Current Pharmaceutical Design, 2005, 11, 2995-3004 2995

Topical Analgesics in Neuropathic Pain

Jana Sawynok*

Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada

Abstract: Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and
significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances
have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular
entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and
the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available
for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, α-
adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide
support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the
site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of
novel topical analgesics for this condition.
Key Words: Neuropathic pain, peripheral nerves, sensory afferents, capsaicin, local anesthetics, opioids, α2-adrenergic
agonists, antidepressants.

INTRODUCTION
Neuropathic pain is initiated or caused by a primary
lesion or dysfunction in the nervous system. It can arise from
traumatic (e.g. post-surgical events, spinal cord injury),
metabolic (e.g. diabetic neuropathy), infective (e.g. post-
herpetic neuralgia), immune (e.g. human immunodeficiency
virus), or ischemic (e.g. central pain) events, compression
(e.g. sciatica, cancer) or toxic drug effects (e.g.
chemotherapeutic agents) [1, 2]. Characteristic features of
neuropathic pain include spontaneous pain (stimulus-
independent pain), allodynia (pain resulting from normally
innocuous stimulation) and hyperalgesia (enhanced pain in
response to a normally noxious stimulus) (stimulus-
dependent pains). Over the past 25 years, significant
advances have been made in understanding the neurobiology
of neuropathic pain due to the introduction of a number of
preclinical nerve injury models. These include peripheral
nerve axotomy [3], loose ligation of the peripheral nerve
(chronic constriction injury, CCI) [4], partial sciatic nerve
ligation [5], tight ligation of spinal nerves (spinal nerve
ligation, SNL) [6], and more recently, several peripheral
nerve branch lesions [7, 8]. Nerve injury initiates a cascade
of events, and both peripheral and central mechanisms
contribute to the expression of pain [2, 9, 10] (Table 1).
Clinically, neuropathic pain can be difficult to treat.
There has been controversy regarding the efficacy of opioids
in treating neuropathic pain [11], but recent studies indicate
that levorphanol [12], oxycodone [13] and methadone [14]
may be useful in such conditions, with appropriate attention
to dosing and adverse effects. Both tricyclic antidepressants
and gabapentin are useful in treating neuropathic pain
*Address correspondence to this author at the Department of Pharmacology,
Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada,
B3H 1X5; Tel: (902)494-2596; Fax: (902)494-1388;
E-mail: jana.sawynok@dal.ca
regardless of the etiology of the pain [15, 16, 17], but their
efficacy is only partial, and usefulness can be limited by
adverse effects. Currently, a great deal of attention is being
directed towards the development of novel therapeutic
strategies for the treatment of neuropathic pain, and
understanding the changes in the neurobiology of pain that
occur following nerve injury enables this to be a mechanism-
driven endeavor [1].
A therapeutic strategy that may be of particular use in the
treatment of neuropathic pain is the use of topical analgesics,
and this approach has been highlighted in recent reviews and
symposia [18, 19, 20, 21, 22]. With topical formulations,
drugs are applied to the surface of the skin as a cream or
patch, and then act on peripheral sensory nerves following
dermal penetration; systemic drug levels that result are low.
