Neuropathic Pain

in Dogs a nd C ats :
I f Only They Could
Tell Us I f They Hur t
Karol A. Mathews, DVM, DVSc

KEYWORDS
 Neuropathic pain  Dogs  Cats  Gabapentin
 Ketamine  Lidocaine

During the past 10 years, the physiology of nociceptive and inflammatory pain and its
management have been taught to student veterinarians and animal health technicians.
This topic has also been presented at many annual veterinary continuing education
programs, wherein the focus of pain management has been predominantly associated
with surgery and osteoarthritis in dogs and cats and, to a lesser degree, with traumatic
and medical pain, but there has been little discussion on neuropathic pain as a primary
focus. In the veterinary literature, textbooks and a few clinical reports present specific
causes of neuropathic pain that is obvious and is presented under the specific aspects
discussed in this article. Often, the clinical signs have been insidious and present for
weeks to several months, with an obvious lesion difficult to find. Because pain in gen-
eral can be difficult to recognize and isolate in many veterinary patients, neuropathic
pain can be extremely difficult to identify unless we appreciate the occult nature of
many of the predisposing causes.
The management of chronic pain, of which neuropathic pain is included, represents
a major human public health issue. Because of the near-epidemic proportions of painful
conditions in human beings, especially as the population ages, the need to improve pain
outcomes is reflected by the congressional declaration of the present decade as the
‘‘Decade of Pain Control and Research,’’ and the acknowledgment in January 2001
of pain as the ‘‘fifth vital sign’’ by the Joint Commission of Healthcare Organizations.1
Harden states that ‘‘Increases in our understanding of the function of the neurologic
system over the last few years have led to new insights into the mechanisms underlying
pain symptoms, especially chronic and neuropathic pain. The rapidly evolving symp-
tom- and mechanism-based approach to the treatment of neuropathic pain holds
promise for improving the quality of life of our patients with neuropathic pain.’’1

Emergency and Critical Care Medicine, Department of Clinical Studies, Ontario Veterinary
College, University of Guelph, Guelph, Ontario, N1G 2W1, Canada
E-mail address: [email protected]

Vet Clin Small Anim 38 (2008) 1365–1414

doi:10.1016/j.cvsm.2008.09.001 vetsmall.theclinics.com
0195-5616/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
1366 Mathews

The quest for relief from pain is pursued in human medicine because the existence
of pain is known; the patient can verbalize his or her pain, what it feels like, where it is,
and the relief he or she feels when treatment is appropriate. Because we all have
experienced pain of various degrees and durations, it is an excellent topic for compar-
ison and understanding with our veterinary patients. Because veterinary patients
cannot tell us how painful they are, we, as veterinarians, have to understand what
can cause pain, how pain manifests,2,3 and how best to treat it. The purpose of this
article is to raise awareness of the existence of neuropathic pain in our patients, in
which pain may be a cause for behavioral changes (1) in the acute pain setting (at home
or in the hospital); (2) at a later period after a traumatic or surgical experience; or (3) as
the result of a chronic primary lesion affecting the (i) somatosensory and visceral
peripheral nerve(s), (ii) the meninges, spine, spinal cord, and its nerve roots, or
(iii) a lesion in the brain. Several alterations in sensory processing occur peripherally
and centrally in the development of chronic neuropathic pain; however, two major
events occur: (1) abnormal peripheral input and (2) abnormal central processing.
The human clinical literature and the research literature are used as potential compar-
isons to the veterinary clinical setting.
The International Association for the Study of Pain (IASP) defines neuropathic pain
as ‘‘pain initiated or caused by a primary lesion or dysfunction in the nervous
system.’’ This definition, however, is still unclear because the term dysfunction is
nonspecific.4 A proposed definition to clarify this is ‘‘pain arising as a direct conse-
quence of diseases affecting the somatosensory system,’’ with further clarification
on the definition of ‘‘disease’’ that may be required.4 How ‘‘normal,’’ physiologic,
or transient (words used for acute pain or true ‘‘nociceptive’’ pain) pain differs
from neuropathic pain is in its origin. The sensory experience of nociceptive pain
is attributable to immediate injury and tissue inflammation. It is a normal adaptive
function of the nervous system signaling the type and location of the injury, and it
is an awareness or warning to the individual experiencing this pain. The initiating
lesion, and subsequent inflammatory process, initiate Ad and C-fiber activity, caus-
ing sensitization, recruitment of silent nociceptors, and ionic channel and membrane
receptor activation.1,4 The origin of neuropathic pain, conversely, may be difficult to
diagnose unless an obvious predisposing lesion or injury to the nervous system is
easily identified.4 Because this is a statement based on the human patient, one
can definitely appreciate the difficulty in identifying such lesions in animals. Under-
standing the events that occur in the nervous system, originating from poorly man-
aged acute pain, chronic pain, or primary lesions within the nervous system, is
important because individual mechanisms causing pain are targets for therapeutic
consideration. Some may be amenable to surgical therapy, whereas others require
specific pharmaceutical intervention. Above all, by understanding these mecha-
nisms, the means to prevent establishment of neuropathic pain is always pursued
by meticulous surgical technique and using recommended current and future ther-
apeutic measures.
A brief overview of ‘‘transient’’ and inflammatory pain transmission is important
before discussing neuropathic pain, because severe noxious and inflammatory insults
are also mediated by the same pathways, resulting in changes within the nervous sys-
tem.5 While making comparisons to our own experiences, it is interesting to note that
although nociceptive processing is similar in human beings and domestic animals,
based on anatomic differences in the ascending fiber densities of the spinothalamic
tract, lower animals may have less refined stimulus characterization and localization
capabilities, which may indicate an increased awareness of the adversive quality of
the stimulus and autonomic responses.
 Neuropathic Pain in Dogs and Cats 1367

PHYSIOLOGY AND PATHOPHYSIOLOGY

Peripheral Nervous System
The sensory nervous system is composed of two distinct classes of cells: glial cells
and neurons. Glial cells nourish and support nerve cells. Neurons sense and conduct
sensory information. The cell bodies of peripheral sensory nerves are located in the
dorsal root ganglia of the dorsal root of the spinal nerves for nerves originating from
lower than the head and in the trigeminal ganglia for nerves transmitting sensory infor-
mation from the head (trigeminal, facial, glossopharyngeal, and vagus nerves).6 In
what might be considered a ‘‘comfortable state’’ (ie, in the absence of high-intensity
sensory stimulation), the sensory afferent nerve fibers (slowly conducting unmyelin-
ated C-fibers or rapidly conducting thinly myelinated Ad fibers) are ‘‘silent,’’ showing
little or no spontaneous traffic.6 Innocuous sensations or a low-intensity stimulus,
such as touch or vibration, is transmitted from the periphery to the central nervous
system (CNS) laminae III and IV of the dorsal horn by way of Ab fibers (Fig. 1).5,7 Nor-
mally Ab fibers are not part of the pain pathway. Transient noxious stimuli (nociceptive

Fig. 1. Under normal conditions, innocuous sensations or a low-intensity stimulus, such as

touch or vibration, is transmitted from the periphery to laminae III and IV of the dorsal
horn by means of Ab fibers; the signal is then relayed to the brain by way of the dorsal col-
umn somatosensory pathway. Noxious thermal or mechanical input (transduction), the pro-
tective nociceptive ‘‘first pain’’ experience, activates the Ad fibers, which have small receptive
fields, and functions as a warning and is protective to the animal. With increased intensity
of the stimulus, C-fibers also conduct impulses along with Ad fibers. C-fibers have a larger
receptive field compared with Ad fibers and are responsible for the ‘‘second pain’’ experi-
ence. The Ad and C-fibers enter the dorsal horn of the spinal cord, wherein Ad fibers solely
and C-fibers predominantly terminate in laminae I and II. The Ad and C-fiber ganglions ex-
press substance P (S-P), and the natural killer 1 (NK1 [S-P]) receptors are expressed in the neu-
rons of lamina II. The signal is then relayed to the brain by way of the spinothalamic tract.
1368 Mathews

pain) occurring in the periphery by a mechanical (eg, stepped on the toe, needle prick),
thermal (eg, hot or cold object), or chemical stimulus evokes intensity-dependent in-
creases in the rate of firing in rapidly conducting Ad afferent fibers.5 The Ad fibers
have small receptive fields and are activated by noxious thermal or mechanical input
(transduction) (see Fig. 1). They conduct impulses (transmission) rapidly, and therefore
are felt as the initial sensation of pain, or the ‘‘first pain,’’ which has a sharp pricking
quality and is localized and transient. This is a protective mechanism and acts as
a warning to remove the body part from the stimulus.7,8 With increased intensity of
the stimulus, C-fibers also conduct impulses along with Ad fibers. C-fibers are polymo-
dal; may be activated by thermal, mechanical, or chemical stimuli; and constitute most
cutaneous nociceptive innervation with larger receptive fields compared with Ad fibers
(see Fig. 1).5,7 They are responsible for the ‘‘second pain,’’ which is burning or throb-
bing.8,9 The frequency of afferent traffic corresponds to the psychophysical report of
pain sensation in human beings and the vigor of the escape response in animals.10
In the absence of tissue injury, termination of the afferent discharges occurs with
cessation of the painful experience. When the stimulus results in tissue injury (inflam-
mation), however, the C-fibers produce an ongoing afferent discharge that persists
after the original insult has ceased and contributes to the ongoing second pain. Ini-
tially, this persistent discharge is facilitated by the injured tissue, whether skin, muscle,
or viscera, resulting in infiltration of inflammatory cells that release chemical mediators
and initiation of the arachidonic acid (AA) cascade by phospholipase-A2 (PLA2) and
subsequent eicosanoid production.11 It seems that the prominent role of this inflam-
matory process is to activate more silent nociceptors, which, in turn, release
substance-P (S-P) (see Fig. 1), a pronociceptive peptide neurotransmitter.5 Together,
this increases the afferent input to the spinal cord, which is accompanied by an
increased pain response for a given stimulus that would normally elicit less pain
(hyperalgesia). This is referred to as peripheral sensitization.12 This process also
results in the pain experience spreading beyond the area of local injury; it is therefore
‘‘poorly localized’’ and described as a burning and throbbing sensation (secondary
hyperalgesia).12 Ad and C-fibers have also been implicated in visceral nociciption.13,14

Central Nervous System

Processing of this nociceptive input at the level of the spinal cord occurs in the dorsal
horn of the spinal cord. The Ad and C-fibers enter the spinal cord by way of the dorsal
roots of spinal nerves and synapse in specific laminae of the dorsal horn. Ad fibers,
solely, and C-fibers, predominantly, terminate in laminae I and II, from which location
the the signal is then relayed, by way of the spinothalamic tract, to the brain (see
Fig. 1).5 Of importance in this process is the group of neurons called the wide-
dynamic-range (WDR) neurons, which seem to be less sensitive to innocuous stimuli
(Ab input) but respond more vigorously to noxious stimulation.9 These neurons receive
input from somatic and visceral structures and are important in the expression of
spinal facilitation of pain, or wind-up.9 Repetitive firing of primary nociceptive affer-
ents, such as occurs with inadequately treated pain of any cause, results in activation
of WDR neurons and their release of glutamate into the synaptic cleft (Fig. 2).9 Gluta-
mate subsequently activates the N-methyl-D-aspartate (NMDA) receptors on the post-
synaptic membrane. The NMDA receptors are only activated under conditions of
persistent membrane depolarization. The glutamate receptor facilitates calcium con-
ductance, resulting in up-regulation of receptors. S-P and brain-derived neurotrophic
factor (BDNF) also participate in activating the intracellular signaling cascade, which
increases the membrane’s sensitivity to subsequent stimulation.9 The reader is
 Neuropathic Pain in Dogs and Cats 1369

Fig. 2. Possible molecular mechanisms for the generation of wind-up. The diagram summa-
rizes the mechanisms that may elicit wind-up. It represents a standard spinal neurone receiv-
ing monosynaptic input from mechanoreceptors and polysynaptic input from nociceptors,
such as may occur in many deep dorsal and ventral horn neurones. Mechanisms are num-
bered from 1 to 7. Build-up of Ca21 in the presynaptic terminal (1) leads to increased
neurotransmitter release (2) of amino acids and S-P. (3) Activation of adenosine monophos-
phate acid (AMPA) receptors in the postsynaptic membrane causes fast membrane depolar-
ization, which contributes to lifting the Mg21 block of N-methyl-D-aspartate (NMDA)
receptors. (4) Activation of NMDA receptors and natural killer-1 (NK1) receptors generates
a long-lasting cumulative depolarization. Cytosolic Ca21 concentration increases as a result
of Ca21 entry through the NMDA ionophore; to a lesser extent, through some AMPA recep-
tor channels; and through voltage-sensitive Ca21 channels activated by depolarization. An
elevated Ca21 concentration (5) and the activation of NK1 receptors by means of second-
messenger systems (6) enhance the performance of NMDA receptors. (7) Finally, activation
of NK1 receptors, cumulative depolarizations, elevated cytosolic Ca21, and other factors
regulate the behavior of membrane channels, which facilitates the production of action
potentials and lead to wind-up. (From Herrero JF, Laird JMA, Lopez-Garcia JA. Wind-up of
spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol
2000;61(2):179; with permission.)

referred to articles by Herrero and colleagues9 and Muir and Woolf15 for a more in-
depth review of the neurobiology of wind-up.
Of recent interest is the identification of a group of PLA2 enzymes (group IVA cPLA2
and group VI iPLA2), constitutively expressed and active in the spinal cord, that have
been implicated in centrally mediated hyperalgesia.16 In addition to supplying sub-
strate for the cyclooxygenase (COX) pathway, AA liberated by PLA2 may play a role
in augmenting nociception.17 For example, AA potentiates NMDA receptor currents,
and thus amplifies glutamate-mediated increases in intracellular calcium concentra-
tion by binding to sites on the NMDA receptor or by modifying the receptor’s lipid
environment. COX-1 and COX-2 are induced to participate in peripheral and central
transmission of pain. Repetitive small afferent activity results in spinal release of pros-
taglandin E2 and amino acids that serve to enhance transmitter release, leading to
1370 Mathews

central sensitization.18 Inhibition of COX by nonsteroidal anti-inflammatory drugs

(NSAIDs) exerts a direct spinal action by blocking hyperalgesia induced by the activa-
tion of spinal glutamate and S-P receptors.19 These findings demonstrate that the
analgesic effects of NSAIDs can be dissociated from their anti-inflammatory actions.
Spinal prostanoids are thus critical for the augmentation of pain processing at the
spinal level.19 Recently, spinal isoprostanes have been identified and shown to sensi-
tize rat sensory neurons, producing a hyperalgesic state, thereby reducing mechanical
and thermal withdrawal thresholds in rats.20 Isoprostanes are a novel group of nonen-
zymatically generated AA metabolites formed directly in a non–COX-dependent
manner by free radical oxidation of AA.21
The net effect of noxious sensory input is that high-frequency action potentials in the
primary afferent neuron facilitate the second-order neurons to respond more vigor-
ously to subsequent stimulation, a phenomenon termed central sensitization. This
effect can last from hours to weeks, or even years (in certain situations, as is discussed
in the section on neuropathic pain) after the causative event ends.15,22
The sensory input from the dorsal horn is transmitted through the ascending noci-
ceptive pathways, and through the brain stem (medulla, pons, and midbrain), with
contributions to the reticular activating system and the periaqueductal gray matter
(PAG).23 The PAG extends projections to the hypothalamus (initiating the neuroendo-
crine and autonomic responses) and the thalamus, providing an indirect alternative
pathway for nociceptive sensory activity. Finally, the sensory activity from the thala-
mus reaches the cortex, in which it is perceived as pain. The perception of pain results
in a normal behavioral response, such as withdrawal from the stimulus (nociceptive
pain), and, depending on the circumstance and severity of the pain experienced,
such as inflammatory or neuropathic pain, many other behavioral characteristics.24
What is important to note is that although general anesthetics block the perception
of pain (cortical component), the events in the dorsal horn are not blocked.25 Whatever
degree of wind-up that has been established during the surgical procedure continues
to be experienced on recovery from general anesthesia. The sensory cortex can
undergo considerable plasticity together with the changes that occur in subcortical
structures; as such, supraspinal plasticity is believed to play a major role in shaping
the pain experience.26 The appropriate analgesics known to block the various steps
along the nociceptive pathway to the thalamocortex can reduce the ‘‘memory’’ and
establishment of chronic and neuropathic pain, and the reader is referred to the article
by Lamont on multimodal pain management elsewhere in this issue for an in-depth
discussion on this topic.

