaluated in a RCT that
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compared the effects of only self-selected music, only massage, or music plus massage for 20
minutes daily for three days on acute background pain.3 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.

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Aromatherapy. A 3-arm RCT compared aromatherapy massage with lavender and almond oil,
to inhalation aromatherapy with rose and lavender oil, 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
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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
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dressing application.35 However, a systematic review of aromatherapy as a complementary
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therapy to facilitate 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
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Extracorporeal shock wave therapy (ESWT). Since the 1980s, ESWT has been used for the
regenerative treatment of musculoskeletal diseases and noninvasive pain management.37 In a

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RCT, patients with chronic burn scar pain received three sessions of ESWT or sham
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procedures.37 The ESWT group had significantly greater reduction in pain scores. Additionally,
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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
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burn scar which blocks central sensitization and decreases substance P synthesis in the dorsal
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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, absorption into the hypnotic state, inducing
analgesia, and bringing the patient out of hypnosis. A mechanism by which hypnosis reduces
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pain is by activation of the anterior cingulate cortex.39,40 The limitations to 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
reduction 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
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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 hypnotherapy sessions,
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influencing the areas of the brain related to the emotional aspects of pain. Neither trial examined
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analgesic consumption.
Summary for the Management of Background Pain

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A number of pharmacologic and non-pharmacologic strategies have been studied for the
management of acute and chronic background pain in burn patients. Ketamine, cooling, music,
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massage, aromatherapy, and ESWT have shown to decrease pain severity, with variable effects
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on opioid consumption. All of these options can be considered as adjuncts for background pain.
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Hypnosis demonstrated mixed results with respect to background pain reduction and requires
further study.
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Management of Neuropathic Pain
Neuropathic pain is caused by the direct injury or inflammation 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
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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
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ganglia, subsequently reducing neurotransmitter release.7,45 A case series of six burn patients that
received 300-600 mg three times per day of gabapentin showed improvements in burning, knife-
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like, stinging, and throbbing qualities of pain.7 In a double-blind RCT, patients with at least 5%
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TBSA burns received either gabapentin or placebo throughout their hospitalization.46 The
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gabapentin group had no improvement in acute pain nor neuropathic pain. Furthermore, opioid
consumption did not differ between the groups.

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Pregabalin is a gabapentin analogue with greater potency and earlier onset of clinical
effect, and commonly used to treat neuropathic pain.14 In a RCT comparing four weeks of
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pregabalin 75 mg twice per day versus placebo, burn patients on pregabalin reported significant
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improvement in the hot and sharp qualities of neuropathic pain as well as a reduction in
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procedural pain.14 Reduction in the amounts of opioids consumed was not observed in either
group.
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Transcranial direct current stimulation (tDCS). Transcranial direct current stimulation
applies a weak, constant, direct current that flows between the electrodes to stimulate the cortex
of interest.47 TDCS is thought to relieve acute pain by changing the excitability and the
concentrations of γ-aminobutyric acid (GABA) and glutamate in the sensory cortex.48 Portilla
studied the utility of tDCS for treating chronic neuropathic pain.47 In the crossover study, three
patients with pain over prior burn areas received either tDCS or sham therapy. During tDCS, 2
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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 two to zero 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 combination of electroacupuncture and
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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
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subgroups of responders and non-responders, with responders experiencing a significant
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reduction in pain. No demographic differences were noted between the subgroups but the non-
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responders were found to have higher pain tolerance and perception prior to treatment, limiting
potential therapeutic benefit. All patients benefited from decreased pruritus and increased
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nociceptive thresholds for both pain perception and pain tolerance. Although opioid consumption
was not a measured outcome, no additional analgesics were initiated during the study.
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Laser Therapy. In the past 20 years, laser therapy has emerged as an effective tool for managing
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burn scar-related complications. Laser inhibits the release of cyclooxygenase 2, prostaglandins,
and cytokines, accelerates collagen synthesis and cell proliferation, and inhibits nerve fiber
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transmission.50 Each type of laser offers distinct advantages depending on the patient’s primary
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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 systematic review evaluating the effectiveness of laser therapy
provided limited support.51 Studies that utilized a validated pain assessment tool reported a
decrease in pain but not statistically significant, whereas studies that assessed patients’
experience with unvalidated questionnaires demonstrated a statistically significant pain

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reduction.52 The systematic review 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
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post-burn neuropathic pain, with mixed results. Acupuncture may be of benefit in patients who
can be identified as responders before the initiation of treatment. Since limited options are
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available for the management of neuropathic pain, gabapentinoids and laser therapy should be
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considered as potential treatment options.
Management of Procedural Pain

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Procedural pain is increased hyperalgesia that occurs during or immediately after a
dressing change or rehabilitation efforts. Burn patients must endure multiple procedures,
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frequent dressing changes, and early mobilization. Wound care is often reported to be as painful
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or more painful as the initial burn event.

