Treatment of Visceral Pain in Horses

15 Pages·2010·0.12 MB·English

Treatment of Visceral
Pain in Horses
Sheilah A. Robertson, BVMS,PhD,MRCVSa,*,
L. Chris Sanchez, DVM,PhDb
KEYWORDS
(cid:1)Colic (cid:1)Visceralpain (cid:1) Analgesia (cid:1)Opioids
(cid:1)Nonsteroidalanti-inflammatoryagents (cid:1)Lidocaine
Visceralpaincanbedefinedaspainoriginatinginanyinternalorganandisoftensub-
dividedtoincludetheorganscontainedwithineachmajorbodycavity,whicharethe
thorax,abdomen,andpelvis(Table1).Usingthiscategorization,painarisingfromthe
bladder would be a form of pelvic visceral pain. The term “colic” should be clearly
defined because it is often misused. “Colic” is not a diagnosis; it is a clinical sign
resultingfromvisceralpainwithintheabdomen.Mairandcolleagues1statethatthere
are approximately 100 conditions that result in abdominal pain in thehorse, but the
most common sources are the small and large intestine, hence the term “colic”
mosttypicallyreferstogastrointestinalpain.Visceralpainmaybeacute,chronic,or
recurrent in fashion, and some individuals may experience a combination of these
manifestations. The cause of visceral pain may be organic (identifiable structural
changeinanorgan)ordysfunctional(anabnormalchangeinorganfunctionwithout
identifiable pathologic changes).2 Irritable bowel syndrome (IBS) in humans is an
example of a dysfunctional disease that may affect up to 25% of the population2;
whethersimilarsyndromesexistinhorsesislessclear,butisconsideredplausible.3,4
Ischemia,inflammation,musclecontraction(spasm)ordistensionmaybetheprimary
underlyingcauseofpain,andidentifyingwhichoftheseisresponsibleforthepatient’s
discomfort is important for directing therapy. Considering the number of internal
organs,itisnotsurprisingthatvisceralpainiscommoninhorses;however,itpresents
achallengetotheclinicianbecauseitcanbedifficulttomakeadefinitivediagnosis.
Ideallytreatmentisaimedataddressingtheunderlyingpathology,butisoftensymp-
tomatic with a primary focus on relieving pain; the latter is the focus of this article.
Although treatment options for visceral pain have expanded in recent years, they
remain suboptimal. In horses, the small and large intestines are the most prevalent
a SectionofAnesthesiaandPainManagement,DepartmentofLargeAnimalClinicalSciences,
College of Veterinary Medicine, University of Florida, PO Box 100136, Gainesville, FL
32610-0136,USA
b DepartmentofLargeAnimalClinicalSciences,CollegeofVeterinaryMedicine,Universityof
Florida,POBox100136,Gainesville,FL32610-0136,USA
*Correspondingauthor.
E-mailaddress:[email protected]
VetClinEquine26(2010)603–617
doi:10.1016/j.cveq.2010.08.002 vetequine.theclinics.com
0749-0739/10/$–seefrontmatter(cid:1)2010ElsevierInc.Allrightsreserved.
604 Robertson&ChrisSanchez
Table1
Originandexamplesofvisceralpaininthehorse
Origin Example:Acute Example:Chronic
Thorax (cid:1) Pleuropneumonia (cid:1) Pleuralabscessation
(cid:1) Lung (cid:1) Choke (cid:1) Neoplasia
(cid:1) Pleura (cid:1) Trauma (cid:1) Pericarditis
(cid:1) Esophagus (cid:1) Pericarditis
(cid:1) Heart
Abdomen (cid:1) Mostcausesofacutecolic (cid:1) Inflammatoryboweldiseases
(cid:1) Stomach (cid:1) Pancreatitis (cid:1) Enterolithiasis
(cid:1) Smallintestine (cid:1) Nephrolithiasis (cid:1) Chronicdiarrhea
(cid:1) Largeintestine (cid:1) Uterinearteryhematoma,rupture (cid:1) Nephrolithiasis
Cecum (cid:1) Metritis (cid:1) Neoplasia
Largecolon (cid:1) Cholelithiasis (cid:1) Cholelithiasis
Smallcolon (cid:1) Uterinetorsion
(cid:1) Spleen
(cid:1) Liver
(cid:1) Pancreas
(cid:1) Kidneys
(cid:1) Ureters
(cid:1) Ovaries
(cid:1) Uterus
Pelvis (cid:1) Cystitis (cid:1) Cystitis
(cid:1) Bladder (cid:1) Urolithiasis (cid:1) Urolithiasis
(cid:1) Testicles (cid:1) Testiculartorsion (cid:1) Neoplasia
(cid:1) Rectum (cid:1) Rectaltear
(cid:1) Anus (cid:1) Foalingtrauma
(cid:1) Vagina (cid:1) Necroticvaginitis
sourceofvisceralpain,andthistypeofpainhasreceivedthemostresearchandclin-
icalattention.Thepleura,kidneys,andstomachare,however,wellrecognizedsour-
cesofpainandresultantsufferinginequinepatients.Horsesofallages,breeds,and
sexmaypresentwithvisceralpain,andexamplesaregiveninTable1.