Endogenous Facilitatory Systems

In addition to descending inhibition of sensory input, descending excitatory or facilita-
tory influences from the brain stem or forebrain have been characterized.27 Although
descending inhibition is primarily involved in regulating suprathreshold responses to
noxious stimuli, descending facilitation reduces the neuronal threshold to nociceptive
stimulation. Descending facilitation has a general impact on spinal sensory transmis-
sion, and it induces sensory inputs from cutaneous and visceral organs.28 One phys-
iologic function of descending facilitation is to enhance an animal’s ability to detect
potential danger signals in the environment. Neurons in the rostral ventromedial
medulla (RVM) not only respond to noxious stimuli but show ‘‘learning’’ type changes
during repetitive noxious stimuli.28 The RVM neurons undergo plastic changes during
and fter tissue injury and inflammation. Descending facilitation is likely activated after
injury, contributing to secondary hyperalgesia.28
 Neuropathic Pain in Dogs and Cats 1371

Descending Inhibitory System

Whereas the ascending sensory pathways ensure delivery of the sensory activity, the
descending modulatory pathways, or inhibitory systems, function to reduce the actual
degree of pain perceived, acting as a ‘‘gate’’ to pain. Nociceptive inputs activate
endogenous analgesic systems, which include structures within the thalamocortex,
PAG, RVM, pons, and medullary and spinal cord dorsal horn.27 The most important
of these is the PAG, with its dense concentration of opioid peptides and receptors.
A group of catecholaminergic nuclei in the pons, the locus ceruleus (LC), receives
noradrenergic efferents from the PAG that descend to the spinal cord dorsal horn.29
Activity of the LC is under the control of an a2-autoreceptor and seems to contribute
indirectly to analgesia at the level of the dorsal horn through these descending projec-
tions.29,30 There is evidence that another nucleus (Kolliker Fuse) may be the primary
source of descending noradrenergic fibers in the cat.29 By activating descending
inhibitory systems, painful information entering the CNS is significantly reduced.
Thus, acute or physiologic pain is bearable, and it does not become chronic or
pathologic pain.27
There are several transmitters and receptors at multiple sites within the
descending inhibitory system.29 The final site involved in the inhibitory pathway
is the dorsal horn of the spinal cord. Substances identified in the dorsal horn neu-
rons that serve to modulate nociceptive transmission are amino acids (g-aminobu-
tyric acid [GABA] and glycine), serotonin (5-hydroxytryptamine [5-HT]),
norepinephrine (NE), and the endogenous opioid peptides (enkephalins, endor-
phins, and dynorphins).31 The spinal cord opioid system acts presynaptically by
blocking release of S-P and postsynaptically. Studies have shown that serotonin
and NE contribute to antinociception in spinal pathways and supraspinal descend-
ing pathways, which are also disrupted in neuropathic pain.31 A recent study sug-
gested that after nerve injury, the tonically active noradrenergic inhibition of
mechanically evoked spinal dorsal horn neuronal responses is lost.32 This alter-
ation in noradrenergic inhibitory control may be one of the many underlying mech-
anisms by which behavioral symptoms of hypersensitivity develop after nerve
damage.32 Although the dissection of the inhibitory system and its disruption
continue to be investigated, it has been known for some time that a component
of neuropathic pain and hyperalgesia is attributable to disruption of the normal
endogenous inhibitory systems, such that the descending inhibitory system and
the opioid system may become deficient at the spinal level.33 For reviews in the
veterinary literature, the reader is referred to articles by Muir and Woolf15 and
Lamont and colleagues.34

Summary of Events of Sensory Stimulation (Neuronal Plasticity)

1. The immediate (<1 second) reflexive and nociceptive responses associated with
C-fiber input (activation)
2. The rapid (seconds) and progressive changes in excitability (wind-up)
3. The development of peripheral and central sensitivity (hours)
4. The activity-dependent alterations in intracellular signal molecules and gene
expression that define a potentiated system (hours later)
All of these, in conjunction with disinhibition and Ab-mediated pain, represent
a series of neurobiologic events that are responsible for activation, modulation, and
modification of the nervous system by sensory stimuli.35
1372 Mathews

NEUROPATHIC PAIN

In veterinary medicine, a major focus for assessing neurologic injury after surgery or
trauma is commonly loss of motor and sensory function, or in certain illnesses, primar-
ily a loss in motor function. In this setting, damage or disease of axons (axotomy) or
myelin disrupts the ability to conduct nerve impulses, causing hypoesthesia and
numbness (as described by human beings), in addition to potential loss of motor func-
tion. Because nerves are protoplasmic extensions of live cells, however, the neurons,
respond actively to injury.4 Surgery, trauma, and inflammatory states result in nocicep-
tive input as previously described. Primary injury to nerves also confers pain. In rat
models of peripheral nerve injury, the onset of ectopic action potential firing in the in-
jured nerve corresponds to the onset of behavioral signs of pain, such as mechanical
allodynia.36
The developing pain (neuropathy) is typically attributable to injury or disease that
damages the axon or soma of sensory neurons or disrupts the myelin sheath that
surrounds many axons (dysmyelination and demyelination).37 Ectopic firing of these
nerves tends to occur; in fact, some human patients with a neuropathic disorder report
enhanced sensation at a certain level of tactile stimulus in areas normally hypoesthetic
at rest.5 Some human patients also experience paresthesias (tingling, prickling, burn-
ing), hyperesthesias (heightened sensation to a nociceptive stimulus), and dysesthe-
sias (unpleasant or painful sensation) (Box 1).5 The quality and pattern of altered
sensitivity in neuropathic pain differ from transient or inflammatory pain. As an exam-
ple, a cold stimulus, such as applying an ice pack to an acutely injured joint to reduce
the inflammatory pain in the ‘‘normal’’ or ‘‘naive’’ painful individual, would be
described as excruciating in a patient with neuropathic pain.5 This difference in
‘‘experience’’ is thought to occur because of a reorganization of sensory transmission
within the nervous system that occurs after nerve injury. Such changes include alter-
ations in expression of neurotransmitters, neuromodulators, receptors, ion-channels
(especially the tetrodotoxin-resistant [TTX-R] sodium channels),38 and structural
proteins. Some of these changes are involved in the reparative process, but others
contribute to neuropathic pain. As an example, the Ab-fibers may sprout into the
laminae II region of the dorsal horn vacated by central terminals of C-fibers, wherein
S-P and S-P (natural killer-1 [NK1]) receptors are expressed (Fig. 3).37 Alternatively,
because of nerve injury, the disruption of the glial ensheathment allows the adjacent
denuded axons to make contact, facilitating electrical (ephaptic) and chemical (by
means of diffusible substances) cross-excitation. A cross-after-discharge can also
occur, whereby normal A-fibers can activate C-fibers.39 When light innocuous stimuli
are applied to the area subserved by the nerve-injured area, the stimuli transmitted by
the Ab-fibers are processed in the dorsal horn as C-fiber sensory afferent stimuli with
subsequent pain transmission (see Fig. 3).5,40 During the healing process, there may
also be a connection between the Ab-fibers and the C-fibers. Therefore, the transmis-
sion of a normal innocuous ‘‘touch’’ stimulus elicited during transduction of the Ab-
fibers is coupled to the axon of the C-fiber. Subsequent transmission is then by means
of the C-fiber, in which it is interpreted centrally as a noxious stimulus (allodynia)
(see Fig. 3).5

Sensory-Sympathetic Coupling
Under physiologic conditions, primary afferent nerve endings are not sensitive to
catecholamines and are functionally distinct from the efferent sympathetic nervous
system.5 Normally, sympathetic activity does not cause pain; nerve injury, however,
can induce noradrenergic supersensitivity.37,41 This sensory-sympathetic coupling
 Neuropathic Pain in Dogs and Cats 1373

Box 1
Stimulus-evoked pain
Nociceptive
It is caused by an intense, noxious stimulus (sensory response) that threatens to damage normal
tissue. It is also known as physiologic, because it is the body’s normal defense mechanism, re-
sulting in withdrawal (motor response) from the potentially external hostile environment.
Hyperalgesia (also called hyperpathia)
 An exaggerated pain response produced by a normally painful stimulus (eg, a pinprick).
 It can arise from peripheral or central mechanisms.
Peripherally
 Sensitization of primary afferent nociceptors (Ad and C-fibers) occurs by inflammatory
mediators, such as bradykinin, histamine, prostaglandins, and substance-P released from
injured tissue. The stimulus in this area hurts more than a non-injured or inflamed area.
 Neuroma: a tangled mass of regenerating nervous tissue embedded in scar and connective
tissue at the site of nerve injury. Neuromas accumulate or ‘‘uncover’’ pathologic and non-
pathologic ion channels (eg, various sodium channels) and receptors (eg, norepinephrine)
that result in foci of hyperexcitability and ectopic activity.
Centrally
 Sensitization: tissue injury triggers an increase in the excitability of neurons in the spinal cord
generated by C-fiber activity. Any prolonged or massive input from C-nociceptors enhances
the response of dorsal horn neurons to all subsequent afferent inputs. As a result, increased
synaptic activity is seen at the dorsal horn of the spinal cord, leading to changes in their
excitability. The receptive field of the dorsal horn also grows. This increased activity outlasts
the original injury at the primary afferents leading to central sensitization. The concept of
central sensitization involves the development of secondary hyperalgesia or allodynia.
Secondary hyperalgesia results in an increased sensitivity to a stimulus that occurs beyond the
area of injury or inflammation (ie, adjacent normal tissue).
 Central pain- pain experienced in the area of the body subserved by the lesion originating
from a primary lesion of the CNS.
Allodynia
Pain produced by a stimulus that is not usually painful (eg, light touch), and may result from
any of the following central mechanisms for stimulus-evoked pain:
 Central sensitization
 Reorganization or
 Loss of inhibitory controls.
Stimulus-independent or spontaneous pain
 Occurs without provocation, so symptoms can occur constantly or at any time.
 Paresthesias: abnormal sensation that is not unpleasant, such as tingling, prickling.
 Dysesthesias: unpleasant, usually burning sensation that can originate peripherally by way of
ectopic impulses along the Ab, Ad and C-fibers, arising as spontaneous activity caused by
processes, such as damaged (‘‘leaky’’) sodium channels, that accumulate along affected
nerves. Paroxysmal shooting or electrical pain and continuous burning pain probably occurs
from ectopic or ephaptic discharges arising in any type of fiber or may occur as a result of
reduced inhibitory input from the brain or spinal cord.

Data from Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug
development. Anesthesiology 2001;95(1):241–9; and Woolf CJ. Dissecting out mechanisms
responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci
2004;74:2605–10.
1374 Mathews

Fig. 3. Nerve injury–induced structural and neurochemical reorganization. After nerve

injury, the transmission of a normal innocuous ‘‘touch’’ stimulus elicited during transduction
of the Ab fibers is coupled to the axon of the C-fiber. Subsequent transmission is then by
means of the C-fiber, in which it is interpreted centrally as a noxious stimulus (allodynia).
This reorganization may be attributable to: (1) the Ab fibers may sprout into the laminae
II region of the dorsal horn vacated by central terminals of C-fibers in which S-P and NK1
(S-P) receptors are expressed; (2) nerve injury when the disruption of the glial ensheathment
allows the adjacent denuded axons to make contact, facilitating electrical and chemical
cross-excitation (a cross-after discharge can also occur, whereby normal A-fibers can activate
C-fibers); or (3) during the healing process, there may also be a connection between the Ab
fibers and the C-fibers. With (1), (2), or (3), dorsal root ganglion neurons in Ab fibers now
express S-P and neurons in lamina II express a greater number of NK1 receptors for pain
transmission.

may contribute to stimulus-independent neuropathic pain in some human patients.

Exogenous administration and endogenous release of NE increase the discharge of
unmyelinated sprouts that have regenerated into a neuroma42,43 After nerve damage
in the rat, NE-containing sympathetic postganglionic fibers that normally innervate
small blood vessels sprout, likely triggered by a neurotrophin, such as BDNF, and
maintain nonsynaptic contact with sensory endings. In some instances, sympathetic
sprouts encircle large-diameter dorsal root ganglia somata forming ‘‘baskets’’5. Clin-
ical evidence for a sympathetic contribution to neuropathic pain is supported by (1) pa-
tients with neuropathic pain often have accompanying signs, such as skin vasomotor
activity and sweating; (2) neuropathic pain is often worsened by stimuli that evoke
a sympathetic response, such as the startle response and emotional arousal; and
(3) surgical destruction or pharmacologic blockade of the sympathetic outflow to
the affected area often produces pain relief.5 The effect of sympathetic blockade is
not consistent, however, and in some patients, symptoms often recur within
6 months.5 Neuropathic pain in animal models with L5 spinal nerve ligation, thought
 Neuropathic Pain in Dogs and Cats 1375

to be sympathetic dependent, was resistant to sympathectomy.44 Even so, when

conservative therapy fails, sympathetic blocks can be of benefit to some individuals
and continue to be recommended for human patients.45 Although noradrenergic
supersensitivity would be extremely difficult to diagnose in veterinary patients, it is
worthy of note should such signs manifest at some point after a triggering surgical
or traumatic event.

Immune Response Mechanisms in Neuropathic Pain

Injury to nerves results in an inflammatory response at the site of nerve injury and in the
CNS, which is similar to that occurring after damage to nonneural tissue. An excellent
review on this topic presents evidence that inflammatory and immune mechanisms in
the PNS and CNS play an important role in neuropathic pain.11 It was found that
infiltration of inflammatory cells, in addition to activation of resident immune cells in
response to nervous system damage, leads to the subsequent production and secre-
tion of various inflammatory mediators. These mediators were shown to promote neu-
roimmune activation and can sensitize primary afferent neurons and contribute to pain
hypersensitivity. Also, the activated macrophages at the site of nerve injury produce
proinflammatory substances, such as tumor necrosis factor-a (TNFa) and interleu-
kin-1b (IL-1b), which are known to produce pain in experimental animals when given
subcutaneously or applied directly to the nerve.11
Neuronal plasticity along the pathway for sensory transmission from the periphery
through the spinal cord and in the cortex plays an important role in chronic pain,
including inflammatory and neuropathic pain.46 Recent studies indicate that microglia
in the spinal cord are involved in neuropathic pain.47,48 Activated microglia exert
important functions, such as phagocytosis of cellular debris or neuronal signal pro-
cessing, through communication with neurons, immune cells, and glial cells.47 Activa-
tion of microglia occurs in most pathologic processes. The activation is accompanied
by changes in morphology, up-regulation of immune surface antigens, and production
of cytotoxic or neurotrophic molecues.48 Spinal microglia are activated after periph-
eral nerve injury and may release many bioactive molecules, such as cytokines,
chemokines, and neurotrophic factors (eg, BDNF), which then modulate the excitabil-
ity of spinal neurons.49 In addition to activation, increased density of microglia has
been reported in the ipsilateral dorsal horn laminae I to III after peroneal nerve ligation
in mice.47 Anatomically, these areas are where primary sensory afferents innervating
mechanoreceptors and nociceptors project (see Fig. 1). Therefore, the excitatory
signals from the injured nerve to these spinal areas may be one of the primary factors
triggering microglia activation.47 Biochemical changes along the neuronal sensory
pathway may be an additional cause for microglia activation.50
In the search for pharmacologic targets of chronic neurogenic pain, a recent finding
is the role of the transient receptor potential (TRP) in neurogenic inflammation.51 As
previously mentioned, neurogenic inflammation is produced by overstimulation of
peripheral nociceptor terminals by injury or inflammation of the tissues (peripheral
sensitization). Small-diameter sensory neurons play a key role in the generation of
neurogenic inflammation. There are several TRP receptors; however, cloning of the
transient receptor potential vanilloid receptor 1 (TRPV1) has contributed significantly
to the understanding of the molecular mechanisms involved in neurogenic inflamma-
tion. TRPV1 plays an integral role in the integration and modulation of various stimuli
and nociceptor excitability, thus making it a true gateway for pain transduction.51 In
addition, TRPV1 is the end-point target of intracellular signaling pathways triggered
by inflammatory mediators.51 There is evidence for the involvement of this receptor
in the etiology of peripheral and visceral inflammatory pain, such as inflammatory
1376 Mathews

bowel disease (IBD), bladder inflammation, and cancer pain.52 Worthy of note are the
important and diverse physiologic functions played by the TRPV1 channel throughout
the body. Targeting this receptor for analgesic purposes may be akin to targeting
prostaglandins with the NSAID analgesics.