This approach is quite distinct from transdermal drug
delivery systems, which may use similar formulations to
deliver drugs systemically to a site remote from the site of
application (e.g. fentanyl patch). With low systemic drug
levels, there are minimal systemic adverse effects and drug
interactions, and the approach may be of particular benefit in
the elderly where multiple drugs are being used due to more
health problems. The extent to which the topical approach is
useful in neuropathic pain conditions will depend on the
extent to which peripheral mechanisms contribute to the
pain, and the extent to which the drug can gain access to sites
relevant to initiating and maintaining the pain. There is clear
evidence to indicate that changes in the excitability and
functioning of peripheral sensory nerves is a significant
contributor to neuropathic pain in humans [23], and that
significant changes occur in the skin following nerve injury
in primates [24]. There is also an increasing body of
preclinical evidence indicating that peripheral administration
of drugs to peripheral sites distal to the site of nerve injury
(i.e. into the hindpaw) can alleviate manifestations of nerve
injury at more central sites (e.g. to the sciatic nerve in the
CCI model, or to spinal nerves in the SNL model) (see

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2996 Current Pharmaceutical Design, 2005, Vol. 11, No. 23
Table 1. Summary of Mechanisms Implicated in Abnormal Pain Signaling Following Nerve Injury
Peripheral mechanisms
-sensory afferent sensitization
-altered ion channel and receptor expression
-spontaneous firing of sensory afferents
-altered phenotype of large fibres
-ectopic activity in neuromas, DRG
-sprouting of sympathetic nerves into DRG
-ephaptic interactions in peripheral nerves, DRG
-inflammation of nerves
Abbreviations: DRG: dorsal root ganglion, DH: dorsal horn
Summarized from [2, 9, 10].
below). The purpose of the current chapter is to consider the
local peripheral analgesic actions of the main classes of
drugs that are currently used topically for treatment of
neuropathic pain in humans, or have the potential to be used
in this capacity in the near future.
PERIPHERAL NERVES AND NEUROPATHIC PAIN
Activation of Afferents
Pain is a subjective experience generated within the
central nervous system, and involves sensory, emotional and
cognitive dimensions. The initial stages of the sensory
aspects of pain involve activation of primary sensory afferent
nerves by temperature changes, pressure and chemicals in
the periphery, and this leads to the generation of action
potentials and the transfer of information to the dorsal horn
of the spinal cord. These peripheral processes are the
primary focus of this chapter. There are several recent
reviews detailing spinal mechanisms involved in pain
transmission in neuropathic pain, and the reader is directed
to those for a consideration of more central mechanisms [25,
26, 27].
Sensory neurons that transduce sensory stimuli and
transmit information to the spinal cord include small
diameter unmyelinated C-fibres, small diameter myelinated
Aδ-fibres and large diameter myelinated Aβ-fibres [25]. C-
Fibres are further subdivided into two main classes: one
contains neurokinins and calcitonin gene-related peptide
(CGRP) and responds to nerve growth factor (NGF), and the
other contains P2X 3 and lectin IB4 receptors and responds to
glial derived neurotrophic factor [28]. Under physiological
conditions, low intensity stimulation leads to activation of
Aβ-fibres and innocuous tactile sensations, while high
intensity stimulation leads to activation of Aδ- and C-fibres
and nociception or pain. Following nerve injury, activation
of Aβ-fibres produces allodynia (pain) while activation of
Aδ- and C-fibres results in enhanced pain [9, 25]. Nerve
injury leads to alterations in the phenotype of A-fibres,
which results in expression of markers such as substance P
[29], growth factors [30], vanilloid receptors (VR) [31] and
bradykinin (BK) receptors [32] that are normally found
Jana Sawynok
Central mechanisms
-spinal sensitization
-sprouting of Aβ fibres into superficial DH
-loss if inhibitory interneurons in DH
-changes in inhibitory pathways
-supraspinal reorganization
-involvement of microglia
primarily in C-fibres. This phenotype switch reflects
alterations in gene expression [33] and contributes to the
altered pain signaling [27].
Nociceptive sensory nerve terminals contain a variety of
ion channels and receptors that contribute, at a molecular
level, to the activation of sensory nerves by heat, pressure
and chemicals [34, 35] (Fig. 1). Some of these lead to
activation of sensory neurons by interacting with ion
channels (e.g. VR1, P2X3), while others lead to sensitization
which results in a reduction in the transduction threshold
(e.g. prostaglandin E 2 or PGE 2, BK). In vitro studies indicate
that phosphorylation of tetrodotoxin (TTX)-resistant
Na+channels by protein kinase A (PKA) is a prominent
mechanism involved in the sensitization of primary afferent
neurons, and accounts for PGE2-mediated sensitization and
aspects of inflammatory hyperalgesia [36, 37].