INCIDENCEANDIMPACTOFVISCERALPAIN
Gastrointestinal and musculoskeletal diseases are two of the most clinically and
economically important medical problems facing horses and their owners. In the
National Animal Health Monitoring Systems (NAHMS) equine study conducted by
the United States Department of Agriculture (USDA) in 2005, “colic” affected 2.4%
of horses on a yearly basis (http://www.aphis.usda.gov/vs/ceah/ncahs/nahms/
equine/equine98/economics.PDF). The economic impact of this was estimated to
be $115 million per year in the equivalent study published in 1998 (http://www.
aphis.usda.gov/vs/ceah/ncahs/nahms/equine/equine05/equine05reportpart1.pdf).
Thesefiguresrepresentoverallcoststotheindustryduetolossofuse,hospitalization,
veterinarycare,andmortality.
VISCERALPAINASSESSMENT
When assessing pain in animals and nonverbal human beings, one must remember
that the assessment is always based on observations and interpretation of what is
seen.Thus,whenaddressingananimal’sstatus,onemustbeawareofinherentdiffer-
encesbasedonspecies,age,sex,genetics,environment,andsourceanddurationof
TreatmentofVisceralPaininHorses 605
thepain.Mostpublishedstudiesonvisceralpaininhorses,whethertheyareresearch
orclinicallybased,areconfinedtoabdominalcausesandmorespecificallytheintes-
tinaltract.
ResearchModels
For research models of pain in animals, Gebhart and Ness5 proposed the following
necessarycriteria:thesubjectmustbeconscious,theexperimentalstimulusmimics
anaturalstimulus,thestimulusisminimallyinvasiveandethicallyacceptable,thesti-
mulus is controllable, reproducible, and quantifiable, and the responses are reliable
and quantifiable. Most models of visceral pain in horses and other species involve
acute distension of a portion of the gastrointestinal tract. Because many naturally
occurringconditionscausingabdominalvisceralpaininvolvedistension,suchmodels
have provided clinically meaningful information regarding analgesic medications for
use in the horse. These models have involved cecal,6,7 duodenal,8–10 and colo-
rectal11,12 distension. The primary advantage of the cecal and duodenal distension
modelsisthatboththestimulus(distension)andassociatedbehaviors(pawing,flank
watching,andsoforth)mimictheclinicalsyndromeof“colic.”Withcolorectaldisten-
sion,theassociatedresponseisnotasclearandresultsmaybemorecloselyassoci-
ated with the “urge to defecate” response in humans, and therefore not truly
nociceptive in nature.11 The major disadvantage of the cecal and duodenal models
istheneedforvisceralcannulation,whichisnotnecessaryforcolorectaldistension;
however, as is discussed later, the response to analgesic agents is not uniform
throughouttheintestinaltract.
