The Veterinary Journal 247 (2019) 50–56

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The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

Review

Therapeutic developments in equine pain management

Khursheed R. Mama* , Rachel C. Hector
Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA

A R T I C L E I N F O A B S T R A C T

Many drugs and non-drug modalities are used to manage pain in horses, but evidence regarding efficacy
Keywords: and safety remains limited. This manuscript will first briefly review tried and tested techniques, e.g. the
Analgesia
use of non-steroidal anti-inflammatory drugs, in the management of pain. Newer approaches to
Equine
Horse
administering medications such as oral use of detomidine, which was previously only administered by
Medications injection, will also be discussed. Finally, introductory information on newer therapies, for example
Other modalities acupuncture and chiropractic manipulation, that the veterinarian may consider for the management of
equine pain will be presented.
© 2019 Elsevier Ltd. All rights reserved.

Introduction aspirin, diclofenac, carprofen]) have been a mainstay in the

Despite many advances in management of equine diseases, the
ability to manage pain in both acute and chronic conditions
remains limited. The importance of pain management for the
wellbeing and welfare of the horse is well described (Taylor et al.,
2002), but is fraught with challenges including side effects of
analgesic medications, cost, lack of evidence in regard to efficacy,
and regulatory considerations in countries where horses are
intended for human consumption. Newer drug formulations and
alternative routes of administration along with non-medication
based modalities for treatment of pain now offer more options
when faced with this situation. This manuscript will summarize
these therapeutic options and discuss their application for horses.
Medications
management of acute, surgical, and chronic equine pain. Their use
in horses is common due to ease of obtaining them, relatively low
cost and limited need for record keeping (Goodrich and Nixon,
2006). They minimize the effect of inflammatory mediators in the
periphery and reduce noxious input to the central nervous system.
In addition to the many benefits, gastrointestinal and renal side
effects have posed concern. Gastrointestinal side effects are
reported to be lower with the newer more COX-2-selective NSAIDs
(firocoxib and meloxicam) especially in horses requiring long-term
administration (Doucet et al., 2008; D’Arcy-Moskwa et al., 2012;
Orsini et al., 2012). Meloxicam may similarly have reduced toxicity
in foals due to rapid clearance when compared to other NSAIDs
(Raidal et al., 2013). For animals where toxicity precludes systemic
use, a product that allows topical administration should be
considered (Levine et al., 2009).

Non-steroidal anti-inflammatory drugs (NSAIDs) Local anesthetics

Corticosteroids and NSAIDs are used in horses for managing
inflammation related to chronic disease such as osteoarthritis
(Owens et al., 1996; Hu et al., 2005; Soma et al., 2012).
Corticosteroids are typically administered intra-articularly and
act on the enzyme phospholipase A2 to prevent the development
of inflammatory prostaglandins and leukotrienes (Papich, 2010).
The NSAIDs block cyclooxygenase (COX) reducing the production
of prostaglandins and many drugs including phenylbutazone and
flunixin meglumine (and to a lesser degree, other drugs [e.g.,
* Corresponding author.
E-mail address: kmama@colostate.edu (K.R. Mama).
Local anesthetic drugs (e.g., lidocaine, mepivacaine, bupiva-
caine) have a long history of use in horses and are administered by
many routes (e.g., intraarticular, perineural, epidural) to facilitate
lameness evaluation and sedated (standing) surgical procedures.
The intraarticular use of local anesthetics as a tool for management
of perioperative pain remains controversial due to the potential for
chondrotoxicity in a surgically manipulated joint. In vitro
investigations indicate mepivacaine (vs. lidocaine and bupiva-
caine) was least toxic to cartilage and therefore safest for clinical
use (Park et al., 2011). Conflicting results were noted in a different
study in healthy horses where bupivacaine and lidocaine did not
increase collagen degradation biomarkers (Piat et al., 2012). Given
these discrepancies, it is left to the individual veterinarian to

