Pain Medicine 2017; 0: 1–27
doi: 10.1093/pm/pnx228
Review Article
Burn Pain: A Systematic and Critical Review of
Epidemiology, Pathophysiology, and Treatment
Michael Morgan, PhD,* Jennifer R. Deuis, PhD,*
Majbrit Frøsig-Jørgensen, MSc,* Richard J. Lewis,
PhD,* Peter J. Cabot, PhD,† Paul D. Gray, MBBS,
PhD,‡,§ and Irina Vetter, PhD,*,†
*Centre for Pain Research, Institute for Molecular
Bioscience, The University of Queensland, St Lucia,
Queensland, Australia; †School of Pharmacy, The
University of Queensland, Wooloongabba,
Queensland, Australia; ‡Tess Cramond
Multidisciplinary Pain Centre, Royal Brisbane &
Women’s Hospital, Metro North Health, Herston,
Queensland, Australia; §School of Medicine, The
University of Queensland, Herston, Queensland,
Australia
Correspondence to: Irina Vetter, PhD, Institute for
Molecular Bioscience, 306 Carmody Road, The
University of Queensland, St Lucia, Brisbane,
Queensland 4072, Australia. Tel: þ61-7-3346-2660;
Fax: þ61-7-3346-2101; E-mail: i.vetter@uq.edu.au.
Disclosures and conflicts of interest: The authors de-
clare no conflicts of interest. Dr. Vetter is supported
by an Australian Research Council Future Fellowship,
and Prof. Lewis is supported by a National Health and
Medical Research Council Principle Investigator
fellowship.
Authors Michael Morgan and Jennifer R. Deuis con-
tributed equally to this work.
Abstract
Objective. This review aims to examine the avail-
able literature on the epidemiology, pathophysiol-
ogy, and treatment of burn-induced pain.
Methods. A search was conducted on the epidemi-
ology of burn injury and treatment of burn pain uti-
lizing the database Medline, and all relevant articles
C 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
V 1
were systemically reviewed. In addition, a critical re-
view was performed on the pathophysiology of
burn pain and animal models of burn pain.
Results. The search on the epidemiology of burn in-
jury yielded a total of 163 publications of interest,
72 of which fit the inclusion/exclusion criteria, with
no publications providing epidemiological data on
burn injury pain management outcomes. The search
on the treatment of burn pain yielded a total of 213
publications, 14 of which fit the inclusion/exclusion
criteria, highlighting the limited amount of evidence
available on the treatment of burn-induced pain.
Conclusions. The pathophysiology of burn pain is
poorly understood, with limited clinical trials avail-
able to assess the effectiveness of analgesics in
burn patients. Further studies are needed to identify
new pharmacological targets and treatments for the
effective management of burn injury pain.
Key Words. Burn Pain; Mechanisms; Analgesia;
Inflammation; Neuropathic Pain
Introduction
Pain is a sensory response that normally helps the body
to respond to a source of danger or tissue damage and
facilitates protection for tissue repair. Acute pain arises
from a range of noxious stimuli including heat, cold, me-
chanical stimuli, and chemicals. In the case of burn-
induced pain, damage to peripheral sensory neurons
and inflammatory processes initiated by the injury exac-
erbate this acute response and transform burn pain into
a complex symptom comprising multiple components,
including ongoing background pain and procedural pain
during surgical interventions and dressing changes. In
addition, burn-induced pain can persist beyond the ini-
tial injury and develop into chronic pain with neuropathic
features.
Typically, the degree of pain is largely determined by
how deep the burn penetrates, with areas of superficial
burns resulting in greater pain than areas of full-
thickness burns, where the nerve endings are
Morgan et al.

Figure 1 The severity of a burn injury is determined by the depth of tissue injury. The skin is intensely innervated with
many morphologically and functionally distinct sensory nerve endings that respond to a multitude of non-noxious and
noxious stimuli. Noxious heat stimuli are generally conducted to the dorsal horn of the spinal cord via nociceptive Ad
and C fiber neurons. Only the epidermis is affected in epidermal or superficial epidermal burns while increasing dam-
age to the dermis occurs in mid-dermal, deep-dermal and full-thickness burns.

functionally compromised or lost. However, full-
thickness burns are typically surrounded by areas of
more superficial injury, so that, clinically, patients with
full-thickness burns report as much pain as those with a
superficial injury [1]. The duration of pain can last from
days to months.
The skin, the largest organ of the human body by
weight, plays many essential roles, including maintaining
body homeostasis, providing an immunological barrier,
and contributing to sensations of touch and pain. The
skin consists of two primary layers (Figure 1): the outer
epidermis, which is predominantly made up of keratino-
cytes plus melanocytes, Merkel cells, and Langerhans
cells; and an inner dermis, comprising connective tis-
sue, fibroblasts, macrophages, and adipocytes. The
skin is intensely innervated with many morphologically
and functionally distinct sensory nerve endings that re-
spond to a multitude of non-noxious and noxious stim-
uli. Noxious heat stimuli are generally conducted to the
dorsal horn of the spinal cord via nociceptive Ad and C
fiber neurons.
The classification of a burn injury is dependent both on
the depth and area of the burn. The depth of burn inju-
ries was first classified by Peter Lowe in 1597 and mod-
ified by Fabricius in 1610 to the terms “first-, second-,
and third-degree burns.” This remained largely
unchanged until recently, when a new system described
burn injuries as either epidermal, superficial epidermal,
mid-dermal, deep dermal, and full thickness [2]. The
burn coverage, also called the total body surface area
(TBSA), provides an estimate of the percentage of the
skin burnt [3] and is determined according to the “Rule
of Nines.” The TBSA, together with burn depth, the
presence of inhalation burn, age, and gender, is used to
calculate the severity of a burn injury using scales such
as the Abbreviated Burn Severity Index (Table 1) [4] that
provide an estimate of prognosis for the patients and
the method of treatment.
The aim of this review is to provide an overview of burn
injury epidemiology, current treatments for burn injury,
and the mediators and mechanisms underlying burn in-
jury pain. We conducted a systematic evaluation of the
literature regarding the epidemiology of burn pain, dis-
cuss the advantages and limitations of various models
of burn injury, summarize key burn injury pain mecha-
nisms, and provide an overview of common approaches
to treating burn pain.
Methods
Epidemiology of Burn Injuries
A systematic search was performed on Medline
(October 18–19, 2016) to retrieve studies related to the
following search key word combinations: burn; burns;
epidemiology; mortality; gender; age. Articles published
between January 2000 and October 2016 in English
were then selected from the list, along with selected
references informing the results of the retrieved studies.
Articles were classified according the level of evidence,
as detailed in Table 2. Searches for national registries
for burn injury were also included in the study. Articles
were excluded if they focused on a particular

2
 Burn Pain

Table 1 Abbreviated burn severity index

Variable Patient Characteristic Score

Sex Male 0
Female 1
Age, y 0–20 1
21–40 2
41–60 3
61–80 4
81–100 5
Inhalation injury No 0
Yes 1
Full-thickness burn No 0
Yes 1
% TBSA <10 1
11–20 2
21–30 3
31–40 4
41–50 5
51–60 6
61–70 7
71–80 8
81–90 9
91–100 10

Total score 2–3 4–5 6–7 8–9 10–11 12–13

Threat to Life Very Low Moderate Moderately Severe Serious Severe Maximum
Probability of survival 99 98 80–90 50–70 20–40 10

Table 2 Levels of evidence used to quantify hospitalized burn patients were included. The titles,
abstracts, and the full texts of these articles were
epidemiological studies screened for relevance. Studies assessing nonpharma-
Level 1 National trauma registry cological interventions were excluded. Studies assessing
Level 2 Systematic review or multicenter study topical and wound care interventions that were aimed
Level 3 Single-center study only at improving the healing process were excluded.
Level 4 Self-reporting
Results and Discussion

