Pain: Mechanisms and

Management in Horses
William W. Muir, DVM, PhD

KEYWORDS
 Pain  Nociception  Sensitization  Disinhibition
 Therapeutics

Pain, what an enigma, is often physically limiting and frustrating to treat. Pain evolved
as a homeostatic warning system associated with tissue or nerve injury.1 Pain is an
everyday, albeit often brief, occurrence for all animals but a few unlucky humans
with congenital insensitivity to pain (not yet reported in animals).2 For some, pain
persists or recurs long after the pain-producing stimulus has been removed resulting
in pain as disease with little or no known cause.3 Most of what we have learned con-
cerning the mechanisms responsible for pain and its consequences continues to be
clarified with key advances being made in the past 25 years.4 Most of these advances
in knowledge in mammalian species have evolved from studies conducted in rats and
mice. This knowledge, however, has resulted in an improved understanding of pain
and its ubiquitous involvement with all aspects of mammalian physiology. Once
thought, as proposed by Rene Descartes, to be a “hard-wired” system wherein infor-
mation is transmitted by pain-specific nerve fibers, it is now appreciated that pain is
a multidimensional sensory experience that is subserved by so-called “wide dynamic
range” (WDR) neurons that respond to both low- and high-threshold cutaneous stimuli
and frequently involves multiple sensing systems, nerve fiber types, and areas of the
central nervous system (CNS; spinal cord, brain).5 Furthermore, the generation and
persistence of pain can be elicited by neural mechanisms that not only activate or
exaggerate excitatory activity (hypersensitivity, sensitization) but also by mechanisms
that decrease inhibitory activity (disinhibition). Persistent (chronic) pain, for example, is
now appreciated for its ability to modify nervous system physiology and anatomy and
has led to the conclusion that the nervous system is malleable or plastic and that
chronic pain can become pain as disease, leading to distress.6 As new information
and knowledge of the mechanisms responsible for pain emerge, new therapies evolve
and many therapies become recognized for their potential therapeutic value.7,8
All animals are entitled to 5 freedoms: freedom from hunger and thirst; freedom from
discomfort; freedom to express normal behavior; freedom from fear and distress; and

Equine Anesthesia and Analgesia Consulting Services, 338 West 7th Avenue, Columbus,
OH 43201, USA
E-mail address: bill.muir@amcny.org

Vet Clin Equine 26 (2010) 467–480

doi:10.1016/j.cveq.2010.07.008 vetequine.theclinics.com
0749-0739/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
468 Muir