https://doi.org/10.1016/j.tvjl.2019.02.010
1090-0233/© 2019 Elsevier Ltd. All rights reserved.
 K.R. Mama, R.C. Hector / The Veterinary Journal 247 (2019) 50–56
determine the risks and benefits to the horses in their care.
Perineural administration and intravenous regional limb perfusion
might provide analgesic benefits without concerns for these side
effects, but residual proprioceptive or motor deficits depending on
the technique and local anesthetic may have an impact on the
horse’s recovery from anesthesia. Due to reports of systemic
toxicity following intravenous bupivacaine in other species,
lidocaine is recommended for intravenous regional limb perfusion
in case of tourniquet failure; mepivacaine may also be suitable
(Colbath et al., 2016).
The use of intravenous lidocaine as a tool for management of
pain has gained popularity upon discovery of its prokinetic actions.
Albeit the mechanism of this effect is not fully elucidated it is
thought to be mediated through free radical scavenging, anti-
inflammatory and analgesic actions (Harkins et al., 1998; Brianceau
et al., 2002; Robertson et al., 2005; Guschlbauer et al., 2011).
Infusion during anesthesia also allows one to reduce the dose of
the inhaled agent and enhance actions of other analgesic drugs
(Doherty and Frazier, 1998; Rezende et al., 2011). This has the
potential benefit of cost saving, but there appears to be no benefit
to cardiovascular function and in some instances, a poorer quality
of recovery from general anesthesia may be observed (Valverde
et al., 2005; Wagner et al., 2011; Schuhbeck et al., 2012).
Transdermal administration of local anesthetic has been sug-
gested, but does not provide sufficient uptake to see systemic
effects; it may however have local benefit over a site of injury
(Sobbeler and Kastner, 2018).
A sustained release liposomal formulation of bupivacaine is
approved for peri-articular use with stifle surgery in dogs, and has
gained (off label) popularity for post-operative pain management
with other procedures (Lascelles et al., 2016). A similar product is
used for post-surgical analgesia in people and warrants study for
use in horses (Knych et al., 2018a).
Alpha-2 adrenoreceptor agonists
Drugs in this class (e.g., xylazine, detomidine, romifidine, dex/
medetomidine) have a long history of use in horses and cause
analgesia, sedation, and muscle relaxation. They decrease release
of excitatory neurotransmitters in the brain and spinal cord and
interfere with sensory processing and transmission (England and
Clarke, 1996). Hence, they allow diagnostic and interventional
procedures to be performed in a manner that is safe for both the
veterinarian and the horse. Behavioral and possibly analgesic
effects may be improved when α2-adrenoceptor agonists are
administered with opioids (e.g., butorphanol) (Robertson and
Muir, 1983; Sellon et al., 2004). However, for the treatment of
colic pain these drugs may also mask signs of clinical deteriora-
tion, especially if higher doses or drugs with longer half-lives are
administered (e.g., romifidine, detomidine) (Lowe and Hilfiger,
1984; Lowe and Hilfiger 1986; Jochle et al., 1989). Further, these
effects are not independent of each other such that one might
take advantage of the analgesia without sedation or muscle
relaxation.
Adverse effects including peripheral vasoconstriction and
subsequent baroreceptor-mediated reflex bradycardia and bra-
dyarrhythmias (e.g., second degree atrioventricular block) with a
profound reduction in cardiac output are also associated with
alpha-2 adrenoceptor agonists (Muir et al., 1979a; Wagner et al.,
1991; Still et al., 1996; Bettschart-Wolfensberger et al., 2005).
Subsequent vasodilation accompanied by hypotension may also be
observed. A peripheral alpha-2 antagonist (Vatinoxan) is being
studied as a way to alleviate these cardiovascular side effects
(Vainionpää et al., 2013; Pakkanen et al., 2015; Tapio et al., 2018).
While this is unlikely to uncouple sedation from analgesia, it has
the potential to be extremely beneficial when using the sedative
51
and analgesic properties of alpha-2 adrenoceptor agonists to
reduce inhaled anesthetic dose (Mama et al., 2015a; Pakkanen
et al., 2015; De Vries et al., 2016).
Regional use of α2-adrenoceptor agonists is another means to
provide analgesia with reduced systemic effects. For example,
caudal epidural administration provides analgesia for surgical
procedures (Goodrich et al., 2002). Lipophilic drugs (e.g.,
detomidine) may demonstrate systemic effects as they are
absorbed from the epidural space, whereas xylazine tends to have
local anesthetic effects (Skarda and Muir, 1994, 1996). Xylazine can
therefore cause a horse to become recumbent if drug migrates to
lumbosacral space. Intraarticular use of α2-adrenoceptor agonists
similarly may provide analgesia; the potential for chondrotoxic
effects is under investigation, with early reports indicating the