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Dexmedetomidine. Dexmedetomidine is an α2-adrenergic receptor agonist used to produce

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analgesia and sedation. Dexmedetomidine has minimal to no risk of respiratory depression,

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making it a safe option in this regard for non-intubated patients.9 However, caution must be
exercised 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 one and two hours after
either dressing changes or reconstructive surgery.9
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Ketamine. Ketamine is not FDA-approved for analgesia, however, 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 20-50% TBSA burned patients.53
Oral dosages administered were ketamine 5 mg/kg and dexmedetomidine 4 mcg/kg. Since both

drugs have low bioavailability (approximately 15% for both), doses administered enterally must
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be higher than parenterally administered doses.54,55 The patients also received morphine 0.1
mg/kg intramuscularly every six hours and oral diazepam 5 mg every twelve hours. Pain scores
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significantly decreased in both groups. Ketamine demonstrated a greater reduction in pain but
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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.

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Zor studied combinations of intramuscular ketamine with other intramuscular analgesics
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and sedatives for burn dressing changes.18 Prior to daily dressing changes for ten days, 24
patients received (I) ketamine only; (II) tramadol, dexmedetomidine, and ketamine; or (III)
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tramadol, midazolam, and ketamine. Groups II & III had significantly lower immediate post-
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procedural pain scores than Group I. Group II had the lowest incidence of hallucinations or
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dizziness. The study did not report trends in pain severity over the ten-day period or examine the
amount of opioids consumed.

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Intravenous Lidocaine. Lidocaine binds to voltage-gated sodium channels in the nerve
membrane, inhibiting nerve conduction in afferent nerves that signal pain.2 While lidocaine has
FDA-approval for local anesthesia, it does not have labeling 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 demand or consumption.2

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Nitrous oxide. Nitrous oxide exhibits an analgesic effect through the release of endogenous
opioids that activate spinal GABA receptors, which block pain transmission, though it does not
have FDA approval for the treatment of pain.56 Do Vale conducted a randomized crossover trial

comparing inhaled nitrous oxide to oxygen during burn dressing changes.56 Fifteen burned
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patients on intravenous fentanyl patient-controlled analgesia (PCA) underwent dressing changes
with 65% nitrous oxide or 10 L/min of oxygen via face mask. No difference in pain scores or
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opioid consumption was observed between the nitrous oxide and oxygen groups.
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Methoxyflurane. Methoxyflurane is a halogenated ether with analgesic properties that is
deliverable via a hand-held inhaler.57 A randomized crossover pilot study compared self-
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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
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groups. However, due to the small size of the study, statistical analysis of pain scores was not
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possible, and the study did not report the use of additional analgesics.
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Music. A RCT by Hsu on 70 burn patients showed that listening to music before, during, and
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after daily dressing changes significantly improved pain scores by the fourth day compared to the
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control group.30 However, there was no difference in the amount of morphine used between the
groups. A limitation of the study was that information on the use of non-opioid analgesics was
not collected.
Music-based imagery (MBI) and music alternate engagement (MAE) are two interactive
forms of music therapy utilized to alleviate psychological and physical symptoms in burn
patients.58 MBI is a relaxation technique during which a music therapist takes the patient’s
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description of a safe and relaxing place and puts it into a song to sing for the patient. MAE
consists of active 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
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music therapies significantly decreased pain levels before, during, and after dressing changes
compared to controls. However, there were no significant differences in the amounts of opioids
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and sedatives used between the music and control groups.
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A systematic review by Li looking at all types of music therapy on burn patients showed
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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
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Whole body vibration. Whole body vibration has been effectively used during rehabilitation for
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muscle strengthening, mobility, and balance, as well as for treating chronic musculoskeletal
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pain.60 The pain reducing effect of whole body vibration is hypothesized to be via gate-control
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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
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mid- and post-session pain compared to the control group. There was no significant difference in
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pain medication use.
Jaw relaxation. Jaw relaxation is simple self-care technique that can be used anytime with
minimal side effects. Jaw relaxation 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
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before and after dressing changes. However, the study did not analyze any effect that jaw
relaxation had on analgesic consumption.
Hypnosis. Hypnosis has been studied as an adjunct for procedural pain as well as background

pain. At one institution, 23 acutely burned patients admitted to the intensive care unit underwent
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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
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requirements. However, a limitation to the study was that 17 of the initial 40 patients screened
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were excluded due to delirium or pre-existing psychiatric conditions.
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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
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the review demonstrated an overall reduction in pain intensity of approximately 9%.63 But this
reduction did not correlate to a decreased need for opioids. The authors encouraged further study
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utilizing a greater array of burn centers to objectively evaluate hypnosis and its role in the pain
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management of burn patients.