Phosphorylation of TTX-resistant Na+ channels by protein
kinase C (PKC) is a further significant contributor to this
process [38, 39]. Similarly, PKA [40] and PKC [41]
phosphorylate and augment VR1-gated ion channel activity,
while PKC augments P2X3-gated ion channels [42]. Earlier
studies performed in vivo suggested that further tissue
mediators (5-hydroxytryptamine or 5-HT, via 5-HT1A
receptors, and adenosine via A2A receptors) could also
produce hyperalgesia by activating the cAMP/PKA second
messenger cascade [43, 44], and in vitro studies revealed that
these affected TTX-resistant Na+ currents in a manner
similar to PGE2 [45]. Collectively, these observations
indicate that phosphorylation of cation channels on sensory
nerve terminals is a significant contributor to the
sensitization and modulation of afferent function that are
encountered in inflammatory hyperalgesia [27, 35].
Involvement of Inflammation
Nerve injury can result in inflammation at the site of
injury, and this is now recognized to contribute to
neuropathic pain [46]. Thus, models of traumatic nerve
injury induce Wallerian degeneration of the axon, whereby
macrophages, neutrophils and lymphocytes invade the
injured nerve at sites of degeneration, and these cells, along
Topical Analgesics in Neuropathic Pain Current Pharmaceutical Design, 2005, Vol. 11, No. 23 2997

Fig. (1). Schematic of sensory afferent nerve terminal depicting some of the ion channels and receptors which either initiate pain or produce
sensitization and hyperalgesia. Following nerve injury, there is an upregulation of certain Na+ channels, VR1 receptors, and P2X3 receptors
in uninjured neurons, and downregulation of the same entities in injured neurons. Inflammation at the site of nerve injury leads to a
local generation of inflammatory mediators which can alter the excitability and sensitivity of afferent nerves. Aspects of inflammation also
affect sensory nerve activity at sites distal to the site of nerve injury, and this may involve phosphorylation of ion channels. See text for
details.

with resident cells (e.g. fibroblasts, Schwann cells,
endothelial cells, mast cells) produce and release
proinflammatory cytokines [46]. Furthermore, local exposure
of a portion of the healthy nerve to pro-inflammatory stimuli
(carrageenan [47], complete Freunds adjuvant [48], zymosan
[49]) produces mechanical allodynia and thermal
hyperalgesia which are characteristic of neuropathic pain,
and such models are regarded as models of inflammatory
neuropathy. The proinflammatory cytokines, tumor necrosis
factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6),
have received particular attention as mediators of
inflammatory neuropathy. Thus, these increase at the site of
nerve injury [50-52], and antibodies to IL-1 and TNF applied
near the site of injury reduce the resulting allodynia and
hyperalgesia [53, 54]. Acute inflammatory mediators also
may be involved. Thus, nerve injury results in enhanced
expression of cyclooxygenase-2 [55] and multiple nitric
oxide (NO) synethetases [56, 57] at the site of injury, and of
BK (particularly B1) receptors in dorsal root ganglia (DRG)
and satellite cells [32, 58]. PGE2, 5-HT and BK, acting
together, can sensitize and excite axotomized nerves
following injury [59, 60], while NO promotes vasodilation
and hyperalgesia following nerve injury [57, 61].
