82nd Western Veterinary Conference

V539
How Do We Manage Pain in Cattle Effectively?
Hans Coetzee, BVSc, Cert CHP, PhD, MRCVS, DACVCP
Department of Veterinary Clinical Sciences, Kansas State University, Manhattan,
KS, USA
It is interesting to note that while carprofen, ketoprofen, flunixin meglumine, tolfenamic acid, meloxicam,
and xylazine are labeled for pain control in England, no products are labeled for pain control in food
animals in the United States. Flunixin meglumine is labeled for control of pyrexia associated with bovine
respiratory disease, endotoxemia, and acute bovine mastitis, and also for inflammation in endotoxemia.
Aspirin is not approved by the FDA/CVM for use in food animals, although there are numerous
products with a “label” indicating use in food animals. We also may resort to phenylbutazone, steroids,
barbiturates, or various anesthetics. This proceedings focuses on selected compounds and regimens used
in addressing pain and inflammation in food animals. We will start with a brief overview of how anti
inflammatory drugs work.

OVERVIEW
Glucocorticoids inhibit the production of inflammatory molecules such as cytokines and adhesion
molecules. These enable inflammatory cells to leave the blood stream and enter the site of inflammation.
Glucocorticoids also maintain membrane integrity and exert a host of effects of protein, lipid and
carbohydrate metabolism.
Dexamethasone (Azium Solution, Schering Plough) and Isoflupredone acetate (Predef, Pfizer) are
the most widely used glucocorticosteroids in production animal medicine. Isoflupredone is described as
having glucocorticoid potency 10 times greater than hydrocortisone but about 1/3 the potency of
dexamethasone. Isoflupredone is unique among these compounds as it does not cause abortion in
pregnant cattle at any stage of gestation. The drug does however have some mineralocorticoid activity
and repeated high doses have been associated with electrolyte imbalances such as hypokalemia.
 Glucocorticosteroids prevent arachidonic acid release by stabilizing cell membranes and inducing
lipocortin production. Lipocortin prevents phospholipase A2 from encountering cell membrane
associated arachidonic acid. This reduces the availability of precursors for prostaglandin production.
Glucocorticoids need to be administered early in the course of disease for maximum efficacy. Arachidonic
acid release occurs early in the cascade of events following a traumatic incident or endotoxin exposure.
Once arachidonic acid is released, lipoxygenase and cyclooxygenase have the substrate required to form
inflammatory intermediates.
Glucocorticoid drugs are also known to inhibit the production of cyclooxygenase 2 (COX-2) which
produces inflammatory prostaglandin from arachidonic acid. Steroids have not been observed to inhibit
COX-1, a constitutive enzyme which is responsible for producing “housekeeping” prostaglandins in the
kidney and gastric mucosa. Steroids should therefore NOT be considered analgesic drugs!
Non-Steroidal Anti-inflammatory Drugs: The primary mode of action of NSAIDs currently used in
food animals is to inhibit the synthesis of prostaglandins (PG) and thromboxanes through the inhibition
of cyclo-oxygenase (COX). Cyclo-oxygenase is composed of 2 isoforms, COX-1 and COX-2. COX-1 is the
“housekeeping” isoform that mediates the formation of constitutive prostaglandins. PG’s generated by
COX-1 are constantly present, providing homeostasis. These include protection of the GIT mucosa,
hemostasis and protection of the kidney against hypotension. COX-2 is the highly “inducible” isoform
that is dramatically up regulated in the presence of inflammation.
All NSAIDs that are commonly used in production animals inhibit both COX isoforms and
consequently the formation of PG E2 in the brain, which effectively reduces fever. Aspirin and Flunixin
meglumine are the only NSAIDs labeled for use in cattle in the United States. Other compounds that are
approved in Europe and which may become available for use in food animals over the next 5 to 10 years
include carprofen, meloxicam, ketoprofen and tolfenamic acid.
Analgesia during castration, dehorning, and tail docking: It is easy to see how this subject would
be considered as a moral issue by the general public. The AVMA position statement on animal welfare
supports the reduction or elimination of pain during castration and dehorning, but does not use the
words analgesia or anesthesia.1 “The AVMA supports the use of procedures that reduce or eliminate the
pain of dehorning and castrating of cattle. These procedures should be completed at the earliest age
practicable. Research in developing improved techniques for painless, humane castration and dehorning
is encouraged. In addition, it is recommended that viable alternatives to castration and dehorning be
developed and applied.” The AVMA does state that flank ovariectomies performed without anesthesia
are inhumane.
Resistance to requiring injectable analgesia for routine castration and dehorning is largely based on
time and logistical issues. However, a recent study evaluating novel methods of analgesia for tail docking
in lambs demonstrated that castrating by banding in 1–2 day old lambs required an average of 28 seconds
without analgesia and 68 seconds when an injectable local anesthetic was administered by jet-injector.2
While the United States has not followed other countries in legislating the use of local anesthesia during
castration and dehorning, it is appropriate for the veterinary profession to pursue practical, rapid, and
effective methods for the relief of pain related to these procedures. The author is aware of practicing
veterinarians that have adopted local anesthesia regimens for these procedures.
It has been suggested that a surgical stimulus such as castration in calves is so brief that little
difference can be observed or measured between animals having or not having local anesthetic applied.3
However, alleviating pain associated with surgical castration by administration of local anesthesia
increased weight gain in cattle for 35 days following castration.4 This suggests that alleviating acute pain
at the time of castration may have economic benefit.5 Ketoprofen, a NSAID analgesic not approved for
use in cattle in the U.S., has been shown to reduce acute plasma cortisol response in cattle following
administration at the time of castration. Giving both a local anesthetic and intravenous ketoprofen before
surgery-cut castration was found to virtually abolish the post-surgery cortisol response.6,7 Ketoprofen
given alone was also found to reduce the plasma cortisol response to Burdizzo castration more effectively
than a local anesthetic or an epidural.7 Similar studies examining NSAIDs that are approved for use in
food-producing animals in the USA have not been conducted. Furthermore, all these studies examining
the efficacy of analgesic drugs in farm animals fail to report associated plasma drug concentrations
essential for designing efficacious analgesic regimens.
Some of the parameters described above may be useful to allow us to determine the efficacy of
analgesics in food animals.