Epidemiology of Burn Injuries

demographic or subsection of a population, if the study
contained fewer than 100 patients, or if a higher level of
evidence was available.
Treatment of Acute Burn Pain
A search was performed in Medline on October 18,
2016, to retrieve included studies. The applied search
strategy was as follows: (((burn[Title] OR burns[Title]) OR
postburn[Title]) AND (“pain”[MeSH Terms] OR “pain”[All
Fields])) AND (“therapy”[Subheading] OR “therapy”[All
Fields] OR “treatment”[All Fields] OR
“therapeutics”[MeSH Terms] OR “therapeutics”[All
Fields]) AND Clinical Trial[ptyp]. Only randomized con-
trolled studies assessing the efficacy of a pharmacologi-
cal intervention in comparison with placebo or other
analgesic(s) with a primary outcome measure of pain in
A number of epidemiology studies have been under-
taken to try to capture the current state of burn injury
prevalence in different regions. These studies include
national burn and trauma registries, multicenter and sin-
gle-center studies, systematic reviews, and question-
naires. In this systematic review, we aimed to capture
the current best evidence for burn injury prevalence
around the world, provide a critical analysis of the qual-
ity of the evidence, and describe where and how data
capture needs to improve.
In total, 163 publications of interest were obtained, and
of those 63 fit the exclusion and inclusion criteria. Three
burn injury registries were identified; one from the
United States, another from Australia and New Zealand,
and a third from England and Wales. These registries

3
Morgan et al.
and their epidemiological reports (annual or cumulative)
added an additional nine references, totaling 72 referen-
ces. A burn registry in Iran that is not accessible online
was identified through publications along with studies
(eight in total) using data from national trauma registries,
and these were considered level 1 evidence. The major-
ity of studies (41) obtained were of level 3 evidence in-
volving single-center studies. This level of evidence was
deemed less reliable as comparisons between level 3
evidence studies within the same country often pro-
duced variability in measures (Table 3).
Burn victims are usually men, with only seven of the 72
studies reporting greater female representation than
male (Table 3). The vast majority of burns occur in the
home (73% USA; 76% Australia and New Zealand;
65.89% England and Wales), and the most common
source of injury is flame and scald exposure (Table 3),
but injuries were also from contact burns, radiation,
chemicals, and electricity (Table 4), with these being ac-
cidental, inflicted, or self-inflicted. No age group is im-
mune from this traumatic experience, but there is a
significant occurrence of burn injuries, predominantly
from scalds, in children age five years and younger
(Table 4) and for adults between 20 and 29 years. In
Europe, burn injuries affect between two and 29 people
per 100,000, with males representing 60% of cases [5],
while in the United States males represent approxi-
mately 70% of all burn cases in the age group of 20 to
60 years (Table 5) [6]. In comparison, 3.98% (four peo-
ple per 100) of those in Sierra Leone self-reported burn
injuries, although the extent of these injuries was not
specified [7]. Burns can lead to morbidity through
wounds and inflammation, scarring, infection, amputa-
tions or surgical resections, psychological conditions,
and ongoing pruritis and acute and chronic pain.
Mortality varied throughout the world, with studies
reporting between less than 1% and up to 60.8%. The
mortality rate correlated with the Human Development
Index (HDI) (Figure 2A), with developing countries more
likely to report higher mortality than developed coun-
tries. Mortality also correlated with the total burn surface
area, with greater surface area resulting in a higher likeli-
hood of death (Figure 2, B and C). In highly developed
countries, burn injuries commonly affect less than 10%
of the total body surface area (84% Australia and New
Zealand; 96.5% England and Wales; 77.9% USA); how-
ever, in countries with lower HDI scores, a greater
TBSA was often reported presenting to hospitals (Table
3). The mortality of clinically presenting cases is reported
as between 0.8% and 1.2% in Australia and New
Zealand, between 1.4% and 18% in Europe [5], and
3.14% in the United States [8]. Mortality resulting from
burn injury was higher in females than males in England
and Wales (1.86% vs 1.31%, respectively) [9] and
Australia and New Zealand (2.32 times more likely to
succumb to injury compared with males, adjusted for
confounding factors) [10].
4
In total, the publications examined in this systematic re-
view covered 58 countries with HDI scores ranging from
0.465 to 0.944, along with regional studies from South
Asia and Europe. It is problematic that few countries
with lower HDI scores have high-quality (level 1 and 2)
evidence as burn injury disproportionately affects those
in developing countries. Globally, more than 11 million
people experience burn injury requiring medical attention
annually, with the majority of severe burn cases affecting
people in emerging economies, including an estimated
50% of cases in Southeast Asia [11]. The World Health
Organization is currently testing a Global Burn Registry,
which allows for standardization of data collection and
will provide greater access to epidemiological data from
developing countries. A systematic review found a de-
crease in burn injury prevalence and injury severity in
very high and highly developed countries over time, but
with data under-reported for low- and middle-income
countries, where the majority of burn injuries occur, no
conclusions could be made on trends there [12].
Databases for burn injury statistics established in highly
developed countries provide high-quality data to draw
conclusions on clinical outcomes and burn injury trends,
but these registries have limitations also. While the
International Burn Injury Database (England and Wales)
provides data describing whether pain scores have
been taken from patients, measures of pain outcomes
are omitted from all repository annual reports.
Epidemiological data for pain scores included in burn in-
jury repositories could provide ongoing measures de-
scribing how adequately burn injury is managed and
where improvements can be made.
Animal Models of Burn Injury Pain
Animal models have provided some important insights
into human pain associated with burn injury. There is a
limited number of randomized placebo-controlled clinical
trials available to evaluate the effectiveness of analgesics
in human burn patients (discussed in detail below), in
part because burn patients are a heterogeneous group
with variable levels of burn severity and background
demographics and are frequently quite unwell, with
multi-organ dysfunction. While a number of human
volunteer studies of burn pain have been
reported—including models of dry heat contact burn, ul-
traviolet (UV) burn, and capsaicin-induced heat
sensitization—these are for obvious reasons not numer-
ous [82–96]. Although all of these models have demon-
strated the development of secondary hyperalgesia,
likely due to central sensitization, such models are un-
likely to address the need for ongoing research into the
pathophysiological mechanisms underlying burn pain.
Given the importance of this area to improving patient
outcomes, a number of animal models have been
established specifically to study the mechanisms of burn
pain (Table 6). However, it is unclear how predictive ani-
mal models of burn-induced pain are of the human con-
dition as many other animal models of pain in the past
have failed to translate to the clinic [97]. Nevertheless,
improvements in experimental design and efficacy end
 Table 3 Epidemiological studies and results

Country Evidence Number of Study Age Predominant

Publication or Region Level HDI Score Patients Period Distribution Mortality TBSA  10% Male, % Source of Injury

[13] Afghanistan 3 0.465 532 2007–2008 Median age 19 y 28 Mean TBSA 36.5% 41.2 Flame
[14] Afghanistan 3 0.465 388 1996–2000 Median age 8 y 16 Median TBSA 15% 57 Scald
[15] Australia & 1 0.935 & 0.913 2,776 2014–2015 Greatest among 1 84% 67 Scald
New Zealand 1–2 y & 20–29 y
[16] Australia & 1 0.935 & 0.913 2,656 2013–2014 Greatest among 1 84% 68 Scald
New Zealand 1–2 y & 20–29 y
[17] Australia & 1 0.935 & 0.913 2,720 2012–2013 Greatest among 1.2 82% 68 Flame & scald
New Zealand 1–2 y & 20–29 y
[18] Australia & 1 0.935 & 0.913 2,772 2011–2012 Greatest among 1 82% 67 Flame & scald
New Zealand 1–2 y & 20–29 y
[19] Australia & 1 0.935 & 0.913 2,480 2010–2011 Greatest among 0.8 80% 67 Flame & scald
New Zealand 1–2 y & 20–29 y
[20] Australia & 1 0.935 & 0.913 2,103 2009–2010 Greatest among 20–29 y 1.6 74% 69 Flame & scald
New Zealand
[21] Brazil 3 0.755 921 1991–1997 Greatest among 20–39 y 8.4 NA 67.1 NA
[22] Bulgaria 3 0.782 2,627 2002–2011 Mean age 41 y 2.3–3.6 Median 10.6% 59 Scald
[23] Brunei 3 0.856 211 2007–2008 Mean age 19.6 y NA Mean TBSA 3.7% 52.6 Scald
[24] China 3 0.727 527 2002–2003 Median age 30 y 2 Median TBSA 10% 71 Flame
[25] China 2 0.727 1,974 2000–2008 Mean age 36 y 2.8 Mean TBSA 14.7% 70.7 Flame
[26] China 2 0.727 172,256 2001–2007 Median age 23 y 0.8 61.44% 70.1 Scald
[27] China 3 0.727 5,321 1980–1998 NA 0.9 68.47% NA NA
[28] Columbia 3 0.72 2,319 1994–2004 Mean age 18.1 y 7.4 Mean TBSA 26.9% 66.8 Scald
[29] Curacao 3 8.11 336 1992–2002 Mean age 24.3 y 3.3 Mean TBSA 13.6% 61.5 Scald
[30] England & 1 0.907 140,076 2003–2015 Greatest among 0–5 y NA 96.5% 58.5 Scald
Wales
[9] England & 1 0.907 81,181 2003–2011 Median age 21 y 1.5 Median TBSA 1.5 63 Contact & scald
Wales
[31] Ecuador 3 0.732 1,106 2005–2014 Mean age 33–34 y 10.2 Mean TBSA 20% 69.4 Heat
[5] Europe 2 NA 186,500 1985–2009 Greatest among 0–16 y 1.4–18 Mean TBSA 11–24% 55–75 Flame
[32] Finland 3 0.833 1,000 1994–2006 Mean age 39 y 4 78% 62.1 Scald
[33] Germany 3 0.916 695 2001–2010 Mean age 44 y 15 Mean TBSA 18% 70.9 NA
[34] Ghana 3 0.579 487 2009–2013 Greatest among 0–10 y 20.5 Mean TBSA 28.79 54 Scald
[35] India 3 0.609 101 2009 Mean age 32.03 y 40.9 Mean TBSA 45.8 45.4 Flame
[36] India 3 0.609 222 2006–2007 Mean age 24.58 y 60.8 Mean TBSA 48.75 37 Flame
[37] India 2 0.609 11,196 1993–2002 80% of cases between 51.8 Mean TBSA 50.35% 44.3 Flame
16–55 y
Burn Pain