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Virtual reality (VR). VR uses engaging visual and auditory stimuli to distract the patient’s
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attention away from painful stimuli.64 A major advantage of VR is that its efficacy persists over
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multiple sessions.65 The level of sensory immersion 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 participation. 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.

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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
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received either relaxing visual scenery through VR goggles and earpiece plus morphine PCA or
PCA alone.68 The VR group had significantly less pain intensity than the standard group during
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and after the dressing change. However, VR did not reduce the amount of patient-administered
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morphine received.
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Relaxation, hypnosis, and virtual reality. A systematic review by Scheffler investigated non-
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pharmacological interventions of relaxation, hypnosis, and virtual reality in treating procedural
pain during burn wound care.69 A meta-analysis of 18 RCTs that assessed pain intensity
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outcomes showed that these interventions significantly reduced procedural pain. However, the
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effect of these interventions on analgesic use was not mentioned.

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Interactive gaming console (IGC). IGCs are a subset of virtual reality technology that are
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becoming more affordable, easier to use, and promote rehabilitative exercises.70 The proposed
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mechanism by which video gameplay decreases pain sensation is due to the increase in dopamine
release in the midbrain in addition to cognitive distraction from noxious stimuli.71 A RCT by
Yohannan on 23 burn patients compared three sessions 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 statistically significant. The use of analgesics was not
mentioned. Another RCT utilizing Nintendo Wii, by Parker, versus routine rehabilitation for five
19
days on 22 patients showed a significant 17% greater pain reduction.71 This study did not assess
analgesia utilization 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
t
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15 mins twice daily, patients performed 15 minutes of Xbox Kinect or self exercises twice daily.
The Xbox group reported significantly longer exercise time per day compared to the control
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group. However, pain scores were not different before and after exercise nor between the Xbox
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and control groups.
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Transcranial direct current stimulation. Hosseini Amiri investigated the effects of tDCS on
M
procedural pain and anxiety.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
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significantly lower pain and anxiety scores both after stimulation and after the dressing change.
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During the study, 20% of the stimulation group and 33.3% of the sham group received morphine
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5 mg, but this difference was not statistically significant.

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Summary for the Management of Procedural Pain

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Ketamine and intravenous lidocaine have been shown to improve pain scores and are
pharmacologic options for the treatment of procedural pain in burn patients whereas nitrous
oxide failed to convey any benefit. Effective non-pharmacologic adjuncts for procedural pain
include music, whole body vibration, jaw relaxation, hypnosis, virtual reality, IGC, and tDCS.
20
Management of Breakthrough Pain
Breakthrough pain is a transient worsening of pain, not associated 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 non-opioid adjuncts that

are suitable for the management of breakthrough pain.
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Adjuncts Studied in Non-burned populations
Due to the limited number of adult burn patient pain studies as well as the lack of power
cr
in existing studies toward clinically relevant endpoints, such as opioid consumption,
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extrapolation of non-burn literature is essential.
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Acetaminophen. Guidelines analyzing published evidence in the field of pain recommend the
use of non-opioids, such as acetaminophen; however, the addition of acetaminophen has not
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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
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other adult surgical populations, the addition of scheduled acetaminophen (1 g every 6 hours),
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has been shown to reduce the amount of opioids required in the post-operative period.75-77 In a
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meta-analysis of eleven RCTs that studied pre-operative adult patients, intravenous
acetaminophen showed significant reduction in postoperative pain after elective surgeries, as

c
well as significant reduction in opioid consumption.78 Whether these outcomes can translate to
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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 neuropathic
pain. Many patients will need the above-mentioned medications to manage the depression,
21
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 patients’ analgesic regimen.
Duloxetine has been shown to improve pain scores in patients with diabetic and chemotherapy-
induced neuropathy, while amitriptyline has been shown to improve pain in patients with chronic