Descending Inhibitory Pathway

Various studies have identified the decreased efficacy of the descending inhibitory
pathways in animals with neuropathic lesions.33,53 These studies demonstrated
reduced sensitivity to intrathecal or intravenous administration of morphine, indicating
reduced opioid receptor function. In one study, after morphine administration,
descending inhibition was almost 50% lower in neuropathic animals compared with
normal controls53 and those with arthritic pain.54 Because descending inhibition nor-
mally acts as a spinal ‘‘gate’’ for sensory information, reduced inhibition increases the
likelihood of the dorsal horn neuron firing spontaneously or more energetically to
primary afferent input.55 Of note, the decreased responsiveness to morphine could
be prevented by pretreatment of the animals with an NMDA-receptor antagonist.53,56
Although opioid receptors are less responsive in neuropathic pain, it seems that
descending noradrenergic inhibition and increased sensitivity of spinal neurons to
a2-agonists may occur still with peripheral inflammation and nerve injury.57 NE is re-
leased in the spinal dorsal horn by descending noradrenergic axons, which mainly
originate from the LC and adjacent nuclei in the brain stem, and produces analgesia
by stimulating a2-adrenergic receptors.58 NE and, to a lesser extent, serotonin
(5-HT) are major components of the endogenous descending pain inhibitory system.57
It has been suggested that chronic pain may partially result from altered or reduced
levels of endogenous NE and serotonin activity at the spinal and supraspinal levels.58
It is presumed that the NE and serotonin reuptake inhibitors (SRIs) attenuate pain by
preventing presynaptic reuptake of NE and serotonin, resulting in increased postsyn-
aptic levels and sustained activation of the descending pain inhibitory pathway.58 This
ultimately results in attenuation of neuronal hyperexcitability and alleviation of pain.
A study focusing on the spinal and supraspinal action of gabapentin demonstrated
that gabapentin activates the descending noradrenergic system in a mouse nerve
ligation model, as measured by increasing cerebrospinal fluid (CSF) NE levels.59 In
a follow-up human clinical study, oral gabapentin also significantly increased CSF
NE concentration, when compared with the placebo group, after orthopedic or
urogenital surgery in patients who had chronic pain. These findings indicate the
responsiveness of the noradrenergic inhibitory system in neuropathic and chronic
pain; however, this effect does not seem to be present when chronic pain is not
established.59
Nerve injury may also disrupt the Ab-fiber–mediated inhibition and the GABA-
mediated inhibition of pain transmission neurons in the dorsal horn.5,60 The loss of
this activity may be within interneurons that ultimately releases the ‘‘brake’’ on central
sensitization of dorsal horn neurons. The loss of this inhibitory process may contribute
to spontaneous pain, hyperalgesia, or allodynia after nerve injury.5,60

Summary of Neuropathic Pain

Pain can be divided into three categories: physiologic, inflammatory, and
neuropathic.35,46,54,60
1. Physiologic pain, such as the pain in response to a needle prick, serves to protect
an animal from injury.
2. Inflammatory pain is caused as a consequence of tissue damage.
 Neuropathic Pain in Dogs and Cats 1377

3. Neuropathic pain is a clinical syndrome of pain attributable to abnormal somato-

sensory processing in the PNS or CNS and may include spontaneous pain, pares-
thesia, dysthesia, allodynia, or hyperpathia (see Box 1). Neuropathic pain serves no
beneficial purpose to the animal and can be regarded as a disease in itself. The
pathophysiology of neuropathic pain is complex and incompletely understood.
There are three pivotal phenomena intrinsic to the development of neuropathic
pain:
A. Central sensitization (ie, the process of ‘‘wind-up’’ and the resulting transcrip-
tional changes in dorsal horn neurons leading to altered synaptic neurotransmit-
ter levels and numbers of receptors)
B. Central disinhibition (ie, an imbalance between the excitatory and inhibitory
sides of the nervous system
C. Phenotypic change of mechanoreceptive Ab-fibers (light touching) to produce
S-P, such that input from them is perceived as pain

BREAKTHROUGH PAIN

Breakthrough pain (BTP) is common in human patients who have cancer and in
a variety of other problems causing pain. The reported incidence of BTP varies widely
from 16% to 95% of those with persistent pain syndromes.61 Such variability is likely
attributable to lack of a clear consensus on the definition of BTP, but it is most com-
monly defined as an abrupt, short-lived, and intense pain that ‘‘breaks through’’ the
around-the-clock analgesia that controls persistent pain.61 The three subtypes of
BTP are incident, idiopathic, and end-of-dose failure. BTP also is categorized as
somatic, visceral, neuropathic, or mixed.61 Appropriate assessment of the patient
takes into consideration the source, severity, pattern, subtype, and cause of pain.
Successful treatment is important because BTP has a profound impact on the
patient’s quality of life.61
BTP is easily recognized in the acute pain setting in hospitalized animals; however,
veterinarians may be unaware of the occurrence of BTP in patients with persistent pain
unless specific questions are asked of the client. Greater knowledge and awareness of
BTP, especially when neuropathic pain may be occurring based on anatomic involve-
ment of a lesion or history of previous events predisposing to neuropathic pain, should
lead to recognition, diagnosis, and, ultimately, treatment of BTP in these patients.

DIAGNOSING NEUROPATHIC PAIN

Neuropathic pain may be difficult to diagnose in veterinary patients. Based on the

various branches from the sensory pathways to subcortical areas in the brain, the
‘‘emotional’’ aspects of pain, in addition to the sensation of pain, are experienced,
which alters the animal’s ‘‘personality.’’ A change in behavior, such as ‘‘dullness’’ or
occasional aggression, may be noted by the owner in addition to obvious signs of
pain. A comparison can be made to the human clinical and research setting as a po-
tential resource for recognizing, diagnosing, and treating neuropathic pain in veteri-
nary patients.
Neuropathic pain is frequently associated with chronic pain; however, it also occurs
in the acute setting before surgery when associated with trauma or a neoplastic or
inflammatory condition encroaching on neural tissue or after surgery when transient
or persistent iatrogenic injury has occurred. In the acute setting in human medicine,
patients noted to be at risk for progression to persistent pain include those with severe
pain and those with injury to any part of the PNS or CNS.62 The importance of being
aware of the animals ‘‘at-risk’’ for development of chronic neuropathic pain in the
1378 Mathews

acute setting is to ensure that appropriate intervention is instituted before, during, or

after surgery to prevent such a debilitating situation, which may be difficult to diagnose
once established at a later date.
In the human setting, the diagnosis of neuropathic pain may be based solely on
history and examination findings as judged by an experienced clinician. This requires
five of eight features suggestive of neuropathic pain:62

1. History consistent with nerve injury

2. Pain within but not necessarily confined to an area of sensory deficit
3. Pain in the absence of ongoing tissue damage
4. Character of pain: burning, pulsing, shooting, or stabbing
5. Paroxysmal or spontaneous pain
6. Associated dysesthesias
7. Allodynia, secondary hyperalgesia, or hyperpathia
8. Associated autonomic features
Obviously, it is difficult to apply all these features to veterinary patients, but a select
few can be applied. The investigators who conducted one study believe that clinical
vigilance, with regard to history taking and sensory examination, remains the key
factor in the diagnosis of neuropathic pain in the acute setting (Box 2).62 This would
certainly be applicable to veterinary medicine. In addition to the eight points listed pre-
viously, the possibility of neuropathic pain was considered when ‘‘unexpected’’ levels
of pain were present for the trauma or surgical procedure time course after surgery or
after trauma. In situations in which the diagnosis of neuropathic pain was uncertain,
a positive response to blinded intravenous lidocaine (0.5-mg/kg bolus, then 3 mg/kg)
given over 20 minutes and a ‘‘placebo’’ of the same volume of saline administered
over the same duration was used to assess a change in the pain severity score in
human patients.62 A positive response to lidocaine was seen as an overall reduction
in the visual rating scale (VRS) of greater than 50% and also a change in VRS at least
twice that of the placebo (saline). In this study group, trauma (43.1%) and surgery
(27.5%) were the leading causes of neuropathic pain. Most members of the trauma
group were victims of motor vehicle accidents (including four traumatic amputations),
with some patients who had sporting injuries and one patient who had received burns.
The surgical group included patients having had gynecologic surgery, laparotomy, or
thoracotomy and those with ischemic limbs after vascular surgery. A total of 29.4% of
cases were classified in the ‘‘other’’ causes group. These included patients with neu-
ropathic pain after intercostal catheter insertion; patients with compartment syndrome
secondary to coagulopathy, acute cancer pain, spontaneous spinal abscess, or vas-
culitis; and other patients with no precipitating cause identified.62 From the patient
population identified with acute neuropathic pain in this study, we can definitely
make the assumption that there is the potential for this to occur in veterinary patients.
When assessing pain in animals, it is important to interact with them to assess their
response to you and to establish if, and how much, pain is detected when moving. It
is obvious from personal experience that our ‘‘injured or ill part’’ frequently hurts
more when we move but may be minimally painful at rest. Movement-evoked pain in
the postoperative period may alert the clinician to the potential for nerve entrapment
if there is an exaggerated vocal and behavioral response for the given stimulus or abso-
lute reluctance to move, although most of these animals tend to appear extremely pain-
ful at rest also.24 Another test of evoked pain is pressing around the surgical wound to
assess the presence of mechanical hyperalgesia, which may be disproportional to that
expected when neuropathic pain exists. It is interesting to note that assessing pain at
rest and then with evoked stimuli, or if BTP or incident pain should occur, can be
 Neuropathic Pain in Dogs and Cats 1379

Box 2
Simple tests for the assessment of stimulus-evoked neuropathic pain in humans
The tests are performed on normal (uninjured) skin. The description of the sensation is included
to give the reader an impression of what a cat and dog may also experience when tested. Tests
using temperature or stroking stimuli would require a shaved area which could be performed
once an area of involvement was identified using the pinprick or pressure tests.
Allodynia
Manual light pressure of the skin
Normally non-painful but elicits a dull, burning pain in the affected area when compared to
an unaffected area

Light manual pinprick with a sharpened wooden stick or stiff von Frey hair
Sharp superficial pain elicited in the affected area but not in the unaffected area

Stroking skin with a brush, gauze, or cotton applicator

Sharp, burning, superficial pain in affected area but not in the unaffected area

Manual light pressure at the joints

Deep pain is elicited at the joints of the affected area but not in the unaffected area

Thermal cold
Contact of the skin with objects at 20 C is painful, often burning, temperature sensation
in affected area but the unaffected area

Thermal warm
Contact of the skin with objects at 40 C is a painful, burning temperature sensation in the
affected area but not the unaffected area
Hyperalgesia
Manual pinprick of the skin with a safety pin
Sharp superficial pain that is normally painful but the stimulus produces a more
exaggerated response in the affected area compared to the unaffected area

Thermal cold
Contact of the skin with coolants such as acetone or cold metal is normally painful, often
a burning, temperature sensation which produces a more exaggerated response on the
affected area when compared to the unaffected area

Thermal heat
Contact the skin with objects at 46 C
Painful burning temperature sensation

Algometer
Ad and C-fibre activity arising from nociceptors and Ab fiber activity arising from
mechanoreceptors
The response is a lower threshold and tolerance, or suprathreshold response to stimuli

Data from Harden RN. Chronic neuropathic pain. Mechanisms, diagnosis, and treatment.
Neurologist 2005;11(2):11–22.
1380 Mathews

confusing when conducting pain studies and assessing various therapeutic modalities.
Recent trials in human medicine suggest that pain assessment at rest should be as-
sessed separately from several types of evoked pain.26 This is an important point to
consider in veterinary medicine, wherein descriptors for assessing pain should be in-
cluded in each scoring system and ‘‘at rest’’ and ‘‘stimulus-evoked’’ components
should be introduced. The algometer and thermal tests have been used in some veter-
inary studies as objective measures for stimulus-evoked assessment of pain.
Neuropathic pain scales are published in human medicine. The Neuropathic Pain
Scale63 and the Leeds assesment of neuropathic symptoms and signs (LANSS)
Pain Scale64 are used in human medicine in an attempt to gain greater precision in
the description and diagnosis of neuropathic pain. Both scales are validated against
the ‘‘gold standard’’ of the clinician’s diagnosis in classic neuropathic pain states,
which tends to be associated with chronic pain conditions. Neither scale has been as-
sessed in human postoperative and posttrauma settings, wherein a mixed presenta-
tion of nociceptive and neuropathic pain is the norm.62 When chronic neuropathic pain
is experienced, however, these scales are valuable in localizing the lesion based on
history of illness or injury and descriptions of pain experienced.63,64 Because the de-
scriptions (eg, dull, aching, burning versus sharp, lancinating) are used to diagnose the
type of neuropathic pain in human patients, these scales are of no value in veterinary
patients. Client observation of behavior may identify sharp, lancinating, and ectopic
firing pain; however, this may coexist with constant dull, burning, and aching pain.
In human medicine, the prevalence of chronic pain is high within the community;
however, it is reported that neuropathic pain may only occur in 1% to 3% of patients
seen in pain clinics.62 Although this may seem to be a small number, the pain experi-
enced by these patients is severe to excruciating and uses a large percentage of the
clinics’ time resources.62 In veterinary medicine, pain severity and precise localization
can be difficult to assess;65 however, with recent history, physical examination with
attention to detail, and experience, pain assessment can be made in most cases.
Chronic neuropathic pain, however, may be difficult to suspect because the present-
ing signs may be subtle and client observations may be vague. A veterinary study
investigating the prevalence and characteristics of pain among dogs and cats exam-
ined as outpatients at a veterinary teaching hospital identified a slightly higher preva-
lence of neuropathic pain (dogs [8%] and cats [7%]) than occurs in human beings.66 In
this study, a total of 1153 dogs and 652 cats were examined as outpatients at The
Ohio State University Teaching Hospital during 2002. Of these, 231 (20%) dogs and
92 (14%) cats had evidence of pain. The characteristics of pain were recorded from
the examination of these patients. The categories of pain were as follows:
1. Inflammatory (pain considered to be initiated by chemical inflammatory mediators
released by tissue damage)
2. Neuropathic (defined as pain caused or initiated by a primary lesion or dysfunction
in the PNS or CNS). Pain was then further categorized as:
A. Primary hyperalgesia (peripheral sensitization) was considered to exist when the
animal responded adversely to light touch directly on the area of the body from
which the pain originated (ie, the area of primary hyperalgesia).
B. Secondary hyperalgesia (central sensitization) was considered to exist when the
animal responded adversely to light touch to an uninjured area surrounding the
area of primary hyperalgesia.
C. Allodynia (pain elicited from noninjured tissues by nonnoxious stimuli) was con-
sidered to exist when the animal responded adversely to light touch applied to
normal (noninjured) tissues distant from the area of primary hyperalgesia.
 Neuropathic Pain in Dogs and Cats 1381

