Neuropathic Mechanisms in the Pathophysiology of

Burns Pruritus: Redefining Directions for Therapy

and Research
Ioannis Goutos, BSc (Hons), MBBS (Hons), MRCSEd

Pruritus in burn wounds is a common symptom affecting patient rehabilitation. Over

the last decades, there has been a resurgence of interest into more effective strategies to
combat this distressing problem; nevertheless, no reports exist in the literature to pro-
pose pathophysiological mechanisms responsible for the generation and persistence of
pruritic symptoms in the late phases of burns rehabilitation. Neuronal pathways mediat-
ing pruritic and painful stimuli share striking similarities, which allows the compara-
tive exploration of the less extensively studied pruritic mechanisms using pain models.
Furthermore, emerging anatomical, neurophysiological, and pharmacological evidence
supports the involvement of neuropathic mechanisms in chronic burns pruritus. This
work updates the conceptual framework for the pathophysiology of burns itch by
embracing the contribution of the central nervous system in the maintenance of symp-
toms into a chronic state. The proposed pathophysiological model paves new avenues
in burns pruritus research and is likely to have implications in the quest for more effec-
tive therapeutic regimens in clinical practice. (J Burn Care Res 2013;34:82–93)

Pruritus or itch is a distressing symptom affecting the
majority of patients recovering from burn injuries.1 Its
pathophysiology is not well understood; nevertheless,
it is widely believed that histamine release in the wound
is the key mediator of symptoms across all phases of
rehabilitation.2 A number of reports have raised the
notion that the central nervous system (CNS) is likely
to be involved in the generation and maintenance of
pruritic symptoms.3–5 This article attempts to provide
an update of the pathophysiology of burns itch by uti-
lizing a comparative exploration of pruritic and pain
mechanisms, as well as by integrating emerging ana-
tomical, neurophysiological, and pharmacological data.
WOUND HEALING AND PRURITIC
SYMPTOMS
Healing represents a dynamic continuum of events
in the direction of restoring the anatomical and
From the Department of Plastic and Reconstructive Surgery, John
Radcliffe Hospital, Headley Way, Oxford, United Kingdom.
Address correspondence to Ioannis Goutos, Department of Plastic
and Reconstructive Surgery, West Wing, John Radcliffe
Hospital, Headley Way, Oxford OX3 9DU, United Kingdom.
Copyright © 2013 by the American Burn Association
1559-047X/2013
DOI: 10.1097/BCR.0b013e3182644c44
82
functional relationships of injured tissues; three
phases of wound healing in response to trauma
including burn injuries are recognized:6
1. Inflammatory phase. The initial days following
injury are characterized by tissue vasodilatation
(secondary to mediator release including hista-
mine) and an influx of neutrophils peaking at
24 hours. At 48 to 72 hours postinjury, tissue
macrophages become the predominant type of
inflammatory cells resident in the wound bed
and appear to act as one of the key regulatory
cells for the repair of damaged tissues.
2. Proliferative phase. This corresponds to the
period between day 4 through to week 3
postinjury and is characterized by fibroblast
activation, secretion of collagen, angiogenesis,
and epithelialization.
3. Remodeling phase. Collagen production and
breakdown continue for 6 to 18 months during
which time fibers reorganize along the lines of
tension. The vascularity of the wound increases
and fibroblasts along with myofibroblasts cause
wound contraction.
Another cellular population important in wound
repair is that of mast cells; they appear in the late
Journal of Burn Care & Research
Volume 34, Number 1 Goutos  83
phases of healing and are involved in key events
including the proliferation and remodeling of con-
nective tissue elements.
A prospective study of adult patients identified itch
as a significant problem over a 2-year period postburn
and specified a pattern of predictors for the persistence
of symptoms.7 At 3 months, pruritic complaints were
predicted by female sex, TBSA, the number of surgi-
cal procedures (implying a deep injury component),
and posttraumatic stress disorder (PTSD) symptoms
measured at 2 weeks postburn. At 12 months, female
sex, the number of surgical procedures, and PTSD
symptoms were significant predictors, whereas at 24
months, only the last two persisted as predicting fac-
tors for postburn pruritus. In addition, the incidence
of itch at 3 months followed a normal distribution,
implying that “acute” pruritus affects the majority of
patients (with superficial partial through to full thick-
ness burns) and relates to a period from wound clo-
sure to the early remodeling phase of healing. On the
contrary, the distribution at 12 and 24 months was
found to be “skewed to the left,” implying that only
a subgroup of patients will continue to be troubled
by “chronic” pruritus, with risk factors being the
presence of a deep burn (requiring surgical interven-
tion) and the psychological state of the individual (as
manifested by PTSD symptoms). It becomes evident
that pruritus is a symptom that can span across a long
period of time extending beyond the conventional
phases of tissue repair and is likely to have several
mechanisms accounting for its occurrence in differ-
ent stages of rehabilitation.
Pruritic Pathway
A wide range of substances are believed to activate
receptors on sensory nerve fibers to initiate pruritic
sensation.8 One of the most widely studied pru-
ritogenic mediators is histamine, which binds to
receptors (mainly the H2 subtype) present on nerve
endings.9 Histamine is released in the context of acute
inflammation and in granulation tissue (formed as a
byproduct of collagen production); this pattern elu-
cidates the involvement of this compound in burns
pruritus in the early phases of wound healing.10
Activation of a subset of C fibers by pruritogenic
mediators leads to the transmission of impulses
orthodromically to the spinal cord via the dorsal root
ganglion.8 These fibers appear to be “itch selective”
with a slow conduction velocity, prolific terminal
branching, and extensive innervation territories.11
Neuronal stimulation also occurs via the antidromic
axon reflex; this refers to the propagation of impulses
spreading from primary afferents in the injured area
to neighboring nerve fibers.1 Neuroinflammatory
transmitters including substance P (SP) released by
a variety of cells, including mast cells, appear to play
a pivotal role in the generation of pruritic impulses
travelling via the antidromic reflex.12 Itch-specific
neurons in the superficial dorsal horn lamina carry
impulses via the contralateral spinothalamic tract
and the thalamus to activate the following brain
domains: contralateral somatosensory cortex, ipsilat-
eral and contralateral motor areas, and the prefrontal
cortex and cingulated gyrus.13 A diagram of the key
stages involved in pruritic transmission is shown in
Figure 1.
Twycross et al14 classified pruritus into the follow-
ing categories:
1. Pruritoceptive, originating in the skin as exem-
plified in urticarial conditions.
2. Neuropathic, arising from anatomical dysfunc-
tion in the afferent pathway (eg, postherpetic
pruritus and brain tumors).
3. Neurogenic, resulting from CNS dysfunction
without evidence of anatomical pathology, indi-
cating abnormal neurochemical activity (eg,
the action of opioid peptides in liver disease).
4. Psychogenic, associated with psychiatric
conditions.
Other authors have advocated merging the neuro-
pathic and neurogenic categories into one, implying
dysfunction of the CNS either because of a neuro-
anatomical or neurochemical underlying cause.15 For
the purpose of this work, the merged terminology
has been adopted, which will be referred to through-
out the article as neuropathic or central in contrast
to the pruritoceptive/inflammatory mechanisms,
which will be referred to as peripheral.
THE ROLE AND EFFECTIVENESS OF
ANTIHISTAMINES IN THE TREATMENT
OF BURNS PRURITUS
Antihistamines have been the mainstay for burns pru-
ritus management to date. A survey among 22 U.K.
burns units revealed that 90.91% use antihistamines
as first line and 70% as second-line agents to combat
pruritus.2
The rationale for using these compounds rests
on the highly histaminic milieu predominating the
wound in the initial (inflammatory and proliferative)
phases of healing because of mast cell activation and
collagen formation.10 It is interesting to investigate
the existing evidence regarding the efficacy of anti-
histamines during the course of burn rehabilitation.
 Journal of Burn Care & Research
84  Goutos January/February 2013

