Alternatives to Local Anesthesia
Ethanol injection demyelinates nerve fibers and may be a promising long-acting local anesthetic for use at the time of disbudding.40 When ethanol was administered as a corneal nerve block before disbudding, calves failed to display increased pain sensitivity in response to pressure algometry relative to their baseline values.
Furthermore, ethanol-treated calves differed significantly from calves treated with the local anesthetic lidocaine at 1-hour post disbudding, when the lidocaine is assumed to be wearing off. Ethanol blocks appeared to desensitize the site of cautery dehorning for longer than 83 hours, at which time the experiment concluded. In this experiment, 2 mL of 100% ethanol were injected at the site of the corneal nerve block. However, more than half the calves subjected to ethanol anesthesia required a second injection to achieve complete loss of sensation in one or both horns. Further studies with respect to the safety and efficacy of ethanol blocks for local anesthesia are needed before this technique can be recommended.NONSTEROIDAL ANTIINFLAMMATORY DRUGS. NSAIDs produce analgesia and antiinflammatory effects by reducing prostaglandin (PG) synthesis through inhibition of the enzyme cyclo-oxygenase (COX) in the peripheral tissues and central nervous system. COX exists in two isoforms. COX-1 is constitutively expressed in both peripheral and central nervous systems, although expression is enhanced by pain and inflammatory mediators. COX-2 is ubiquitous in the CNS but only becomes the major enzyme for PG synthesis after induction by factors released during cell damage and death. It takes 2 to 8 hours for maximal COX-2 mRNA expression to occur in the peripheral tissues, therefore initial release of PG is primarily due to COX-1. PG in the peripheral tissues lowers the activation threshold of sensory neurons and may initiate nociceptive activity.
PG also works in concert with substance P, histamine, calcitonin gene-related peptide (CGRP), and bradykinin to lower the firing threshold of sensory nerves and produce inflammation. Therefore NSAIDs that inhibit COX-1 may have a more immediate impact on pain by inhibiting PG production in the periphery than COX-2 selective compounds. However, NSAIDs that inhibit COX-1 may be associated with increased risk for adverse gastrointestinal and renal effects.Spinal PG, notably PGE2, is responsible for increased excitability of the dorsal root ganglia leading to centrally mediated hyperalgesia. Given that COX-2 is constitutively expressed in the CNS, inhibition of spinal PGE2 production by NSAIDs that inhibit COX-2 may be an important mechanism in preventing the establishment of hyperalgesia. The effect of NSAIDs on both central and peripheral PG synthesis suggests that these compounds have an important role in multimodal analgesic protocols.
The dose and pharmacokinetic parameters of the commonly used NSAIDs in the United States are summarized in Table 3.4.
FLUNIXIN MEGLUMINE. Flunixin is a highly substituted derivative of nicotinic acid. Currently flunixin meglumine is the only NSAID approved for use in cattle in the United States.37 The plasma elimination half-life of flunixin after IV administration is
■ TABLE 3.4
Nonsteroidal Antiinflammatory Compounds Available for Use in Cattle
| Drug | Approved Species | Indications | Dose (Cattle) | T12 | Withhold Period |
| Flunixin meglumine | Cattle, horses, and pigs | NSAID—antipyretic, antiinflammatory | IV 2.2 mg/kg Topical 3.3 mg/kg | 3-8 hours | IV Meat—4 days Milk—36 hours Topical Meat—8 days |
| Phenylbutazone | Horses and dogs | NSAID—anti- inflammatory | 4 mg/kg IV ONLY! | 40-55 hours | Not approved in cattle in the USA |
| Ketoprofen | Horses and dogs | NSAID—anti- inflammatory | 3 mg/kg IV, IM | 0.42 hours | Not approved in cattle in USA |
| Aspirin | No FDA approval Horses and cattle | NSAID—reduction of fever Relief of minor muscle aches and joint pain | 50-100 mg/ kg PO Oral F < 20% | 0.5 hours (IV salicylate) | No formal FDA approval Not for use in lactating cattle |
| Carprofen | EU approval in cattle Dogs | NSAID—adjunctive therapy of acute respiratory disease and mastitis | 1.4 mg/kg bodyweight IV or SC | Age Dependent treatment of fever, inflammation, and pain relief, these have never been approved by the FDA Center for Veterinary Medicine for such indications.49 Therefore the legality of using salicylic acid derivatives in cattle is questionable because these are technically compounded products. Aspirin elimination half-lives after oral administration range from approximately 4 hours after oral administration in cattle to approximately 38 hours in cats.49 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 hours)50 and oral acetylsalicylic acid (3.70 ± 0.44 hours).51 The elimination half-life is longer after oral administration of aspirin because the rumen acts as a slow-release reservoir for aspirin absorption. The low volume of distribution (0.24 ± 0.02 L/kg) is indicative of limited distribution to tissues. It is noteworthy that salicylic acid derivatives are not associated with clotting deficits in cattle. CARPROFEN. Carprofen is a member of the propionic acid class of NSAIDs.52 The relative antiinflammatory, analgesic, and antipyretic activity of carprofen is reported to be greater than phenylbutazone or aspirin in calves.53 Carprofen is approved in the European Union as an adjunct to antimicrobial therapy to reduce clinical signs in acute infectious respiratory disease and acute mastitis in cattle. The recommended dose for SC or IV administration is 1.4 mg/kg body weight. Carprofen is commonly used in small animal medicine in the United States, but there are currently no approved formulations for use in livestock.36 MELOXICAM. 