freedom from pain, injury, and disease. Pain has been defined as, “an unpleasant
sensory and emotional experience associated with actual or potential tissue damage
or described in terms of such damage” (Table 1). A more appropriate definition for
pain in animals states: “Animal pain is an aversive sensory and emotional experience
representing an awareness by the animal of damage or threat to the integrity of its
tissues; it changes the animal’s physiology and behavior to reduce or avoid damage,
to reduce the likelihood of recurrence and to promote recovery; unnecessary pain
occurs when the intensity or duration of the experience is inappropriate for the
damage sustained or when the physiologic and behavioral responses to it are unsuc-
cessful at alleviating it.”9 The emotional component of this definition is all too often
created by unexpected events, strange environments, and proceedings that produce
fear. Pain in horses is a valuable clinical sign (apprehension, anxiety, reluctance to
interact, lameness, stomping, rolling) and is often the first and only sign of a current
or impending problem.10 When pain is severe or becomes chronic, behavioral signs
are exaggerated and can result in a failure to thrive (“sickness syndrome”).11 Pain
prevention (preventative therapy) and treatment (palliative therapy) are dependent
upon knowledge of the anatomy, physiology, and pathologic processes responsible
for sensory processing in health and disease. This knowledge precludes and is
prerequisite to the development and application of rational pain therapies and appre-
ciation of their consequences.
Consider, for example, a 12-year-old, 510 kg, retired Thoroughbred racehorse
trained as a children’s hunter-jumper that is presented with an acute history of
a deep wire cut on its left front pastern. The horse is noticeably lame on the affected
limb. Historically the horse was reported to have “sensitive” front feet that responded
to phenylbutazone, local steroid (methyprednisolone acetate) injections, and sarapin
administration. Two weeks before this traumatic event the horse was moved to
a new stable at which time the farm farrier “balanced” the feet resulting in severe lame-
ness and swelling of both front limb fetlocks, which persisted for approximately 5 to 7
days. The horse was reluctant to move, almost 3-legged lame, refusing to put weight
on its left front limb, standing with most of its weight on its hind limbs. The horse walked
with a “rocking-horse” type gate, was alert and anxious, hypersensitive to touch on the
affected limb, and highly sensitive to palpation of the wound and the affected limb. The
horse was administered 2.5 mg/kg detomidine intravenously (IV) and a low palmar
(volar) nerve block was performed by injecting 2.5 mL of 2% lidocaine in the area of
the medial and lateral plantar nerves just distal to the buttons of the splint bones.
The horse became sedate and markedly less painful on the left front limb when moved
but noticeably lame on the right front limb. The horse’s presenting signs are suggestive
of acute adaptive primary and secondary hypersensitivity of the affected limb resulting
in hyperalgesia and allodynia. Primary hypersensitivity was likely related to the wound
and the development of peripheral sensitization. The horse’s response to initial therapy
is suggestive of a chronic painful condition, likely involving both front limbs, resulting
from central sensitization and maladaptive pain. The wound was cleaned and
bandaged and a multimodal therapeutic pain program recommended and instituted
to be administered during the next 7 to 10 days. The program incorporated both inter-
mittent and rescue recommendations that used multiple pharmacologic therapies,
complementary remedies, and rehabilitative recommendations.

NOCICEPTION AND PAIN TERMINOLOGY

The case presented in the preceding paragraph emphasizes that a cogent discussion
of pain and pain therapy cannot occur without consensus regarding the terms and
 Pain: Mechanisms and Management in Horses 469

phrases used to describe pain and its causes (Tables 1 and 2).12 These terms and
phrases constitute the language of pain and have evolved from the neurobiological,
biochemical, and pathophysiologic processes responsible for its production and
effects. Nociception is a term used to describe the neural processes for the transduc-
tion (detection), transmission, modulation, projection, and central processing of actual
or potentially tissue-damaging stimuli (Fig. 1). Nociception can occur without pain
(general anesthesia). Nociception is inclusive of all the sensory neural mechanisms
used to detect and process noxious (harmful) or pain-producing stimuli. Nociception
begins in the periphery and is dependent upon the sensitivity and activity of nocicep-
tors, nociceptive neurons, and the prevailing status of the central nervous system
(spinal cord and brain). Under normal circumstances, noxious stimuli (mechanical,
thermal, chemical, electrical) activate a variety of comparatively high threshold uni-
and polymodal nociceptors located throughout the body. Nociceptive neurons
express transient receptor potential (TRP) channels that subserve a protective func-
tion and are highly implicated in the immediate detection of noxious stimuli such as
heat or tissue damage.13 The TRP vanilloid (TRPV1) receptor, is activated by capsa-
icin, the hot ingredient in chili peppers, and has been identified in the central and
peripheral nervous systems of most mammals, including horses.14 It is known to
play a central role in the development and/or maintenance of persistent pain states,
particularly those caused by inflammation.12 Noxious stimuli are converted (trans-
duced) to electrical impulses by pain receptors or nociceptors. The electrical signals
(action potentials) are transmitted to the spinal cord by thinly myelinated (Ad) and
unmyelinated (C) primary (first-order) sensory nerve fibers. The Ad nerve fibers trans-
mit electrical nerve impulses much faster than C fibers and are responsible for the
rapid onset of the sharp or first pain that triggers aversion and withdrawal from the
stimulus. Activation of C fibers results in a slower onset pain (second pain) that in
humans is associated with a dull throbbing or burning sensation. It is worth noting
that visceral pain is transmitted exclusively by C fibers that travel with nerves of the
autonomic nervous system, which may help to explain the exaggerated physiologic
responses (tachycardia, hyperpnea, hypertension, sweating) associated with visceral
pain.15 First-order nerve fibers terminate and connect (synapse) on second-order
nerve fibers located in the dorsal horn of the spinal cord. Second-order neurons
and interneurons feed into nociceptive pathways that terminate in the brain. Nocicep-
tive pain, sometimes referred to as “physiologic” pain, is produced by noxious stimuli
that activate high-threshold nociceptors and continues to occur so long as the noxious
stimulus is maintained, thereby serving as a warning system that protects against
tissue injury (see Table 2). If the noxious stimulus is intense enough to cause tissue
injury and a subsequent inflammatory response, pain persists and the sensory
nervous system undergoes graded adaptive or maladaptive changes dependent
upon the cause and severity of the pain-producing stimulus.3 Said another way, the
sensory nervous system is plastic, initially adapting (adaptive pain) to minimize or
prevent tissue injury and subsequently through mechanisms that protect and aid in
the healing and repair of the injured body part. Chemical substances (prostaglandins,
leukotrienes, bradykinin, nerve growth factors, histamine) produced by tissue damage
and inflammation, for example, activate and sensitize (decrease threshold) nocicep-
tors resulting in peripheral sensitization, an exaggerated and prolonged response to
noxious stimuli (hyperalgesia) and the sensation of pain by normally innocuous stimuli
(allodynia). Severe or prolonged (chronic) pain can result in central sensitization, which
is often initiated by peripheral sensitization and is frequently characterized by hyper-
algesia, allodynia, and secondary hypersensitivity (pain outside the injured area). Mal-
adaptive pain is uncoupled from the noxious stimulus or healing, is spontaneous or
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Muir
Table 1
Definitions of pain and associated terms