Inflammatory aspects of nerve injury are also expressed
at sites peripheral to the actual site of injury. Thus,
peripheral nerve injury (CCI) leads to neurogenic
inflammation (i.e. activation of peripheral aspects of sensory
nerves, leading to release of the neuropeptides substance P
and CGRP from C-fibres [62]), and this results in
vasodilation, increased vascular permeability, edema, and
accumulation of immune cells in the nerve injured hindpaw
[63, 64]. Substance P can then release TNF, IL-1 and IL-6
from immune cells [65, 66] which could then act on sensory
nerve endings to enhance pain [67, 68], thus creating a pro-
inflammatory loop at the nerve ending. The direct
involvement of inflammatory mediators at peripheral sites
distal to the site of injury in neuropathic pain models is
supported by the observation that local injections of
cyclooxygenase inhibitors into the hindpaw attenuates
aspects of neuropathic pain following partial sciatic nerve
transection or ligation [55, 69]. Furthermore, local injection
of BK into the hindpaw following peripheral nerve injury
results in activation of sensory afferents via B1 receptors
[32]. The importance of these latter observations is that they
indicate that peripheral mechanisms involved in sensory
afferent hypersensitivity in inflammation (see above) may
also be relevant to neuropathic pain (Fig. 1). It is important
to appreciate that inflammation of peripheral nerves may be
more prominent in some models (e.g. models of inflam-
matory neuropathy, as noted above, but also models of
peripheral nerve injury such as CCI and partial sciatic nerve
ligation) than in others where the injury is more central (e.g.
SNL) [70, 71].
Injured and Uninjured Afferents
With nerve injury, it is important to distinguish between
the contributions of different populations of sensory afferents
to the abnormal mechanisms involved in neuropathic pain
[72, 73]. Some models are amenable to addressing the
distinction between injured and uninjured afferents, but
others do not allow for this distinction to be made. Thus, the
hindpaw is innervated by the L3, L4, L5 and L6 spinal
nerves, and lesions of L5 or L5/L6 allow for separate
analysis of nerves in uninjured and injured pathways [73].
2998 Current Pharmaceutical Design, 2005, Vol. 11, No. 23
Several electrophysiological studies provide evidence for the
contribution of both injured and uninjured afferents to
neuropathic pain [74, 75, 76, 77, 78]. Similarly, the
expression of ion channels, inflammatory mediator receptors
and excitatory neuromodulators in these two populations of
nerves has been addressed individually. The TTX-resistant
Na+ channel NaV1.8 is implicated in neuropathic pain
because of its unique properties and pattern of expression
[79]. Nav1.8 is downregulated in the cell body of injured
neurons and does not distribute to injured terminals [80, 81],
while it is upregulated in uninjured afferents along the sciatic
nerve [80, but see 81]. An identical pattern of
downregulation in injured afferents and upregulation in
uninjured afferents is observed with substance P, brain-
derived neurotrophic factor, VR1 receptors, P2X3 receptors
and BK receptors [73, 82, 83]. These approaches indicate
that injured and uninjured afferents make qualitatively
different contributions to the expression of the sensory
changes that occur in neuropathic pain.
TOPICAL ANALGESICS
Capsaicin
Topical applications of extracts of the capsicum pepper
have been used for pain relief for over 150 years. Capsaicin,
the active ingredient in hot peppers, was isolated in 1846 and
its structure determined in 1919 [84]. Capsaicin is currently
understood to produce excitatory effects and the sensation of
heat by interacting with VR1 receptors selectively localized
on C-fibres and some Aδ-fibres; this receptor is also
activated by heat, protons and lipid mediators [85].
Activation of the VR1 receptor leads to depolarization
resulting in release of peptides and other mediators from C-
fibres (following Na+ and Ca2+ entry), desensitization
(following Ca2+-dependent dephosphorylation of the
receptor) or tackyphylaxis (following peptide depletion), and
neurotoxicity (following Ca2+ overload, NGF depletion) [84,
85]. The consequences of exposure to capsaicin on
nociceptive signaling vary depending upon the dose, the
route of administration and the age of the animal [86]. As
noted above, following nerve injury, VR1 receptors are
decreased in damaged nerves but increased in uninjured
nerves, and there is a change in phenotype in that A-fibres
(which normally do not express VR1 receptors) now express
these receptors [31, 73, 87].