5
(continued)
6
Table 3 Continued
Country Evidence Number of Study Age Predominant
Publication or Region Level HDI Score Patients Period Distribution Mortality TBSA  10% Male, % Source of Injury
Morgan et al.

[38] Iran 3 0.766 13,248 2010–2012 Mean age 27 y 1.6 Median TBSA 4% 50.5 Scald
[39] Iran 1 0.766 14,227 2010–2011 Mean age 28.85 y 8.9 Mean TBSA 23% 65.9 Flame
[40] Iran 3 0.766 713 2008–2010 Mean age 19.8 y 22.6 NA 54.5 Flame
[41] Iran 3 0.766 6,082 2003–2007 Greatest among 0–10 y 8 Mean 38.7 55.7 Flame
[42] Iraq 3 0.654 884 2009 Mean age 25.6 y 29.4 NA 38.2 Flame
[43] Israel 1 0.894 5,269 2004–2010 Greatest among 0–2 y 3.7 71% 67.3 Scald
[44] Israel 2 0.894 5,000 1997–2003 Greatest among 0–1 y 4.4 56% 68.9 Scald
[45] Italy 2 0.873 2,067 2008 Majority between 0–5 y 5.3 NA 59.3 Flame
[46] Japan 1 0.891 6,401 1983–2003 Mean age 40.4 y 15.4 Mean TBSA 18.8% 63 Flame
[47] Kenya 3 0.548 109 1984–2004 Mean age 14.4 y 12.0 Mean TBSA 22.3% 56 Scald
[48] Kenya 3 0.548 269 2006–2010 Majority less than 5 y 12 NA 59 Scald
[49] Kuwait 3 0.816 1,702 2006–2010 Greatest among 17–45 y 5.8 NA 71 Flame
[50] Kuwait 2&3 0.816 3,680 1982–1997 Greatest among 16–39 y 6.4 Mean TBSA 71% 47.9 Flame
[51] Lebanon 3 0.769 1,524 1992–2012 Mean age 34 (5–98) y 18 NA 61 Scald
[52] Lithuania 1&2 0.839 132,428 1991–2004 Greatest among 0–14 y 3.1 NA 67 NA
[53] Malawi 3 0.445 1,825 1994–1999 Majority less than 30 y 12 71% 52 Scald
[54] Malaysia 3 0.779 110 1991–2001 NA 6.3 Mean TBSA 19% 67 Scald
[55] Morocco 3 0.628 291 2004–2009 Majority between 20–59 y 5 Mean TBSA 21% 62 Flame
[56] Netherlands 3 0.922 9,031 2006–2011 Greatest among 0–4 y 4.1 Median TBSA 4–8% 65 Scald & flame
[57] Nigeria 3 0.514 407 2006–2010 Greatest among 20–29 y 30 16.32% 67.3 NA
[58] Norway 1 0.944 726 2007 Mean age 26.9 y 2.1 NA 65 NA
[59] Oman 1&2 0.793 3,531 1987–2011 Greatest among 0–10 y 8.2 49.4% 60.1 Flame & scald
[60] Pakistan 3 0.538 403 2010–2011 Median age 25 y 5.2 NA 67.2 Scald
[61] Pakistan 3 0.538 1,498 2007–2008 Majority 0–46 y NA NA 60 NA
[62] Pakistan 3 0.538 1,979 2010–2011 NA 36.1 17.50% 53.1 NA
[63] Portugal 1&2 0.83 14,797 1993–1999 Mean age 30 y 3.7 NA 59 NA
[64] Saudi Arabia 3 0.837 240 1997–2003 Majority 0–18 y 7 36.7% 59.2 Scald
[7] Sierra Leone 4 0.413 145 NA Greatest among 0–14 y NA NA 60 Scald
[65] Singapore 2 0.912 2,019 1997–2003 Mean age 32.5 y 4.6 70.5% 68.8 Scald
[66] Singapore 3 0.912 655 2011–2013 Mean age 42.6 y 2.7 Mean TBSA 9% 70.6 Scald
[67] Slovakia 2 0.844 20,865 1993–2004 NA 3.0 NA 59 Scald
[68] South Asia 2 NA 28 studies 1970–2001 NA 0–54 NA 37–88 Flame & scald
[69] South Korea 3 0.898 19,157 1986–2003 Greatest among 0–5 y 8.2 46.9% 66.2 Flame
[70] South Africa 2 0.666 NA NA Mean 4.3 y 27 Mean TBSA 48.5% 54.7 Scald
[71] South Africa 3 0.666 1,024 2001–2004 NA 7.9 NA NA NA
[72] Sri Lanka 3 0.757 345 1999–2001 Median age 22 y 27 Mean TBSA 16% 64.3 Flame
(continued)
 Burn Pain

points are likely to increase the clinical validity of animal

Male, % Source of Injury

Predominant models of pain in the future.

Animal models of burn-induced pain are typically based

Flame
Scald

Scald
Scald
Scald
Scald
Scald
NA on a burn injury that is induced on the plantar skin of

NA
one hind paw in rodents, in contrast to animal models
43.1 used to study other aspects of burn injury, such as
46.1
65.2
67.8

67.6
wound healing, metabolic changes, and infection,
69
67

61
69
where a larger burn injury is commonly induced on the
dorsum or ventral skin of mice, rats, or pigs [119,120].
Mean TBSA 12–19%

The advantage of using the plantar skin of the hind

Mean TBSA 17.5%

Mean TBSA 4.82% paw is that it readily allows the quantification of pain
behaviors, including changes in mechanical and ther-
Mortality TBSA  10%

mal thresholds or weight-bearing behaviors in the ipsi-

lateral hind paw.
77.9%
76%

82%
NA

NA

NA

Dry Contact Heat

10.5

3.14
3.7
1.5
NA

0.4
1.5
3

Dry contact heat is the most commonly used method

for inducing burn injury in rodents and involves exposing
the plantar skin of one hind paw to a heated—often
Greatest among 0–4 y

Greatest among 0–4 y

Greatest among 0–5 y

metal—surface while the rodents are under anesthesia.