PainAssessmentTools
To claim that one has treated pain effectively implies that one can recognize it and
measure or quantify it. Objective measures such as vital signs and plasma cortisol
concentration circumvent the subjective nature of assessment; however, vital signs
thatmightbepredictedtobeusefulareaffectednotonlybypainbutavarietyofother
factors including hydration status, perfusion, sepsis and/or endotoxemia, fear,
anxiety, and sedative or analgesic drugs. Pain-scoring tools must therefore be
primarily based on behavioral indicators,13 in combination with the judicious use of
vitalsignssuchasheartrate.14
To be useful, a pain-scoring system should meet the following criteria: it should
include clearly defined assessment criteria, be suitable for all observers, be simple
andquicktouse,besensitive,haveidentifiedstrengthsandweaknesses,andbevali-
dated.Possibledeficienciesincludebiasandinter-andintraobservervariability.Alack
ofagreementbetweenobserversisoneoftheflawsofsimplescoringsystemssuchas
thevisualanalogscale(VAS).Whencriticallyassessingscoringsystems,theinvesti-
gatorshouldcontrolforsignalment(age,breed,sex),observer(veterinarian,student,
owner/trainer), type and source of pain, and other effects (eg, food withdrawal and
anesthesia). In a review of behavioral assessments of pain in equidae, Ashley and
colleagues13pointoutthatalthoughsomenonspecific“painbehaviors”arereported,
specificbehaviorscanbeidentifiedandthesedifferdependingonthecauseofpain;
forexample,abdominalversuslimbandhoofordentalpain.Vocalization(groaning),
rolling, kicking at the abdomen, flank watching, and stretching are overt behaviors
associatedwithabdominalpain13;however,otherindicatorscanbeeasilyoverlooked.
Pritchett and colleagues14 recorded physiologic and behavioral variables in horses
thatunderwentexploratorylaparotomyforavarietyofsurgicallycorrectableintestinal
lesions, and compared these with control horses (no anesthesia, no surgery) and
horsesanesthetizedfornonpainfulprocedures.Horseswerevideotapedanddetailed
606 Robertson&ChrisSanchez
“time budgets” were calculated. Observers used a numerical rating scale (NRS) of
behavior,whichincludedheadposition,earposition,locationinthestall,activity,lift-
ingofthefeet,andresponsetofood.Aftersurgery,horsesspentsignificantperiodsof
time doing nothing (resting) and had higher NRS scores compared with the other 2
groups,butdisplayedveryfewovertpainbehaviorssuchasrolling,kicking,andpaw-
ing.Inclinicalpracticetheseanimalswilloftenbeoverlookedandnotgivenanalge-
sics. Thus, this or similar scoring systems can be used to guide pain management
in horses with abdominal pain, with the aim being to restore normal behaviors and
activitylevels(Table2)andnotsimplytoavoidovertpainbehaviors.
TREATMENTOPTIONS
ApproachestoTreatmentofVisceralPain
When identifiable, treatment is focused on correcting the underlying pathology;
however,inmanycasesadefinitivediagnosismaynotbemadeormaytaketimeto
reach.Ithasbeenarguedthatpainmanagementshouldbewithhelduntilthecause
ofthepainhasbeenidentifiedbecausemaskingitwillconfoundanyongoingdiagnostic
tests.However,thisapproachmustbeweighedagainstthedangersthatpainfulhorses
posetopersonnelworkingonthem,theimpositionofadditional“proceduralpain,”for
example,abdominocentesisandthoracocentesis,and,clearly,thewelfareofthehorse.
Table2
Numericalratingscaleforscoringabdominalpaininhorses
BehaviorCategory 1 2 3 4
Overtpain None Occasional Continuous
behaviorsa,b
Headpositionb Abovewithers Atwithers Belowwithers
Earpositionb Forward, Slightlyback,
frequently infrequent
moving movement
Locationinstallb Attheexit, Inthecenter, Inthecenter, Atthemiddle
watching watchingexit watching orback,facing
walls awayfromexit
Spontaneous Movingfreely Occasionalsteps Nomovement
locomotionb
Responsetodoor Movestoward Looksatdoor Noresponse
openingc door
Responseto Movestoward Looksatperson, Movesaway Doesnotmove,
approachc theperson,with withears fromthe earsback
earsforward forward person
Footlifting Liftsfeeteasily Canliftfeetif Unwillingto
ifasked encouraged liftfeet
Responseto Reachesforfood Looksatfood Nointerest
offeredfoodc infood
a Overtpainbehaviorsincludepawing,sweating,flankwatching,flehmen,rolling,lyingdown
andstandinguprepeatedly,groaning.
b Combineallthesescorestoobtainaposturescore.
c Combinethesescorestoobtainasocializationscore.
DatafromPritchettLC,UlibarriC,RobertsonMC,etal.Identificationofpotentialphysiologic
andbehavioralindicatorsofpost-operativepaininhorsesafterexploratoryceliotomyforcolic.