Topical capsaicin preparations of 0.025% and 0.075% are
available for human use, and these produce some degree of
neuropathic pain relief in randomized trials, open label trials
and clinical reports in a number of conditions. This includes
post-herpetic neuralgia, diabetic neuropathy, postmastec-
tomy pain syndrome [88, 89], as well as polyneuropathy [90]
and surgical neuropathic pain [91]. While pain relief is
widely reported, the degree of pain relief is usually modest
(although some individuals have good results), such that
capsaicin is regarded as an adjunct therapy to be used in
combination with other agents [88]. Burning pain at the site
of application, particularly in the first weeks of application,
reflects the initial activation of sensory afferents that occurs
prior to the desensitization and/or neurotoxicity, and can
make it impossible to blind studies and lead to significant
dropout rates. A further factor in compliance is the delay in
Jana Sawynok
onset of therapeutic effect (sometimes several weeks). One
approach to minimizing adverse effects has been to deliver
higher concentrations of capsaicin (5-10%) under regional
anesthesia, and this produces substantial analgesia in
complex regional pain syndrome and neuropathic pain [92].
However, EMLA (a topical formulation of local anesthetics,
see below) applied with 1% capsaicin in healthy humans,
was not sufficient to block the pain induced by capsaicin
[93]. Desensitization of small diameter sensory afferents that
normally contain VR1 receptors is generally invoked to
explain the analgesic properties of topical capsaicin [84, 85].
However, part of the topical activity may also result from an
actual loss of epidermal nerve fibres [94] and/or desensiti-
zation of VR1 receptors expressed on A-fibres following a
phenotype change [87].
Local Anesthetics
Voltage-gated sodium channels are essential for the
initiation and propagation of action potentials in nerves.
Nerve injury results in an increase in the excitability of
peripheral A- and C-fibres, and this hyperexcitability
manifests at the site of injury, in the DRG, and at sites along
the axon including the peripheral nerve terminals [95]. These
changes contribute to spontaneous pain and abnormal pain
signaling (hyperalgesia, allodynia). Sensory neurons in the
DRG contain multiple, distinct sodium channels that are not
expressed at significant levels in other cell types including
Nav1.8 (formerly SNS/PN3) and Nav1.9 (formerly
SNS2/NaN), and these provide molecular correlates for
distinct TTX-resistant sodium currents [79, 96].
Phosphorylation of Na+ currents in DRG neurons by PKA
and PKC contributes to hyperexcitability in inflammatory
pain [36-39], and potentially may also contribute to
neuropathic pain (see above). The expression of both Nav1.8
and Nav1.9 is reduced in injured afferents in multiple models
of nerve injury, while Nav1.8 expression is increased in the
axons of uninjured afferents [80, but see 81]. Modulation of
the expression of Na+ currents represents a unique form of
neuroplasticity, and Na+ channels on sensory afferents may
represent a viable target for the treatment of pain [79].
Systemically administered local anesthetics (i.v.
lidocaine, oral mexilitine and tocainamide) produce some
degree of analgesia in a number of neuropathic pain
conditions, but the effectiveness of systemic application can
be limited by adverse (central nervous system,
cardiovascular) effects [97]. Topical formulations of local
anesthetics are also available. Thus, topical lidocaine as a 5%
gel [98] or patch [99, 100] produces pain relief in post-
herpetic neuralgia with no systemic adverse effects and
minimal local adverse effects. Open label studies for mixed
neuropathic pain indications reveal evidence for some degree
of pain relief in the majority of cases [22, 101]. This was
confirmed in a follow up controlled trial using a unique
neuropathic pain scale to record efficacy [102]. The
mechanism by which topical lidocaine produces pain relief is
thought to reflect decreased ectopic discharges within
peripheral sensory afferents (i.e. a selective effect on
hyperexcitability), as pain relief occurs in the absence of
anesthetic effects [22]. Local anesthetics are also now
recognized to exert anti-inflammatory effects [103], and as
inflammatory processes can contribute to neuropathic pain,
Topical Analgesics in Neuropathic Pain
such actions could also contribute to pain relief. EMLA
(eutectic mixture of local anesthetics) cream produces
anesthetic actions at the site of application and is used for
localized painful procedures (venipuncture, biopsy), but
efficacy in neuropathic pain in inconsistent [104, 105].