Term Definition
Pain An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such
damage.
Note: Stress (anxiety, fear) and distress exaggerate pain.
Animal pain Animal pain is an aversive sensory and emotional experience representing an awareness by the animal of damage or threat to the
integrity of its tissues; it changes the animal’s physiology and behavior to reduce or avoid damage, to reduce the likelihood of
recurrence, and to promote recovery; unnecessary pain occurs when the intensity or duration of the experience is inappropriate
for the damage sustained or when the physiologic and behavioral responses to it are unsuccessful at alleviating it.
Stress response Responses to acute injury or environmental change that leads to an increase in metabolic rate, blood clotting, water retention, and
immune function; a “fight or flight” alarm reaction with autonomic activation.
Note: Chronic stress results in “sickness syndrome” or a so-called “poor doer.”
Noxious stimulus An actual or potentially tissue-damaging event.
Note: A painful mechanical, chemical, thermal, or electrical event.
Nociceptor A sensory receptor capable of transducing and encoding noxious stimuli.
Nociception Neural process of encoding and processing noxious stimuli.
Note: Inclusive of the neural processes responsible for stimulus transduction, transmission, modulation, projection, and perception.
Nociceptive pain Pain arising from activation of nociceptors.
Note: Generally considered to be “Physiologic or Adaptive” and serving as an alarm mediated by high-threshold (Ad, C) sensory
neurons.
Inflammatory pain Pain caused by peripheral tissue inflammation.
Note: Inflammation can be acute or chronic and produces hypersensitivity (peripheral sensitization) that can lead to central
sensitization.
Neuropathic pain Pain arising as a consequence of a lesion or disease affecting the somatosensory (central or peripheral) nervous system.
Note: Pain may occur in the absence of a stimulus.
Dysfunctional pain Amplification of nociceptive signaling in the absence of inflammation or neural lesions.
Adaptive pain Pain that contributes to survival by the initiation of responses and behaviors that protect the animal from injury and promote
healing when injury has occurred.
Maladaptive pain Pain as disease; pain that is uncoupled from the noxious stimulus; an expression of abnormal sensory processing.
Note: Pain that persists or is recurrent after the healing process has occurred.
First pain The initial well-localized and brief pain produced by a noxious stimulus.
Note: Produced by high-threshold pain receptors.
Second pain The delayed, diffuse, and protracted pain produced by polymodal pain receptors. Second pain persists after the termination of the
noxious stimulus.
Note: Severe acute painful events, chronic pain, and visceral pain are predominantly of the “second pain” type.
Superficial somatic Pain associated with ongoing activation of nociceptors in the skin, subcutaneous tissue, or mucous membranes.
pain
Deep somatic pain Pain associated with ongoing activation of nociceptors in muscles, tendons, joint capsules, fasciae, or bones.
Visceral pain Pain arising from visceral organs (eg, heart, lungs, gastrointestinal tract, liver, kidneys, bladder).
Perioperative pain Pain that is present in a surgical patient because of preexisting disease; the surgical procedure.
Breakthrough pain Pain that overwhelms or “breaks through” any pain relief afforded by ongoing analgesics.
Intractable pain Intense, usually chronic and unremitting, pain for which no accepted medical intervention has provided relief.
Sensitization Increased responsiveness to neurons to normal input or recruitment of a response to normally subthreshold inputs.
Peripheral Increased sensitivity of peripheral nociceptive neurons owing to a decrease in threshold and increase in excitability.

