Update on managing pain in food animals (Proceedings)

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 ⅓ 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, 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.

Focus on specific NSAIDs

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 *g/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.

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. 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. 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.

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). 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 .Gingerich and Baggot (1975) 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.

Our research group recently conducted a study to examine the effect of oral sodium salicylate in the drinking water. Calves weighing 108 to 235 kg received the following treatments prior to a sham and actual castration and dehorning: (i) 0.9% saline solution (PLACEBO; n = 10) (ii) sodium salicylate (SAL; n = 10) dissolved in water and supplied free-choice to provide concentrations from 2.5 to 5 mg/mL beginning 24 hours prior to Period 1 to 48 hours after Period 2; (iii) 0.025 mg/kg butorphanol, 0.05 mg/kg xylazine, 0.1 mg/kg ketamine concurrently administered intramuscularly immediately prior to Periods 1 and 2 (XKB; n = 10); and (iv) a combination of treatments (ii) and (iii) (SAL + XKB; n = 10).The average daily gain in bodyweight (ADG) was significantly greater for calves in the SAL and SAL + XKB. Serum cortisol concentrations were significantly increased in all groups during Period 2 compared to Period 1. The results indicate XKB attenuated the acute cortisol response within the first hour after castration and dehorning while oral salicylate mitigated longer term effects from one hour to 6 hours, likely associated with inflammation. Orally administered sodium salicylate may have utility during routine management practices in cattle for preventing losses in ADG and attenuating cortisol response associated with noxious stimuli.

Meloxicam is an NSAID of the oxicam class that is approved in the European Union for adjunctive therapy of acute respiratory disease; diarrhea and acute mastitis when administered at 0.5 mg/kg IM or SC. Heinrich et al. demonstrated that 0.5 mg/ kg meloxicam IM combined with a cornual nerve block reduced serum cortisol response for longer compared with calves receiving only local anesthesia prior to cautery dehorning. Furthermore, calves receiving meloxicam had lower heart rates and respiratory rates than placebo treated control calves over 24 hours post-dehorning. Stewart et al. found that meloxicam administered IV at 0.5 mg/kg mitigated the onset of pain responses as measured by heart rate variability and eye temperature, compared with administration of a cornual nerve block alone.

Our research group 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.

Gabapentin

Gabapentin (1-(aminomethyl) cyclohexane acetic acid) is a γ-aminobutyric acid (GABA) analogue originally developed for the treatment of spastic disorders and epilepsy. Subsequent studies have established that gabapentin is also effective for the management of chronic pain of inflammatory of neuropathic origin. Although the mechanism of action of gabapentin is poorly understood, it is thought to bind to the α2-δ subunit of voltage gated calcium channels acting pre-synaptically to decrease the release of excitatory neurotransmitters. Efficacy of gabapentin in humans is associated with 2 µg/mL plasma drug concentrations. It has also been reported that gabapentin can interact synergistically with NSAIDs to produce antihyperalgesic effects. In a recent study we report a mean peak plasma gabapentin concentration (Cmax) of 3.40 µg/mL (Range: 1.70 – 4.60 µg/mL) at 7.20 hours (Range: 6 – 10 hours) after administration with an elimination half-life (T ½ λz) of 7.9 hours (Range: 6.9 – 12.4 hours). Oral administration of gabapentin at 15 mg/kg could therefore maintain plasma concentrations of > 2 µg/mL for up to 15 hours. The PK of gabapentin suggests that this drug may be useful in mitigating chronic neuropathic and inflammatory pain in ruminant cattle.

References available from the authors