Figure 1.  Schematic diagram of the pruritic pathway. Healing/healed burned skin releases a wide variety of pruritic media-
tors including histamine and neuroinflammatory transmitters like substance P (SP).8,12 A subset of C fibers transmits impulses
in an orthodromic manner to the spinal cord via the dorsal root ganglion.8 In addition, impulses spread from afferents in the
injured area to neighboring nerve fibers via the antidromic axon reflex (arrow); this involves the release of SP from neurons
and mast cells (depicted in the skin), which enhances the input to the CNS.46 Impulses are carried via the ascending spinotha-
lamic tract and the thalamus to higher CNS areas (including the contralateral somatosensory cortex, ipsilateral, contralateral
motor areas, and the prefrontal cortex and cingulated gyrus) for sensory registration.13

1. Inflammatory and early proliferative phases. antihistamines (diphenhydramine, hydroxy-

An open trial of burns inpatients in the inflam-
matory and early proliferative phase of heal-
ing compared the therapeutic response to two
stepwise therapeutic protocols: one employ-
ing chlorpheniramine and the other gabapen-
tin initially with both gradually escalating to a
combination of agents. Results revealed that
74% patients achieved satisfactory symptomatic
relief with a comprehensive histaminic block-
ade using chlorpheniramine, cyproheptadine,
and hydroxyzine. Interestingly, the response to
gabapentin monotherapy was higher compared
to the single antihistamine-chlorpheniramine
(41.46 vs 10%; t = 3.80; df = 89; P < .001).
Additionally, the combination of gabapentin
with two antihistamines (cetirizine and cypro-
heptadine) was superior to three antihistamines
(chlorpheniramine, hydroxyzine, cyprohepta-
dine; x2 = 12.2; df = 1; P = .001).16 This study
reveals that in the early stages of healing, com-
prehensive histaminic blockade can be effec-
tive in relieving symptoms; nevertheless, agents
acting on the CNS have a superior therapeutic
contribution in these phases of recovery.
2. Late proliferative and remodeling phases. A
study investigating the use of a variety of
zine, and chlorpheniramine) in burns outpa-
tients showed only 20% achieved complete
symptomatic relief, whereas 60% reported par-
tial relief and 20% had no response to any of
the employed agents.17 A recent randomized,
controlled trial of 20 burns patients in the early
remodeling phase (wounds completely healed
<1 month postinjury) confirmed the superior-
ity of gabapentin to cetirizine in terms of symp-
tomatic benefit. The mean Visual Analogue
Scale (VAS) reduction was higher for gaba-
pentin compared to cetirizine (95 vs 52%, P <
.01) with the additional benefit of a much faster
onset of symptomatic relief (day 3 VAS of 74 vs
32%; P < .01).18 In addition, in patients receiv-
ing a combination of gabapentin and cetirizine,
the reduction in VAS was 94%, a response not
statistically significant compared to gabapentin
monotherapy (P > .05).
Summation of the existing evidence for the treat-
ment of burns itch suggests that in the early phases
of healing, an aggressive histaminic blockade can be
effective in relieving symptoms. In the later stages
of healing, burn wounds appear to become increas-
ingly unresponsive to antihistaminic therapy. There
are several possible explanations for this, including
Journal of Burn Care & Research
Volume 34, Number 1 Goutos  85

a) lack of successful “peripheral” therapeutic strat- considered a submodality of pain until a dedicated
egies. Given the large number of pruritogenic neuronal circuitry was discovered to elucidate pru-
agents released in the burn wound, it is plau- ritic transmission.24
sible that studies so far have not targeted the
1. Peripheral circuitry. No specific “itch receptor”
“key peripheral players” in the complex periph-
has been identified as yet, and pruritic media-
eral component of the pruritic pathway;
tors appear to act on terminals of C fibers,
b) involvement of pathophysiological mecha-
which along with Aδ fibers are known to trans-
nisms different from histamine release.
mit painful signals. Itch-specific C fibers differ
The superiority of agents acting on the CNS raise
from pain C fibers by having slower conduc-
the possibility that central/neuropathic mechanisms
tion velocities, extensive innervation territo-
come into play in a similar manner to those involving
ries, and prolonged responses to histamine.11
sensitization in neuropathic pain models. This expla-
Pruritic mediators include histamine, tryptase,
nation appears plausible in the face of evidence sup-
and interleukins, whereas pain predominantly
porting the maintenance of pruritic symptoms into a
utilizes acetylcholine, muscarinic, and adenos-
chronic phase in a considerable number of patients.7
ine transmitter systems.25 Nevertheless, SP
and other neuropeptides (including calcitonin
NEUROPATHIC PAIN AND BURNS gene–related peptide [CGRP]) are common in
ITCH—SIMILARITIES IN CLINICAL the induction and maintenance of both sensa-
PRESENTATION tions via the antidromic axon reflex.26
2. Central circuitry. Both painful and pruritic stim-
Neuropathic nociception can be defined as unpleasant
uli are carried via the spinothalamic tract to acti-
sensation arising as a result of a primary biochemical
vate a variety of CNS areas including the nucleus
or anatomical abnormality in the CNS or secondary
medialis dorsalis (thalamus), anterior cingulate
to changes in the peripheral nervous system. In terms
dorsal insular cortex, premotor, supplementary
of its temporal pattern, it can develop within the time
motor area, primary somatosensory cortex, and
scale of an acute injury; nevertheless, in most cases, it
cerebellum.13,27–29 These areas are activated in
presents as a chronic and persistent sensory disturbance
pain pathways, and the differences between pain
following an initial injury to the nervous system.19
and itch processing are thought to result from
Neuropathic pain is characterized by the copresence
different activation patterns of these identical
of positive symptoms (increased sensitivity to stimuli)
areas.30 Striking similarities exist in sensitization-
including hyperalgesia and negative symptoms includ-
associated signs in patients affected by chronic
ing hypoesthesia as manifested by elevated thresholds to
painful and pruritic conditions. Hyperknesis
touch, vibration, pinprick, and cold/warmth stimuli.20
(increased sensitivity to pruritic stimuli) is a
A number of studies in healed second- and third-degree
common feature in pruritic disorders and mir-
burns and grafted wounds in the late remodeling phase
rors hyperalgesia (mildly painful stimuli felt as
of healing have confirmed the presence of similar phe-
more painful in the zone surrounding the injury)
nomena accompanying pruritic symptoms (see section
in painful conditions. Alloknesis (nonpruritic
on ‘emerging evidence of neuropathic mechanisms
stimuli evoking itching) is similar to allodynia
involved in burns pruritus from neurophysiologi-
(normally painless touch sensation in uninjured
cal’).21,22 In addition, neuropathic phenomena appear
surroundings being felt as painful).31,32
to be more pronounced at night time and in nonam-
bulatory states in contrast to inflammatory/acute pain,
which usually worsens with activity; this temporal pat- MECHANISMS UNDERLYING
tern has been a widespread observation in patients NEUROPATHIC CONDITIONS
troubled with burns itch.2,23 These similarities in clinical
A neuropathic state is characterized by two main
features provide an indication that a neuropathic ele-
processes in the nervous system20:
ment is likely to be present in burns pruritus.
1. Peripheral sensitization. Injury to the periph-
eral afferent nerves results in an altered sum-
COMPARISON BETWEEN PAIN AND
mative stimulatory input to the CNS.
ITCH NEUROLOGICAL PATHWAYS
2. Central sensitization. Autonomous ongoing
Both pain and pruritus describe unpleasant sensa- aberrant activity develops in the CNS, which
tions with a distinct but converging neurophysi- accounts for the “chronic” persistent sensory
ological and anatomical basis. Itch was initially disturbance.