Opioids
Peripheral analgesic properties of opioids in
inflammation are now well recognized [106, 107, 108].
Multiple opioid receptors (µ, δ, κ) produce peripheral
analgesia, and actions on sensory afferent nerves are
prominent. Opioids decrease the excitability of sensory
afferent nerves via inhibition of adenylyl cyclase and
subsequent inhibition of cation entry, and this is particularly
pronounced when cAMP levels are enhanced by
inflammatory mediators (e.g. PGE2); further factors that
contribute to the efficacy are the low pH of inflamed tissue
which enhances opioid receptor interactions with G-proteins,
and a disrupted perineurial barrier [106, 107, 108]. The
immune system plays a prominent role in peripheral opioid
analgesia, functioning as a source for endogenous opioids,
and further contributing to altered pain expression [107, 108,
109]. In clinical studies, intra-articular administration of
morphine produces analgesia following arthroscopic knee
surgery [107, 110] as well as in osteoarthritis where
inflammation is more chronic [111, 112]. Furthermore,
morphine, injected locally along with local anesthetics,
provides analgesia in dental surgery paradigms and
especially in the presence of inflammation [113]. Topical
application of morphine to the skin has been reported to
alleviate burn pain [114], while topical morphine in the form
of a mouthwash reduces mucositis-associated pain resulting
from chemoradiotherapy [115].
There is a more limited literature on peripheral opioid
analgesia in neuropathic pain. Using the CCI model: (a) a
peripheral component of analgesia is observed following
systemic morphine administration [116, 117], (b) intraplantar
injection of morphine produces peripheral analgesia [118],
and (c) near nerve infusions reverse thermal hyperalgesia at
different stages of nerve repair [119]. However, because the
CCI injury may cause inflammation and hypersensitivity
[70], and inflammation can contribute to neuropathic pain,
there is the potential for these observations to reflect effects
of opioids on inflammation (see above). To address this
issue, morphine was administered into the hindpaw
following SNL, where inflammation of peripheral nerves is
much less [71]. Morphine did produce a relief of mechanical
hyperalgesia, but the degree of effect was relatively mild
[120]. Mechanisms proposed to be involved in the peripheral
efficacy of opioids following nerve injury are actions on
degenerating and regenerating sensory neurons, on activated
macrophages in the peripheral nerve, and on immune cells
which regulate inflammation [118, 119, 120].
α2-Adrenergic Agonists
Sympathetically maintained pain reflects a condition in
which nerve injury to a large nerve produces pain maintained
by, and relieved by interruptions to, sympathetic innervation
[121, 122]. Following nerve injury, the sympathetic nervous
system can influence the function of sensory afferents by
Current Pharmaceutical Design, 2005, Vol. 11, No. 23 2999
actions within the DRG, at the site of injury, and in the skin
[123]. In a number of preclinical models where the injury is
to a major nerve(s), manifestations of pain are alleviated by
lesions to the sympathetic nervous system, but the degree of
involvement varies depending on whether the lesion is more
peripheral (e.g. CCI) or more proximal (SNL) to the ganglia
[124]. The mechanism of sympathetic involvement also
varies, as distal lesions lead to sprouting of undamaged
sympathetic axons while more proximal lesions lead to
regenerative sprouting of injured sympathetic nerves [125].