This is a clinically relevant model as contact with a dry
Median age 29.2 y

1–2 y & 20–29 y

Mean age 25.3 y
Mean age 17.0 y
Mean age 25.3 y

Mean age 22.5 y

2006–2015 Greatest among

heat source such as an iron, vehicle exhaust, or heater

accounts for 9–14% of burns cases [8,16]. To induce a
Distribution

mild burn injury or superficial burn in rats, the metal sur-

face is set to a temperature of 52–52.5  C and the skin
is exposed for 45 seconds, with constant pressure
Age

maintained by applying a sand pouch with a set weight

to the dorsal surface of the hind paw. This model leads
1987–2004
1997–1999

1996–2002
2012–2014
2010–2011
2003–2007

to the rapid development of mechanical and thermal

2010
2008
Period
Number of Study

allodynia in the injured hind paw, evident within

30 minutes of burn injury and persisting for at least
seven days [104,98,106]. This protocol has also been
205,033

modified for use in mice by reducing the exposure time

24,538
4,741
7,630

1,752
Patients

230
742
264

203

to 25 seconds [121]. In the mouse model, mechanical

and thermal allodynia develop rapidly and persist for at
least four days, along with changes in weight-bearing
behavior. The main advantage of mouse models of burn
HDI Score

injury pain is in the ability to study the specific effects of

0.907
0.822
0.822
0.761
0.761
0.761
0.747
0.835

0.915

NA ¼ not available; TBSA ¼ total body surface area.

gene deletion on the development of burn pain in

knockout mice.

To induce a partial-thickness injury (with blistering) in

Evidence

rats, the contact surface is set to a temperature of

1&2

1&2
Level

3
3
3
1
3

85  C and the skin is exposed for 15 seconds. This

model leads to the rapid development of mechanical
allodynia in the injured paw that persists for eight
United State of

weeks; however, unlike the mild burn injury model, lit-

United Arab
Emirates
Continued

America

tle to no thermal allodynia is observed [110]. The

Publication or Region

Sweden
Country

Ukraine

above protocol used in rats can be slightly modified

Taiwan
Taiwan
Turkey
Turkey
Turkey

to produce a partial-thickness injury model in mice,

using a temperature of 65  C and exposing the plantar
surface of one hind paw for 15 seconds [113]. This
Table 3

model leads to the rapid development of mechanical

and thermal allodynia that will persist for seven to
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]

[81]

14 days.

7
Morgan et al.

Table 4 Patient distribution by age and type of burn injury

Australia USA Europe

Infant, % Child, % Adult, % Infant, % Child, % Adult, % Pediatric, % Elderly, % All, %

Scald 71.6 54.8 27.7 51.5 48.9 23.3 65.9 33.9 36.6
Contact 16.4 19.9 14.0 19.8 14.0 5.3 9.3 10.8 9.6
Flame 4.3 12.1 43.9 7.6 23.0 47.1 13.7 49.1 42.5
Friction 7.8 9.6 3.7
Electrical 3.6 2.4 <1 1.8 4.1 4.1 1.8 7.6
Radiation 2.1 <1 <1 <1
Chemical 6.1 <1 1.2 3.8 2.4 2.2 3.9
Other <1 3 4 7.6
Unknown 16.2 6.9 8.5

Averaged percentages from three studies [5,8,82], with results shown for infants (0–12 mo), children (1–15 y), adults (16 y),
pediatric (0–16 y), and elderly (60 y).

Table 5 Burn patient distribution by age and sex plantar surface of the hind paw to induce a burn injury
in rats [117,118]. This model results in a full-thickness
Australia, % USA, % burn injury that takes four weeks to resolve. Mechanical
and thermal allodynia is not present at the actual site of
Male Female Male Female the burn injury, consistent with local destruction of cuta-
neous nerve endings, but can be detected in the adja-
Infants 2.6 2.1 3.2 2.2
cent skin for two weeks after burn injury [118]. Although
Children 21.6 11.2 14.5 9.0
no changes in thermal hyperalgesia or mechanical allo-
Adults 45.2 17.4 50.7 20.5 dynia were detected in the contralateral paw, expression
of both calcitonin gene–related peptide (CGRP) and
Average percentages from two studies (N ¼ 197,063 patients,
Substance P was upregulated in the contralateral dorsal
including infants [0–12 mo], children [13 mo–15 y], and adults
horn, suggesting changes consistent with central sensi-
[>16 y]) [8,14].
tization. This method is associated with significant tissue
damage that necessitates wound management and an-
tibiotic treatment and may thus lead to ethical concerns
Scalding that would be justified predominantly for studies aiming
to determine effects on wound healing and systemic im-
Scalding is a method where burn injuries are induced pact of burn injuries. However, this method may be suit-
by immersing the dorsum or ventral skin of mice or rats able to model burn injury induced by direct contact with
in water (60–100  C) to induce burns of varying degree, a flame, the most common cause of burn injury in the
dependent on the time and temperature of exposure, clinic [8,16].
and is commonly used to study other aspects of burn
injury as opposed to the pain-related behavior [119].
However, modified scald methods that produce burn in- Ultraviolet Radiation
jury on the hind paws of rats have been described
[114,116]. This model is relevant to the clinic as scald- The UV method involves exposure of the plantar surface
ing is responsible for a third of burns requiring hospital- of the hind paw of rats to ultraviolet B radiation to in-
ization [8,16]. Immersing only the dorsal surface of the duce a burn injury. A dose of 1,000 mJ/cm2 causes a
hind paw in water at 85  C for 12 seconds induces a superficial burn injury without blistering, along with me-
third-degree burn injury, resulting in mechanical and chanical and thermal allodynia that develops rapidly and
thermal allodynia on the plantar surface of the hind paw persists for seven days [122,123]. While UV radiation
of rats that lasts for at least seven days, albeit this can be dosed more precisely than scalding or dry heat
method is associated with significant tissue damage contact, it is unclear whether the mechanisms underly-
and thus raises ethical concerns [116]. ing a burn injury induced by UV radiation are similar to
other causes of thermal injury. It is clear that UV radia-
tion is associated with DNA damage, and in humans
Soldering the long-term effects of UV burns include development
of skin cancers. Surprisingly, thermal burns are associ-
This recently described method utilizes a soldering iron ated with a significant increase in cancer burden, possi-
to apply a 100  C heat stimulus for 30 seconds to the bly due to systemic inflammatory processes [124,125].

8

Figure 2 Mortality was found to be correlated with the
(A) human development index score (HDI; R2 ¼ 0.335)
and (B and C) total burn surface area (R2 ¼ 0.616 and
0.752, respectively). TBSA ¼ total body surface area.
It thus remains to be determined whether exposure to
UV radiation is a suitable model for assessing mecha-
nisms underlying burn-induced pain more generally.
Clinical Applicability of Animal Models
Researchers have an ethical obligation to refine
approaches in studies involving animals to minimize the
pain, suffering, and distress as much as possible.
Therefore, in the case of animal models of burn pain,
careful consideration must be given to determine the
severity of burn injury and study duration necessary to
achieve experimental outcomes. As such, most
animal models of burn-induced pain reported in the liter-
ature are of mild severity (equivalent to a superficial or
Burn Pain
partial-thickness burn) and of short duration (days to
weeks). It is unclear if the severity of the burn has an
impact on the underlying mechanisms of pain, and thus
whether these milder pain models serve as appropriate
models for more severe burns typically necessitating
clinical intervention. In addition, the duration of these
animal studies is typically relatively short, thereby mod-
eling acute pain as opposed to chronic pain, which, as
described below, is clinically more difficult to manage
and can continue for months to years despite healing.
The animal models described thus far tend to focus on
stimulus-evoked rather than background pain as they
apply mechanical or thermal stimuli to the injured area
and quantify withdrawal responses. It could be argued
that stimulus-evoked pain is a surrogate measure of
procedural pain, which, as described below, can often
be severe and difficult to manage. Quantifying back-
ground pain in animals can be challenging, although
behavioral methods that quantify non-stimulus-evoked
pain are increasingly being developed [126–128]. Finally,
the majority of animal models of burn pain induce a
burn injury on glabrous or nonhairy skin, which in
humans is located on palms of the hands and soles of
the feet. The sensory innervations between hairy and
nonhairy skin differ [129,130], and it is unclear what im-
pact this has on the translation to pain from burns that
occur on hairy skin.
Burn Injury Pain Mechanisms
Both human and animal studies have provided signifi-
cant insight into the mechanisms underlying pain after a
burn injury, which has a complex pathology with both
peripheral (Figure 3) and central processes [131,132]
and combines features of acute nociceptive, inflamma-
tory, and neuropathic pain. However, the significant di-
versity in the causes and severity of burn injuries make
it difficult to determine the relative contribution of differ-
ent pathways in individual cases. It should thus be
noted that, in the context of this review, it is not cur-
rently possible to attribute the relative importance of
those mechanisms to the individual pain experience or
analgesia.
Peripheral Nociceptive Mechanisms and
Adaptations in Burn Injuries
Acute Burn Injury Pain. The threshold temperature for
formation of edema in the skin in response to heat is
43  C, which is also the threshold temperature for acti-
vation of the transient receptor potential vanilloid type 1
ion channel (TRPV1) [133,134]. Accordingly, TRPV1 ac-
tivation has been functionally linked to the development
of thermal allodynia in partial-thickness burns [112].
Oxidized linoleic acid generated by thermal injuries also
acts as an agonist at TRPV1 and activates the receptors
post–burn injury [112]. Stimuli above 52  C result in acti-
vation of TRPV2 [135], while TRPV3 and TRPV4 are
9
 Table 6 Animal models of burn-induced pain

10
Duration
Duration of Burn Mechanical Thermal of Pain
Model Species Location Temperature Exposure, s Severity Allodynia Allodynia Behaviors Reference
Morgan et al.