86  Goutos January/February 2013
Peripheral Sensitization
Two main theories have been proposed to account
for the occurrence of abnormal peripheral affer-
ent signals capable of sensitizing components of
the CNS:
•• Injured afferent hypothesis. Injury to peripheral
afferent fibers causes neuromas, which con-
sist of unmyelinated C-fiber sprouts growing
from the damaged axons. These show ongoing
spontaneous neuronal activity and abnormal
excitability because of increased sensitivity to
chemical, thermal, and mechanical stimuli.33,34
•• Intact nociceptor hypothesis. According to this
theory, the nociceptors that survive injury
innervating the affected region by the tran-
sected nerve afferents become sensitized
and develop spontaneous activity.34 Periph-
eral nerve lesions cause several changes at the
molecular level including the release of chemi-
cal substances including prostaglandins, bra-
dykinin and cytokines, and tumor necrosis
factor-α as well as changes in the expression of
receptors and ion channels. These substances
are known to be capable of sensitizing nocicep-
tors, thereby altering the properties of unin-
jured afferents.20,33
Central Sensitization
The following mechanisms have been proposed to
underlie central sensitization:
•• Increase in the activity of dorsal horn projection
neurons. Peripheral injury induces an upregula-
tion of the α2δ subunit of calcium channels in
the dorsal root ganglion and spinal cord35 with
a resulting increased release of the excitatory
neurotransmitter glutamate.34 Depolarization
of nerves by mediators including SP leads to
the opening of N-methyl-d-aspartate (NMDA)
glutamate channels with subsequent calcium
release and lowered sensitivity of nerves to
glutamate.36 One of the mechanisms account-
ing for the effectiveness of gabapentin in neu-
ropathic disorders, involves blockade of the
upregulated α2δ subunit of calcium channels in
the CNS.37,38
•• Loss of afferent inhibition (deafferentation
theory). Under physiological conditions, the
CNS receives an equilibrium of excitatory and
inhibitory input from several types of afferent
(myelinated and unmyelinated) fibers. Loss of
Journal of Burn Care & Research
Aβ myelinated fiber input as a result of injury
appears to be pivotal in promoting hypoactivity
of interneurons that inhibit nociceptive affer-
ents, hence allowing more noxious stimuli to
reach higher CNS centers.39
•• Loss of CNS inhibitory neurons. Following
peripheral nerve injury, the ongoing activ-
ity from primary afferents has been shown
to cause a degeneration of dorsal horn nerve
fibers including γ-aminobutyric acid (GABA)
interneurons. This results in decreased inhibi-
tion to nociceptive pathways and contributes to
hypersensitivity and chronic pain.40 This type
of response allows the CNS to compensate for
the loss of peripheral neurons by increasing the
system “gain” (concept of CNS plasticity).41
•• Loss of descending inhibition. Descending path-
ways with antinociceptive activity exist in the
CNS, the contribution of which is inhibited
in neuropathic pain resulting in increased
excitability in the CNS. The disinhibition in
these parts of the nervous system has been
proposed to act as an additional compensa-
tory mechanism for the loss of sensory input
resulting from peripheral nerve injury in neu-
ropathic models.42 These descending pathways
are dependent on monoamines such as nor-
epinephrine, 5-hydroxytryptamine (5HT) or
serotonin and dopamine as well as opioids.20
Ondansetron is a selective antagonist for spi-
nal 5HT3 receptors, which accounts for the
therapeutic benefit observed in blocking neu-
ropathic pain signals.43
•• Synaptic reorganization. Neuropathic states
have been linked with alterations to the func-
tional topography in the primary somato-
sensory cortex. Peripheral nerve transection
induces a state of acute deafferentation in
the nervous system, and misdirected axonal
growth at the site of injury results in an abnor-
mal input to cortical maps. This induces a reor-
ganization of the somatosensory cortex with a
resulting new and “distorted” mapping of the
skin originally innervated by the injured affer-
ents. The potential for restoration of cortical
reorganization (plasticity) appears to be related
to the severity of the injury and the ability of
injured afferents to reinnervate their former
targets.41
A schematic overview of the key peripheral and cen-
tral sensitization mechanisms involved in a neuro-
pathic state is shown in Figure 2.
Journal of Burn Care & Research
Volume 34, Number 1 Goutos  87