potential for chondrotoxicity with some but not all drugs in this
class (Ullmer et al., 2013; Di Salvo et al., 2014; Mama et al., 2015b).
Perineural co-administration with local anesthetics increases
analgesia duration as compared to local anesthetics alone
(Abdallah and Brull, 2013).
Recently the availability of a gel preparation of detomidine for
transmucosal administration has provided another route for
administration of this analgesic and sedative alpha-2 agent. When
given by this route it reportedly facilitated completion of ‘non-
painful’ procedures (e.g., shoeing, grooming etc.). The onset of
sedation averaged 36 min and sedation lasted approximately 2 h
after a dose of 40 mg/kg. The efficacy of this route of administration
for painful procedures needs further evaluation.
Other dose dependent side effects of α2-adrenoceptor
agonists including changes in respiration, relaxation of pharyn-
geal muscles, hyperglycemia, increased urine production, and
decreases in gastrointestinal motility should be considered
when using these drugs as analgesics (Ducharme et al., 1991;
Valdes-Vazquez et al., 1993; Lester et al., 1998; Merritt et al.,
1998; Sutton et al., 2002; Nuñez et al., 2004; Ringer et al., 2013).
Complete antagonists including yohimbine and atipamezole
will reverse central (e.g., sedation, analgesia) and peripheral
(e.g., hyper/hypotension, bradycardia) effects but may them-
selves be associated with other complications (Hubbell and
Muir, 2006).
Opioids
Many opioids including pure m-agonists (e.g., morphine,
methadone, fentanyl, alfentanil), partial m-agonists (e.g.,
buprenorphine), and k-agonist/m-antagonists (e.g., butorpha-
nol, nalbuphine) have been used in horses. When given on their
own intravenously, they may cause excitement, but have a
beneficial role in modifying behavior when used in conjunction
with sedative or tranquilizing drugs in the horse (Muir et al.,
1979b; Combie et al., 1981; Robertson and Muir, 1983; Hellyer
et al., 2003). Their role as analgesics is less clear-cut albeit some
studies suggest that at low doses, painful horses appear calmer
and have an improved recovery from anesthesia (Taylor, 1986;
Clark et al., 2008). For example, where traditionally m-agonist
opioids are considered to provide better analgesia, butorphanol
is reported to be equally as or more effective (with potentially
fewer adverse effects) in the treatment of gastrointestinal pain
in horses (Combie et al., 1983; Kalpravidh et al., 1984; Muir and
Robertson, 1985; Sellon et al., 2004). Similarly, intravenous
fentanyl appears to be a relatively ineffective analgesic with
undesirable behavioral effects in adult horses (Sanchez et al.,
2007; Ohta et al., 2010), but is sedating in foals (Knych et al.,
2015). While age clearly has an effect, differences in efficacy and
side effect profiles between horses may also be due to genetic
polymorphisms, which are only now being investigated (Wet-
more et al., 2016).
52 K.R. Mama, R.C. Hector / The Veterinary Journal 247 (2019) 50–56
The interested reader is referred to detailed reviews of benefits
and side effects of opioids in horses (Bennett and Steffey, 2002;
Clutton 2010; Hector and Mama, 2017) to determine drug and dose
for systemic administration in a given patient. Interestingly,
alternative routes of administration (e.g., intraarticular, perineural,
epidural) show efficacy with reduced side effects. For example
epidural morphine provides useful and prolonged analgesia for a
variety of surgical procedures (Goodrich et al., 2002; Van
Hoogmoed and Galuppo, 2005; Martin-Flores et al., 2014), and
intraarticular morphine provides lasting analgesic actions as
evidenced by a reduction in lameness (Lindegaard et al., 2010a,
b; van Loon et al., 2010).
N-Methyl-D-aspartate (NMDA) receptor antagonists
NMDA receptor activation is key to development of hyper-
algesia and central sensitization (De Kock and Lavand’homme,
2007; Mion and Villevieille, 2013). Ketamine, which is commonly
used in equine anesthesia, is an NMDA receptor antagonist and has
been used in an attempt to mitigate this in awake and anesthetized
horses with largely anecdotal success. Some studies report efficacy
when ketamine is used as an adjunct for the management of
laminitic pain (Guedes et al., 2012). As with people and small
animals, low dose infusions do not seem to cause behavioral
changes including delirium or hallucinations as seen with higher
doses (Wagner et al., 2002; Fielding et al., 2006; Carstensen and
Møller, 2010; Mion and Villevieille, 2013).
Magnesium is both an NMDA receptor and calcium channel
blocker and likely both mechanisms play a role in its analgesic
actions (Tramer et al., 1996). These have been studied in people
where magnesium reduces postoperative pain, decreases opioid
requirements and delays the development of tolerance after a
variety of surgical procedures (Albrecht et al., 2013; Guo et al.,
2015). Hence, its investigation in management of equine pain has
merit.