oral-facial pain.79-81
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Cannabinoids. While somewhat controversial, cannabinoids may be considered as part of a
patient’s analgesic regimen. Currently, the synthetic cannabinoids agents dronabinol (synthetic
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delta-9-tetrahydrocannabinol), tetrahydrocannabinol, and cannabidiol sprays are not FDA-
us
approved for analgesia, but are available in the United States. The cannabidiol spray formulation
an
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 non-
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burn population and have shown promise and may be considered for burn patients in the
future.82-84
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c ep
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22
Discussion
Pain associated with the treatment of burns is multifactorial and long-lasting; thus, pain
management requires a multifaceted approach. In 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 non-opioid adjuncts, anxiolytics, and non-
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pharmacologic treatment strategies.1 This strategy correlates with the most recent Clinical
Practice Guidelines for the management of pain in non-burned patients, which highlights the
cr
need for multi-modality therapy in order to optimize patient outcomes.85 Individualized
us
analgesic treatment plans should include multiple modalities to address background pain,
an
breakthrough pain, and neuropathic pain. Multiple non-opioid and non-pharmacologic options
have been studied in burn patients. Ketamine, gabapentin, pregabalin, music, extracorporeal
M
shock wave therapy, jaw relaxation, whole body vibration, hypnosis, laser, tDCS, IGC and
virtual reality offer promise and can be considered when designing an analgesic regimen for a
d
burn patient. Despite the above-mentioned meta-analysis on dexmedetomidine showing no pain

te
benefit, in a double-blind RCT conducted in non-burned women, dexmedetomidine was shown

ep
to have synergy with opioids, leading to a decrease in post-operative opioid requirements,86
which has correlated with the clinical experience at our institution. Similarly, methadone lacks
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strong clinical evidence in the burned population; however it is recommended in the ABA 2006
Ac
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 available evidence and will require
further investigation of their ability to help manage burn pain.
Despite many of the studies showing significant reduction in pain scores after the
addition of adjunctive analgesics and non-pharmacologic strategies, there were not significant
23
changes in the amount of opioids consumed. This may be due to the common practice of pre-
medicating patients in anticipation of procedural pain. Additionally, many of the studies
presented were not powered to detect a difference in opioid consumption. Also, investigators
may have maintained opioid use constant so that any difference in pain severity could be

attributed solely to the intervention. Establishing an analgesic reduction protocol is warranted to
t
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further examine analgesic consumption as a meaningful clinical endpoint.
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Implications for Future Investigations
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In order to develop optimal adjunctive therapies, a bedside-to-bench and back again cycle
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should be considered. A complete characterization of pain should be performed on every patient,
including patient characteristics and clinical factors, along with concomitant symptoms and drug
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side effects.87-90 The experience of concomitant symptoms, including depression and anxiety, as
well as opioid side effects may lower the patient’s quality of life.91 Therefore, through a
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thorough characterization of pain, clinicians and researchers will be better able to diagnosis and
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treat pain.
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Along with the previously mentioned points of pre-medicating patients, underpowered
studies, and maintaining consistent opioid consumption that we found during this review, several
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additional factors should be considered in future research. Given the dynamic nature of pain in a
Ac
burn population, longitudinal studies should investigate the long-term effect of adjunctive
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 pre-clinical models to
correlate with clinical observations.
24
Conclusion
An effective pain management plan incorporates both pharmacologic and non-
pharmacologic modalities that must be tailored to each patient. While opioids are essential for
burn pain control, adjunctive non-opioid pain treatments show improvement in pain scores, and

have the potential to reduce opioid use in well-designed, adequately powered studies. In light of
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the national opioid abuse crisis, as well as widespread shortages of intravenous opioids,
alternative pain management strategies must be considered for burn patients.
cr
us
an
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c ep
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25
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35
Figure 1. Flow chart of study selection process.
Studies identified in Studies identified in Studies identified in

PubMed Ovid ClinicalKey

n = 378 n = 147 n = 317
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Studies after duplicates removed
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n = 630
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Studies screened
an Studies excluded
n = 630 n = 574
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Full text articles
Full text articles
examined
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excluded with reasons

n = 56 n = 15
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Examined by other
General summary 4
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Additional studies from No pain analysis 3