Figure 2.  Schematic representation of key processes involved in a neuropathic state. Peripheral sensitization can occur in
accordance with the injured afferent hypothesis involving neuroma formation at the site of transected nerve fibers (square
blocks) or because of sensitization of uninjured fibers at the periphery of the injury site—intact nociceptor hypothesis (bro-
ken line).33,34 Central sensitization involves various mechanisms including 1) increased activity of dorsal horn/spinal neurons
because of upregulation of the α2δ subunit of calcium channels,35 2) degeneration of inhibitory CNS neurons,40 3) hypoac-
tivity of interneurons because of deafferentation,39 4) disinhibition in descending antinociceptive pathways,42 and 5) synaptic
reorganization.44

Emerging Evidence of sensory phenomena associated with peripheral loss

Neuropathic Mechanisms
Involved in Burns Pruritus
From Neurophysiological
Studies
Several studies have confirmed the high prevalence of
sensory dysfunction in healed burn wounds in terms
of the copresence of positive and negative sensory
phenomena.
In a study of 60 patients who had undergone skin
grafting procedures for burns (mean of 27 months
postburn and 26.5 months postgrafting), 58 (97%)
showed markedly diminished or absent responses to
sharp, dull, cold, and light touch stimulation and 59
(98.3%) to heat application over the grafted areas.
These patients had a number of sensory complaints
in their wounds including tingling and burning sensa-
tions, whereas 25% of the symptoms concerned chronic
itching.21 Depth of injury appeared to be the best pre-
dictor of altered sensation in this cohort of patients.
In other words, itch in the late stages of rehabili-
tation represents a positive sensory phenomenon in
wounds with otherwise decreased sensibility. This
work provides evidence of the coexistence of negative
of myelinated afferents (deafferentation) and occur-
rence of positive symptoms (itch) in the wound.
This association represents an important mechanism
of CNS sensitization in neuropathic models accord-
ing to which deafferentation leads to hypoactivity
of interneurons, which normally inhibit nociceptive
afferents from reaching higher CNS centers.39
Another group investigated tactile, thermal, and
pain sensibility thresholds in 121 adult patients with
healed second- and third-degree upper limb burns
more than 18 months postinjury.22 Significantly
higher sensory thresholds for all sensory tests (pres-
sure, two-point discrimination, heat, cold, and heat
pain) were revealed in burned patients compared to
healthy controls (P < .0001). The severity of the sen-
sory deficit was found to be a function of burn depth,
with deeper injuries (which had required skin grafts)
displaying significantly higher thresholds. In con-
trast, superficial burn wounds had sensory thresh-
olds comparable to control patients. Given that these
cutaneous sensitivity deficits (modalities carried by
myelinated fibers) were significantly associated with
the presence of paraesthetic sensations at these sites,
the study is of great importance in establishing a link