Pain: Mechanisms and Management in Horses

sensitization Note: Hypersensitivity is produced by a variety of inflammatory mediators (“sensitizing soup”), including prostaglandins, bradykinin,
serotonin, histamine, and H1.
Central Increased excitability and responsiveness of central (spinal dorsal horn) nociceptive neurons to normal subthreshold afferent input
sensitization from synaptic facilitation or a decrease in inhibition.
Note: Involves activation of NMDA receptors.
“Windup” The temporal summation of repetitive nociceptive neuron activity resulting (“use” or activity-dependent) in prolonged discharge of
dorsal horn neurons.
Disinhibition Removal of normal CNS inhibitory pathways that modulate the spinal transmission of nociceptive inputs.
Note: Predominantly GABA-ergic in the spinal cord.
Primary Pain produced by peripheral sensory neurons inside the inflamed or tissue-damaged area.
hypersensitivity
Secondary Pain produced by normal peripheral sensory neurons outside the inflamed or tissue-damaged area.
hypersensitivity
Hyperesthesia Increased sensitivity to normal stimulation.
Paresthesia/ Abnormal unpleasant sensation that can be spontaneous or evoked.
Dysesthesia
Hyperalgesia An increased response to a stimulus that is normally painful.
(continued on next page)

471
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Muir
Table 1
(continued)

Term Definition
Allodynia Pain caused by a stimulus that normally does not provoke pain, such as the light touch of a hand or finger.
Hyperpathia A syndrome characterized by an abnormally exaggerated reaction to a stimulus, especially a repetitive stimulus.
Pain behavior Nonverbal actions understood by observers to indicate that the animal is experiencing pain.
Note: Includes abnormal activities, gait and postures; avoidance of interaction or activity; abnormal expressions and vocalization.
Pain management The systematic study of clinical and basic science and its application for the reduction of pain and suffering.
Analgesia Absence of pain in response to a normally painful stimulus, typically without loss of consciousness.
Adjuvant A medication that is not primarily an analgesic but that has independent or additive pain-relieving effects.
Multimodal “Balanced analgesia”: more than one method or modality of controlling pain (eg, drugs from 2 or more classes, plus nondrug
analgesia treatment).
Note: With the goal of producing additive or synergistic effects, reducing side effects, or both.
Preemptive Interventions, frequently involving drug therapy, performed before a noxious event (eg, surgery) intended to minimize or prevent
(preventative) the impact of a pain-producing stimulus.
analgesia Note: Preventing peripheral and/or central sensitization.
Rescue analgesia The administration of analgesic therapy for the treatment of pain.
Tolerance Adaptation to a single (acute) or repetitive exposure to therapy that results in a diminution of one or more of the therapy’s effects.