ApplAnimBehavSci2003;80:31–43.
TreatmentofVisceralPaininHorses 607
Painitselfcanresultinileus,whichhasmanynegativeconsequences(reflux,fluidand
electrolytelosses)andaddstotheoverallpainburdenofthepatient.Inaddition,itis
nowwellunderstoodthatthelongerpaingoesuntreated,thegreatertheriskoflong-
term sensitization and hyperalgesia that result from an unmitigated afferent barrage
of noxious stimuli into the central nervous system.15 Thus, pain control emerges as
thesinglemostimportanttherapeuticfactorwhentreatingvisceralpaininhorses.
Surgery
Whereasmanypainfulvisceralconditionscanbetreatedmedically,conditionssuchas
strangulatingandnonstrangulatingbowelobstructionsandremovalofrenal,cystic,or
ureteral calculi require surgical intervention, and pleuritis typically requires thoraco-
centesisataminimum,possiblywiththoracoscopyorribresection.Ifsurgicaltherapy
isnotapracticalorfinancialoptionforagivenindividualwithsuchacondition,eutha-
nasiamayrepresentthemostpracticalandhumanemethodofanalgesia.Ifsurgical
therapyiselected,analgesiaisanimportantcomponentofperioperativemanagement.
SYSTEMICPHARMACOLOGICTHERAPY
Therearealimitednumberofanalgesicsavailabletotreatseverepaininhorses.At
present, the most commonly used analgesic medications include the a -adrenergic
2
agonists, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Because
many of these do not always produce the desired results or are associated with
adverse effects, other more novel analgesic drugs are currently under investigation
foruseinthehorse,andarealsodiscussedhere.Inthehorse,mostavailableinforma-
tionpertainingtovisceralpainisrestrictedtothegastrointestinaltract.However,the
drugsdiscussedinthisarticlearelikelytohavesimilareffectsonvisceralpainarising
fromotherorgans.Thecommonlyuseddrugsandtheirsuggesteddosesareoutlined
inTable3.
a -AdrenergicDrugs
2
Majordisadvantagesofallthea -adrenergicagonistsforprolongedanalgesictherapy
2
includetheimmediateandprofounddecreaseingastrointestinalmotilitythatoccurs
aftertheiradministrationandtherelativelyshortdurationofanalgesiaprovided.16–19
Fewer undesirable side effects are seen when butorphanol is administered as
aconstantrateinfusioninsteadofboluses;whetherthisapproachwouldbebeneficial
when using a -adrenergic drugs to treat horses with abdominal pain has not been
2
thoroughlyexplored.
Specifica -adrenergicdrugs
2
Xylazine Xylazineisverycommonlyusedtoprovidesedationandanalgesiaforboth
diagnostic procedures and treatment of visceral pain in horses. Xylazine provides
excellentvisceralanalgesiaofshortduration;upto90minutesinsomemodels.7,20,21
Adverseeffectsassociatedwithitsadministrationincludetheaforementionednega-
tiveeffectsonmotilitycombinedwithhypertensionandbradycardiafollowedbyhypo-
tension.17,22–24Duetotherelativelyshortdurationofitseffects,xylazine,eitheralone
orinconjunctionwithbutorphanol,isanexcellentchoiceforsedationandanalgesia
during the initial evaluation of horses presenting for colic. Dosagesfrom 150 to 250
mgforanaverage450to550kgadulthorsetypicallyfacilitatepassageofanasogas-
trictubeandrectalpalpation.