88  Goutos January/February 2013
between loss of primary afferents (deafferentation)
and abnormal sensations as a neuropathic mecha-
nism in burns pruritus.
The presence of negative symptoms including
hypoesthesia in burn wounds is explained by
considering the damage inflicted to neurons by the
thermal injury and the incomplete/abnormal fiber
regeneration associated with healing (surgery or
secondary intention). Large Aβ myelinated axons have
specialized preneuronal elements necessary for their
mechanical detection function (eg, Merkel bodies for
vibration, Pacinian for pressure/vibration, and Ruffini
corpuscles for temperature registration); hence, their
absence from the healed skin explains functional deficits
for the corresponding sensory modalities revealed
during these neurophysiological experiments.44–47
Emerging Evidence of
Neuropathic Mechanisms
Involved in Burns Pruritus
From Neuropeptide Expression
Studies
Scar hypertrophy is a common sequel of many burn
wounds and is more common in injuries with a deep
dermal component, which is a known risk factor for
chronic burns pruritus.7
Neuropeptides are expressed by sensory neurons
and a variety of other cells in the skin including kera-
tinocytes, endothelial cells, and fibroblasts.26 SP and
CGRP are the two most commonly investigated
neuropeptides in humans. They appear to have both
efferent functions (mediating neurogenic inflam-
mation) and afferent functions by acting as cotrans-
mitters in the spinal cord mediating nociceptive
processing and leading to CNS hyperexcitability.48
SP is an undecapeptide, which is synthesized in the
dorsal root ganglia and transported to the peripheral
sensory nerve terminals. At the level of the wound,
low concentrations of SP have been found to sen-
sitize mast cells and enhance the release of tumor
necrosis factor-α, histamine, leukotriene B4, and
prostaglandins. These substances are known to be
involved in pruritus by priming afferent nerve fibers,
establishing a reinforcing interaction among neu-
rons, keratinocytes, and mast cells.24
CGRP is another abundant neuropeptide in the
skin, which often colocalizes with SP. One of the
prominent effects of CGRP is local vasodilatation
and potentiation of effects caused by other peptides
including SP released from mast cells.26
Several studies investigating neuropeptide expres-
sion in hypertrophic scars and skin grafts provide a
platform to understand the neurochemical basis of
Journal of Burn Care & Research
itch in deep dermal injuries. Hypertrophic scar biop-
sies from nine patients with pain and itch complaints
of varying etiology including burns were investi-
gated for the presence of a variety of neuropeptides
and compared to five nonhypertrophic scars and
three controls. Biopsies from patients with hyper-
trophic scars demonstrated a higher density of neu-
ropeptides including SP and CGRP compared to
controls, whereas those with nonhypertrophic scars
lacked both.49 Interestingly, only SP-immunoreactive
nerves appeared to be able to penetrate the densely
packed collagen and fibroblast matrix of the hyper-
trophic scar, whereas nerves expressing other neuro-
peptides including CGRP were found in regions of
more loosely packed connective tissue. The authors
of this work proposed that the abnormal sensory
phenomena in hypertrophic scars are attributed to
the presence of neuropeptides, whose nociceptive
inflammatory activity confers low sensory threshold
for impulse transmission and results in spontaneous
afferent firing.
In line with the above findings, another study
showed an overall decrease by 54% of axon immu-
nostaining in grafted human skin postburn com-
pared to control (P < .005); this was demonstrated
using protein gene product 9.5 (PGP9.5), which is a
pan axonal marker. In contrast, SP nerve fibers were
significantly elevated by 177% compared to control
unburned skin (P < .05) and appeared to correlate
with reports of pruritus in 10 out of the 11 grafted
patients. A statistically significant negative correlation
was also identified between total nerve fiber count
and sensory thresholds carried by myelinated fibers
for vibration, touch, warm, and pinprick stimuli.47
Since SP neurons form a prominent component
of the unmyelinated nerve population, and PGP9.5
stains all axons irrespective of diameter, a gross defi-
ciency of myelinated nerve fibers was identified. In
other words, pruritic phenomena in grafted skin are
mediated by a state of C-fiber hyperinnervation in
a milieu of deafferentation; this disturbs the normal
balance of peripheral stimuli that the CNS receives
under uninjured circumstances, contributing to a
neuropathic state. Additionally, emerging evidence
suggests that under conditions of physiological and
psychological stress, there is an upregulation in the
number of intracutaneous SP positive nerve fibers
and SP immunoreactivity in the dorsal root gan-
glia.50 The above findings help elucidate the link
between deep burn injuries, PTSD, and chronic pru-
ritic symptoms.
In another prospective study, burn wound biop-
sies from 22 patients with spontaneously healed