D. Hyposensitivity (an apparently reduced pain response when pain would have
been expected to be present because of tissue or nerve injury) was considered
to exist when a dog or cat with obvious tissue or nerve damage demonstrated
reduced or no signs of pain during physical examination.
The findings were as follows: 82% of dogs and 83% of cats demonstrated a primary
hyperalgesic response; 17% of dogs and 15% of cats demonstrated a secondary
hyperalgesic response; and hyposensitivity was noted in 2% of cats and dogs. The
mechanism assessed to cause pain was inflammatory in 76% of cats and dogs and
neuropathic in 8% of dogs and 7% of cats, with inflammatory and neuropathic pain
identified in 16% of dogs and 17% of cats. The presence of pain was noted to last
for less than 7 days in most animals, with 11% of dogs and 13% of cats experiencing
pain for longer than 1 month but less than 1 year and 6% of dogs and 1% of cats
experiencing pain for longer than 1 year.66 As a comparison, a slightly higher rate of
neuropathic pain was diagnosed in the emergency setting of the same hospital, using
similar criteria.67 In this study of 179 dogs and 60 cats examined during 2003, neuro-
pathic pain alone was identified in 9% of dogs and 3% of cats and combined neuro-
pathic and inflammatory pain was identified in 23% of cats and dogs. Hyposensitivity
was diagnosed in none of these animals. There were no individual patient case
histories given on specific behavior patterns, potential causes, or development of neu-
ropathic pain.
Some conditions are well known to cause neuropathic pain in cats and dogs, but the
major challenge is the recognition of the not so well-known, or previously unreported,
conditions that cause neuropathic pain.
In addition to history taking and neurologic examination, electrodiagnostic testing is
used in the overall neurologic assessment in human patients.68 Electrodiagnostic
methods are available for veterinary patients,69,70 and the reader is referred to these
texts for an in-depth discussion on potential utility and findings in detecting neuro-
pathic pain. Although sensory nerve and dorsal nerve root conduction studies do
not specifically evaluate nociceptive fibers, detailed evaluation of the sensory periph-
eral nervous system (PNS) by means of sensory nerve action potential studies and
conduction, along with dorsal nerve root and dorsal horn studies using cord dorsum
potential analysis, can provide a wealth of information on the involvement of the
peripheral sensory nervous system as a whole (Paul Cuddon, personal communica-
tion, 2008).69 This has been demonstrated in the evaluation of feline diabetic
neuropathy.71

NEUROPATHIC PAIN^ASSOCIATED CONDITIONS

Neuropathic Pain Associated with Trauma: Accidental and Surgical
Intraoperative considerations for the prevention of neuropathic pain
Specific details are described for surgical procedures on peripheral nerves in veteri-
nary surgical texts.72 Caution is mentioned to identify and handle neural tissue at
the surgical site carefully; however, there often is not the same emphasis for many
surgical procedures in which neural tissue may be inadvertently incorporated in the
surgical procedure. Because nerve ligation is a model for the study of neuropathic
pain, it may be prudent to identify neural tissue and ensure that this is not incorporated
in ligatures at any surgical site to prevent the potential for development of neuropathic
pain that may be difficult to identify and treat at a later date. Should transection or
excessive manipulation or traction of neural tissue be necessary, application of a lido-
caine and bupivacaine mixture to neural tissue at least 5 minutes before handling is
recommended. Lidocaine confers its effect earlier than bupivacaine, with bupivacaine
1382 Mathews

having a longer duration of effect. Overall, gentle handling of tissue to reduce the
inflammatory response is essential.

Inguinal hernia repair

Inguinal hernia repair is a relatively common procedure in veterinary medicine. The
potential for nerve injury during the repair may be similar to that for human patients.
In a prospective study of 315 human patients undergoing inguinal hernia repair,
patients were seen for follow-up at 6, 12, and 24 months and were assessed for the
presence of pain, numbness, paresthesia, and recurrence.73 At 1 year, 62.9% of
patients had groin or inguinal pain and 11.9% of patients had moderate to severe
pain. Two hundred seventy-six patients were seen at 2 years after surgery; of these
patients, 53.6% had pain and 10.6% continued to report moderate to severe pain.
The predictors for long-term postoperative pain in this study were lack of preoperative
bulge at the hernia site and the presence of numbness in the surgical area after sur-
gery. Three distinct types of chronic pain were identified. The most common and
most severe pain was somatic, localized to the common ligamentous insertion to
the pubic tubercle. The second type of pain was neuropathic and was referable to
the ilioinguinal or genitofemoral nerve distribution. This was likely attributable to injury
to the genitofemoral nerves, at surgery or subsequently by encroachment of scar
tissue. The third type of pain was visceral ejaculatory pain. Twenty-four percent of
patients had postoperative numbness at 2 years. Numbness was most common in
the distribution of cutaneous branches of the ilioinguinal and iliohypogastric nerves.73
The conclusions of this study were to consider surgical strategies to reduce associ-
ated long-term painful experiences. Again, an association of numbness and pain
may occur in veterinary patients, and such assessment would be beneficial during
follow-up examination. Perineal hernia repair is also a standard procedure in veterinary
patients with the potential for neuropathic pain to occur.

Pelvic fractures
Pelvic fractures occur with some frequency in veterinary medicine, and it would be
a reasonable assumption that complications in our patients might parallel those in
human patients. A high incidence of chronic pain (48.4%) was found in a follow-up
study of 161 human patients at a median of 5.6 years after pelvic fracture repair.74
Most of these patients had a combination of somatic nociceptive, visceral nociceptive,
and neuropathic pain, along with a high incidence of other complications. One com-
plication noted related to leg dysfunction, which was significantly higher in the group
with chronic pain than in the group without chronic pain (62.8% versus 20.5%).
A lower health-related quality of life was also seen when compared with patients with-
out chronic pain.74 No comment was made as to whether the primary injury, surgical
repair, or progressive scarring and neural reorganization contributed to outcome.
When assessing complications associated with motor function in veterinary
patients, a sensory examination (see Box 2)66 or electrodiagnostics69 to identify the
potential of established neuropathic pain to be a cause of, or to be coexistent with,
motor deficits may identify a neuropathic pain component. Pelvic fractures and repair
may result in nerve injury to the femoral nerve and cauda equina. The cauda equina lies
within the lumbosacral canal and is composed of the seventh lumbar (L7), sacral, and
coccygeal nerve roots. Injury of these roots causes deficits of sciatic, pudendal,
pelvic, perineal, and caudal rectal nerve function. Motor dysfunction is readily recog-
nized in these injuries in veterinary patients; however, sensory dysfunction, such as
subtle hypoesthesia (which may reflect hyperalgesia depending on the stimulus) or
 Neuropathic Pain in Dogs and Cats 1383

hyperesthesia, may not consistently be evaluated. When present, this may suggest
the presence of persistent or intermittent neuropathic pain.

Pudendal nerve entrapment

Pudendal nerve entrapment is a potential problem after perineal hernia repair or pelvic
or sacral trauma. The injury may happen during trauma or the surgical procedure, or at
some later point should the nerve become entrapped in a postsurgical or traumatic
fibrous scar. Pudendal nerve entrapment is a cause for chronic disabling perineal
pain (anorectal or urogenital, especially when sitting); urinary hesitancy, frequency,
or urgency; constipation or painful bowel movements; and sexual dysfunction in
men and women.75 The diagnosis of pudendal nerve entrapment was based on clinical
factors, neurophysiologic studies, and response to pudendal nerve infiltrations. The
neurophysiologic testing included bilateral pudendal nerve distal motor latency tests
and electromyography (EMG) in pudendal nerve innervated muscles.75 Acute injury
was defined as acute denervation with increased insertional activity or fibrillations.
Chronic injury was defined as chronic neurogenic change illustrated by complex
repetitive discharges, increased compound muscle action potential (CMAP) ampli-
tude, long duration motor units, and CMAP polyphasia.75 Patients refractory to con-
servative management underwent surgical decompression. After surgical
decompression, 60% of patients were classified as responders based on one of the
following three criteria: a greater than 50% reduction in visual analog score (VAS),
a greater than 50% improvement in global assessment of pain, or a greater than
50% improvement in function and quality of life.75 Pudendal nerve entrapment may
be suspected in dogs and cats when there is a historical event compatible with entrap-
ment for which the owner describes similar findings to those occurring in human
beings and if pain can be elicited on rectal or vaginal examination, lifting of the tail,
or when forced to sit. Pain on rectal examination can commonly be elicited in dogs
with cauda equina syndrome. Electrodiagnostic testing would be a valuable tool to
confirm clinical suspicion.69

Limb nerve entrapment

Iatrogenic nerve entrapment is a complication of surgical limb procedures but most
notably occurs during limb fracture repair. A case report describing neuropathic
pain in a cat after sciatic nerve entrapment during femoral fracture repair76 under-
scores the importance of vigilance and awareness required to recognize this compli-
cation. The day after repair, deep pain was absent in this cat but severe pain was
present on manipulation of the coxofemoral joint. Corticosteroid therapy was insti-
tuted for 48 hours with no improvement. Hind limb amputation was performed
because of lack of function. At 38 days after amputation, the cat was presented again
because of continually progressive behavioral changes of hiding, inappropriate urina-
tion, and shaking of the stump. This was treated as a primary urinary tract problem; in
addition, amitriptyline was prescribed. The urinary clinical signs did improve; however,
shaking of the stump and difficulty in walking and standing gradually worsened. On
repeat presentation at 60 days after amputation, pain could not be elicited at the
hip joint or stump of this cat. Neuropathic pain was suspected, however. Treatment
with morphine, lidocaine, and ketamine was instituted until the signs of pain resolved.
The duration of treatment was 37 hours: ramping up to effect over 18 hours, with
a gradual reduction during the remaining 19 hours (details given in the section on treat-
ment using ketamine). After this, the cat seemed to be pain-free and was discharged
home on amitriptyline at a dosage of 10 mg every 12 hours for 21 days. At 10 months,
the cat still seemed to be free of pain.76 This case illustrates the presence of
1384 Mathews

neuropathic pain even when hypoesthesia was present and when there was evidence
for central pain. Frequently, amputation is performed because of motor nerve injury;
however, it is important to identify the exact level of the lesion to ensure that the nerve
injury is relieved so as to prevent ongoing or potential future development of neuro-
pathic pain.
Another potential cause for nerve entrapment is that attributable to heterotopic
calcification associated with hematoma formation at a site of trauma. Heterotopic
calcification, otherwise known as heterotopic osteochondrofibrosis, has been identi-
fied in von Willebrand–depleted Doberman pinschers.77 A mass composed of osse-
ous, chodrous, or fibrous tissue, or a combination thereof, formed in or around the
muscles of the hip in these dogs. The mass severely limited the coxofemoral joint
range of motion, especially when the joint was extended. Trauma was associated in
two cases. Similar ossification attributable to injury, hematoma, and unstable fractures
may entrap a peripheral nerve, potentially resulting in delayed neuropathic pain.

Amputation
Phantom limb pain is a known syndrome in human patients, but it also may occur in
veterinary patients. The cause may be attributable to peripheral sensitization as
a result of spontaneous activity from sprouting regenerating nerve endings or neuroma
formation that gives rise to secondary changes in otherwise silenced small dorsal root
ganglia cells, central sensitization, or cortical reorganization.37,41 There has been an
association of severity of preamputation pain with postamputation phantom pain. Pre-
vention of phantom pain by preoperative epidural analgesia and postoperative local
anesthesia, however, resulted in variable responses.78 There seems to be no consis-
tent effective treatment. Many therapies, including surgical exploration, tricyclic anti-
depressants (TCAs), sodium channel blockers, topical capsaicin, and gabapentin, all
used with efficacy in other neuropathic states, may be ineffective or unproved in con-
trolled studies of phantom limb pain.78 Interestingly, neuropathic pain occurs in 60%
of human patients after limb amputation but usually not until 1 year after surgery. This
highlights the ongoing changes occurring in the PNS and CNS established by a precip-
itating event before experiencing neuropathic pain in some patients and conditions.
Phantom limb pain is rarely reported in veterinary medicine.76 Potential clinical signs,
other than those occurring in nerve entrapment noted previously, may be chewing at
the stump, intermittent unprovoked crying, or ‘‘jumping up or away’’ indicating lanci-
nating pain attributable to ectopic firing.

Lumbosacral lesions
A common cause for neuropathic pain in dogs is degenerative lumbosacral stenosis or
the cauda equina syndrome. Many other terms have been used to describe this
syndrome, which is attributable to soft tissue and bony changes, possibly in conjunc-
tion with abnormal motion of the lumbosacral joint impinging on the nerve roots or vas-
culature of the cauda equina.79 There are many causes for lumbosacral lesions
(degenerative lumbosacral stenosis [the most common disease of the cauda equina
in large-breed dogs], idiopathic stenosis, discospondylitis, trauma, neoplasia, inflam-
matory disease, vascular compromise, and congenital abnormalities), and they are
discussed in detail elsewhere.79 A full description of the physical examination to
identify subtle abnormalities is well described and beyond the scope of this article;79
however, inclusion of a rectal examination and palpation of the lumbosacral joint with
manipulation of the tail is one of many maneuvers to include in the neurologic exam-
ination.79 A thorough focused neurologic examination in dogs exhibiting signs of pain,
as described for human patients with pudendal entrapment, dysesthesias, or motor
 Neuropathic Pain in Dogs and Cats 1385

dysfunction secondary to sciatic or caudal rectal nerve compression, is important

because results of diagnostic imaging may be misleading. A study evaluating the
severity of clinical signs (lumbosacral pain, paresis, lameness, urinary and fecal incon-
tinence, and dysesthesias) to severity of cauda equina compression using diagnostic
imaging revealed a lack of correlation.80 Although correlation of clinical signs and
diagnostic imaging was poor, the investigators recommended pursuing MRI because
it is invaluable in accurately identifying the underlying disease process and giving the
surgeon in-depth preoperative knowledge of the site and extent of the lesion. In dogs
with minimal MRI changes, the investigators commented that cauda equina neuritis
may be the cause of pain. Cauda equina neuritis has been described in dogs in which
marked interstitial and perivascular infiltration with mononuclear cells, axonal degen-
eration, and demyelination was present.81

Spinal cord injury

Spinal cord injury (SCI) may be attributable to trauma, ischemia, hemorrhage, or extra-
dural compression (eg, intervertebral disc extrusion resulting in persistent or intermit-
tent somatic or visceral neuropathic pain). Several problem-based conditions
discussed may also apply to lesions associated with SCI.