The local peripheral application of noradrenaline (NA), or
activation of the sympathetic nervous system, does not
normally activate sensory afferents in the uninjured state, but
such actions are observed following nerve injury in
preclinical models [126, 127, 128]. Intradermal injections of
higher [129], but not lower [130], doses of NA provoke pain
or produce hyperalgesia following nerve injury, and pain can
be rekindled by low doses of NA following alleviation by
sympathectomy [130, 131]. In clinical reports, intradermal
injections of NA provoke pain in patients with
sympathetically maintained pain or neuralgias [132, 133,
134], and rekindle pain following pain relief by sympathetic
blockade [132].
The nature of the adrenergic receptor (AR) subtype
mediating these pain facilitating effects is unclear. Thus,
there is evidence for the involvement of both α1- [24, 135,
136] and α2-AR subtypes in producing pain following nerve
injury [126, 129, 137, 138], and for α2-ARs in rekindling
following sympathectomy [130]. Sensory neurons contain
mRNA for, and express, multiple α2-AR subtypes [139, 140,
141, 142] as well as α1-ARs [143]. The nature of the changes
in α2-ARs induced by nerve injury is unclear. For α2A-ARs,
there are reports of increases in receptor immunoreactivity
and mRNA in sensory afferents following nerve injury [140,
141, 142], but a reduction in immunoreactivity also has been
noted [144]. Similarly, α2C-ARs mRNA in DRG neurons
was unchanged or decreased [140], while α2C-AR immuno-
reactivity was unchanged or increased in the spinal cord
following nerve injury [144]. A clearer distinction of
changes in uninjured versus injured afferents would be
helpful in delineating the nature of the changes involved.
Some aspects of α2-AR actions following nerve injury are
indirectly mediated via the sympathetic nervous system [129,
145]. The α-AR involved in the indirect action of NA on
sympathetic afferents has been proposed to be the α2B-AR
based on functional studies [146].
In addition to the pain facilitating effects noted above,
there are several reports that α2-AR agonists produce
peripherally mediated pain relieving effects following nerve
injury by actions at different sites. Systemic administration
of dexmedetomidine produces relief of mechanical and
thermal hyperalgesia, and following spinal nerve ligation, the
dose-response curve is shifted to the left; injection of a
peripherally restricted α2-AR antagonist blocks the action of
dexmedetomidine in neuropathic, but not uninjured rats,
implicating unidentified peripheral sites in its activity [147].
In another study, local intradermal injections of clonidine
into the hindpaw produced a local alleviation of mechanical
allodynia following SNL, implicating peripheral actions in
the skin (i.e. at a site distal to the site of injury) in this effect
of clonidine [130]. Finally, peripheral administration of
3000 Current Pharmaceutical Design, 2005, Vol. 11, No. 23 Jana Sawynok

clonidine adjacent to the site of injury following partial Antidepressants also exhibit a number of further acute
sciatic nerve ligation relieved mechanical allodynia in the pharmacological actions, including block of biogenic amine
affected hindpaw, and this was blocked by local reuptake as well as block of receptors for biogenic amines,
administration of an α2A-AR antagonist [148]. In that study, histamine, acetylcholine, 5-HT and N-methyl-D-aspartate,
α2A-AR immunoreactivity was increased in nerves and in and a number of these may potentially further contribute to
immune cells near the site of injury, and it was suggested their peripheral efficacy; it is even conceivable that a
that clonidine might produce some of its peripheral pain multiplicity of these actions contributes, in a unique manner,
relieving efficacy by actions on immune cells. This is now to their efficacy [163]. The potential involvement of actions
reminiscent of peripheral effects of opioids following that are more unique to chronic administration paradigms
inflammation (see above), and this mechanism merits further (e.g. on cAMP-response element binding protein, BDNF)
exploration. Finally, there is a clinical report of a locally [164] when antidepressants are applied chronically remains
mediated action following topical application of clonidine to be determined.