FOCUS ON SPECIFIC DRUGS

Phenylbutazone: Values reported for elimination half-times are 55–65 hours in cattle compared with
approximately 3–6 hours in dogs. The authors of a study in adult Holstein cows extrapolated a
therapeutic serum concentration of 60–90 µg/mL from human literature and proposed a dosing regimen
of a 10–20 mg/kg loading dose and a daily maintenance doses of 2.5–5.0 mg/kg.8
An IV dose of 10 mg/kg in adult Holstein bulls maintained serum concentrations above 65 µg/mL
for 10 hours and above 55 µg/mL for 20 hours.9 Serum concentrations at 30 hours were near 50 µg/mL.
The authors recommended a regimen of a 17–25 mg/kg loading dose followed by a maintenance dose of
4–6 mg/kg every 24 hours. Alternatively, loading and maintenance doses of 14–24 mg/kg and 10–14
mg/kg Q48h were suggested. These doses were based on maintaining serum concentrations sufficient to
address skeletal pain. The antiinflammatory activity of phenylbutazone may persist much longer than
serum concentrations due to irreversible binding to the cyclooxygenase enzyme. A phenylbutazone
slaughter withdrawal time of 21 days and a milk withdrawal time of 120 hours has been recommended
by the Food Animal Residue Avoidance Databank (FARAD) for a dose of 4–6 g/animal IV or IM,
followed by up to 2 g/animal daily.12 It would be wise to periodically review the FARAD withdrawal
time by calling 1-888-US-FARAD. The use of phenylbutazone in dairy cattle greater than 20 months of
age has been prohibited by the Food and Drug Administration Center for Veterinary Medicine.10
Aspirin is a cyclooxygenase inhibitor. Peripheral actions of inhibiting the synthesis of inflammatory
mediators are responsible for relieving both inflammation and pain. Antipyretic effects are due to both
central (temperature control center in the hypothalamus) and peripheral (vasodilation and redistribution
of body water).
Aspirin is a weak acid with a pKa of 3.5. In the relatively alkaline environment of the rumen (pH
ranging from 5.5 to 7.0) approximately 1000 times as much aspirin is in the ionized form compared to the
more diffusable nonionized form. This results in a slow absorption rate in cattle. Aspirin is also highly
protein bound (70–90%), a characteristic shared by all NSAIDs discussed here. Administration of 2
NSAIDs at one time, or a NSAID in conjunction with another highly protein bound drug (sulfas) will
result in higher concentrations of free drug in the plasma due to competition for binding sites.
Aspirin elimination half-times after oral administration range from approximately 4.0 hours after
oral administration in cattle to approximately 38 hours in cats. The slow absorption rate after oral
administration demonstrated in adult dairy cows is evident in the difference between elimination half-
times for IV sodium salicylate (0.54±0.04 hrs) and oral acetylsalicylic acid (3.70±0.44 hrs).11 The rumen
acting as a slow release reservoir for aspirin absorption is responsible for the T½β being longer after oral
administration. The low volume of distribution (0.24±0.02 L/kg) is indicative of limited distribution to
tissues. In this study, an oral dose of 100 mg/kg (70 grains/100 lbs) maintained serum concentrations in
excess of 30 µg/mL between approximately 1 hour and 5 hours after administration. The mean peak
serum concentration was close to 50 µg/mL. An oral dose of 50 mg/kg failed to reach serum
concentrations of 30 µg/mL. The authors used 30 µg/mL as the minimum concentration for pain relief
based on human serum concentrations required for relief of headaches, aches, and pains. Serum
concentrations near 100 µg/ml are necessary in man to relieve severe arthritic pain. The authors noted
clinical improvement in two cows with nonsuppurative tarsitis at 100 mg/kg orally, but noted no
improvement at this dose in a bull with suppurative tarsitis. They recommended 100 mg/kg every 12
hours to maintain serum concentrations above 30 µg/ml. A milk and slaughter withdrawal of 24 hrs has
been recommended by FARAD for all usual dosages.12
Our research group recently conducted a study to examine the effect of oral aspirin and intravenous
sodium salicylate on acute plasma cortisol response following surgical castration.13 Twenty bulls,
randomly assigned to the following groups; 1) uncastrated, untreated controls, 2) castrated, untreated
controls, 3) 50mg/kg sodium salicylate IV pre-castration and 4) 50mg/kg aspirin (acetylsalicylic acid) per
os pre-castration, were blood sampled at 3, 10, 20, 30, 40, 50 minutes and 1, 1.5, 2, 4, 6, 8, 10 and 12 hours
post-castration. Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence
polarization immunoassay for cortisol and salicylate respectively. Data were analyzed using
noncompartmental analysis, a simple cosine model, ANOVA and t-tests. Intravenous salicylate Vdss was
0.18 L/kg, ClB was 3.36 mL/min/kg and T½λwas 0.63 hours. Plasma salicylate concentrations above 25
µg/mL coincided with significant attenuation in peak cortisol concentrations (p=0.029). Peak salicylate
concentrations following oral aspirin administration was less than 10 µg/mL and failed to attenuate
cortisol response. Once salicylate concentrations decreased below 5 µg/mL, cortisol response in the
castrated groups were significantly higher than uncastrated controls (p=0.018). To our knowledge this is
the first study relating plasma analgesic drug concentrations directly to mitigation of plasma cortisol
response post-castration.