Intervertebral disc herniation

One of the most common causes of neuropathic pain is intervertebral disc herniation.
Dogs and cats are almost always painful on presentation (or exhibit pain during the
neurologic examination), some excruciatingly so. The occurrence of acute cervical
disc extrusions was reported to occur at C2 to C3, C3 to C4, and C4 to C5 in decreas-
ing frequency in one study82 and with the same frequency in another.83 Signs of pain
are low head and neck carriage, neck guarding, stilted and cautious gait, and spasms
of cervical spinal muscles. Pain can also be identified if the animal is lame. Radicular
pain (root signature or referred pain) is observed with impingement of nerve roots C5
to C8, with a frequency up to 50%.84 Pain may also be elicited during the neurologic
examination with manipulation of the affected limb. Surgical treatment is recommen-
ded because conservative management using corticosteroids, muscle relaxants, and
cage rest has a high recurrence rate.85 The reason given for this is the presence of
a large amount of disc material present in the spinal canal and difficulty with total
immobilization of the cervical region. Based on the pathophysiology of neuropathic
pain, and the experience of this for the individual, it would be inhumane not to treat
the patient with moderate to excruciating pain adequately. By reducing the pain, how-
ever, the animal tends to move the cervical region more, potentially compromising
neurologic function further. Relieving the pain by surgical treatment is paramount in
the author’s opinion. The pain may not be relieved in some cases, however, when
extruded disc material is still present and impinging on nerve roots. Occasionally,
re-exploration is required when the pain is excruciating and nonresponsive to
multimodal analgesic therapy.
Thoracolumbar intervertebral disc disease (IVDD) also results in pain and neurologic
dysfunction of varying degree in cats and dogs.85 Spinal hyperesthesia, kyphosis, and
reluctance to walk are obvious signs of pain and may occur without neurologic deficits
in a percentage of cases.86 Despite the lack of motor neurologic dysfunction, these
dogs can have substantial spinal cord compression as seen on diagnostic imaging.
Another report indicated that 64% of dogs had back pain and paresis.87 If recurrence
of clinical signs occurs after surgical treatment, it may be related to a second disc
extrusion; cicatrix formation at the previous surgery site; or hyperesthesia resulting
from surgical manipulation, residual hemorrhage, or disc material.88 As with cervical
1386 Mathews

disc disease, pain management is extremely important to avoid continuing acute pain
and establishment of chronic neuropathic pain. The reader is referred to an article by
Coates85 for a review of conservative versus surgical treatment and recurrence rates
of thoracolumbar IVDD.
Thoracolumbar IVDD in cats does occur but at a much lower rate than in dogs, and it
is reported in older and younger (<5 years of age) cats. Similar diagnostic and surgical
techniques are recommended in cats as in dogs.

Fibrocartilaginous Embolic Myelopathy

Fibrocartilaginous embolic myelopathy (FCEM) is noted to be painful on acute disc
extrusion because the owners note a yelp followed by the neurologic deficits. Pain
may also be elicited on presentation, but pain is reported to subside abruptly in
most dogs. (The reader is referred to an article by Dewey89 for further information
on this topic.) It is not unexpected for dogs with FCEM to remain extremely painful
for several days, however, requiring constant analgesic administration titrated to
effect (observation of the author and Neurology Service at the Ontario Veterinary
College). This may be attributable to secondary hemorrhage or release of vasoactive
substances at the site of ischemia (Paul Cuddon, personal communication, 2008) or to
associated epaxial muscle tear at the site of extrusion (observation of Neurology Ser-
vice at the Ontario Veterinary College). Based on these observations, pain assessment
and management must be considered in dogs or cats that have FCEM.

Discospondylitis and Vertebral Osteomyelitis

Discospondylitis and vertebral osteomyelitis are most commonly reported in medium-
to large-breed dogs but may occur in any dog or cat.90 The most common presenting
sign is mild to severe spinal pain. This may or may not be associated with neurologic
deficits or fever.90 Because any bacterial or fungal organism may be the causative
agent, a definitive diagnosis should be attempted with culture and sensitivity testing
performed on aspirates from the affected area and blood cultures. Because the diag-
nostic yield from blood cultures in veterinary medicine is low in general, aspirates from
the lesion are recommended. Cytologic examination of the aspirate should be
performed immediately as an aid in selection of empiric therapy before receiving the
antibiogram, which may take several days. Suggested antimicrobial drugs can be
found an the article by Thomas.90

Potential Sources of Neck and Back Pain in Cats and Dogs

The previous sections provide examples of the more common clinical conditions
causing neuropathic neck and back pain in cats and dogs; however, there several
others that should be considered. The reader is referred to an article by Webb91 for
a review on this topic.

Polyradiculoneuritis
Polyradiculoneuritis is most commonly associated with motor nerve and ventral nerve
root and ventral horn motor dysfunction, although a milder but significant dorsal nerve
root and dorsal root ganglial inflammation can result in hyperesthesia with touch and
manipulation. This is made worse by the fact that the animal cannot withdraw from the
stimulus. Electrophysiologic studies in dogs with acute polyradiculoneuritis did reveal
a sensory dysfunction in some affected dogs (Paul Cuddon, personal communication,
2008).92 Physiotherapy, a recommended management for these dogs, can be ex-
tremely uncomfortable. It is important for the caregiver to be cognizant of this when
 Neuropathic Pain in Dogs and Cats 1387

treating these patients and to consider adding some form of pain management, espe-
cially in the first several days of the disease.

Vascular Innervation as a Cause of Spinal Pain

Myelinated fibers of spinal cord blood vessels in dogs and cats may function in
sensory innervation. It may be that innervation of blood vessels shares pathways
with nerves that supply other structures in the bony vertebral canal and also contribute
to pain development in this area.93

PRIMARY LESIONS OF THE PERIPHERAL OR CENTRAL NERVOUS SYSTEM

Peripheral Nervous System
A fairly common yet sometimes difficult lesion to identify initially is a tumor involving
the PNS. Malignant peripheral nerve sheath tumors (MPNSTs), previously called
schwannomas or neurofibromas, are a primary cause of chronic neurogenic lameness
in dogs94 and cats.95 When a source for limb pain and lameness cannot be identified in
the thoracic or pelvic limbs, an MPNST should be considered. Ultrasonographic
examination and fine-needle aspiration (US-FNA) of an identifiable mass are frequently
diagnostic.96–98 Because there are potential limitations to obtaining a definitive diag-
nosis using US-FNA as the result of an extremely proximal location of the mass, lack of
tumor identification on US, or false-negative results of nondiagnostic aspirates of the
mass, this technique should not necessarily be seen as a single diagnostic tool but as
being complementary to CT and MRI, which allow evaluation of proximal nerve struc-
tures and the spinal cord.99 When limb dysfunction occurs, potentially attributable to
motor and sensory dysfunction (hyperesthesia or hypoesthesia), and amputation is the
suggested treatment, it is essential that the primary lesion also be removed. This may
require a hemilaminectomy should the tumor extend into, or beyond, the proximal
nerve roots.74 Leaving the tumor would continue to cause chronic pain and result in
an extremely poor quality of life.
Masses within subcutaneous tissue100 and within muscle with local invasion of
neural tissue can present similar to nerve sheath tumors.101–103
There are many other neurologic conditions causing lameness in dogs and cats, the
discussion of which is beyond the scope of this article; however, the reader is referred
to a review on the topic by McDonnell and colleagues.94

Diabetic Neuropathy
Diabetes mellitus is a well-recognized cause for neuropathic pain in human beings.
Dogs and cats also can develop a neuropathy associated with this endocrinopathy,
although cats have a much more dramatic clinical presentation when compared
with dogs, whose neuropathy is often subclinical. Despite the subclinical nature of
canine diabetic neuropathy, peripheral sensory nerve conduction slowing was
described in one report.104 The small number of early reports of diabetic-associated
neuropathy in cats concentrated on the clinically obvious motor dysfunction, consist-
ing of a palmigrade and plantigrade stance and gait and a generalized weakness, with
no mention of peripheral sensory abnormalities.105 More recently, however, an exten-
sive electrophysiologic, biochemical, and histologic study performed on feline diabetic
neuropathy definitively demonstrated equal involvement of sensory and motor nerves
in these cats, with the sensory dysfunction involving the most proximal dorsal
(sensory) nerve roots and the entire length of the peripheral sensory nerves in the
thoracic and pelvic limbs.71 It is the presence of this sensory neuropathy and radicul-
opathy that may explain the observation that many cats with diabetes exhibit an
1388 Mathews

aversion to being petted and cuddled and are commonly ‘‘cranky and aloof.’’ Many of
these cats also resent having their paws touched, reminiscent of people who have
a ‘‘diabetic hand and foot’’ (Dr. Paul Cuddon, personal communication, Colorado
State University). When these behaviors are observed in dogs or cats, a trial of amitrip-
tyline is suggested to see if behavioral patterns improve.

Central Pain Syndrome

Tumors of the central nervous system
In human beings, tumors involving pathways subserving somatic sensibilities of pain
and temperature, such as the dorsal horn; the spinothalamic, spinoreticular, and spi-
nomesencephalic tracts; and the cerebral cortex, can result in pain. The area of pain
experienced is that subserved by the location and the pathway involving the neoplas-
tic process. This is referred to as central pain.106 In people, the highest incidence of
these tumors is within the spinal cord, lower brain stem, and ventroposterior
thalamus.106 Hemihyperesthesia and hyperresponsiveness resembling the central
pain syndrome in human beings have been reported in a dog with a forebrain oligo-
dendroglioma.107 This 4-year-old boxer dog presented with alterations in behavior,
mentation, and circling, but the most notable clinical finding was right-sided hemihy-
peresthesia and hyperresponsiveness. Exaggerated responses, such as flinching,
jumping away from the stimulus, and biting, were elicited by nonnoxious stimuli,
such as a light pinprick and pinching of the skin, applied to various areas on the right
side of the body. The clinical impression was that the dog was experiencing a signifi-
cant amount of pain during the examination. Similar stimuli applied to the left side did
not elicit a response. Although the lesion in this case was highly suspicious for a brain
tumor because of the altered mentation and circling, the recognition of hyperesthesia
required a careful and methodical examination. Spinal cord lesions causing central
pain may be more subtle, nonspecific, and more difficult to diagnose unless a similar
examination is performed.

Congenital/developmental lesions
A Chiari-like malformation with syringomyelia (also known as syringohydromyelia) is
a cause for central pain syndrome associated with moderate to severe neuropathic
pain in human beings and dogs.108 This seems to be a genetic disorder in Cavalier
King Charles spaniels and is characterized by a mismatch between the caudal fossa
volume and its contents (the cerebellum and caudal brain stem).108 Because of
obstruction of normal CSF movement through the foramen magnum by means
of the normal outflow pathways, syringomyelia, a fluid-filled cavitation, and dilation
of the central canal within the spinal cord result. The behavior exhibited by affected
dogs is suggestive of neuropathic pain because it has the characteristics of allodynia,
or dysesthesia. For example, dogs seem to dislike touch to certain areas of skin and
may be unable to tolerate grooming or a neck collar. Signs may be unilateral, such as
scratching on one side only at rest and while walking, and often without making skin
contact.108 For details on diagnostic findings and therapeutic suggestions, the reader
is referred to articles by Rusbridge and Jeffery108 and Rusbridge.109
The examples of central pain presented here highlight the importance of history
taking with respect to obvious or subtle changes in behavior. Questions must be
asked relating to potential behavior elicited by the cat or dog, extrapolated from the
human experience (eg, crawling insects, itchiness), such as ‘‘scratching motion with-
out touching the skin,’’ continually biting or attacking an area on the body, frequently
turning (looking) at the same area, or yelping for no reason (lancinating pain). The
 Neuropathic Pain in Dogs and Cats 1389

physical and neurologic examination and the diagnostic modalities presented here
can be considered for all patients that are suspected of having central pain syndrome.

Vasculitis
Vasculitis associated with the meninges and spinal cord can be a cause for central
pain. The recommended diagnostic tests, however, differ from those previously dis-
cussed because of the inflammatory nature of these diseases. Vasculitis has been
identified as a cause of neuropathic pain in beagle dogs, and has been termed ‘‘beagle
pain syndrome.’’ This pain syndrome is associated with a generalized vasculitis, peri-
vasculitis, and vascular thrombosis. The small- to medium-sized muscular arteries in
many organs, including the cervical meninges, are consistently involved. The clinical
signs, laboratory abnormalities, and vascular lesions suggest that the condition is
immune mediated and may serve as a naturally occurring animal model of human
immune system–mediated vasculitides, such as polyarteritis nodosa, infantile polyar-
teritis, and Kawasaki disease. Neuropathic pain is reported in some of these human
conditions.110,111 There are many other diseases that produce inflammation of the
meninges, especially involving the cervical region, resulting in varying severity of
cervical pain. These include granulomatous meningoencephalomyelitis (GME), asep-
tic meningitis, and breed-associated aseptic meningitis seen in such breeds as the
Bernese Mountain dog.

NEUROPATHIC PAIN OF VISCERAL ORIGIN

The evidence for neuropathic pain of visceral origin is presented in the section on the
individual clinical syndrome, in which veterinary and human illnesses are compared.

Feline Interstitial Cystitis

Feline interstitial cystitis (FIC) is a well-recognized problem in cats and is an example
of visceral inflammation resulting in neurogenic pain, which also occurs in human
beings.112 Human patients who have interstitial cystitis (IC) have bladder pain and uri-
nary urgency. Studies in cats with IC have demonstrated abnormalities in the bladder,
sensory neurons, CNS, and sympathetic efferent neurons.113 These cats have
decreased excretion of glycosaminoglycan (GAG), increased bladder permeability,
and neurogenic inflammation. The reduced protection of bladder uroepithelium by
lowered GAG levels may facilitate increased contact of urine with the primary afferent
nerve terminals innervating the bladder, resulting in a local release of neurotransmit-
ters and neurogenic inflammation. S-P is increased in the urinary bladders of people
and cats with IC.114 High-affinity S-P receptors have also been identified in the blad-
ders of cats with FIC.114 Experimentally induced cystitis in rats produces neurogenic
sensory and reflex changes similar to those seen in human patients who have cysti-
tis.115 Inflammation of the bladder activates A-d and C-fiber mechanosensitive
afferents with significant recruitment of ‘‘silent’’ afferents. The silent afferents are me-
chanically insensitive afferent neurons that develop mechanosensitivity during
inflammatory states. The afferent fiber barrage generated from the inflamed bladder
is believed to result in a slowly developing, and maintained, increase in the excitability
of spinal cord dorsal horn neurons producing central sensitization.115 Treatment in
human beings consists of pentosan polysulfate sodium, which is primarily thought
to be effective through GAG layer replacement, amitriptyline, muscle relaxants, and
alpha-blockers. For pain management, gabapentin, hydrocodone, and opioids have
proved to be helpful.112,116 Amitriptyline is recommended for cats diagnosed with
FIC.117
1390 Mathews

Gastrointestinal System
There are indications that central sensitization may contribute to a secondary pain
hypersensitivity in the gastrointestinal tract in a way that resembles secondary hyper-
algesia in the skin.118–120 The following are illnesses that cause neuropathic pain in
human beings and potentially could produce the same pain syndromes in cats and
dogs.

Visceral Pain Associated with Spinal Cord Injury

Human beings with SCI resulting in partial to complete paraplegia or partial to com-
plete tetraplegia may experience visceral pain without identifiable gastrointestinal,
genitourinary, or pelvic abnormalities that could account for visceral pain symp-
toms.121 The mechanisms of this are unknown. Theories put forth are that visceral
pain may be caused by (1) a continuous slow fiber discharge caused by unrecognized
alterations in visceral function, (2) a phenomenon occurring at the sympathetic chain
ganglia, or (3) a distortion of the afferent impulses from the viscera crossing the zone of
injury in the spinal cord.121 Another theory proposed is that the neurologic mecha-
nisms of visceral pain are different from those in somatic pain and that brief acute
visceral pain may initially be triggered by the activation of high-threshold afferent
impulses.121 Visceral pain seems to have a substantially delayed time of onset, with
the average onset time after SCI being 4.2 years. Although the number of persons
with visceral pain is less than the number of persons with musculoskeletal or neuro-
pathic pain, visceral pain was the pain most often described as severe or excruciat-
ing.121 A question veterinarians may ask is ‘‘does visceral pain occur after SCI in
our patients, and how would we know?’’