Abbreviations: CNS, central nervous system; GABA, gamma-amino-butyric-acid; NMDA, N-methyl-D aspartate.
 Pain: Mechanisms and Management in Horses 473

Table 2
Types of pain

Functional
Stimulus Category/Response
Type of Pain Dependency Characteristics Clinical Examples
Nociceptive Evoked by Adaptive and Response to
“Physiologic” high-intensity protective: brief, everyday noxious
(noxious) stimuli localized; signals stimuli: needle
potential tissue prick, hoof testers
damage
Inflammatory Evoked by low- and Adaptive and Laceration, joint
high-intensity reversible: inflammation,
stimuli secondary protection and sprain, strain,
to tissue injury promotion of surgery
healing by
producing sensory
amplification
(hypersensitivity);
duration of pain
parallels active
inflammation (eg,
tissue trauma)
Neuropathic Evoked by low- and Maladaptive and Nerve trauma,
high-intensity persistent: neuroma, viral
stimuli; peripheral Independent of infections
or CNS lesion or disease;
neuropathies central sensory
amplification
maintained;
spontaneous or
stimulus
dependent;
marked immune
response
Dysfunctional Evoked by low- and Maladaptive, Cause unknown:
high-intensity potentially intermittent but
stimuli or in the persistent but chronic GI pain
absence of often may be an
a stimulus intermittent; example
sensory
amplification
maintained;
spontaneous or
stimulus
dependent

Abbreviations: CNS, central nervous system; GI, gastrointestinal.

recurrent, and results from the abnormal operation of the nervous system: it is pain as
disease.16

SENSITIZATION AND DISINHIBITION

Sensitization, involving the peripheral or central nervous systems, can be

produced by the production and dissemination of the by-products of damaged
or infected tissues (lymphocytes, neutrophils, mast cells, macrophages). Tissue
474 Muir

Fig. 1. Nociception includes the transduction, transmission, modulation, projection, and

perception of noxious stimuli. Peripheral and central sensitization exaggerate and amplify
the noxious stimulus. NSIADs, glucocorticoids, local anesthetics, opioids, alpha-2 agonists,
NMDA antagonists and antiepileptic drugs (AEDs) are effective in modifying these
responses.

trauma releases prostaglandins, bradykinin, and neurotrophic growth factors

(NGFs) and ions (H1 K1) into the injured area and is responsible for peripheral
sensitization and the development of primary hyperalgesia and allodynia.
Activation of immune cells increases the production of cytokines (interleukin [IL]-1,
IL-6, tumor necrosis factor [TNF]-a) that lower the threshold and activate central
sensory neurons, amplifying the pain response.4 Repetitive stimulation of periph-
eral sensory nerves can temporally summate to produce prolonged and exagger-
ated responses in dorsal horn sensory neurons resulting in central sensitization.6,17
Central sensitization can last for hours to days, is largely caused by the removal of
the magnesium blockade and activation of N-methyl-D-aspartate (NMDA) recep-
tors by glutamate, and is believed to be responsible for pain outside the area
 Pain: Mechanisms and Management in Horses 475

of tissue injury (secondary hyperalgesia).6 Central sensitization enables low-inten-

sity stimuli to produce pain owing to changes in sensory processing in the spinal
cord. Finally, descending pathways originating in the brain (amygdala, hypothal-
amus) and relayed via the brain stem and rostral ventral medulla to the spinal
cord release inhibitory neurotransmitters (5-hydroxy tryptamine; norepinephrine;
endogenous opioids) that provide tonic and phasic inhibitory control of nociceptive
input.18 Noradrenergic inhibition normally occurs because of activation of central
alpha-2 receptors and the release of the inhibitory neurotransmitters, gamma-
amino-butyric-acid (GABA) and lysine. Peripheral nerve injury caused by severe
trauma or conditions that produce neuropathic pain (laminitis; neurodegenerative
disease) contribute to hypersensitivity. Peripheral sensitization, central sensitiza-
tion, and disinhibition represent a continuum of the pain process. Pain produces
stress, which is short-lived in most horses because of the short duration of expo-
sure to the stressor. Surgery and anesthesia are common sources of relatively
short periods of pain and stress, respectively, in horses but osteoarthritis and
laminitis can produce pain that persists for months or years and can lead to
suffering.19–21 Suffering occurs when horses are forced to endure the imposition
of untreated or chronic painful conditions, is maladaptive, and initiates neural
and endocrine responses that negatively affect homeostatic functions critical to
the animal’s well-being.22