[149]. It was suggested that this pain relief might result from
a presynaptic effect of clonidine to decrease NA release from SUMMARY
sympathetic nerves [149] (the α2A-AR is a major presynaptic
The potential for topical analgesics to represent a viable
receptor subtype regulating such release, [150]). It could also
approach to the treatment of neuropathic pain requires
result from activation of α2C-ARs on sensory afferents which
peripheral sites to be responsive to drug application. In many
mediate peripheral analgesic responses in the uninjured state
cases, the site of nerve injury is remote from the site of
[146, 151].
application, or occurs diffusely over extensive portions of the
Antidepressants nerve. Both clinical and preclinical studies demonstrate that
the local peripheral application of drugs can indeed alleviate
Antidepressants are currently widely used orally for the aspects of neuropathic pain, and may act on mechanisms that
relief of neuropathic pain [15, 16]. Following oral reflect changes in the nerve that are initiated at a site of
administration, actions within the spinal cord and brain have injury but spread to even the most peripheral aspects of the
generally been invoked to explain the pain relieving nerve. Defining the role of inflammation in the initial stages
properties of antidepressants [152]. More recently, there of injury, and its contribution to the initiation and
have been clinical reports that topical application of maintenance of neuropathic pain is a significant advance in
antidepressants also can produce relief of neuropathic pain. understanding this difficult clinical condition. The
Thus, doxepin, a tricyclic antidepressant, reduces appreciation of a differential contribution of injured and
neuropathic pain of mixed etiology in randomized controlled uninjured afferents to the pain, and the mechanisms involved
trials [153, 154]. In addition, doxepin, formulated as an oral in plasticity may further allow for the development of novel
rinse, also produces analgesic effects with oral mucosal pain topical analgesics.
due to cancer or cancer chemotherapy [155]. There is also a
preliminary report that a combination of amitriptyline ABBREVIATIONS
(another tricyclic antidepressant) with ketamine produces
AR = Adrenergic receptor
pain relief in neuropathic pain [156]. In the latter study, pain
relief occurs in the absence of significant systemic drug ASIC = Acid sensitive ion channel
levels, indicating a peripheral site of action. BDNF = Brain derived neurotrophic factor
Preclinical studies with nerve injury models also reveal
BK = Bradykinin
peripheral pain relieving properties for antidepressants.
Thus, local intraplantar administration of amitriptyline cAMP = Cyclic AMP
following SNL [157], and in a diabetic model of neuropathy CCI = Chronic constriction injury
[158], produces a locally mediated alleviation of thermal
hyperalgesia and mechanical allodynia, respectively. These CGRP = Calcitonin-gene related peptide
local actions of amitriptyline involve endogenous adenosine, DRG = Dorsal root ganglion
as methylxanthine adenosine receptor antagonists
substantially reduce the alleviation of hyperalgesia and EMLA = Eutectic mixture local anesthetics
allodynia [157, 158]. Neurochemical studies provide direct 5-HT = 5-hydroxytryptamine
evidence for an increase in tissue availability of adenosine
following local administration of amitriptyline to the IL = Interleukin
hindpaw [159]. At higher doses, antidepressants exhibit local NA = Noradrenaline
anesthetic actions [160, 161]. It is not clear to what extent
NGF = Nerve growth factor
classical local anesthetic properties contribute to peripheral
pain relief at lower doses of amitriptyline where prominent NO = Nitric oxide
reversal by methylxanthines is observed. Thus, low doses of PGE2 = Prostaglandin E2
amitriptyline which alleviate neuropathic hyperalgesia/
allodynia do not affect thermal thresholds in the uninjured PKA = Protein kinase A
state, but higher doses do increase such thresholds reflecting PKC = Protein kinase C
such local anesthetic actions [162]. It may be that, as with
lidocaine (see above), there is a selective action on SNL = Spinal nerve ligation
mechanisms contributing to hyperexcitability at low doses.
Topical Analgesics in Neuropathic Pain
TNF = Tumor necrosis factor
TTX = Tetrodotoxin
VR = Vanilloid receptor
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