Inflammatory Bowel Disease

Idiopathic IBD is frequently diagnosed in dogs and cats122 but occurs more frequently
in cats.123,124 From a neuropathic perspective, IBD is similar to other conditions of
persistent afferent barrage to the dorsal horn. As with the urinary bladder, true ‘‘noci-
ceptors’’ may be ‘‘disguised’’ within the mechanoreceptors that have a low or high
threshold for response and encode for the intensity of the stimulus in the gastrointes-
tinal tract.125 Both classes of mechanoreceptors are capable of processing and
transmitting sensory input in the noxious range. Also, low- and high-threshold mech-
anoreceptors are capable of becoming sensitized in the presence of inflammation.125
The presence of silent fibers and their recruitment during inflammatory conditions has
also been documented.115,118 Therefore, visceral afferent fibers innervating the gas-
trointestinal tract are capable of changing their behavior during organ inflammation
to increase the peripheral barrage into the spinal cord, giving rise to visceral pain
and hyperalgesia.119,122 In situations in which cats that have IBD and are being treated
with an appropriate dose of corticosteroids still appear uncomfortable to the owner,
the author has recommended amitriptyline. Anecdotal reports from veterinarians
indicating noticeable improvement in behavior suggest that a potential neuropathic
component exists.

Pancreatitis/Pancreatic Pain
Abdominal pain is a key feature of acute and chronic pancreatitis in dogs and human
beings but not consistently so in cats. There is evidence that pain in chronic pancre-
atitis and pancreatic cancer is triggered by pancreatic neuropathy.126 Damage to
intrapancreatic nerves seems to support the maintenance and exacerbation of neuro-
pathic pain in people. In chronic pancreatitis, intrapancreatic nerves are invaded by
 Neuropathic Pain in Dogs and Cats 1391

immune cells. This observation led to the hypothesis that neuroimmune interactions
play a role in the pathogenesis of chronic pancreatitis and the accompanying abdom-
inal pain syndrome. Similarly, pancreatic cancer cells infiltrate the perineurium of local
extrapancreatic nerves, which may partially explain the severe pain experienced by
human patients. In recent years, the involvement of a variety of neurotrophins and
neuropeptides in the pathogenesis of pancreatic pain was discovered.126 In another
human study, electrical stimulation of the gastrointestinal tract with concurrent record-
ings using an electroencephalogram showed that pain in chronic pancreatitis leads to
changes in cortical projections of the nociceptive system.127 Similar findings have
been described in somatic pain disorders, including neuropathic pain.127 Potentially
these mechanisms exist in cats and dogs, explaining the apparent severe to excruci-
ating pain experienced in some animals with repeated episodes of pancreatitis.

TREATMENT

Several animal models of neuropathic pain are used to assess individual and combi-
nation pharmacologic therapies. The therapies discussed are those that have been
tested using these models. The peripheral mononeuropathy models receive ligation,
partial ligation, and transection of various peripheral nerves to simulate the common
human clinical setting. These include nerve root injuries or plexus avulsion injuries
resulting in thermal and mechanical hyperalgesia, cold allodynia, and tactile allody-
nia.128–130 These models also resemble peripheral nerve injuries in cats and dogs.
Central neuropathic models of pain have been created by ischemia of the spinal
cord, which correlates to the ischemic, traumatic, or radiation injuries in the human
clinical setting.131 Based on the response to various analgesic drugs, these models
offer guidelines for treatment of neuropathic pain in human patients, which may also
be extended to veterinary patients.
Neuropathic pain cannot be adequately managed with a single pharmacologic class
unless tapering from a multimodal regimen. Severe pain requires several classes of
medications and procedures. A recent report on pain management in the human
trauma patient reported that with aggressive pain management, the military has de-
creased acute and chronic pain conditions.132 The individual medications discussed
here are intended to be administered in conjunction with those from a different class
in an attempt to block the various mechanisms involved in sensory transmission. Be-
fore, and often during, any surgical procedure, various different analgesics and anal-
gesic modalities can be used to reduce the inciting nociceptive afferent impulse. Many
of these can be continued after surgery to reduce peripheral and central sensitization
(the reader is referred to the articles by Lamont, Lemke and Creighton, Valverde, and
Dyson elsewhere in this issue and an article by Lemke and Dawson133 on local and
regional analgesia).

Stimulus-Evoked Pain
Movement-evoked pain can be difficult to manage, especially when associated with
nerve involvement. When increasing dosages of analgesics are given to stop move-
ment-evoked pain, the patient may experience the adverse effects of the analgesic
when at rest (ie, dysphoria, panting with opioids). Because movement is essential
for a rapid recovery, local delivery of local anesthetics (ie, intrapleural, intra-articular,
amputation site) or administration of two or more classes of analgesics (ie, multimodal
therapy) is recommended. Other examples of stimulus-evoked pain could be related
to pressing around the surgical wound to assess the presence of mechanical hyper-
algesia. In one study, low-dose ketamine infusion reduced the intensity of mechanical
1392 Mathews

hyperalgesia around the surgical wound for 24 hours after surgery.134 Similarly with
postoperative dental pain, a research analgesic had little effect on pain at rest but
was quite effective in reducing pain on opening the mouth.135 Managing pain in situ-
ations other than when the patient is at rest can be challenging, requiring analgesic
protocols and procedures specifically prepared for the individual patient and the
associated problem.

Breakthrough Pain
Breakthrough pain (BTP) can definitely be associated with neuropathic pain. This may
occur in the postoperative setting or intermittently at home in animals on chronic pain
medication for cancer or neuropathic pain. As described by human patients, this pain
is severe or excruciating and of rapid onset, which can disable or even immobilize
the patient.136 Should this occur in the hospital, intravenous administration of an opioid
is the primary treatment. The analgesic protocol should be reassessed for duration and
dose of the prescribed medication and to ensure that there is no underlying problem
causing this pain. If the pain seems to be severe, this may be an indication of a neuro-
pathic component. Careful observation as to the cause of BTP is required. If a single an-
algesic agent is being used, consider the addition of other analgesics of a different class
(the reader is referred to the articles by Lamont and Robertson elsewhere in this issue).
When BTP occurs at home, a careful history is required to obtain clues about the
cause and pattern of BTP. Opioid analgesics are the primary treatment (eg, tramadol,
oxycodone); however, it may be difficult to administer oral medication when animals
exhibit excruciating pain. If this cannot be controlled, parenteral administration has
to be considered. Fentanyl buccal tablets seem to be effective in human patients
for breakthrough of neuropathic pain;137 however, no veterinary studies as to efficacy
are available. The dose or dosing frequency of an around-the-clock analgesic should
be adjusted for patients with end-of-dose BTP. Short-acting oral opioids are useful
when given preemptively in human patients with predictable incident BTP, whereas
rapid-onset transmucosal lipophilic opioids (eg, fentanyl buccal tablet) are most effec-
tive for patients with unpredictable incident or idiopathic BTP. In addition to pharma-
cologic therapy, nonpharmacologic strategies are often helpful in alleviating pain and
anxiety and should be considered on an individual patient basis as a supplement to
pharmacologic intervention for BTP.
Pain management must be considered throughout the hospital stay, and a plan
should be formulated based on the severity of injury, the invasiveness of the surgical
procedure (controlled injury), the anatomic area of surgery (assumed descending
order of discomfort: oral cavity, rectum/vagina/testicles/penis, thorax, abdomen,
and limbs), the definite or potential involvement of neural tissue, and pain experienced
before surgery.

The Hospitalized Patient: Acute Pain Management

Opiates/Opioids
Opiates/opioids are frequently used to manage pain in veterinary patients. Opioids
bind to opioid receptors peripherally and centrally. Peripherally, they prevent neuro-
transmitter release and nociceptor sensitization, especially in inflammatory tissue.
Centrally, opioids modulate afferent input into the substantia gelatinosa of the dorsal
horn, wherein the C-fibers terminate, and in cortical areas that blunt the perception of
pain.138 Because opiates have a specific effect on C-fiber input and not on Ab-fibers,
in which tactile allodynia (Ab-stimulus) is a component of the pain syndrome, opioids
may not be beneficial. Therefore, the effectiveness of the opioids depends on the
underlying mechanism causing the pain. As previously mentioned, opioid receptors
 Neuropathic Pain in Dogs and Cats 1393

in the descending pathway may be reduced or inactivated in neuropathic pain; there-

fore, their efficacy is frequently inadequate when used alone. Of interest, the closer the
nervous system lesion is to the CNS, the less effective the opiates are.139 For example,
peripheral nerve injuries tend to respond better to opioid therapy than nerve root
injuries, which respond better than spinal cord injuries. Because neuropathic pain is
not as responsive as nonneuropathic conditions to opioids, titration of the dose to
effect, which may be beyond the maximum recommended in textbooks, while avoid-
ing side effects, is suggested for human patients.139 Notable side effects in dogs and
cats are dysphoria, panting, respiratory depression, inappropriate antidiuretic
hormone secretion with oliguria and edema, urinary retention, nausea and vomiting,
inability to ambulate, and ileus as an infrequent finding. Frequently used systemic opi-
oids are fentanyl, morphine, and hydromorphone. Should side effects occur, switching
to another opioid is recommended because higher dosages may be better tolerated in
any individual given a different opioid.139 It is the author’s experience that fentanyl
seems to have fewer side effects than morphine and hydromorphone at higher dos-
ages, especially in cats. The shorter half-life of fentanyl also makes it the best choice
in patients with CNS pain because withdrawal for assessment is more easily planned.
With the understanding that opioids may be ineffectual in some neuropathic pain
states, it may be unwise to increase the dose to that which results in noticeable
side effects. Nausea and vomiting raise intracranial pressure (ICP), and thus would
be a concern in patients who have head injuries. Cortical depression may mask
increasing ICP and delay administration of hypertonic saline or mannitol therapy.
Also, peripheral neurologic signs may seem to be worse because bladder emptying
and limb motion beyond the area of spinal injury are significantly decreased with
opioid use. As an example, the author has noted continual lack of voluntary bladder
emptying in cats with sacrococcygeal injuries while on opiate analgesia. With
a 1-mL/min titration of diluted naloxone at 0.1 mL naloxone (0.4 mg/mL) diluted in
10 mL saline to ensure that analgesia is not totally reversed, while gently palpating
the urinary bladder to initiate voluntary micturition, it is possible to reverse the inhibi-
tory effects of the opiate on detrusor function should this be a factor. Detrusor dys-
function may occur after systemic or epidural use of opiates, regardless of the
cause of pain, usually in the postoperative setting. The author frequently uses the nal-
oxone titration technique to reverse the side effects of opioids, especially if the patient
is dysphoric. In larger animals, a mixture of naloxone, 0.25 mL (0.4 mg/mL), diluted in
saline, 10 mL, is used for titration. Once the side effects are reversed and a ‘‘pleasant’’
state of rest is achieved, or the patient is aware and can respond during the neurologic
assessment, titration is halted. A frustrating situation for criticalists and neurologists
is the requirement for withdrawal from analgesics before neurologic examination. It
is suggested that an appointment be made for the neurologic assessment, which is
strictly adhered to so that withdrawal of the analgesics can be planned, therefore
avoiding long periods when the patient is without analgesic therapy.
Methadone is probably the preferred opioid to manage neuropathic pain because in
addition to its opioid analgesic properties, it is an NMDA receptor antagonist and
SRI.132 The prolonged half-life of methadone in human beings with drug accumulation
and delayed onset of adverse effects132 does not occur in dogs at doses up to 1 mg/kg
administered parenterally.140 Oral methadone is not absorbed in dogs, however.141
Buprenorphine may also be suitable for moderate pain, but increasing the dose to
greater than that recommended has no advantage because of the ceiling effect (the
reader is referred to the article by Robertson elsewhere in this issue).
Based on the actions of opiates, it is recommended that they be included in
a multimodal regimen to manage neuropathic pain rather than as a single agent.
1394 Mathews

N-methyl-D-aspartate receptor antagonists

The NMDA receptor is located on postsynaptic neurons in the dorsal horn. It has
various binding sites that regulate its activity, which include glutamate, magnesium,
glycine, and polyamine binding sites. Nerve injury causes an increase in spinal gluta-
mate, which opens the NMDA ionophore channel, causing an influx of calcium and
resulting in a cascade effect leading to spinal wind-up. The channel may be blocked
by the NMDA receptor antagonists, such as ketamine, amantadine, and dextrome-
thorphan. In animal models of neuropathic pain, the allodynic and hyperalgesic states
were sensitive to NMDA receptor antagonists. Ketamine is a commonly used anes-
thetic and analgesic agent in veterinary medicine. Amantadine is a drug recently intro-
duced for chronic pain management in veterinary medicine. Recent studies in dogs,
however, report that dextromethorphan is not absorbed in this species,142 and it is
therefore not recommended for chronic neuropathic pain.

Ketamine
Ketamine is the most commonly used NMDA receptor antagonist in veterinary medi-
cine. Its use is increasing for postoperative and other acute pain management situa-
tions in human medicine, including severe trauma.132,143,144 Ketamine binds
noncompetitively to the phencyclidine site of the NMDA receptor and to the s-opioid
receptor, resulting in intense analgesia and prevention of wind-up.132 The combination
of ketamine and a benzodiazepine or ketamine and morphine has been shown to be
beneficial in human patients.145 Dosages as low as 2.5 mg/kg/min or less have reduced
opioid requirements in postoperative human patients. There are similar reports on the
use of low-dose ketamine in the veterinary literature. These reports include pre- and
intraoperative use;146–148 pre- and postoperative use;149 or, pre-, intra-, and postop-
erative use in dogs.150 In one study assessing the efficacy of ketamine (0.5 mg/kg
administered intravenously as a bolus before surgery, 10 mg/kg/min during surgery,
and 2 mg/kg/min for 18 hours after surgery) for amputation pain, in which neuropathic
pain is certainly a concern, an improvement in postoperative pain scores was noted
over a 3-day duration when compared with an opioid-alone regimen.150 Another
study, however, compared two doses of ketamine (loading dose of 150 mg/kg with
a constant rate infusion [CRI] of 2 mg/kg/min versus a 700-mg/kg loading dose and
CRI of 10 mg/kg/min) on feeding behavior in bitches after mastectomy and noted
that the higher dose of ketamine resulted in improved patient feeding behavior.151 It
is the experience of the author and her colleagues at the Ontario Veterinary College
that low doses of ketamine (<0.5 mg/kg intravenous loading dose and <1.0 mg/kg/h
CRI), even in combination with opiates, with or without lidocaine or with or without
NSAIDs, are frequently inadequate to manage severe pain in dogs and cats with
multiple and massive bite wounds, severe pancreatitis, multiple orthopedic injuries
after surgery, and postoperative cauda equina syndrome or cervical disc herniation
as examples. Most of these cases have a component of neuropathic and inflammatory
pain. A point to consider when comparing doses with those used in human patients is
the fact that a typical intravenous anesthetic induction dose for ketamine in human
patients is 0.6 to 2.1 mg/kg, whereas a dose of 5 to 10 mg/kg is generally recommen-
ded in dogs. Because the anesthetic induction dose of ketamine is approximately five
times higher in dogs compared with people, there is the potential that a higher ‘‘low-
dose’’ for analgesia may be required in cats and dogs, which is the author’s observa-
tion. As an example of potential requirements, a dog with severe refractory cauda
equina pain before surgical correction required an intravenous titrated dose of
ketamine of 4 mg/kg to manage the violent postoperative behavior. This was followed
by a 4-mg/kg CRI (in combination with morphine) for several hours to maintain ‘‘sleep’’
 Neuropathic Pain in Dogs and Cats 1395

overnight. The ketamine CRI was slowly reduced over 16 hours to assess analgesic
requirements and avoid the hyperalgesic state. After this, the dog seemed to be com-
fortable and demonstrated normal behavior and appetite on a reduced dose of mor-
phine. An NSAID could not be administered because of previous administration of
corticosteroids.
The 6-kg cat with neuropathic pain associated with hind limb amputation reported
previously76 received medetomidine at a dose of 100 mg to induce anesthesia, mor-
phine at a dose of 1.5 mg, and ketamine at a dose of 20 mg given intramuscularly.
A CRI of lactated Ringer’s solution containing morphine at a dose of 0.06 mg/mL,
lidocaine at a dose of 0.24 mg/mL, and ketamine at a dose of 0.06 mg/mL of solution
was established. The initial infusion was started at 5:00 PM at a rate of 5 mL/h. This was
increased to 11 mL/h the next morning at 8:00 AM, was increased to 18 mL/h at 9:00 AM,
was increased further to 24 mL/h at 10:00 AM, and was then decreased at 11:00 AM to
11 mL/h when the cat began to show signs of excessive sedation. The infusion was
continued for a further 19 hours for a total of 36 hours. Amitriptyline at a dosage of
10 mg administered orally every 12 hours was continued for 21 days. This treatment
led to resolution of the neuropathic pain the cat had experienced for 60 days after
amputation.76 Similar acute treatment strategies are reported in human patients
who have reflex sympathetic dystrophy.
When considering analgesic therapy, it is also prudent to be aware of potential
adverse effects, especially in critically ill or traumatized patients. Reports in the litera-
ture have documented concerns for increased ICP with ketamine administration; how-
ever, this was documented in subjects in which the PCO2 was not controlled152,153
When the PCO2 was held constant, an increased ICP did not occur during ketamine
administration.154 It has also been shown that ketamine does not directly dilate cere-
bral vessels, which potentially increases ICP.154 In fact, when combined with a benzo-
diazepine, ketamine attenuated the increasing ICP in patients with an already
increased ICP.155,156 Ketamine demonstrated no adverse effects on cerebral hemody-
namics in patients that had head trauma and, in fact, reduced the ICP.157 The adverse
effects on the cardiovascular system of analgesic doses of ketamine have also been
questioned.132 When comparing total intravenous anesthesia using a propofol-
ketamine combination with an inhalation-opioid technique in coronary artery surgery
in human patients, it was found that there was a reduced need for inotrope support
in the patients receiving ketamine and that there was also a reduced incidence of myo-
cardial infarction.157 Because pain in head-injured dogs and cats can be difficult to
manage, especially when there are other neurologic and orthopedic injuries, low-
dose ketamine may be a potential addition to the multimodal analgesic regimen.
Beginning with a low dose initially with frequent assessment is required, however,
because there are no treatment strategy reports in the veterinary literature using
ketamine for pain management in dogs and cats that have head injuries.