Dry contact heat Rat Hind paw (plantar) 52  C 45 Superficial Y Y 90 min [98–100]
Dry contact heat Rat Hind paw (plantar) 52.5  C 45 Superficial N/A Y 90 min [101]
Dry contact heat Rat Hind paw (plantar) 52  C 45 Superficial N/A Y 120 min [102]
Dry contact heat Rat Hind paw (plantar) 52  C 45 Superficial Y N/A 60 min [103]
Dry contact heat Rat Hind paw (plantar) 52 C 45 Partial thickness Y N/A 7d [104]
Hind paw (dorsal) 52  C 30–40 Partial thickness Y N/A 15 d
Dry contact heat Rat Hind paw (plantar) 52.5  C 45 Superficial Y N/A 120 min [105]
Dry contact heat Rat Hind paw (plantar) 52.5  C 45 Superficial Y N/A 90 min [106]
Dry contact heat Mouse Hind paw (plantar) 52.5  C 25 Superficial Y Y 4d [107]
Dry contact heat Rat Hind paw (plantar) 55  C 30 Not specified Y Y 120 min [108]
Dry contact heat Rat Hind paw (plantar) 85  C 15 Partial thickness Y N 4–8 wk [109–111]
Dry contact heat Rat Hind paw (plantar) 100  C 30 Partial thickness N/A Y 7d [112]
Dry contact heat Mouse Hind paw (plantar) 65  C 15 Partial thickness Y Y 14 d [113]
Scalding Rat Hind paw 60  C 20 Not specified Y N/A 180 min [114]
Scalding Rat Hind paw (dorsal) 85  C 12 Full thickness Y Y 7d [115,116]
Soldering Rat Hind paw (plantar) 100  C 30 Full thickness Y Y 2 wk [117,118]

NA ¼ not assessed.
 Burn Pain

Figure 3 Burn pain mechanisms. A thermal insult to the skin initiates a cascade of mechanisms that are believed to
be involved in the signaling of pain. The group of transient receptor potential vanilloids (TRPV) 1–4 and transient re-
ceptor melastatin (TRPM) 3 are activated by different temperatures. Activation of the thermosensitive channels causes
the release of calcitonin gene–related peptide (CGRP) from the primary sensory nerves, which in turn results in the el-
evation of intracellular Ca2þ levels. The deteriorating cell membrane releases ATP, which targets P2X receptors on
primary sensory nerves. The voltage-gated sodium channel (NaV) 1.7 is essential for thermal allodynia. The trauma
caused to the cell membranes will result in the release of damage-associated molecular pattern molecules (DAMPs)
that will bind to Toll-like receptors, P2X receptors and AIM2-like receptors (ALRs). Following this trigger histamine,
catecholamines, TNF-a, IL-1b, IL-6, oxygen free radicals, nitric oxide (NO), bradykinin, and arachidonic acid cascade
products are released. Furthermore, leukocytes, eicosanoids (including prostaglandins [PGs]), and platelet-activating
factors (PAFs) are recruited. PGE2 activates prostanoid EP1–4 on mast cells, and subsequently histamine is released.
Prostanoid EP3–4, located on the primary afferent terminals and mast cells, furthermore results in release of IL-6.
Lastly, a catecholamine 5-hydroxytryptamine (5-HT) is also released at the site of injury and sensitizes the peripheral
nerves by acting at 5-HT2A.

11
Morgan et al.
thermosensitive channels that are gated by innocuous
temperatures above 33  C and 25  C, respectively.
However, while thermal injury-induced keratinocyte
death has been at least partially attributed to TRPV1-
TRPV4 isoforms, the contribution of these thermosensi-
tive channels, specifically TRPV2-TRPV4, to burn-
induced pain has to-date not been systematically
assessed [136]. Similarly, the transient receptor melasta-
tin 3 ion channel (TRPM3), which is activated at rela-
tively low temperatures, has also been shown to play a
role in heat nociception, with TRPM3-deficient mice dis-
playing attenuated avoidance of noxious heat stimuli
[137]. Activation of these thermosensitive channels has
been shown to evoke the release of the neuropeptide
CGRP from the terminals of primary sensory nerves,
and, accordingly, elevated circulating CGRP levels have
been found shortly after burn injury [138]. In addition,
the neuropeptide Substance P has been found to be
significantly higher in the blood of patients within
12 hours of suffering a burn injury [138]. CGRP acts di-
rectly on a subset of dorsal root ganglion (DRG) neu-
rons, causing elevated intracellular Ca2þ and enhancing
tetrodotoxin (TTX)-resistant sodium current density in
cultured sensory neurons [139]. Substance P also has
direct effects on nociceptors, with lumbar DRGs super-
fused with Substance P displaying a prolonged depolar-
ization [140]. Levels of both Substance P and CGRP in
different layers of the skin have been correlated to the
sensation of pain during wound healing and scarring in
burn patients [141], suggesting that they play a role in
the maintenance of pain after the initial heat insult.
The loss of cell membrane integrity due to elevated heat
results in the release of cell contents, some of which
have also been shown to directly activate nociceptive
neurons. Specifically, ATP is released from the deterio-
rating cell membrane, with the ATP metabolite adeno-
sine found in the fluid of burn blisters [142]. The
pharmacological targets of ATP are the P2X receptors
on primary sensory fibers, where both P2X2 and P2X3
are thought to play a role in burn injury pain. The P2X3
receptor in particular is upregulated in peripheral nerve
terminals of rats after burn injury, and P2X3 antagonists
also inhibited P2X-activated currents in isolated DRGs
from the same animals [143]. In addition, the release of
protons from the acidified inflamed environment likely
further enhances the effect of ATP on P2X2 receptors,
resulting in enhanced perception of pain [144].
The voltage-gated sodium channels (NaV) play select
roles in burn injury pain. The NaV blocker TTX was ef-
fective at reducing thermal hyperalgesia and mechanical
allodynia after full-thickness burn injury in rats [117],
suggesting that TTX-resistant isoforms, specifically the
sensory neuron-specific NaV1.8 and NaV1.9, play a lim-
ited role in burn pain. Consistent with this observation,
the TTX-sensitive isoform NaV1.7 was essential for ther-
mal allodynia in a mouse model of a partial-thickness
burn injury, albeit mechanical allodynia was unaffected
in NaV1.7 knockout mice. In addition, burn injury
resulted in reduced threshold of TTX-sensitive DRGs
12
from wild-type mice but not from NaV1.7 knockout
mice, suggesting that NaV1.7 is essential for thermal hy-
persensitivity after burn injury [113]. These observations
are consistent with the clinical phenotype of humans
with a congenital mutation resulting in loss of function of
NaV1.7, who frequently present with painless burn inju-
ries [145]. Given the intense drug discovery efforts di-
rected at identifying subtype-selective NaV1.7 inhibitors,
it appears likely that novel analgesics with efficacy in
acute burn pain will be developed in the future.
Inflammatory Burn Injury Pain. A burn results in an acute
inflammatory response that can be restricted to the site
of injury or involve systemic inflammatory processes that
trigger a syndrome associated with significant morbidity
and mortality. Trauma from a severe burn injury results
in denaturing of proteins and the leakage of cell plasma
due to the loss of cell membrane integrity. A necrotic
trauma like this results in the release of damage-
associated molecular pattern molecules (DAMPs) [146]
from the cell plasma, which subsequently bind to vari-
ous inflammatory receptors including Toll-like receptors
[147–149], P2X receptors, and AIM2-like receptors
(ALRs) [150], among others. Activation of DAMP recep-
tors and localized ischemia/reperfusion events result in
activation of the alternative complement pathway [151],
the release of histamine [152], catecholamines, TNF-a,
IL-1b, IL-6 [153], oxygen free radicals, nitric oxide, bra-
dykinin, and arachidonic acid cascade products, as well
as the activation and recruitment of leukocytes.
Histamine release results in early local vascular leakage
and peripheral edema, while reperfusion events result in
localized cell apoptosis [154]. Accordingly, activation of
peripheral sensory nerve terminals after burn injuries as
well as sustained nociceptive input post-injury occurs
through a range of stimuli, including the initial thermal
insult, vascular damage, hypoxia from ischemic events,
DAMP receptor activation, and local release of pro-
inflammatory and algogenic mediators and transmitters
such as bradykinin, histamine, eicosanoids, platelet-
activating factor (PAF), nerve growth factor (NGF),
Substance P, and CGRP.
Bradykinin, an important mediator of peripheral vascular
permeability and pain, has been implicated in burn injury
pain since a bradykinin-like substance was found in the
urine of patients with burn injuries [155]. In addition, in-
tradermal administration of the selective bradykinin 2 re-
ceptor antagonist, HOE-140, reduced the occurrence of
edema in a model of burn injury [156] and reduced me-
chanical allodynia in a model of sterile inflammatory pain
[157,158].
Similarly, histamine was detected in the urine of burn
patients [157] and in blister fluid, with levels correlating
to edema formation [152]. Burn injury pruritus or itch is
also mediated by histamine, with 70% of patients
reporting effective relief with antihistamines [159].
A number of eicosanoids have been identified both at
the site of burn injury and systemically, including