partial thickness injuries were investigated for nerve
Journal of Burn Care & Research
Volume 34, Number 1 Goutos  89
outgrowth and neuropeptide expression at 1, 4,
and 7 months postinjury.51 The nerve fiber density
gradually increased over the course of the study but
never reached levels observed in the matched con-
trolled skin. Additionally, no significant difference
was observed in neuropeptide expression including
SP and CGRP between burned and control skin.
In conclusion, superficial burns (characterized
by an acute pattern of pruritic symptoms) are
accompanied by neuropeptide expression identical to
normal skin, whereas deep dermal injuries (prone to
chronic pruritus) are associated with an abundance
of neuropeptides. The exact temporal pattern of
neuropeptide expression in human scars and how
it relates to neuropathic phenomena remains to be
elucidated with more research.
Neuropathic Pruritus Disease
Model—Postherpetic Itch
Very few pruritic diseases with a neuropathic patho-
physiology have been described in the literature.
Their clinical presentation in terms of the nature of
symptoms (including their persistence beyond the
conventional time span of tissue repair), histologi-
cal findings, and response to treatment are strikingly
similar to burns pruritus. The underlying patho-
physiological mechanisms that have been proposed
are largely based on models of neuropathic pain
and provide a useful platform to reinforce theories
explaining chronic burns itching.
Postherpetic itch provides an excellent model for
the study of neuropathic pruritic processes. Despite
the very limited attention drawn to this condition
in the literature, it represents the most common
cause of a neuropathic pruritic disorder because of
reactivation of varicella zoster virus in the sensory
ganglia.52 A case report investigated a 39-year-old
patient who developed intractable right forehead
postherpetic itch. Her symptoms were unresponsive
to a variety of conventional medications, including
antihistamines, as well as to transection of the supra-
orbital nerve supplying the affected area. Sensory
testing concluded to increased thresholds to heat,
cold, pinprick, and mechanical stimuli in the pruritic
area, whereas a biopsy of the affected integument
demonstrated 96% loss of sensory neurons by means
of loss of PGP9.5 staining. In pathophysiological
terms, pruritus featured in a histological background
of overall diminished innervation (deafferentation)
in the affected cutaneous territory. The laboratory
findings combined with the lack of response to
therapeutic interventions prompted the authors to
propose the involvement of “central” mechanisms.
These include, apart from the deafferentation theory,
the intact nociceptor hypothesis, according to which
symptoms are generated from stimulation of itch
fibers in adjacent unaffected dermatomes because
of neurotransmitters released in the affected area.53
The latter mechanism is highly plausible in pruritic
phenomena given the nature of the unusually large
innervation territories of itch-specific neurons (up to
8.5 cm), which allows them to extend beyond tradi-
tional small dermatomal territories.11
Another study elucidated a different aspect of
the deafferentation theory in postherpetic neural-
gia. Epidermal immunolabeling against PGP9.5
in patients with or without postherpetic neuralgia
revealed that the absence of chronic pain requires the
preservation of a minimum density of primary noci-
ceptive neurons of approximately 650 neurons/mm2
skin surface area.54 This finding is reminiscent of the
“minimum residual structure” hypothesis, which
states that near-normal function can be maintained
following neural injury, provided a certain minimum
number of neurons survive.55 In other words, deaf-
ferentation resulting from the injury of a critical
number of peripheral neurons causes a maladaptive
hyperexcitability in the CNS provoking chronic sen-
sory phenomena.
Evidence Arising From the
Effectiveness of Therapeutic
Approaches Acting on the CNS
Gabapentin
Gabapentin has been shown to reduce neuropathic
pain associated with many syndromes including
postherpetic neuralgia and diabetic neuropathy in
double-blinded, placebo-controlled trials.56,57 In
the burns literature, apart from the studies already
quoted supporting the superior therapeutic benefit
of gabapentin in itch, it appears that the agent con-
fers significant advantages in the arena of pain man-
agement. A recent study revealed that administration
of gabapentin to 10 acutely burned patients (for 21
days beginning from day 3 postburn) compared to
a retrospective control group resulted in decreased
morphine requirements both in the acute and in
the posttreatment period (P < .05).58 The persis-
tent therapeutic effect into the posttreatment period
is attributed to the ability of gabapentin to prevent
CNS sensitization. Binding sites for gabapentin are
concentrated in the outer layer of the cerebral cortex
and in the superficial laminae of the dorsal horn.37,59
The exact mechanism of action is thought to rely on
a combination of effects including