Sodium channel blockers

Sodium channels are responsible for the voltage-dependent sodium flux that serves to
depolarize the excitable membrane.139 After nerve injury, there is up-regulation of
distinct types of TTX-insensitive, or TTX-R sodium channels in the neuroma, including
C-afferent neurons and small-diameter dorsal root ganglion neurons that may serve as
ectopic generator sites. The reader is referred to the articles by Lamont elsewhere in
this issue for further discussion on this topic. This channel is blocked by local anes-
thetic agents at plasma concentrations that do not produce an afferent conduction
block.158 The TTX-sensitive (S) sodium channels are preferentially expressed in large
1396 Mathews

and medium dorsal root ganglion neurons and are reported to be four times more sen-
sitive than TTX-R sodium channels to lidocaine therapy.

Lidocaine
Systemically administered lidocaine has been shown to be effective in the treatment of
several neuropathic pain disorders at doses that do not produce anesthesia or slow
cardiac conduction. This class 1B antiarrhythmic provides analgesia separate from
the direct local anesthetic properties. When administered systemically, lidocaine
blocks the ectopic afferent neural activity at the NMDA receptor within the dorsal
horn.132 Several veterinary studies have shown benefit of lidocaine infusions during
anesthesia in dogs.159,160 One veterinary study reports lidocaine at a 1.0-mg/kg intra-
venous bolus followed by a 0.025-mg/kg/min intravenous CRI administered during
and after surgery having similar efficacy to morphine at a 0.15-mg/kg intravenous
bolus followed by a 0.1-mg/kg/h intravenous CRI.161 No veterinary studies have eval-
uated lidocaine’s analgesic efficacy when used alone in neuropathic pain states; how-
ever, a case report included lidocaine with morphine and ketamine to treat
neuropathic pain in a cat.76 Infusions of lidocaine have led to a significant improve-
ment in human patients experiencing chronic neuropathic pain.162 Based on the differ-
ent sensitivity of lidocaine on the TTX-R and TTX-S sodium channels, the response to
lidocaine therapy varies depending on the neural lesion and sodium channel involve-
ment.163 In human medicine, patients report that the pain associated with spontane-
ous ectopic discharges seems to be responsive to lidocaine therapy in most
instances; however, this type of pain may also be mediated by a-adrenergic receptor
sensitization, which may not respond to lidocaine.163 Also, not all neuropathic pain
symptoms in human beings are underlined by ectopic discharges; therefore, this
type of pain may respond differently to lidocaine therapy.163 The clinical importance
of this is that when neuropathic pain is suspected in dogs and cats, lack of lidocaine
responsiveness should not be interpreted as the nonexistence of neuropathic pain but
that the underlying mechanism is not primarily involving the TTX-S sodium channel.
Lidocaine infusions have been evaluated in cats with no apparent benefit when
used alone164 and may be associated with adverse effects in this species. The reader
is referred to the articles by Lamont and Robertson elsewhere in this issue for further
information.

Tocainide, mexiletine, and flecainide

These agents are analogues of lidocaine and have also been shown to relieve neuro-
pathic pain in some human patients.165 Again, there are no veterinary reports on
analgesic efficacy in dogs or cats with neuropathic pain; however, mexiletine is
used chronically in dogs with cardiac arrhythmias.166

a2-Receptor agonists
The a2-receptor is coupled through G-proteins to hyperpolarize spinal projection
neurons and to inhibit transmitter release from small primary afferents. Spinally admin-
istered a2-agonists have been shown to reverse the dysesthetic and allodynic compo-
nents of pain states observed after peripheral nerve injury in rats and human
beings.165,167 The a2-agonists function in the inhibitory pathway by binding receptors
in the LC, which receives efferent noradrenergic axons from the PAG; the noradrener-
gic axons then extend to the spinal cord. Activation in the LC seems to contribute to
analgesia indirectly at the level of the dorsal horn through these descending
projections.165,167 Several studies have shown a benefit of clonidine, an a2-agonist,
in reducing pain scores and opioid use for a variety of human painful states.168 Mede-
tomidine is the most commonly used a2-agonist in veterinary medicine in North
 Neuropathic Pain in Dogs and Cats 1397

America; however, dexmedetomidine is also approved for use in veterinary patients in

other parts of the world (the reader is referred to the articles by Lamont elsewhere in
this issue for an in-depth discussion on a2-agonist agents in veterinary medicine and
an article by Sinclair169 for a review of the clinical use of medetomidine in small animal
practice). Medetomidine may be administered by means of several routes, including
the epidural, intra-articular, perineural, and parenteral routes, alone or in combination
with several other medications. As an example of its use in neuropathic pain in the
dog, the author has administered medetomidine (1–3 mg/kg/h) in addition to fentanyl
at a low dosage (3–4 mg/kg/h) and corticosteroids for management of the severe
pain associated with meningitis. Intra- and postoperative pain management for inter-
vertebral disc herniation is another example for a2-agonist administration to otherwise
healthy dogs.

Regional analgesia
There are significant benefits to the use of regional analgesia, epidural analgesia, or
continuous peripheral nerve blocks (CPNBs).170 Regional analgesia improved pain
control, improved outcomes, and produced greater satisfaction in human patients.171
CPNBs are being used more frequently in human medicine, in which greater satisfac-
tion is reported compared with systemic analgesia.132 Of interest is the use of CPNBs
in veterinary medicine. The local anesthetic agent can be delivered as a continuous
infusion or as an intermittent bolus. There are no reports in the veterinary literature
as to the efficacy of this technique; however, the main technical problem with all the
available multiple-hole delivery tubes tested as a slow rate continuous infusion is
the poor dispersion of the local anesthetic, resulting in erratic results (please see
the article by Hansen elsewhere in this issue). For bolus infusion, however, in which
a sufficient pressure can be generated to deliver the local anesthetic through the tub-
ing, the dispersion into the wound seems to be uniform (please see the article by Han-
sen elsewhere in this issue). For cavitary (eg, joints, pleural space) analgesia, the
continuous infusion through an open-ended tube may work satisfactorily. This tech-
nique can be also be used with ambulatory infusers (and various ambulatory infusion
systems, Mila International Inc., Erlanger, Kentucky) in dogs on an outpatient basis af-
ter joint surgery. There must be strict adherence to aseptic technique in placement
and maintenance of the catheters and in the dosing of lidocaine. Although the benefits
of local analgesia far outweigh the potential risks, these risk factors must also be
considered. In human medicine, the major risks for this technique are local anesthetic
toxicity and nerve injury; however, phrenic nerve blockade, inadvertent epidural or
subarachnoid spread, infection, and hematoma have also been reported to occur
infrequently.132 The reader is referred to more in-depth discussions on veterinary
application of nerve blocks133 and epidural analgesia (see the article by Valverde in
this issue) and to a recent review on applications and outcomes in human medicine.132

Nonsteroidal anti-inflammatory analgesics

The NSAIDs are widely used in human and veterinary medicine for acute and chronic
pain management. The NSAIDs variably target COX-1 and COX-2, or specifically
COX-2, to manage osteoarthritic pain while sparing the constitutive functions of
COX-1. Although COX-1 is mainly recognized for its constitutive functions, it is
induced to participate in some pathologic states, such as transmission of pain periph-
erally and centrally, and may also generate prostaglandins at sites of inflammation.
COX-2 is also induced, especially in inflammatory conditions like osteoarthritis, and
functions in central and peripheral pain transmission. COX-2, however, has several
important constitutive functions, especially in the gastrointestinal tract and kidney.
1398 Mathews

COX-3, characterized as generated from COX-1, is expressed in the brain and brain
microvasculature and has been proposed to be a target of the analgesics/antipyretics
acetaminophen and dipyrone. The NSAIDs act peripherally at sites of inflammation but
also have direct spinal cord action by blocking hyperalgesia induced by the activation
of spinal glutamate and S-P receptors.19 These findings demonstrate that the analge-
sic effects of NSAIDs can be dissociated from their anti-inflammatory actions in the
periphery. Spinal prostanoids are thus critical for the augmentation of pain processing
at the spinal cord level.19 The NSAIDs have been shown to be effective analgesics for
moderate to severe pain in cats and dogs. No veterinary studies specifically assessing
the efficacy of managing neuropathic pain have been reported, however. When neu-
ropathic pain is assumed to be present, such as with limb amputation and crushing
injuries, the addition of a parenterally administered NSAID to an opioid improves an-
algesia and pain scores compared with an opioid alone (Karol Mathews, DVM, DVSc,
unpublished data, 2001). Of interest, inhibition of COX-2 has been shown to benefit
recovery after injury to the brain or spinal cord in laboratory animals.172 The proposed
mechanism is that the CNS injury increases COX-2 expression. Prolonged elevation of
COX-2 contributes to inflammation, programmed cell death, free radical–mediated tis-
sue damage, and alterations in cellular metabolism. The action of COX-2 inhibitors de-
creases synthesis of prostanoids and free radicals. Because of this dominant
metabolic reaction, however, COX-2 inhibition results in shunting of AA away from
the COX pathway down alternate enzymatic pathways (eg, cytochrome P450 epoxy-
genase), resulting in the synthesis of potentially neuroprotective eicosanoids.172
Strauss172 proposed that COX-2 inhibition blocks delayed cell death and neuroinflam-
mation. Although the role of NSAIDs may prove to be of benefit in CNS injury in labo-
ratory animals, the benefits in the clinical setting have yet to be confirmed. Prior to
NSAID therapy, the individual patient must be identified for potential adverse effects
and the absolute contraindication for coadministration with corticosteroids.

Gabapentin
Gabapentin is an antiepileptic agent. The analgesic effect is attributable to gabapen-
tin’s ability to bind with the high-affinity a2d-subunits of voltage-dependent calcium
channels, blocking calcium currents at the spinal and supraspinal levels and blocking
maintenance of spinal cord central sensitization.173–175 It is suggested that gabapentin
activates the descending noradrenergic system and induces spinal NE release, which
subsequently produces analgesia by means of spinal a2-adrenoceptor stimulation.
Recently, gabapentin has also been recommended for acute postoperative pain in
human patients, in whom the most benefit seems to be when chronic pain is pres-
ent.59,176 Further studies confirm gabapentin’s supraspinal analgesic action in activat-
ing the descending noradrenergic system after peripheral nerve injury in rats.177
These studies indicate that perioperative administration of gabapentin to animals
with nerve injury may reduce the potential establishment of, or ongoing, neuropathic
pain. It is the author’s observation that gabapentin has reduced the pain in dogs
and cats experiencing refractory neuropathic pain secondary to cervical or thoraco-
lumbar intervertebral disc disease or pelvic trauma. Initially, gabapentin is adminis-
tered in combination with an opioid and an NSAID; however, gradually, these
analgesics may be tapered and gabapentin remains as the sole method of analgesia.
There is an extremely wide dose range for gabapentin, and it should be given to effect.
The dose-limiting side effect is usually sedation. Frequently, some animals need
several weeks to months for resolution of their pain, potentially requiring a lifetime
of medication. Careful lowering of the drug dosage is recommended to assess the
dosing requirement. Initially, eliminating the middle dose in the three times daily
 Neuropathic Pain in Dogs and Cats 1399

treatment regimen is suggested to assess the ongoing requirement. Because dosing

to effect is the method by which the appropriate dose is selected, once this effect is
reached, treatment twice daily rather than three times daily may suffice. Gabapentin is
excreted by the kidneys, and animals with renal insufficiency may require less frequent
dosing because of slower elimination. Tapering of the dose is important because stop-
ping the drug abruptly may lead to rebound pain that may be severe. The author’s
method of dosing is to start with 10 mg/kg administered orally every 8 hours in
dogs and 5 mg/kg administered orally in cats and to ramp up or taper down to effect
(dose range: 5–25 mg/kg). There may be a potential advantage to commencing gaba-
pentin before any surgical procedure involving the PNS and CNS.
Gabapentin is also used in human patients for management of neuropathic pain
associated with diabetes, cancer, and primary nerve compression.139

Acupuncture
Because neuropathic pain is difficult to manage with pharmaceutical agents, there is
a growing interest in the use of acupuncture as an adjunct to a multimodal pharmaceu-
tical regimen. For the past 12 years at least, the National Institutes of Health have listed
pain management as an indication for acupuncture therapy. There is a sound physio-
logic mechanism for the analgesic effects of acupuncture.178,179 Acupuncture is the
stimulating of specific anatomic points in the body to produce therapeutic or analgesic
effects. Placement of fine-gauge needles may decrease muscle spasms when
inserted into trigger points. Placement of needles at specific acupuncture points
can induce the release of a variety of neurotransmitters, which can affect the process-
ing of sensory input, including blockade of C-fiber input and amplification of the inhib-
itory system, as previously discussed. Proper needle placement, with administration
of various frequencies of electrical stimulation, releases endorphins, serotonin, and
NE. Another benefit of acupuncture therapy is that there are no associated adverse
effects, such as those that may occur with any pharmaceutical agent. Based on sound
physiologic evidence for the benefit of acupuncture in acute and chronic pain states,
the details of which are given in the section on chronic pain management, acupuncture
is highly recommended in the management of neuropathic pain.