prostaglandins (PG) E2, PGF1a, PGF2a, thromboxane
B2 [160], and leukotrienes [161], and these are believed
to contribute to burn pathology. PGE2 is a particularly
important inflammatory mediator in burn pain and con-
tributes to hyperalgesia in a number of ways. These in-
clude activation of the prostanoid receptors EP1–4,
which causes the release of histamine from mast cells
[162], activation of prostanoid EP3 and EP4 receptors
on primary afferent terminals and mast cells, causing
the release of IL-6 [162,163], sensitization of the activa-
tion threshold of TTX-resistant NaV channels [164], inhi-
bition of voltage-gated potassium currents [164], and
sensitization of TRPV1 through prostanoid EP1 recep-
tors [165]. Accordingly, nonsteroidal anti-inflammatory
drugs (NSAIDs) are a firstline treatment for burn pain
and are discussed further in the Treatments section.
Cytokines and inflammatory mediators released both
locally and from recruited leukocytes mediate inflamma-
tion and wound healing, but also contribute to burn-in-
duced allodynia and hyperalgesia. The cytokine and
immune modulators IL-1b, IL-6, IL-8, TNF-a, and TGF-
b, as well as platelet-derived growth factor, have all
been found in the blister fluid of burn patients [153].
While IL-1b has been shown to be an important media-
tor of burn-induced inflammation, knockout of caspase-
1, an enzyme that cleaves IL-1b into its active form, had
no effect on burn-induced mechanical or thermal allody-
nia in mice [166]. IL-6, on the other hand, has been
shown to be an important mediator of burn injury pain
[146]. In rats subjected to a partial-thickness burn, IL-6
concentrations were elevated at the site of the burn cor-
relating with the duration of pain, and treatment with in-
tradermal anti-IL-6 antibodies significantly reduced pain
[167]. In addition, subcutaneous administration of IL-1b,
IL-8, and TNF-a result in mechanical and thermal hyper-
algesia, suggesting that it is likely that these cytokines
contribute to burn injury hyperalgesia [168–170].
PAF has been isolated from polymorphonuclear leuko-
cytes of burn injury patients [171], and administration of
exogenous PAF results in hyperalgesia [172]. PAF
receptor-deficient mice display normal thermal and me-
chanical allodynia but show decreased persistent pain
in response to tissue injury, suggesting that PAF plays a
role in sensitizing peripheral sensory nerves [173].
Similarly, in animal models of peripheral nerve injury, in-
trathecal administration of PAF receptor antagonists de-
creased mechanical and thermal allodynia mediated by
the glycine receptor 3a [174]. Thus, while the contribu-
tion of PAF to burn-induced pain has not been system-
atically assessed, modulation of this inflammatory
mediator may prove a viable option for treatment of in-
flammatory pain associated with burn injury.
Given the substantial body of literature describing the
role of NGF in pain, it is not surprising that this impor-
tant growth factor has also been ascribed a specific
contribution to burn-induced pain. NGF is released into
regenerating skin [175] and contributes to the develop-
ment of systemic hyperalgesia as administration of
Burn Pain
anti-NGF serum resulted in the inhibition of hyperalgesia
in burn injury [176]. NGF-induced systemic hyperalgesia
is mediated by a reduced expression of lumbar l–opioid
receptor expression and increased activation of gluta-
mate receptors. Accordingly, administration of MK-801,
an NMDA receptor antagonist, inhibited systemic hyper-
algesia after thoracic burn injury, consistent with upre-
gulation of NMDA receptor transcripts in DRG neurons
from mice following burn inury [107,177]. It appears that
the high-affinity receptor for NGF, tropomyosin receptor
kinase (TrkA), likely mediates these hyperalgesic effects
as intrathecal administration of antisense oligodeoxynu-
cleotides to TrkA resulted in dose-related decrease of
burn-induced primary mechanical hyperalgesia. Thus,
anti-NGF treatment may provide substantial benefits to
burn patients, albeit this remains to be assessed clini-
cally [104].
The catecholamine 5-hydroxytryptamine (5-HT) is also
released at the site of burn injury and found systemically
[178]. Administration of exogenous 5-HT results in noci-
ceptive behavior including mechanical and thermal
hyperalgesia and allodynia [179–181], which is mediated
by the 5-HT1A, 5-HT2A, and 5-HT3 receptors [180–182].
In an animal model of mild plantar thermal injury, a se-
lective 5-HT2A receptor antagonist resulted in a reduc-
tion in mechanical and thermal allodynia when
administered at the site of injury [183], demonstrating
that locally released 5-HT sensitizes peripheral nerves
by acting at 5-HT2A [183].
Activation of peripheral adrenoceptors is known to result
in the production of cytokines and in nerve regeneration.
In the subsequent weeks after a full-thickness burn, the
expression of the a1-adrenoreceptor is increased in pe-
ripheral nerve terminals and in keratinocytes at the site
of injury [184], albeit changes in expression of a1-adre-
noreceptor subtypes were not systematically assessed.
While administration of the selective a1-adrenoceptor
agonist phenylephrine resulted in increased hyperalgesia
in a human study of mild burn that could be inhibited by
a selective a1-adrenoceptor antagonist, analgesia after
administration of selective a1-adrenoceptor antagonists
alone has not yet been shown [185].
Neuropathic Burn Injury Pain. By definition, neuropathic
pain occurs as a result of lesions or disease of the so-
matosensory nervous system [186]. While the contribu-
tion of neuropathic components to burn pain is not
routinely considered, perhaps due to the parallel experi-
ence of other forms of pain, it is not surprising that
patients can develop both acute and chronic neuro-
pathic pain given the extensive damage to the somato-
sensory system in burn injury. Burn-induced damage to
cutaneous nociceptors and their superficial conducting
fibers likely gives rise to ectopic firing and other patho-
logical processes that cause features of acute and
chronic neuropathic pain, which are often described as
“burning pain,” “on fire,” “pins and needles,” and
“stabbing” sensations [187]. These descriptors, com-
bined with the underlying mechanism of injury, may
13
Morgan et al.
indicate that the patient is suffering from a form of acute
neuropathic pain [188]. Indeed, this pain could very ap-
propriately be referred to as “phantom skin pain”—a
phrase first coined by Atchison and colleagues in
1991 [1].
While the mechanisms underlying burn-induced neuro-
pathic pain have not been studied in detail, treatments
including gabapentin and pregabalin are reportedly ef-
fective in some patients with neuropathic pain symp-
toms [189,190], suggesting that the pathophysiology of
burn-associated neuropathic pain resembles that of
other types of neuropathic pain, at least to some
degree.
Central Nociceptive Mechanism and Neuronal
Adaptations to Burn Pain
Central sensitization appears to be a key contributor to
burn-induced pain. Chronic, bilateral hyperexcitability of
wide dynamic range neurons and microglial activation in
the spinal cord accompany burn injuries [109]. Reversal
of these changes by treatment with minocycline, a tetra-
cycline antibiotic that inhibits microglial activation and
prevents neuropathic pain in other models with central
components, was paralleled by a decrease in burn-
induced allodynia, lending further support to the impor-
tance of central mechanisms.
Early spinal sensitization is thought to develop through
the activation of the NMDA glutamate receptor and sub-
sequent calcium influx as intrathecal administration of
MK-801 has been shown to block both behavioral and
electrophysiological measures of spinal sensitization
[191,192]. In addition, the development of secondary
hyperalgesia seen in burn injury is prevented by intrathe-
cal administration of AMPA receptor antagonists [103],
suggesting that enhanced glutamatergic signaling plays
a key role in central sensitization after burn injury [193].
In addition, due to systemic activation of DAMP recep-
tors and the direct effects of C5a, TNF-a, IL-1b, matrix
metalloproteinases, and other pro-inflammatory media-
tors, the blood-brain barrier becomes compromised af-
ter burn injury. DAMP receptor activation within the
brain results in cerebral inflammation characterized by
increased levels of pro-inflammatory cytokines (IL-1b,
IL-6, and TNF-a) in the brain and cerebral edema.
Central inflammation can be seen as a result of a scald-
ing burn. This can lead to states of delirium and dizzi-
ness. The upregulation of IL-1b within the brain
activates cyclooxygenase and the subsequent produc-
tion of prostaglandins, and this has been shown to con-
tribute to centrally mediated hyperalgesia [194]. TNF-a
in the brain contributes to the development of neuro-
pathic pain [195].
Moreover, based on pathophysiological similarities to
other types of pain, a contribution of descending
14
inhibitory pathways to modulation of burn pain could be
expected, although this has not been systematically
investigated.
Treatment of Acute Burn Pain
Acute pain occurs immediately following burn injury and
can continue for several months until wound healing is
complete as patients undergo many return trips to the
operating theater, repeated dressing changes and
baths, and regular sessions of rehabilitation that include
stretching and physiotherapy. Acute burn pain has a
complex pathology with central and peripheral pro-
cesses, consisting of three dominant pain types: back-
ground pain, procedural pain, and neuropathic pain.
Effective treatment of each of these pain types, which
will be discussed further below, requires the prescription
of regular multimodal analgesia with the addition of
carefully titrated breakthrough analgesia accompanied
by frequent review and assessment by experienced
health professionals. Treatment is generally based on lo-
cal burn center guidelines as limited randomized
placebo-controlled clinical trials are available to evaluate
the effectiveness of analgesics specifically in the burns
population.
A number of techniques have been described to assess
the level of pain experienced due to a burn injury, which
should take into account the intensity of the pain as well
as behavioral and physiological responses. In general,
adult patients are asked to describe their pain using a
numeric pain scale (0–10), visual analog scale (trans-
ected line), or verbal scale (no pain to worst pain)
[196,197]. Assessing the severity of pain in small chil-
dren and infants is more complex, with face scales
(e.g., Wong-Baker Faces Pain Rating Scale) and behavi-
oral observations by medical staff being a more com-
mon measure [198].
Our search strategy yielded a total of 213 articles de-
scribing treatment of burn pain, of which only 14 articles
fitted our inclusion/exclusion criteria (Table 7), highlight-
ing the limited availability of randomized placebo-
controlled clinical trials to assess analgesic efficacy in
the burns population. Most studies (11/14) focused on
the treatment of procedural pain; two studies focused
on background pain, and one study focused on neuro-
pathic pain. Although topical interventions are likely to
have an impact on burn pain, studies assessing phar-
macological treatments alone are difficult to carry out as
wound care interventions, such as dressing changes
and debridement, form the standard of care for partial-
and full-thickness burns.
Background Pain
Background pain is a continuous nociceptive inflamma-
tory pain that is present while the patient is at rest. Pain
management strategies that apply to other forms of pain
 Table 7 Randomized double-blind clinical trials for the treatment of burn pain