TREATING PAIN IN HORSES

Most studies examining the analgesic effects of drugs in horses lack controls, are
inadequately powered, not objectively evaluated, or reflect the biases of the investi-
gators.23 Furthermore, most investigations have been conducted in experimental
pain models (balloon colic, heat lamp, endotoxin administration, hoof nail) using
otherwise normal horses. Few studies of therapeutic efficacy have been conducted
in horses with naturally occurring disease, making it difficult to determine their clinical
efficacy. Regardless, what has been learned suggests that horses respond to pain
similar to other mammals and the data from alternate species are likely to be relevant
in the horse. Pharmacologic approaches to the treatment of pain in horses should be
mechanism based and selected for specific purposes (inflammation, nerve injury), for
specific reasons (peripheral vs central sensitization), scaled to the severity and type
of pain (somatic vs visceral; mild vs severe), and formulated to produce the greatest
success (multimodal therapy; preventative; rescue).16 Most drugs used for the treat-
ment of pain in horses fall into 1 of 4 broad categories: steroidal and nonsteroidal
anti-inflammatory drugs (NSAIDs), opioids, alpha2 agonists, and local anesthetics
(Table 3). Similarly, complementary and alternative therapies that include acupunc-
ture, chiropractic, and neutriceutical approaches to pain relief have only begun to
be objectively evaluated in horses.24 The terms complementary and alternative ther-
apies are often used interchangeably but are distinct. Complementary therapies are
used together with traditional therapies to produce the desired effect. For example,
opioids may be combined with NSAIDs to manage breakthrough pain and are there-
fore complementary. Alternative therapies are frequently used in conjunction with
conventional approaches.

LOCAL ANESTHETICS

Local anesthetics (lidocaine, mepivicaine, bupivicaine, ropivicaine) are applied topi-

cally or injected at a specific site (local; perineurally [regional]) to produce a loss of
sensation.25 Analgesia is produced by the blockade of sodium ion channels,
476 Muir

Table 3
Classes of analgesic drugs

Analgesic Drugs
Evidence for
Drug Class Representative Mechanism of Action Clinical Efficacy
Opioids Primarily mu (m) opioid agonists; Good
Morphine kappa (k) opioid agonistic activity
Meperidine may be important for butorphanol
Methadone
Hydromorphone
Fentanyl
Butorphanol
Buprenorpine
Alpha-2 agonists Primarily alpha-2A receptor Good
Xylazine stimulants; possible imidazoline (I1)
Detomidine receptor agonist
Medetomidine
Romifidine
NSAIDs Inhibition of cyclooxygenase Strong
Aspirin and Y in prostaglandins:
Phenylbutazone PGE2, PGI2, TXA2
Flunixin
Ketoprofen
Firocoxib
Diclofenac
Local anesthetics Block voltage–gated sodium channels Strong
Lidocaine (Na1 channels) – impair nerve
Mepivacaine conduction
Bupivacaine
Ropivacaine
Corticosteroids Inhibition of phospholipase A2 Good
Triamcinolone acetonide
Methylprednisolone acetate
Dexamethasone
Others NMDA antagonist Good
Ketamine, tiletamine Calcium channel a2-d blocker Poor
Gabapentin Mu (m) opioid receptor agonist Poor
Tramadol Desensitization of C-fibers by Unknown (Fair)
Capsaicin overactivation of TRPV1 channel Fair to Poor
Sarapin Irritant