Detomidine Detomidine is commonly used in horses to provide sedation for diag-
nosticproceduresandtoalleviateabdominalpain.25Itsuseresultsinacharacteristic
6
0
8
R
o
b
Table3 er
t
Commonlyusedvisceralanalgesicmedications so
n
ClassofDrug Drug Dosage(mg/kg) Route DosingInterval(h) Comments &
NSAIDs Flunixin 0.25–1.1 IV,PO 8–24 Avoidmax.dose>2(cid:3)/d Ch
r
Ketoprofen 2.2 IV 24 is
Phenylbutazone 2.2–4.4 IV,PO 12–24 Avoidextravascular S
a
injection n
c
a2-Agonists Xylazine 0.2–1.1 IV,IM prn Sedationtypicallyoutlasts hez
analgesia
Detomidine 0.005–0.04 IV,IM prn Sedationtypicallyoutlasts
analgesia
Medetomidine 0.004–0.01 IV prn
Opioids Butorphanolbolus 0.02–0.1 IV,IM 3–4 Canincreaselocomotionif
usedassoleagentin
adults
Butorphanolinfusion 18mg/kgbolusover15min IV CRI Typicallynotusedlonger
then13–23mg/kg/h than12–24h
Morphine 0.12–0.66 IV Combinewitha -agonist
2
Other Lidocaine(2%,20mg/mL) 1.3mg/kgbolusover10–15 IV CRI Mainadverseeffectsare
minthen3mg/kg/h neurologicand
(75mL/hfor500kg) associatedwithrapid
administrationor
accumulation
N-Butylscopolammonium 0.3mg/kg SlowIV Once Causestransient
bromide tachycardia
Ketamine 0.4–1.2mg/kg/h IV CRI Hyperexcitabilitypossible
athigherdosages
Pleasenotethatthesearesuggesteddosagesandroutesonly.Thedose,route,andfrequencyofadministrationshouldbeconsideredindividuallyforeachcase.
Specialconsiderationshouldbegiventothecurrentmedicalstatus,organfunction,andconcurrentlyadministeredmedications.
Abbreviations:CRI,continuousrateinfusion;IM,intramuscular;IV,intravenous;PO,bymouth;prn,“asneeded.”
TreatmentofVisceralPaininHorses 609
dose-dependentheaddrop,ataxia,anddecreaseinheartrate,respiratoryrate,and
gastrointestinalmotility.26,27Inanexperimentalmodelofcecaldistension,detomidine
was effective in alleviating the associated pain.28 In a duodenal distension model,
a marked and immediate decrease in duodenal contractions occurred after 10 and
20 mg/kg (intravenously), but analgesia was both dose and location dependent; 10
mg/kg provided no visceral antinociception whereas 20 mg/kg provided 15 minutes
ofantinociception.Theeffectsoncolorectaldistensionweredifferent,with10mg/kg
and 20 mg/kg increasing colorectal distension threshold for 15 and 165 minutes,
respectively.16 Elfenbein and colleagues16 measured the plasma concentration that
correlated with visceral analgesia, which provides the pharmacokinetic data neces-
sarytodesigninfusionratesforfuturestudy.Theseinvestigatorsalsodemonstrated
that the plasma concentration required for analgesia was in the order of 10 times
thatrequiredforsedation,whichemphasizesthatsedationdoesnotequalanalgesia,
especiallywiththea -agonists.
2
Medetomidine/dexmedetomidine Medetomidine and dexmedetomidine are not
licensedforuseinthehorseandareconsiderablymoreexpensivethanxylazine,deto-
midine,andromifidine.Medetomidineinfusionshavebeenusedsuccessfullyaspart
of a balanced anesthetic protocol.29 Medetomidine combined with morphine (both
givenasinfusions)providedsuitableconditionsforstandinglaparoscopyinhorses30
and is discussed later in the section Multimodal Approaches to Therapy. Commer-
cially,medetomidinehasnowbeenreplacedbydexmedetomidine,andtotheauthors’
knowledgethisdrughasnotbeenevaluatedinhorsesforitsvisceralanalgesicprop-
ertiesinaresearchorclinicalsetting.
NonsteroidalAnti-InflammatoryDrugs
NSAIDs have well-documented visceral analgesic and anti-inflammatory properties,
but adverse effects including gastric and colonic ulceration, impairment of jejuna,
epithelial restitution following ischemic injury, and renal tubular necrosis are
reported.21,31–33Despitethisfact,flunixinmeglumineremainslikelythemostimpor-
tant and commonly used medication available for the treatment of visceral pain in
horses.Assuch,manyhorseswithabdominalpainwillrecovercompletelywithone
administration of 1 mg/kg flunixin via the intravenous, intramuscular, or oral route.
Thepositiveand negativeeffects ofthisclass ofdrugsare discussed indetail else-
whereinthisissueandthusarenotfurtherdiscussedhere.