Mean Double- Placebo- Primary Significant Mean Score

Study Pain type Population Size, N TBSA, % Randomized blinded controlled Outcome Comparison Difference Reduction

[119] Background Adult 43 6 Y Y Y NRS (0–10) Propranolol (p.o) vs placebo N N/A

[200] Background Adult 53 16 Y Y Y NRS (0–10) Gabapentin (p.o) vs placebo N N/A
[201] Procedural Adult 60 39 Y Y N VAS (0–10) Ketamine (p.o) vs dexmedeto- Y –1.2
midine (p.o)
[203] Procedural Adult 240 N.R Y Y N VAS (0–10) Nitrous oxide/oxygen vs Y –7.7
oxygen
[203] Procedural Adult 45 13 Y Y Y VRS (0–10) Lidocaine (i.v) vs placebo Y –0.4
[204] Procedural Adult 24 38 Y N N VAS (0–10) Ketamine (i.m) vs ketamine/ Y –2.3
dexmedetomidine/tramadol Y –2.1
(i.m)
Ketamine (i.m) vs ketamine/
midazolam/tramadol (i.m)
[205] Procedural Adult 26 7 Y Y Y NRS (0–10) Fentanyl (intranasal) vs N N/A
morphine (p.o)
[206] Procedural Pediatric 24 N.R Y Y Y NRS (0–10) Fentanyl (intranasal) vs N N/A
morphine (p.o)
[207] Procedural Pediatric 8 45 Y Y Y Face Pain Fentanyl (transmucosal) vs N N/A
Rating morphine (p.o)
Scale (0–5)
[208] Procedural Pediatric 14 20 Y Y Y VAS (0–10) Fentanyl (transmucosal) vs N N/A
hydromorphone (p.o)
[209] Procedural Pediatric 19 18 Y ? N Visual Ketamine (p.o) vs paracetamol/ Y –5.4
algometer codeine/diphenhydramine
(0–10) (p.o)
[210] Procedural Pediatric 60 5 Y Y N CHEOPS (4–13) Ketamine (p.o) vs acetamino- Y –1.5
phen/codeine (p.o)
[211] Procedural Adult 79 14 Y Y Y VAS (0–10) Lorazepam (p.o) vs placebo Y –1.6
[189] Neuropathic Adult 90 N.R Y Y Y NPS 2 (0–10) Pregabalin (p.o) vs placebo Y –0.7*
NPS 3 (0–10) –0.9*

CHEOPS ¼ Children’s Hospital of Eastern Ontario Pain Scale; NPS ¼ Neuropathic Pain Scale; NRS ¼ numerical rating scale; VAS ¼ visual analog scale; VRS ¼ verbal rating
scale.
*Week 1 values.