Chronic Pain Management

Opiates/Opioids
As in the acute setting, opioids can be used in the chronic pain state. The opioids most
frequently used in veterinary medicine for chronic pain management are the fentanyl
patch, oxycodone, sustained-release morphine (with the greatest potential side
effects), and tramadol (a synthetic codeine analogue that is a weak m-receptor ago-
nist). Although methadone may be taken orally in people, it is not absorbed orally in
dogs, and is therefore not recommended for oral administration in this species.140,141
Rarely should opioids be used alone for neuropathic pain; however, in severe pain,
a high dose of an opiate, in addition to other drugs, may be necessary. Should pain
seem to worsen with increasing doses of an opioid, however, opioid-induced hyper-
algesia (OIH) should be considered. Experimental evidence in human patients
suggests that opioid tolerance and OIH do occur within 1 month of continuing opioid
use. Some investigators thus indicate that these findings might limit the clinical utility
of opioids in controlling chronic pain.180 This is a point to consider in veterinary
patients because there may be the potential for opioid tolerance to occur; therefore,
pain should not necessarily be interpreted as worsening of the underlying condition.
A recent review identified OIH to occur in rats, mice, and human beings after acute
or chronic administration of opioids.181
1400 Mathews

Tramadol
Tramadol is a synthetic codeine analogue that is a weak m-receptor agonist. Of inter-
est, when managing neuropathic pain, tramadol inhibits neuronal reuptake of NE and
serotonin, in addition to possibly facilitating their release.182,183 It is thought that these
effects on central catecholaminergic (descending inhibitory) pathways contribute sig-
nificantly to the drug’s analgesic efficacy.183 These effects may be an advantage in an-
imals that have neuropathic pain. Tramadol is recommended for the management of
acute and chronic pain of moderate intensity associated with a variety of conditions,
including neuropathic pain in human patients.184 There are no reports in the veterinary
literature assessing the efficacy of tramadol in neuropathic pain. One study, however,
reported comparable analgesia in dogs when they were administered preoperative
tramadol at a dose of 2 mg/kg or morphine at a dose of 0.2 mg/kg for pain manage-
ment after ovariohysterectomy for pyometra.185 In North America, only oral formula-
tions of tramadol are commercially available (the reader is referred to the article by
Lamont elsewhere in this issue). In the United States, tramadol is available in various
tablet strengths, in an extended-release formulation, and in combination with acet-
aminophen (the reader is referred to the article by Lamont elsewhere in this issue).
Only the extended-release preparation and the combination with acetaminophen
are currently available in Canada (the reader is referred to the article by Lamont else-
where in this issue) in the noncompounded formulations. Tramadol is commonly
prepared by a local compounding pharmacy, however. At the Ontario Veterinary
College, 5-mg, 10-mg, 25-mg, 50-mg, and 100-mg capsules and a 5-mg/mL suspen-
sion are prepared from tramadol powder. A recent study reported a pharmacokinetic
study of a tramadol solution prepared from the pure dry powder and administered
intravenously to dogs.186 Using doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, the elimina-
tion half-life ranged from 1.5 to 2 hours and the active metabolite was detected only in
low amounts. In this small group of dogs, intravenous tramadol administration seemed
safe, with increasing sedation noted with increasing dose.186 These investigators sug-
gest that further investigation using larger numbers of dogs of various breeds is war-
ranted. The oral dosing guidelines at this time are based on extrapolation from human
patients in addition to clinical experience with animal patients. KuKanich and Pa-
pich187 reported that a simulated oral dosing regimen of 5 mg/kg every 6 hours in
dogs resulted in plasma concentrations of tramadol and its principal metabolite that
were consistent with levels associated with analgesia in people. Based on current in-
formation, a starting dosage range of 1 to 5 mg/kg administered orally every 6 to
8 hours for cancer pain, 1 to 2 mg/kg administered every 8 to 12 hours for osteoarthri-
tis in dogs (increasing to effect), and 1 to 2 mg/kg administered every 12 to 24 hours for
cats is recommended. Because dysphoria has been a common side effect in cats,
dose recommendations for this species are more conservative. As with any medica-
tion for managing pain, titration of the dose is required to minimize sedation or dys-
phoria in cats and dogs. Dosing guidelines for the extended-release formulations
are more difficult to estimate; at this time, there are no published pharmacokinetic
data in dogs or cats to guide recommendations for this formulation (the reader is
referred to the article by Lamont elsewhere in this issue). Combination products,
such as those combined with an NSAID (eg, tramadol, acetaminophen), are not
recommended because the NSAID has a dose-limiting requirement that restricts the
dosing of tramadol or any other opioid-NSAID combination. An NSAID of choice
can be administered separately from the tramadol or any other opioid. Acetaminophen
is toxic to cats; thus, this combination product should never be used in this species.
Common side effects associated with tramadol administration include sedation and
dysphoria, especially in cats. It has also been reported to decrease the seizure
 Neuropathic Pain in Dogs and Cats 1401

threshold in certain human patients.188 Because of its inhibitory effect on serotonin up-
take, tramadol should not be used in patients that may have received monoaminoxi-
dase inhibitors, such as selegiline (Anipryl).

Gabapentin
In addition to its use in surgical or traumatic neurologic conditions, gabapentin is used
in human patients for management of neuropathic pain associated with diabetes, can-
cer, and primary nerve compression.139 The reader is referred to the section on acute
pain management for details.
Pregabalin
Pregabalin has a similar pharmacologic profile as gabapentin and is used to manage
neuropathic pain in human patients.177,189 Pregabalin seems to cause less mental
confusion and sedative side effects than those reported with gabapentin. A dosage
for pregabalin has not been established for veterinary patients. Pregabalin is much
more expensive than gabapentin.
Amantadine
Amantadine is an oral NMDA receptor antagonist with activity similar to that of
ketamine.190 The only study reporting the chronic use of amantadine in the veterinary
literature showed improved activity and lameness scores in refractory canine osteoar-
thritic pain when used in combination with meloxicam compared with meloxicam
alone.191 The dosage of amantadine used in this randomized, blind, placebo-con-
trolled study was 3 to 5 mg/kg administered orally every 24 hours; however, a starting
dosage of 3 mg/kg administered orally every 24 hours is suggested. Meloxicam was
administered at a standard dose of a 0.2 mg/kg orally administered loading dose, fol-
lowed by a dosage of 0.1 mg/kg administered orally every 24 hours thereafter. This
study gives hope to the potential benefit of amantadine in managing chronic neuro-
pathic pain similar to that of ketamine in the acute pain setting. In the United States
and Canada, amantadine is available commercially as 100-mg capsules and as
10-mg/mL oral syrup. A 100-mg tablet formulation is also available in the United States
(the reader is referred to the article by Lamont elsewhere in this issue).

Dextromethorphan
Dextromethorphan is an oral NMDA receptor antagonist and has been recommended
for management of neuropathic pain in human beings. Unfortunately, however,
dextromethorphan is not absorbed when given to dogs by the oral route, and is there-
fore not recommended in this species.192
Tricyclic antidepressants
Imipramine and amitriptyline are two commonly recommended TCAs for veterinary
patients. The TCAs block the reuptake of catecholamines, thereby enhancing adren-
ergic transmission.139 In addition, amitriptyline serves as an NMDA receptor antago-
nist. The TCAs may be effective adjunctive analgesics for a range of neuropathic
conditions or can be used alone in IBD and FIC.117 In people, the analgesic effects
of these drugs seem to occur at lower than antidepressant doses.139 When other
traditional analgesics have failed to achieve complete analgesia, the addition of imip-
ramine or amitriptyline may prove successful in managing refractory chronic pain.
These products may be distasteful and may require some creative method of admin-
istration. Although it has been reported that it can take 2 to 4 weeks for these drugs to
achieve maximal effectiveness, in the author’s experience, clinical improvement oc-
curs within 48 hours of amitriptyline administration when combined with other analge-
sics or when used in combination with corticosteroids for feline IBD and continues to
1402 Mathews

improve further over time. In FIC, however, no improvement was observed after 7 days
of administration of amitriptyline at a dosage of 10 mg per cat administered every 24
hours.193 The recommended dosage of amitriptyline for dogs is 1 to 2 mg/kg admin-
istered orally every 12 to 24 hours; for cats, the recommended dosage is 2.5 to 12.5
mg per cat administered orally every 24 hours. The dosage of imipramine for dogs
is 0.5 to 1 mg/kg administered orally every 8 hours; for cats, the recommended dosage
is 2.5 to 5 mg per cat administered orally every 12 hours.

Lidocaine dermal patches

Lidocaine 5% dermal patches (Lidoderm patch, Endo Pharmaceuticals, Chadd Ford,
Pennsylvania) are frequently used in human patients with neuropathic pain attributable
to a variety of causes. The low systemic concentrations achieved by transdermal lido-
caine application suggest that efficacy is achieved by means of blockade of PNS
rather than CNS sodium channels.194 Successful results with the application of this
patch have been obtained in children who have intractable and disabling neuropathic
pain originating at and around the site of previous surgical procedures. These sites
were identified at a nephrectomy scar, laminectomy scar, an inguinal area scar from
a cardiac catheterization procedure, and a laparotomy scar in which surgical involve-
ment of a nerve was suspected.195 Worthy of note is that these procedures, and many
others in which nerve entrapment may occur, are performed in cats and dogs.
Pharmacokinetic studies of the lidocaine patch in dogs found that lidocaine peak
levels occurred at 9.5 to 12 hours after patch application, reached steady-state con-
centrations between 24 and 48 hours, and decreased dramatically at 60 hours after
application. Low plasma lidocaine concentrations remained for 6 hours after patch
removal.196,197 No analgesic efficacy studies have been reported in dogs or cats.

Lamotrigine
Lamotrigine is an anticonvulsant and is the oral sodium channel antagonist of choice in
human patients with chronic neuropathic pain. Dosing requires a slow titration to 400
mg/d.139 Lamotrigine is not suitable for use in dogs because the plasma elimination
half-life is only 2 to 3 hours (compared with 22–24 hours in human beings) and its me-
tabolite has cardioactive properties that may have significant cardiovascular depres-
sant effects.52

Acupuncture
Acupuncture has been used for centuries as a primary or complimentary treatment
modality for the treatment of acute and chronic pain states in human patients. Acu-
puncture has more recently become a widely accepted treatment for pain in veterinary
medicine. The relief of pain by acupuncture can be explained neurophysiologically by
neuromodulatory actions at the local, regional (segmental), and CNS (suprasegmental)
levels. Specific acupuncture points are rich in neurovascular endings. Because a spe-
cific region of the body is served by the same myelotome (specific spinal cord
segment), sensory cutaneous stimulation by means of acupuncture needle placement
causes functional reflex reactions to the muscles, muscle vessels, and the ligaments
that receive sensory or motor innervation from that same myelotome. In addition,
acupuncture is thought to block pain signals from reaching the spinal cord ascending
nociceptive pathways and the thalamocortex by a mechanism called the ‘‘gate
theory.’’ Acupuncture primarily stimulates proprioceptors in skin and muscle, which
send impulses to the dorsal horn of the spinal cord by way of heavily myelinated Ab
and 1A sensory nerves, with a rapid conduction velocity. Pain is carried to the spinal
cord by way of thinly myelinated Ad and unmyelinated C-fibers, which have a much
slower conduction velocity. Because proprioceptive impulses reach the spinal cord
 Neuropathic Pain in Dogs and Cats 1403

first, they cause blockade of Ad and C-fiber input by the prior release of endogenous
opiates (endorphins). In addition, mechanical stimulation of somatic and visceral
‘‘fields’’ by acupuncture needle placement has been shown to decrease the sponta-
neous and noxious evoked activity of most dorsal horn neurons, including WDR cells,
high-threshold cells, and high-threshold inhibitory cells, reducing the perception of
pain. At the suprasegmental spinal cord and brain level, there is strong evidence to
indicate that acupuncture exerts its analgesic effect by means of modulation of the
descending pain control system, consisting of three parts, above the level of the dorsal
horn of the spinal cord. These are the pontine system (nucleus raphe magnus), the
mesencephalic system (PAG and periventricular gray system), and the cortical/dien-
cephalic system. Each system uses different endogenous opioid peptides, which
are all stimulated by means of acupuncture and electroacupuncture. The long-term
analgesic effect of acupuncture has been suggested to be related to the activation
of a serotonergic and metencephalinergic neurologic circuit in the mid-diencephalon,
resulting in continuous inhibition of nociceptive stimuli, in addition to being related to
longer lasting peripheral activation of low-threshold muscular mechanoreceptors,
increasing the activity of large-diameter heavily myelinated nerve fibers and resulting
in blockade of Ad and C-fiber input into the spinal cord178 (Paul Cuddon, personal
communication, 2008).

FUTURE THERAPEUTIC MODALITIES

Vanilloid Receptor-1 Antagonists
The identification and cloning of the TRPV1 represented a significant step in the under-
standing of the molecular mechanisms underlying the transduction of noxious chem-
ical and thermal stimuli by peripheral nociceptors.198 The TRPV1 channel activity is
potentiated by proinflammatory agents, a phenomenon that is thought to underlie
the peripheral sensitization of nociceptors that leads to thermal hyperalgesia. The
validation of the TRPV1 receptor as a key therapeutic target for pain management
has resulted in the development of orally active antagonists. Because of the many
physiologic roles of this receptor, the real challenge is to develop effective antagonists
involved in pain transduction but to preserve the physiologic activity of TRPV1 recep-
tors.198 The TRPV1 receptor is also expressed in the CNS, and it seems to play an
important role in pain mediated by central sensitization. The TRPV1 antagonists cur-
rently being investigated effectively reduce thermal hyperalgesia and mechanical allo-
dynia associated with inflammatory and osteoarthritic pain in research models. With
identification of peripheral and central roles of the TRPV1 receptor, the future potential
of TRPV1 antagonists as analgesics for neuropathic pain may be a consideration.

Serotonin and Norepinephrine Reuptake Inhibitors

As the descending inhibitory system seems to be dysfunctional in neuropathic pain
states, SRI and norepinephrine reuptake inhibitor (NRI) mixed compounds are being
investigated for analgesic efficacy. Recently, duloxetine, a mixed SRI and NRI with
potency at both transporters, was the first reuptake inhibitor approved for the treat-
ment of diabetic neuropathy.199 Published preclinical data evaluating this compound
in neuropathic and inflammatory models of pain have demonstrated analgesic activ-
ity.199 In a more recent study investigating the SRI and NRIs, the investigators suggest
that compounds with affinity for NE and serotonin reuptake inhibition may be benefi-
cial for the treatment of neuropathic pain, whereas compounds with greater affinity for
NE reuptake inhibition may be more beneficial for the treatment of visceral pain.31
1404 Mathews

As these agents gain more popularity in human medicine as being effective in treating
neuropathic pain, they may also become available for veterinary investigation.

SUMMARY

Cats and dogs share a nervous system similar to that of human beings. They also
encounter similar surgical, traumatic, inflammatory, and metabolic conditions. Be-
cause human beings experience neuropathic pain associated with these and other
pathologic situations, it would seem reasonable to assume that cats and dogs share
this experience. Neuropathic pain is difficult to diagnose in veterinary patients
because they are unable to verbalize their pain. By assuming that neuropathic pain
may exist based on the history of events that each patient has experienced, a focused
client history and neurologic examination may identify a lesion resulting in persistent or
spontaneous pain. Should neuropathic pain be diagnosed, it is important to identify
the particular cause responsible for generating a particular pain because this repre-
sents the first anatomic target for treatment. Although it is impossible to discriminate
burning from prickling and lancinating from stabbing in veterinary patients, behavioral
patterns described by owners may assist with lesion localization. Once neuropathic
pain is diagnosed, a trial analgesic or acupuncture session(s) should be prescribed
with instructions for owners to observe behavior. Dosing of the analgesic can be
titrated to the patient’s needs while avoiding adverse effects. When a particular anal-
gesic may be ineffectual, an alternate class should be tried. As research into the
neurobiologic mechanisms of neuropathic pain continues, specific therapies for its
management should eventually appear in the human clinical setting and should
subsequently be investigated for veterinary clinical use.

ACKNOWLEDGMENTS

The author is extremely grateful to Dr. Paul Cuddon, Colorado State University, for
his contribution on electrodiagnostics (especially its application to cats with diabetic
neuropathy), the physiologic action of acupuncture, and his critical review of this
manuscript.

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