Other medications
Butylscopolamine is a short acting anticholinergic that has been
used to increase heart rate in the horse. Because of its short
duration of effect and actions as a spasmolytic agent, it is also used
to facilitate rectal palpation and may be used to treat spasmodic
colic (Roelvink et al., 1991; Boatwright et al., 1996; Sanchez et al.,
2008).
Dipyrone (metamizole) is an anti-inflammatory and anti-
pyretic drug licensed for use in several species, including horses.
It has been used successfully to treat mild visceral pain in a clinical
setting (Kohn and Muir, 1988) and in an experimental model when
combined with butylscopolamine (Roelvink et al., 1991; Abutar-
bush et al., 2013). It weakly inhibits COX-1 and COX-2, but it
strongly inhibits COX isoenzyme 3 actions. COX-3 is a splice variant
of COX-1 that is thought to be the main therapeutic target of
acetaminophen (paracetamol) (Chandrasekharan et al., 2002).
Acetaminophen has a high oral bioavailability and has been used in
a limited number of cases as a successful analgesic adjunct in
horses (West et al., 2011; Tavanaeimanesh et al., 2018). Expression
of COX-3 has been documented in several species, but definitive
data in horses are lacking. However, the efficacy of dipyrone and
acetaminophen warrants further study on COX-3 and its inhibition
in horses.
The bisphosphonates, tiludronate and clodronate are given
intravenously or intramuscularly (drug dependent) and inhibit
osteoclast and macrophage actions to limit bone resorption
(Catterall and Cawston 2003; Cremers and Papapoulos, 2011).
Improvement in lameness from chronic lameness caused by
arthritis (hock), vertebral and navicular disease has been
demonstrated (Kamm et al., 2008; Gough et al., 2010). Potential
side effects include colic and renal damage which should be
considered prior to treatment.
Tramadol, a synthetic weak m-opioid receptor agonist and
serotonin and norepinephrine reuptake inhibitor is available in
injectable and oral form in many countries (Grond and Sablotzki,
2004; Vettorato et al., 2010). It has been studied in horses and
demonstrates only limited efficacy in reducing pain associated
with equine laminitis when given systemically (Guedes et al.,
2012; Guedes et al., 2016). Reports of excitement in absence of
efficacy were reported from other investigative efforts (Dhanjal
et al., 2009; Milaré et al., 2013; Carregaro et al., 2014).
Gabapentin mediates its effect through the α2d-subunit on
voltage-gated calcium channels. Gabapentin is frequently used to
treat neuropathic pain in people (Finnerup et al., 2015). However,
and perhaps due it its low oral bioavailability in horses (Terry
et al., 2012), it is not efficacious in reducing the degree of chronic
lameness (Caldwell et al., 2015). There is however a single case
where efficacy in treating neuropathic pain was reported with
oral administration (Davis et al., 2007). Intravenous administra-
tion does result in mild sedation suggesting behavioral modula-
tion when given by that route (Terry et al., 2012). At this stage its
role as an analgesic for chronic or neuropathic pain remains
unclear and warrants further investigation. Pregabalin, which
works by the same mechanism, has been used extensively in
human medicine. However, in horses only one pharmacokinetic
study has been published and no efficacy data are available
(Mullen et al., 2013).
A soluble Epoxide Hydrolase inhibitor (t-TUCB) has been
recently evaluated for its efficacy and shows promise as part of a
multi-modal approach to pain management for laminitis in
horses (Guedes et al., 2013, 2017). This compound works by
inhibiting transformation of fatty acids into epoxides
which are thought to be increased in laminitis. While this is
currently only experimental, these early promising results are
encouraging.
Grapiprant (Galliprant), a prostaglandin receptor antagonist,
similarly deserves additional study in horses. It is well tolerated
and has been used successfully in the long-term treatment
osteoarthritis pain in dogs. Because its mechanism of action does
not involve COX inhibition, this drug should theoretically provide a
lower risk for side effects associated with normal housekeeping
functions of COX enzymes while still providing effective analgesia.
Therapeutic dose and efficacy have not been investigated in horses,
though the drug has been shown to be well tolerated when given
orally at 2 mg/kg (Knych et al., 2018b).
Although not yet studied in horses, antibodies against Nerve
Growth Factor (anti-NGF antibodies) are an efficacious treatment
for several experimental pain models in rodents and naturally
occurring degenerative joint disease pain in dogs and cats. Side
effects in dogs and cats were not seen with their use, but clinical
and pre-clinical models in human medicine have shown that anti-
NGF antibodies can exacerbate joint damage (e.g., cartilage
degeneration), especially when used in conjunction with NSAIDs