Abbreviations: NMDA, N-methyl-D aspartate; NSAID, nonsteroidal anti-inflammatory drug; TRPV1,

transient receptor potential vanilloid.

thereby preventing the initiation and conduction of electrical impulses in small-

diameter (C, Ad) sensory nerve fibers. Larger (clinical) dosages of local anesthetics
can produce a loss of motor function and temporary motor paralysis. Most local
anesthetic drugs administered systemically produce mild CNS depression, are
anesthetic sparing, and have antiarrhythmic, antishock, and gastrointestinal pro-
motility effects. Large IV dosages, however, can produce hypotension, anxiety,
seizures, and apnea. These effects are more common in stressed or sick horses.
 Pain: Mechanisms and Management in Horses 477

ANTI-INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs: phenylbutazone, flunixin meglu-

mine, firocoxib) produce anti-inflammatory and analgesic effects by inhibiting
cyclooxygenase (COX), the enzyme that metabolizes arachidonic acid to prosta-
glandins.26 Prostaglandins and leukotrienes are key factors in the production of
peripheral sensitization and likely are important in augmenting central sensitization.
NSAIDs are effective analgesics for the treatment of mild to moderate inflamma-
tory pain, emphasizing the importance of prostaglandin production in the initiation
and maintenance of pain. Prostaglandins (PGE2, TXA2) activate prostaglandin (EP)
receptors throughout the body, producing pain, inflammation, and fever. They are
also responsible for the production of a protective gastric barrier to intralumenal
acidity, sustaining normal gastric secretory activity, and maintaining normal gut
motility. Prostaglandins also regulate renal blood flow and maintain normal renal
tubular function. There are 2 types of COX: COX-1 and COX-2. COX-1 is consti-
tutive and helps to maintain normal cell homeostasis. COX-2 is also constitutive in
the CNS, kidney, eye, and reproductive organs but becomes markedly upregu-
lated during inflammation and infection. COX-1 inhibition can produce altered
gastrointestinal motility and gastrointestinal ulceration, renal or liver toxicity, and
has the potential to delay clotting. Both COX-1 or COX-2 inhibition can cause
renal failure, which is more common in very young, old, or dehydrated horses.
Glucocorticoids (triamcinolone, methyprednisolone acetate) act one step earlier
in the metabolic cascade, producing anti-inflammatory effects by inhibiting phos-
pholipase-A2, the enzyme that facilitates the break down of membrane phospho-
lipids to arachadonic acid, subsequently leading to prostaglandin and leukotriene
production.27,28

OPIOIDS

Opioids (morphine, meperidine, methadone, hydromorphone, fentanyl, butorphanol,

buprenorphine) are generally considered to be effective analgesics in horses, although
their range of potential therapeutic effects likely overlaps with the development of side
effects and toxicity. Furthermore, little is known concerning the horse’s potential to
develop tolerance or delayed hyperalgesia to opioid agonists, although their ability
to induce ataxia and hyperexcitability has been known for decades. Opioids are
believed to produce most, if not all of their clinically relevant analgesic effects by inter-
acting with mu (m) and possibly kappa (k) opioid receptors, although solid evidence for
their analgesic efficacy in horses with clinical disease is sparce.25 Opioid agonist-
antagonists (butorphanol) and partial agonists (buprenorphine) produce morphinelike
effects but are less potent than fentanyl, morphine, and methadone. Opioids are most
effective when used as complementary or multimodal therapy in conjunction with
other drugs including NSAIDs, alpha-2 agonists, and ketamine. Opioids require
special licensing and record keeping; predispose to ileus, constipation, and colic;
and can produce excitement (increased locomotor activity), agitation, disorientation,
and ataxia in some horses. Large or repeated dosages of opioids may result in urine
retention. Urine retention is an important postsurgical consideration in some horses.
Fentanyl is a particularly potent, short-acting, m opioid receptor agonist that can be
administered by constant rate infusion. Alternatively, fentanyl transdermal patches
are available but may need to be replaced every 24 to 36 hours in horses to maintain
analgesia. Opioid antagonists (naloxone, nalmafene) are devoid of agonist activity and
are used clinically to antagonize opioid effects.
478 Muir