90  Goutos January/February 2013
•• Blockade of upregulated α2δ subunits of volt-
age-gated Ca channels resulting in the reduced
release of excitatory amino acid transmitters.37,38
•• Increased synthesis and release of γ-aminobutyric
acid in the CNS, which can counteract the
effects stemming from the degeneration of
GABA dorsal horn inhibitory interneurons.40,60
Ondansetron
Several reports and clinical trials have demonstrated
benefit from the use of 5HT3 receptor antagonists in
cholestatic pruritus, the neuropathic basis of which
is believed to rely on increased activity of excitatory
CNS pathways.61,62 A double-blinded, randomized,
crossover trial compared the efficacy of a single dose
of 4 mg ondansetron to 25 mg dyphenhydramine
in pruritic burn wounds. The study concluded that
ondansetron is more effective than the antihistamine
tested as judged by the greater reduction of pre- and
posttreatment itch scores (3.70 vs 2.59; P < .05).
Serotonin has a well-recognized excitatory contri-
bution to descending modulating pathways in the
nervous system and the inhibitory effect of the 5HT
antagonist is considered pivotal in terms of its thera-
peutic value in burns pruritus.63
Transcutaneous Electrical Nerve Stimulation
This therapeutic modality involves the applica-
tion of controlled, low-voltage electrical impulses
to the nervous system via electrodes placed on the
skin.64 A randomized, controlled study evaluated
the effectiveness of TENS in 20 patients complain-
ing of severe pruritus in the remodeling phase of
burn healing. The results revealed a statistically sig-
nificant change in the pre- and posttreatment VAS
trends for pruritus over the 3-week treatment period
(P = .0086).65
The main mechanism proposed to explain the ben-
eficial effect of TENS apart from the “gate theory”
relates to the inhibitory action of endogenous opi-
oids on descending excitatory CNS pathways.66–68
Proposed Integrated Model
of Pruritus Pathophysiology
in Burns
Upon summation of the emerging evidence in the
literature, it transpires that the CNS is likely to play
a pivotal role in the generation and maintenance of
pruritic symptoms in burns patients. Deriving from
pharmacological data, histamine appears to be a key
initiator of impulses predominantly in the initial
Journal of Burn Care & Research
stages of healing. Strikingly, even in these stages,
agents acting on the CNS are more effective in
relieving symptoms16; this observation might reflect
the ability of these drugs to block peripheral sig-
nals (including those mediated by histamine) from
reaching the CNS; alternatively, it is possible that
central/neuropathic mechanisms come into play
early on in burns healing. In more advanced stages
of rehabilitation, histamine appears to be less impor-
tant in mediating symptoms especially in burn vic-
tims with deep injuries and PTSD symptoms; these
patients enter a chronic phase of itch characterized
by markedly antihistamine-resistant wounds point-
ing toward mechanisms relying on a sensitized CNS.
Drawing upon proposed pathophysiological mecha-
nisms in postherpetic sensory symptoms, it is pos-
sible that the reason why pruritic symptoms enter
a chronic phase relates to injury of a critical num-
ber of neurons enough to produce a maladaptive
response in the nervous system.54,55 Based on avail-
able neurophysiological data, it appears that pruritus
manifests itself as a positive sensory phenomenon
in skin, which exhibits hypoesthesia especially to
modalities carried by myelinated fibers (sharp, dull,
cold, light touch); in other words, itch occurs in the
context of deafferentation because of the damage
inflicted from the burn injury/treatment resulting
in an altered summative input to the CNS.21,22,39 An
additional mechanism for setting up a neuropathic
state in chronic burns itch is likely to relate to the
abundant expression of neuropeptides including
SP in grafted wounds and hypertrophic scars.47,49
Their importance in propagating pruritic symptoms
becomes more evident considering the fact that they
are preferentially expressed in the presence of a deep
dermal injury, which is a risk factor for the develop-
ment of chronic itch.7 Furthermore, emerging evi-
dence in the neuroimmunology field suggests that
psychological stress results in SP overexpression in
the skin and dorsal root ganglia50; this finding may
explain a link between PTSD and the development
of chronic symptoms via CNS sensitization mecha-
nisms. As far as the underlying mechanisms in the
peripheral nervous system are concerned, it is pos-
sible that the variety of mediators released in the
zone of burn injury (including SP) results in selec-
tive sensitization in accordance with the intact noci-
ceptor hypothesis.34 This mechanism appears to be
plausible given the large innervation territories of
itch-specific C fibers, which allows them to extend
beyond traditional dermatomal distribution.11 There
are no studies confirming the presence of neuromas
in burn scars to support an injured afferent hypoth-
esis as a source on peripheral sensitization at present.
Journal of Burn Care & Research
Volume 34, Number 1 Goutos  91