Opioids
Opioidshavenotbeenwidelyusedtotreatclinicalpaininhorsesincomparisonwith
otherspeciesincludinghumans.Reasonsforthisincludetheapparentnarrowmargin
betweenanalgesiaandexcitationorarousal,anddifficultyindemonstratingaconsis-
tentandquantifiableanalgesicaction.34Inpain-freehorses,opioidadministrationhas
resulted in adverse effects, predominantly excitement, whereas clinical reports of
opioiduseinpainfulanimalsaremoreencouraging.Opioidreceptor–bindingstudies
demonstrate distinct differences in the distribution and density of opioid receptors
withinthecentralnervoussystembetweenhorsesandotherspecies,buttheclinical
significanceofthesedataisstillunclear.35,36
Specificopioids
Butorphanol Butorphanol is a k (OP2) agonist and competitive m (OP3) antagonist,
whichislabeledforuseinhorses.Whenadministeredbybolusinjection,butorphanol
providesamoderatedegreeofsomaticandaslightlygreaterdegreeofvisceralanal-
gesia in the horse; however, it also causes decreased gastrointestinal
610 Robertson&ChrisSanchez
motility.17,21,37,38 Adverse effects such as ataxia, decreased defecation, and borbo-
rygmiafterasingleintravenousinjectionarelessapparentwhenitisgivenasacontin-
uousinfusion.39Noantinociceptivepropertiesweremeasurablewhenaninfusionwas
usedinaresearchmodelofvisceraldistension.10Theeffectofbutorphanolongastro-
intestinal motility appears to vary with the segment of the gastrointestinal tract,
dosage, and method of administration. Bolus administration of butorphanol did not
significantlyalterantroduodenalmotilityinonestudy40butresultedindelayedgastric
emptyinginanother.18Whenadministeredasaconstantrateinfusion,butorphanoldid
not significantly alter duodenal motility.10 In clinical patients undergoing exploratory
laparotomyforcolic,butorphanolinfusion(13mg/kg/hfor24hours)diddelaypassage
offecesfollowingsurgery.However,overalltherewereclearadvantagestoitsusein
thismanner39:painscoresweresignificantlydecreasedintheimmediatepostopera-
tiveperiod;horseslostsignificantlylessweight,hadimprovedrecoverycharacteris-
tics, and on average were discharged 3 days earlier than control horses (flunixin
meglumine only).39 These benefits translated to an overall cost savings of approxi-
mately$1000.
Morphine Theuseofmorphineinhorsesiscontroversial.Whenusedatdosesof0.1
to 0.2 mg/kg intravenously or as an infusion (0.1 mg/kg/h) in horses undergoing
surgery,noundesirableeffectswerereportedanditsignificantlyimprovedthequality
of recovery, presumably because of its analgesic effects or perhaps its sedative
effects in a clinical setting.41–43 Morphine provided pain relief in a cecal distension
modelbutinhibitedcolonicmotility.6Theroleofsystemicallyadministeredmorphine
forthealleviationofabdominalpainiscurrentlyunclear;aswiththea -agonists,short-
2
termusemaybeeffectiveandbeneficial,butlong-termuse(severaldays)mayresult
in ileus. As with butorphanol, infusions may reduce the unwanted side effects, and
deservefurtherstudy.
Thebiggestconcernsregardingtheuseofmorphineareitseffectsongastrointes-
tinalmotilityandthereforethepotential increasedriskofcolic.A doseof0.5mg/kg
intravenouslyevery12hoursfor6daystonormalhorsesresultedindecreaseddefe-
cationfrequency,fecalmoisturecontent,andgastrointestinalsounds.44Thoseeffects
were mostly mitigated by the concurrent administration of N-methylnaltrexone, an
opioidantagonistthatdoesnotcrosstheblood-brainbarrier.45
Inastudyof496horsesthatunderwentorthopedicsurgery,14developedcolic;the
useofmorphinewasassociatedwithafourfoldincreasedriskofcoliccomparedwith
theuseofnoopioidsorbutorphanol.46Inanotherstudyof533horsesthatunderwent
anesthesiabutnotsurgeryornonabdominalsurgery,3.6%ofhorsesdevelopedcolic
within7daysofanesthesia;significantlymorehorseswereinthesurgerygroup,but
theuseofmorphinewasnotassociatedwithanincreasedrisk.47
Fentanyl Inconsciousresearchhorses,fentanylfailedtoproducesignificantvisceral
orsomaticantinociceptionatserumconcentrationsabovethenociceptivethreshold
inotherspecies.9Athighplasmaconcentrations(>5ng/mL),somebutnotallhorses
becameagitated.Also,veryhigh(13.31ng/mL)serumconcentrationsoffentanylare
necessarytoachieveminimal(18%)isofluraneminimumalveolarconcentrationreduc-
tioninhorses.48Theuseoftransdermalfentanylpatcheswasinitiallymetwithenthu-
siasm,butuptakeoffentanylfromatransdermalpatchishighlyvariableinhorses.49,50
Thisinformation,combinedwiththedisappointingresultsofintravenousinfusionsand
cost,limittheutilityoffentanylfortreatmentofvisceralpaininhorses.