cited references Full text in Chinese 1
n=5 Trial not complete 1
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Studies included in
systematic review
n = 46
36
Table 1. Studies from 2008-2019 examining the use of adjunctive therapies to treat burn pain.
Adjunct Studied Year Author Study type Number of Findings
t
Subjects
ip
Management for Background Pain
Ketamine 2011 McGuiness19 SR 106 Hyperalgesia was reduced in the ketamine group. Clinical relevance
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was questionable since subjects were voluntary and thermode burns
were small.
Methadone 2013 Jones15 Retrospective 70 Methadone group had more ventilator-free days. No difference was
us
CCS observed in opioid or benzodiazepine consumption.
Ibuprofen 2011 Promes22 RCT 61 Pain scores did not differ between treatment 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.
an
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.
M
Low-frequency 2015 Prather28 RCT 27 The ultrasound group had a nonsignificant trend towards reduced
ultrasound pain.
Music 2016 Najafi RCT 100 The music group had significantly reduced pain. The music group
Ghezeljeh29 had significantly less opioid use.
Massage 2014
2018
Cho32
Ault33
RCT
e
SR
d 146
166
The massage group had a greater reduction in scar pain. Analgesic
consumption was not mentioned.
Massage significantly decreased pain. Analgesic use was not
mentioned.
pt
Music + Massage 2017 Najafi RCT 240 Music, massage, and music plus massage all significantly lowered
Ghezeljeh31 pain scores. Opioid use was not measured.
ce
Aromatherapy 2016 Seyyed- RCT 90 Massage aromatherapy and inhalation aromatherapy both
Rasooli34 significantly reduced pain during dressing changes. Analgesics
were not available.
2016 Bikmoradi35 RCT 50 Inhaled damask rose essence decreased pain during dressing
Ac
application. Both aromatherapy and control groups received

identical morphine and diazepam doses prior to procedure.
2018 Choi36 SR 248 There was no evidence to support routine use of aromatherapy for
pain treatment.
Extracorporeal 2016 Cho37 RCT 40 The treatment group had greater reduction in scar pain than the
shock wave therapy placebo group. Analgesic use was not mentioned.
37
Shakibaei41

Hypnosis 2008 RCT 44 Reduction in pain intensity was observed in dose-responsive
manner with hypnosis. Analgesic consumption for hypnosis and
control groups was not altered.
t
2018 Jafarizadeh42 RCT 60 Hypnosis decreased pain quality but not pain intensity after
ip
multiple sessions. Morphine dosage was not recorded.
Management for Neuropathic Pain
Gabapentin 2008 Gray7 CS 6 All patients reported improvement in their neuropathic pain.
cr
46
2014 Wibbenmeyer RCT 53 There were no differences in acute and neuropathic pain nor in
opioid consumption between the gabapentin and placebo groups.
us
Pregabalin 2011 Gray14 RCT 90 Pregabalin significantly reduced neuropathic and procedural pain.
There was no significant difference in opioid consumption.
Transcranial direct 2013 Portilla47 CS, randomized 3 1 patient had improvement in pain from 2 to 0. The other 2 patients
current stimulation crossover trial had no pain improvement.
an
Electroacupuncture 2015 Cuignet49 CS 32 Acupuncture reduced pain in the subgroup of responders. All
patients had decreased pruritis and increased peripheral sensory
thresholds. Opioid consumption was not measured.
Ebid50
M
Laser 2017 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
Management for Procedural Pain

Dexmedetomidine 2013 Asmussen9
e
MA/SR
d
Retrospective
cohort
93
266
Laser therapy reduced pain, but questionnaire utilized was not
validated for burn patients.
There were no difference in pain scores between treatment and

pt
control groups.
Ketamine 2013 Kundra53 Randomized 60 Pain score reduction was significantly greater for the ketamine
ce
crossover trial 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
Ac
effects. Opioid consumption was not examined.