(Miller et al., 2017). Whether these drugs represent a useful
option for pain management in horses should be a topic of future
study.
Other modalities
Autologous treatment with Interleukin-1 receptor antagonist
protein (IRAP) in horses with osteoarthritis improves lameness
scores in horses over placebo (Frisbie et al., 2007). This anti-
inflammatory cytokine is obtained by incubating whole blood with
beads that enhance IRAP production and then separating out the
serum to inject intraarticularly (Meijer et al., 2003).
 K.R. Mama, R.C. Hector / The Veterinary Journal 247 (2019) 50–56
In addition to facilitating surgical anesthesia and analgesia,
epidurals by needle or catheter placement provide a viable non-
systemic route to treat animals with chronic hind limb or
genitourinary pain. Lumbosacral administration is possible in
foals whereas the sacrococcygeal or intercoccygeal location is
preferred in adults. Many of the aforementioned drugs and drug
classes including opioids, alpha-2 adrenoceptor agonists, local
anesthetics, and to a lesser degree ketamine and tramadol have
been administered to horses via this route. Knowledge of the
beneficial (e.g., analgesia, anesthesia) and side effects (e.g., motor
blockade, pruritus) of each drug is necessary and may be found in
other reviews (Robinson and Natalini, 2002; Vigani and Garcia-
Pereira, 2014).
Cold or low-level lasers are anecdotally reported to have
beneficial effects for musculoskeletal pain without causing
tissue trauma. Possible mechanisms of action include modula-
tion of local inflammatory mediators and their distribution
(Bjordal et al., 2006). Scientific evidence while limited in horses
(Martin and Klide, 1987) is emerging in human medicine in
reference to wound healing (Hagiwara et al., 2007; Smoot et al.,
2015; Ginani et al., 2015). Variability in the type of lasers
restricts direct comparisons, but early positive aspects support
additional study.
Extracorporeal shock wave therapy is used to treat a variety of
musculoskeletal injuries in horses (Waguespack et al., 2011). The
basic principle is that focused, pulsed, high-energy waves when
applied to an injured area lead to neovascularization and tissue
remodeling (Imboden et al., 2009; Waguespack et al., 2011). In
some studies, shock wave therapy produced acute local analgesia
for 48–72 h after treatment (McClure et al., 2005; Dahlberg et al.,
2006). In other studies targeting specific lesions, shock wave
therapy did not reduce lameness acutely post-treatment (Brown
et al., 2005).
Acupuncture and electro-acupuncture provide analgesia by the
stimulation of specific (acupuncture) points (Takeshige et al., 1993)
that result in modulation of nociceptive input at the level of the
dorsal horn of the spinal cord (Tobaldini et al., 2014). Acupuncture
is an appealing modality because of its relative safety and the lack
of measurable systemic drug may facilitate its use in performance
horses during competition. However its efficacy in clinical studies
has been inconsistent with one study suggesting a possible clinical
improvement in chronic lameness (Steiss et al., 1989) and another
stating a failure to consistently affect pain in horses with palmar
heel pain (Robinson and Manning, 2015). Further investigation and
clinical studies are needed to better define the role of acupuncture
in treatment of equine pain.
Chiropractic manipulation relies on manual “high-velocity,
low-amplitude” thrusts to try restore normal joint motion and
improve tissue function of the equine spine (Gomez Alvarez et al.,
2008). A change in kinematics of horses with back pain and an
increase mechanical nociceptive thresholds in healthy horses has
been demonstrated (Gomez Alvarez et al., 2008; Sullivan et al.,
2008; Langstone et al., 2015). The significance of these findings
with respect to acute or chronic pain control is unknown.
Case examples
Caseexamples can be found in Appendix A: Supplementary
material.
Conclusions
As with management of pain in any species, there is still much
work to be done. However, there are several promising analgesic
drugs in development, including but not limited to prostaglandin
receptor antagonists, soluble epoxide hydrolase inhibitors, and
53
anti-Nerve Growth Factor antibodies. In addition, scientific data
continues to emerge validating the use of different complementary
analgesic techniques (e.g., chiropractic work, acupuncture) in
horses. As no single medication or modality will provide relief in all
circumstances, it is up to the veterinarian to seek and apply
knowledge of both established and evolving options appropriate to
the types of horses being treated.
Conflict of interest
None of the authors of this paper has a financial or personal
relationship with other people or organisations that could
inappropriately influence or bias the content of the paper.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tvjl.2019.02.010.
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