ANALGESIA AND RESTRAINT FOR STANDING PROCEDURES IN CATTLE

A protocol for use of IM butorphanol/xylazine/ketamine (BXK) was presented by Dr. Matt Miesner, with
credit given to Dr. Eric Abrahamsen, at the 2007 Kansas State University June Conference.14 The regimen
consists of butorphanol (0.01–0.025 mg/kg) + xylazine (0.02–0.05 mg/kg) + ketamine (0.04–0.1 mg/kg).
Dr. Miesner noted that for a 450 kg animal, 5 mg butorphanol, 10 mg xylazine, and 20 mg ketamine
would constitute the low end of the dosing range. Note that the calculation should involve 2x ketamine as
compared to xylazine and 2x ketamine as compared with xylazine. They have noted up to an hour of
cooperation using this protocol but more fractious patients may require increased doses. Dr. Miesner
suggests giving no more than 10 mg butorphanol or 20 mg of xylazine the initial dose (this would be for
the 450 kg animal on up). The following withdrawal times are recommended by FARAD.15
 Ketamine, up to 2 mg/kg IV, up to 10 mg/kg IM, 3 days meat, 48 hours milk
 Xylazine, 0.016–0.1 mg/kg IV, 0.05–0.3 mg/kg IM, 5 days meat, 72 hours milk
 Xylazine, 0.3–2.0 mg/kg IM, 10 days meat, 120 hours milk

A reasonable withdrawal time for opiates in cattle of at least 48 hours has been suggested in the
literature.16
Twenty-two male beef cattle were randomly assigned to one of four treatment groups. 1)
Uncastrated, untreated control (n=4), 2) Castrated, placebo treated control (n=6), 3) Castrated, IV xylazine
(0.05 mg/ kg) and ketamine (0.1 mg/kg) (n=6), 4) Castrated, intravenous xylazine (0.05 mg/ kg) (n=6).
Calves were castrated with a Henderson castration tool and blood samples were collected at 3, 10, 20, 30,
40, 50 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 10 hours thereafter. Ketamine, norketamine and xylazine
were determined by LC-MS-MS and substance P (SP) and cortisol were determined by use of competitive
and chemiluminescent enzyme immunoassays, respectively.
The volume of the central compartment (Vc = 132.82 ± 68.23 mL/kg), distribution clearance (CLD =
15.49 ± 2.56 mL/min/kg), volume of the peripheral compartment (VT = 257.05 ± 41.65 mL/kg) and
ketamine clearance by the formation of the norketamine metabolite (CL2M = 8.56 ± 7.37 mL/kg/min) were
estimated. Plasma ketamine, norketamine and xylazine concentrations were associated with mitigation of
plasma cortisol and SP response.

MELOXICAM
We conducted a study to investigate the pharmacokinetics and oral bioavailability of meloxicam in
ruminant calves. Six Holstein calves (145–170 kg) received either meloxicam IV at 0.5 mg/kg or oral
meloxicam at 1 mg/kg in a randomized cross-over design with a 10-day washout period. Plasma samples
collected up to 96 hours post-administration were analyzed by LC-MS followed by noncompartmental
pharmacokinetic analysis. A mean peak plasma concentration (Cmax) of 3.10 ug/mL (Range: 2.64–3.79
ug/mL) was recorded at 11.64 hours (Range: 10–12 hours) with a half-life (T ½ λz) of 27.54 hours (Range:
19.97–43.29 hours) after oral meloxicam administration. The bioavailability (F) of oral meloxicam
corrected for dose was 1.00 (Range: 0.64–1.66). These findings indicate that oral meloxicam administration
could be an effective and convenient means of providing long-lasting analgesia to ruminant calves.
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