Tramadol Tramadol is an analogue of codeine and although not a controlled
substance, some of its analgesic properties are related to its opioid properties.
TreatmentofVisceralPaininHorses 611
Tramadolhasashorthalf-life,loworalbioavailability(w3%),andtheactivemetabolite
M1 is a minor metabolite that may limit its usefulness in horses relative to other
species.51 No opioid-related excitement was reported but somatic analgesia could
not be demonstrated with tramadol administration at doses ranging from 0.1 to
1.6 mg/kg intravenously.52 Epidural administration of tramadol (1.0 mg/kg) resulted
in significant antinociception at lumbar and thoracic dermatomes within 3 hours of
administration, which lasted for 5 hours,53 but it is currently unknown whether this
wouldtranslatetovisceralanalgesia.Thus,theroleoftramadolforthealleviationof
paininhorsesremainstobedetermined.
SodiumChannelBlockers
Lidocaine is an aminoamide local anesthetic that prevents propagation of action
potentialsbybindingtovoltage-gatedsodiumchannels.Lidocaine,administeredas
anintravenousinfusion,iscommonlyusedinhorsesforitspotentialanalgesic,proki-
netic,andanti-inflammatoryproperties.8,54–58Variabledosesofintravenouslidocaine
arereported;loadingdosesvaryfrom1.3to5.0mg/kgandinfusionratesvaryfrom25
to100mg/kg/min.Clinicalsignsoftoxicityinconscioushorsesincludeskeletalmuscle
tremors, altered visual function, anxiety, ataxia, collapse, and electrocardiographic
changes, which can occur at serum concentrations between 1.65 and 4.53 mg/mL
(mean3.24(cid:4)0.74[SD]mg/mL).59Itisnoteworthythattheneurologicmanifestations
oftoxicosismaybemaskedbygeneralanesthesia.
Usingelectroencephalographicchangesasanobjectivemeasureofnociceptionin
anesthetizedponies,intravenouslidocaineinfusion(5mg/kgloadingdose,100mg/kg/
mininfusion)obtundedtheresponsetocastration,lendingsupporttotheroleoflido-
caineasavisceralanalgesic.60
Lidocaine administration following exploratory laparotomy has been associated
withreducedsmallintestinalsizeandperitonealfluidaccumulation,57andimproved
survival.61Inonehospitalsetting,theintraoperative useoflidocaine wasthoughtto
reduce theincidence of postoperative ileus by approximately 50%62 and in a multi-
center study of horses with enteritis or postoperative ileus, lidocaine infusion
decreasedthevolumeanddurationofrefluxcomparedwithsaline-treatedcontrols.56
Following experimentally induced small intestinal ischemia, lidocaine improved
mucosal healing by an unknown mechanism that may be related to the decreased
productionofinflammatorycytokines.63
Because treatment of horses with gastrointestinal disease may need to be pro-
longed,itisimportanttounderstandhowthedurationofinfusionaffectsthedisposi-
tion oflidocaine and also how thepharmacokinetics might bealtered by diseaseor
generalanesthesia,sothatappropriatechangesintheinfusionratecanbemadeto
avoidtoxicosis. The target steady-stateconcentration oflidocaine forthetreatment
ofileusisthoughttobebetween1.0and2.0mg/mL(mean0.98mg/mL).64Inhealthy
horses,steady-stateserumconcentrationsslightlybelowthissuggestedthattargets
were reached 3 hours after starting a continuous rate infusion at 50 mg/kg/min (no
bolus),anddidnotaccumulateovera96-hourstudyperiod.65However,inaclinical
settingaccumulationcanbedemonstrated.66Cetiofursodiumandflunixinmeglumine
decreasethe proteinbinding of lidocaine,therefore lowerinfusion ratesof lidocaine
shouldbeusedinhorsesreceivinghighlyproteinbounddrugs.66Plasmaconcentra-
tionsmayalsobeaffectedbyliverdiseaseorbychangesinliverbloodflowthatoccur
under general anesthesia. A bolus dose of 1.3 mg/kg followed by an infusion of
50 mg/kg/min results in higher serum concentrations in anesthetized as compared
with awake horses,67 and in the former these were within the range reported to be
toxicinconscioushorses.59
612 Robertson&ChrisSanchez
Lidocaine:otherapplications
Manyhorsesthatpresentwithabdominalpainwillundergoarectalpalpation.Intra-
rectallidocaine(15mL,2%solution)increasesrectalwallcomplianceandfacilitates
rectal palpation, and likely decreases the risk of rectal tears.11 The pain associated
with other diagnostic procedures such as thoracocentesis and abdominocentesis
canbedecreasedbylocalinfiltrationwithlidocaineoranotherlocalanesthetic.