Figure 3.  Schematic diagram of the proposed pathophysiological model for chronic burns pruritus. In the peripheral ner-
vous system, selective substance P overexpression and loss of myelinated fiber input result in sensitization of the CNS via
mechanisms concordant with the intact nociceptor hypothesis and deafferentation. Upregulation of calcium channel α2δ sub-
units in the spinal cord, degeneration of inhibitory CNS neurons, interneuron hypoactivity (secondary to deafferentation),
and disinhibition in descending antinociceptive pathways are critical mechanisms in setting up a neuropathic state. As a result,
the CNS develops aberrant autonomous activity to account for the maintenance of pruritic symptoms into a chronic state.

The therapeutic benefit of centrally acting agents
(gabapentin, TENS, ondansetron) further elucidates
possible mechanisms involving the CNS, including
the upregulation of α2δ subunits in the dorsal root
ganglia, degeneration of inhibitory dorsal horn neu-
rons, interneuron hypoactivity (secondary to deaf-
ferentation), and the action of excitatory descending
pathways (Figure 3).35,37–40,42,43,63,66–68 The proposed
model for chronic burn itch appears to be concor-
dant with existing hypotheses on keloid and posther-
petic pruritus, which are thought to have the intact
nociceptor hypothesis, deafferentation, and selective
neuropeptide expression as key elements in their
pathophysiology.53 The inherent limitation of this
work is its heavy reliance on chronic neuropathic
pain models; this approach is considered valid at
present given the paucity of studies on neuropathic
itch disorders. The pathophysiology concepts elabo-
rated upon in this work need to be confirmed using a
combination of physiological, microneurographical,
and histological experiments.
CONCLUSION
Pruritus is a significant symptom complicating the
recovery of burns victims and affecting their quality
of life. Current models of pathophysiology and ther-
apeutic protocols to date have been highly reliant on
the contribution of histamine across the time span
of burns rehabilitation; their main limitation is that
they are inadequate in fully explaining the generation
and persistence of pruritic symptoms into a chronic
state. This article presents the available evidence to
support a neuropathic element in burns pruritus. A
unique pattern of neuropeptide-mediated selective
hyperinnervation within a state of deafferentation
in the peripheral nervous system appears to produce
secondary excitation in the CNS responsible for the
development of longstanding symptoms. This work
is the first attempt in the burns literature to integrate
clinical features, neurophysiological, and pharma-
cological data into a unified theory elucidating this
highly distressing symptom in burns rehabilitation
and forms a platform for the exploration of novel
therapeutic interventions.‍‍‍
ACKNOWLEDGMENTS
I would like to thank Dr. Patricia M. Richardson (Con­
sultant Anesthetist, St Andrew’s Centre for Plastic Surgery
and Burns, Broomfield Hospital, Essex, UK) for her useful
comments on the article as well as for all the support and

92  Goutos January/February 2013
inspiration she has provided toward my research interest
on burns pruritus.
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