The capacity to experience pain is considered to have a protective role by eliciting behavioral responses aimed at reducing
further tissue damage and enhance wound healing. However, persistent pain syndromes offer no biological advantage and are
associated with suffering and distress. Pathological pain states in cattle occur as a result of tissue damage, nerve damage
and inflammation and are frequently associated with pain hypersensitivity. Pain hypersensitivity manifests as hyperalgesia
(exaggerated responses to painful stimuli) and allodynia (pain resulting from normally innocuous stimuli). Hyperalgesia has
been reported to persist in dairy cattle and lame sheep for at least 28 days after the causal lesion has resolved. Consequently,
chronic pain associated with lameness is considered one of the most significant welfare concerns in dairy cows. In addition
pathological pain, several routine management practices are recognized to cause pain in cattle. For example, castration of
male calves intended for beef production is one of the most common livestock management practices performed in the United
States amounting to approximately 15 million procedures per year. Negative public perception of pain associated with routine
livestock management procedures such as castration and dehorning is increasing. Several organizations, including the National
Cattlemen's Beef Association and the American Veterinary Medical Association, have stated that pain and physiologic stress
resulting from castration should be minimized. Studies have demonstrated that non-steroidal anti-inflammatory drug (NSAID)
administration prior to dehorning and castration mitigates plasma cortisol response. However, there are currently no analgesic
drugs specifically approved for the alleviation of pain in livestock in the United States.
Specific drug options
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
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, lipooxygenase 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.
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. However, alleviating pain associated with surgical
castration by administration of local anesthesia increased weight gain in cattle for 35 days following castration. This suggests
that alleviating acute pain at the time of castration may have economic benefit. 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. Ketoprofen given alone was also found to reduce the plasma cortisol
response to Burdizzo castration more effectively than a local anesthetic or an epidural. 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.