15
Burn Pain
Morgan et al.
also apply to burn injury pain—that is, the utilization of
well-directed, carefully titrated, and regularly reviewed
multimodal analgesia to cover a myriad of receptors and
pain pathophysiologies. This typically includes regular
acetaminophen (paracetamol), regular NSAIDs where
appropriate, and the use of long-acting opioid prepara-
tions, with specific recommendations varying between
burns centers [212].
The use of ketamine in the burn-injured patient is largely
reserved for the facilitation of procedures such as dress-
ing changes, which will be discussed in the next sec-
tion. A constant ketamine infusion to assist with
background pain management is utilized in some burns
centers. In addition to assisting with analgesia, ketamine
is thought to produce benefits through effects on the
NMDA receptor, which may reduce central sensitization,
as discussed above. However, the psychomimetic
effects of ketamine may be distressing for some
patients, which limits its use [213].
Procedural Pain
An especially distressing aspect of burn care for
patients is procedural pain from interventions including
physiotherapy, baths, and dressing changes. Due to the
constraints of hospital services, many of these interven-
tions are done on the ward rather than in the operating
theater under general anesthesia. The pain during these
interventions naturally reaches quite intense levels for a
brief period of time and is often difficult to manage.
Options to manage procedural pain include combina-
tions of short-acting opioids, benzodiazepines, and sub-
anesthetic doses of nitrous oxide/oxygen or ketamine.
Short-acting parenteral or immediate-release opioids,
such as morphine, oxycodone, or fentanyl, can be used
for procedural pain. These can be given in addition to
the sustained-release oral or transdermal opioids that
are providing assistance with the constant background
pain. The choice of opioid, dose, and route of adminis-
tration depend on the patient and type of procedure be-
ing performed. Although they are effective analgesics,
opioids have many dose-limiting adverse effects, includ-
ing sedation, respiratory depression, nausea, vomiting,
and constipation. Depending on the duration of treat-
ment, dose escalation may also be required as toler-
ance to the analgesic effects of opioids develops over
time. However, the risk of opioid-induced hyperalgesia
must always be considered if there is escalating use of
opioids in the presence of poorly controlled pain. This
effect may also be seen acutely when higher doses of
remifentanil are used intraoperatively with subsequent
hyperalgesia and difficult-to-control pain during the re-
covery phase after surgery. Polymorphisms in the l-opi-
oid receptor may also result in variable responses to
opioid analgesics [214].
Although not considered analgesic, benzodiazepines
can be effective in alleviating pain symptoms in
16
combination with other analgesics, most likely due to
their sedative and anxiolytic effects [215]. This has been
demonstrated in a randomized, placebo-controlled trial
in burn patients, which found lorazepam to be effective
in reducing pain scores compared with placebo when
administered in combination with opioid analgesics
[216]. Benzodiazepines with a short to moderate dura-
tion of action, such as midazolam and lorazepam, are
preferred to longer-acting drugs.
Nitrous oxide is an inhalant anesthetic that has modest
analgesic properties when delivered at subanesthetic
doses [216]. Inhaled nitrous oxide and oxygen mixtures
can be a very effective form of analgesia for short pro-
cedures, such as dressing changes [202], as it has a
rapid onset (within seconds) and short duration of ac-
tion. Although it is generally well tolerated, nitrous oxide
can cause nausea and vomiting, precluding its use in
some patients. Repeated or prolonged administration of
nitrous oxide can interfere with vitamin B12 metabolism,
causing serious hematological and neurological adverse
effects and necessitating monitoring and vitamin B12
supplementation as required [217].
Ketamine is an intravenous anesthetic that can have po-
tent analgesic effects when administered at sub-
anesthetic doses. For the management of procedural
pain, ketamine is generally administered by the intrave-
nous or intramuscular route, with a fast onset of action
(1–5 minutes) and relatively short duration of action (10–
30 minutes) [218]. Ketamine induces a dissociative state,
where patients appear awake but are nonresponsive,
and requires close monitoring by an experienced health
professional for potential adverse effects, including air-
way obstruction due to hypersalivation and transient re-
spiratory depression [219]. Upon recovery, patients can
experience distressing psychomimetic symptoms, in-
cluding delirium, agitation, and hallucinations. The inci-
dence of psychomimetic effects is much lower in
children compared with adults and can be reduced by
co-administration with a benzodiazepine [218]. Despite
these adverse effects, ketamine has been demonstrated
to provide effective analgesia for procedural pain in both
adult and pediatric burn patients [201,209,210]. Some
burns centers use an intravenous patient-controlled se-
dation device where patients can provide their own se-
dation using a solution containing ketamine and
midazolam [220].
Regional anesthesia, where a large part of the body,
such as an arm or leg, is anesthetized, can also be
used. This can include using a fascia iliaca block to pro-
vide anesthesia to the antero-lateral thigh, a common
site used to acquire donor skin, or a brachial plexus
block, which provides anesthesia for procedures involv-
ing the arm. On occasion, patients may require a major
procedure, which for various reasons cannot be per-
formed in the operating theater under general
anesthesia. Therefore, a deeper level of analgesia and
sedation, using a combination of the above analgesic/
anesthetics may be required on the burns ward.

Staff appropriately trained with skills in pharmacotherapy
and airway management are required to perform this
task.
In addition to pharmacological interventions, the power
of nonpharmacological approaches cannot be underes-
timated. Hypnosis with post-hypnotic suggestion and
virtual reality, a technologically advanced method of dis-
traction where patients are actively engaged in another
task while undergoing procedural interventions, are
emerging as important nonpharmacologic options with
strong evidence and support [221,222].
Neuropathic Pain
Many of the signs and symptoms in patients with burn
injuries resemble features that are often present in those
with neuropathic pain, which is not surprising given ex-
tensive damage to cutaneous nociceptors and conduct-
ing nerve fibers following burn injury. This neuropathic
pain can occur acutely, being present only at the time
of burn injury, and may become chronic despite healing
of the burn injury. As is generally the case with burn-
induced pain, limited randomized placebo-controlled
trials assessing the effectiveness of treatments for neu-
ropathic pain in the burn population are available.
Systematic reviews have concluded that gabapentin
and pregabalin are effective in the treatment of other
neuropathic pain states, such as diabetic neuropathy,
post-herpetic neuralgia, and fibromyalgia [223,224], and
their use in burn pain has therefore been investigated.
Gabapentin was shown to be ineffective in the treat-
ment of acute burn pain compared with placebo in a
small randomized trial; however, this result could be
explained by a large proportion (70%) of patients with-
out neuropathic pain being included in the study [200].
In contrast, pregabalin was demonstrated to be effective
in alleviating acute neuropathic symptoms following
burn injury in a study that only included patients with
neuropathic pain symptoms [189]. Use of systemic
lignocaine has also been investigated, although no con-
clusions can be drawn about effectiveness in burn injury
based on current evidence [225]. While one study found
a statistically significant reduction in pain scores follow-
ing intravenous administration of lignocaine, the pain
score reduction (–0.4 on a 10-point pain scale) was un-
likely to be clinically relevant [203]. The use of tricyclic
antidepressants and other anticonvulsants that are usu-
ally used to treat neuropathic pain has not been sys-
tematically investigated in the burn population, although
they are used in some burn centers.
Treatment of Chronic Pain Following Burn Injury
Chronic pain following healing of a burn injury can have
a debilitating impact on the function and quality of life of
patients, and finding effective management remains a
significant challenge. The incidence of chronic pain
Burn Pain
following burn injury is reported to be between 25% and
36%, and it is correlated with the severity of the initial
burn injury [226–228]. To date, there is no evidence that
any one intervention is able to reduce the incidence of
chronic pain in the burn-injured population. However,
this lack of evidence does not negate the absolute need
for effective multimodal analgesia in the acute period fol-
lowing the injury and the requirement for this therapy to
be reviewed and titrated on a regular basis. General
principles of chronic pain management should be
employed and should include multimodal analgesia in
the setting of a supportive interdisciplinary team with
psychological intervention as required. The use of long-
term opioid therapy for the management of chronic pain
following burn injury should, as for all forms of chronic
noncancer pain, be diligently monitored for ongoing
benefit and adverse outcomes.
Conclusions
A burn injury is one of the most severe forms of trauma
that a person may experience and is associated with
significant pain and numerous physical, psychological,
material, and social losses. The impact of a burn injury
on the patient is a result of a multitude of factors and
complex processes that together drive the experience of
pain. First and foremost, the physical damage to the
skin not only determines the acute nociceptive re-
sponse, but also contributes to the transition to chronic
pain states. Pain after a burn encompasses nociceptive,
inflammatory, and neuropathic components and may
persist well beyond healing of the injury, with central
sensitization being a key contributor to ongoing pain.
The complex pathophysiological mechanisms underlying
burn pain contribute in part to the difficulties in effective
clinical management, but also present significant oppor-
tunities for synergistic analgesic approaches, albeit
mechanism-based treatments specific to burn pain are
not widely used clinically as yet. Current treatment se-
lection is driven by patient symptoms and is based on
analgesics that are efficacious for other pain types with
similar symptoms, with the assumption that the underly-
ing mechanisms are comparable.
Given the high incidence of burn injuries and the signifi-
cant morbidity associated even with minor burns, im-
proved pain management is essential to improve the
quality of life of burn patients. However, relatively few
human clinical studies have been reported as burn
patients typically belong to a very heterogeneous popu-
lation and frequently present with significant
comorbidities. Accordingly, animal models of burn pain
have provided considerable insight into the underlying
mechanisms of pain from burn injuries and may contrib-
ute to the development of novel analgesic strategies.
With a better characterization of the underlying mecha-
nisms that drive burn pain, improved mechanism-based
treatments promise to deliver analgesia with fewer side
effects and ultimately improve quality of life for these
patients.
17
Morgan et al.
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