In mares undergoing laparoscopic ovariectomy, the addition of 10 mL of 2%
lidocaineinjectedintothemesovariumtoaprotocolofintravenousxylazineandbutor-
phanolandepiduraldetomidineresultedinfewerpainresponsescomparedwithintra-
ovarianinjectionofsaline.68
N-Methyl-D-AspartateAntagonists
Ketamine,an N-methyl-D-aspartate(NMDA)receptorantagonist commonlyusedfor
dissociative anesthesia, may have a very important role to play in the prevention of
centralhypersensitivity,15andhassomaticantinociceptivepropertieswhenadminis-
tered as a constant rate infusion at subanesthetic doses in both anesthetized and
conscioushorses.69,70Subanestheticdosesofketaminedecreasedoverallgastroin-
testinal transit time in comparison with saline control,71 in contrast to studies in
dogs.72 The ability for ketamine to produce visceral analgesia in horses is currently
unknown.Ketaminealsohaswell-documentedanti-inflammatorypropertiesinseveral
species; it reduced the production of tumor necrosis factor a, interleukin (IL)-6, and
IL-8inhumanbloodandindogsinresponsetoendotoxinstimulation.73,74
AntispasmodicMedications
N-Butylscopolammoniumbromide(NBB)hasbothanticholinergicandantispasmodic
properties, and is labeled for the treatment of spasmodic colic. In an experimental
model of cecal balloon distension, NBB had an analgesic effect in 6 of 8 ponies.75
Inanothersimilartrial,NBBhadabriefanalgesiceffectaswellasatransientnegative
effect on cecal contractions.76 In horses, administration of NBB produced visceral
antinociception, as indicated by a significantly increased colorectal distension
thresholdandasmallbutnonsignificantincreaseinduodenaldistensionthreshold.10
TheadministrationofNBBalsodecreasesrectaltoneforfacilitationofarectalexam-
ination.77Inallreportsthedurationofeffectisofshortduration(15–20minutes).
NONPHARMACOLOGICTHERAPY
Despiteanecdotalreportsinindividualhorses,thebenefitsofacupunctureforthereliefof
abdominalpaininhorseshavenotbeensubstantiatedbylargeclinicaltrialsorinaresearch
modelofduodenaldistension.78Thisisclearlyanareainneedoffurtherresearch.
MULTIMODALAPPROACHTOTHERAPY
Severe pain may be refractory to single analgesic therapy and may require a multi-
modal approach to pain management, employing drugs with different mechanisms
ofaction.Despitethepotentialforimprovedanalgesia,forexampleinasmallclinical
studyofhorseswithpainthatwasrefractorytoNSAIDtherapyalone,theadditionof
the fentanyl transdermal therapeutic system appeared to be effective based on
subjectiveevaluation.79However,othershavewarnedthattheuseofsuchcombina-
tions may also increase the potential for adverse effects, especially alterations in
gastrointestinalmotilityorbehavior.17
Aspreviouslydiscussed,infusionsofdrugsoftenresultinfeweradverseeffects.An
infusionofmedetomidine(5mg/kg/h)combinedwithmorphine(30mg/kg/h)provided