ALPHA-2 AGONISTS

Alpha-2 agonists (xylazine, detomidine, medetomidine, romifidine) produce stupor

(sedation), ataxia, reluctance to move (muscle relaxation), and pain relief (analgesia)
by differentially activating various alpha-2 receptors in the CNS and peripherally.29
Individual drug effects vary dependent upon their alpha-2 versus alpha-1 selectivity;
stimulation of CNS alpha-1 receptors causes arousal. Alpha-2 agonists are effective
therapy for the acute treatment of superficial wounds, particularly those on the head
and neck and mild to moderately severe visceral pain (colic). Sedation is attributed
to activation of the CNS alpha-2A/D receptors in areas of the brain that are responsible
for awareness, arousal, and vigilance. Clinically, the administration of alpha-2 agonists
generally produces dose-dependent sedation, bradycardia, respiratory depression,
and, rarely, violent behavior. Atropine or glycopyrrolate are effective therapy for brady-
cardia and atrioventricular block. Respiratory stridor, snoring, irregular breathing
patterns, and upper airway obstruction can occur in horses with upper airway
diseases. Alpha-2 agonists promote sweating, urine production, and ileus, resulting
in gas accumulation and the occasional development of colic. Their effects can be
antagonized by the alpha-2 antagonists yohimbine, tolazoline, and atipamazole.

NONTRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE ANALGESIC THERAPIES

New drugs are continuously being developed for the treatment of acute and chronic
pain. Gabapentin, an antiseizure drug that reduces calcium influx through N-type
Ca12 channels thereby reducing cellular excitability, has been administered to horses
to produce complementary analgesic effects, but its efficacy as analgesics is debat-
able.30,31 Tramadol, a mild mu opioid agonist, is purported to produce analgesia when
administered IV or in the epidural space, but it is not effective after oral administration
owing to poor bioavailability and relatively rapid elimination.32 Ketamine is being
promoted as pain therapy for the prevention of central sensitization and hyperalge-
sia.33 Capsaicin and similar analogs overstimulate C-fiber afferents resulting in acute

Box 1
Alternative and complementary pain therapies

Acupuncture
Biofeedback
Chiropractic
Herbalism
Homeopathy
Hydrotherapy
Kinesiology
Massage
Prolotherapy
Neural therapy
Reflexology
Static magnets
Herbal therapy
 Pain: Mechanisms and Management in Horses 479

pain and hyperalgesia; however, repeated or prolonged treatment decreases chronic

pain.34,35 Sarapin, a drug with no known mechanism, has been advocated for nerve
blocks in horses.36 It is suggested that injection into the affected ligaments or tendons
produces localized inflammation, triggering a “wound-healing” cascade, resulting in
new collagen that shrinks as it matures. To date, no studies have confirmed these
claims. Additionally, interventional techniques have been use to guide the administra-
tion of neurolytics (alcohol, phenol) for long-term pain relief in horses. Finally, alterna-
tive therapies, including but not limited to acupuncture, chiropractic, and
neutraceuticals, are used for the treatment of pain in horses as adjuncts to more tradi-
tional regimens (Box 1).24

SUMMARY

Pain is a multidimensional sensory phenomenon that has evolved as a protective

method for maintaining homeostasis and facilitating tissue repair. Both excitatory
and inhibitory physiologic and pathologic mechanisms are involved in its generation
and maintenance. Untreated pain and nervous system changes (plasticity) that occur
during chronic pain make pain much more difficult or impossible to effectively treat.
Therapies directed toward the treatment of pain should be mechanism based and
preventative whenever possible. Prospective, randomized clinical trials conducted
in horses that suffer from naturally occurring pain will help to determine the current
best approaches to effective pain therapy.37

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