Intravenous 2012 Wasiak2 SR 45 The lidocaine group had significantly lower pain ratings but no
lidocaine difference in opioid demand or consumption.
Nitrous oxide 2016 do Vale56 Randomized 15 There was no difference in pain scores or opioid consumption
crossover trial between the inhaled nitrous oxide and control (oxygen) groups.
Methoxyflurane 2016 Gaskell57 Randomized 8 Pain score analysis was not performed. Use of additional analgesics
38
crossover trial 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
t
control groups.
ip
2010 Tan58 Randomized 29 Music therapy decreased pain levels before, during, and after
crossover trial dressing changes compared to standard care. There was no
difference in the amount of opioids and sedatives given.
cr
2017 Li59 MA/SR 260 Music interventions had a positive effect on burn pain relief. No
data on analgesic use was extractable.
us
Whole body 2017 Ray60 RCT 31 The vibration group had significant decrease in mid- and post-
vibration 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 reduced pain before and
an
Fakhar61 after dressing change. Effect on analgesic consumption was not
reported.
Hypnosis 2010 Berger62 Cohort with 46 Daily pain scores were significantly reduced in the hypnosis group.
M
matched historical Daily opioid requirements were significantly reduced after
controls introduction of hypnosis.
2018 Provencal63 MA/SR 234 Hypnosis had a 9% decrease in pain intensity, but no decrease in
opioid requirement.
Virtual reality 2018
2009
Scapin66
Carrougher67
SR
e
Randomized
d
crossover trial
Not pooled
39
Majority of studies showed significant reduction in pain scores
during procedures.
The VR session had significant reduction in pain scores but average
opioid equivalents administered was not different.
pt
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.
ce
Relaxation + 2018 Scheffler69 MA/SR 516 Non-pharmacological interventions are favored to provide
hypnosis + virtual improvement in procedural pain. Analgesic use was not mentioned.
reality
Ac
Interactive gaming 2012 Yohannan72 RCT 23 The Wii group had greater pain reduction but not statistically
console 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.
39
Transcranial direct 2016 Hosseini RCT 60 Stimulation group had lower pain anxiety score after stimulation
current stimulation Amiri48 and after dressing. There was no difference in opioid consumption.
Abbreviations: SR = scientific review; CCS = case control study; RCT = randomized controlled trial; CS = case series; CR = case report; MA = meta-
t
analysis
ip
cr
us
an
M
e d
pt
ce
Ac
40

A Review of Adjunctive Therapies For Burn Injury Pain During The Opioid Crisis

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A Review of Adjunctive Therapies For Burn Injury Pain During The Opioid Crisis

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A Review of Adjunctive Therapies for Burn Injury Pain during the Opioid Crisis

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Conflicts of Interest: None

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development of individualized analgesic regimens with the incorporation of adjunctive therapies

national opioid shortage.

opioid treatment, non-pharmacologic therapy.

of post-burn pain is exceedingly complex, as it is variable in quality and intensity among

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of side effects, such as constipation.9

prescription monitoring databases before prescribing these drugs.

In the midst of this opioid epidemic, there is a simultaneous national shortage of

of morphine, hydromorphone, and fentanyl.12

therapies for pain management in adult burn patients.

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reviews, or RCT, then manually screened for adult, human studies.

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summarized below. Additionally, we present a brief discussion of adjuncts well-utilized in the

Management of Background Pain

accelerated hepatic biotransformation of opioids resulting in increased analgesic clearance and

receptors. Ketamine blocks pain transmission by inhibiting central sensitization.18 Although it is

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different between the two groups.

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Propranolol. Post-burn activation of β-adrenoreceptors releases catecholamines, which may

contribute to hyperalgesia; accordingly, β-adrenergic antagonists may have an analgesic effect.23

A multicenter RCT was performed on acutely burned patients comparing propranolol to

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Noncontact low-frequency ultrasound (NLFU). NLFU is purported to improve wound healing

by destroying bacteria, reducing biofilm, down-regulating inflammatory cytokines, and up-

of analgesic consumption was not studied.

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analgesic use was not mentioned.

reduced pain but did not work synergistically.

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regenerative treatment of musculoskeletal diseases and noninvasive pain management.37 In a

Hypnosis. Medical hypnosis provides analgesia by helping patients accept clinicians’

of hypnosis to reduce burn-related background pain. The first demonstrated a significant

reduction in pain intensity after multiple sessions, revealing a dose-responsive effect of

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Summary for the Management of Background Pain

Management of Neuropathic Pain

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consumption did not differ between the groups.

Transcranial direct current stimulation (tDCS). Transcranial direct current stimulation

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burn scar-related complications. Laser inhibits the release of cyclooxygenase 2, prostaglandins,

scar-related complaint. A double-blind RCT demonstrated a significant decrease in scar pain

completed.50 However, a systematic review evaluating the effectiveness of laser therapy

experience with unvalidated questionnaires demonstrated a statistically significant pain

Summary for the Management of Neuropathic Pain

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Management of Procedural Pain

or more painful as the initial burn event.

Dexmedetomidine. Dexmedetomidine is an α2-adrenergic receptor agonist used to produce

analgesia and sedation. Dexmedetomidine has minimal to no risk of respiratory depression,

either dressing changes or reconstructive surgery.9

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study did not examine ketamine’s effect on opioid consumption.

amount of opioids consumed.

Intravenous Lidocaine. Lidocaine binds to voltage-gated sodium channels in the nerve

did not lower opioid demand or consumption.2

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