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.54 It has been shown 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 before cautery dehorning.16 Furthermore, calves receiving meloxicam had lower heart rates and respiratory rates than placebo-treated control calves over 24 hours post dehorning. It was recently reported 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.55 We also observed that meloxicam administered at 0.5 mg/kg IV before dehorning in 16-week-old calves reduced plasma substance P concentrations and improved weight gain over 10 days compared with untreated controls.56 These reports demonstrate that administration of meloxicam before dehorning at 0.5 mg/kg IV or IM may be effective at alleviating pain and distress associated with painful procedures in cattle. Meloxicam (20 mg/mL) is approved for use in cattle in several European countries with a 15-day meat withdrawal time and a 5-day milk withdrawal time after administration of 0.5 mg/kg IM or SC.54 An oral meloxicam suspension (1.5 mg/ mL) and injectable formulation (5 mg/mL) are approved in the United States for the control of pain and inflammation associated with osteoarthritis in dogs. Furthermore, an injectable formulation (5 mg/mL) is approved for the control of postoperative pain and inflammation in cats. The pharmacokinetics of meloxicam after oral and IV administration to cattle have recently been described.57 A mean peak plasma concentration (Cmax) of 3.10 ug/mL (range: 2.64 to 3.79 ug/mL) was recorded at 11.64 hours (range: 10 to 12 hours) with a half-life (T 12 λz) of 27.54 hours (range: 19.97 to 43.29 hours) after oral meloxicam administration. The bioavailability (F) of oral meloxicam corrected for dose was 1.00 (range: 0.64 to 1.66). These findings indicate that oral meloxicam administration could be an effective and convenient means of providing long- lasting analgesia to ruminant calves. Several inexpensive generic tablet formulations containing meloxicam (7.5 and 15 mg) have recently been approved for relief of signs and symptoms of osteoarthritis in human medicine. In the absence of specific FDA analgesic approvals for conditions other than foot rot in cattle, use of oral meloxicam tablets for alleviation of pain could be considered under AMDUCA. SEDATIVE-ANALGESIC DRUGS. Opioids, α2-adrenergic agonists, and V-methyl D-aspartate (NMDA) receptor antagonists are the most commonly used sedative analgesic compounds in veterinary medicine. These compounds may act synergistically and are therefore increasingly coadministered. A recent survey of Canadian veterinarians found that respondents who did use an analgesic at the time of castration used xylazine (>50% of respondents) more frequently than lidocaine (morphine because κ agonists cause less respiratory depression compared with μ receptor agonists. Furthermore, κ agonists carry a significantly lower risk of dependency because opioid addiction is mediated primarily through activation of the μ receptor. As a result, nalbuphine is presently not scheduled as a controlled substance in most parts of the United States in accordance with the Controlled Substances Act (21 U.S.C. § 812) on the basis of the exclusion detailed in 21 C.F.R. § 1308.12. Therefore, special storage and record keeping are not necessary. The potential for fewer adverse effects and reduced regulatory restrictions may make nalbuphine an attractive narcotic analgesic option for use in cattle if clinical efficacy were demonstrated.α2-ADRENERGIC AGONISTS. O2-Adrenergic agonists produce profound sedation, chemical restraint, and analgesia in cattle. Activation of o2-adrenergic receptors inhibits the positive feedback mechanism for release of norepinephrine from the presynaptic nerve endings by reducing calcium conductance. Attenuation of norepinephrine release causes dose-dependent sedation and inhibits the afferent pain pathway. In addition, θ2-adrenergic agonists decrease cardiac output, cause a centrally mediated reduction in respiratory rate, produce muscle relaxation, and depress gastrointestinal motility. Epidural administration of o2-adrenergic agonists can produce analgesia with minimal sedative and cardiovascular effects compared with IV administration. Xylazine is the most commonly used o2-adrenergic agonist used in cattle and is approved in the European Union for IM administration at 0.05 to 0.3 mg/kg. Administration of the lower dose is characterized by a slight decrease in muscle tone, but the ability to stand is maintained. Higher doses cause recumbency, deep sedation, and a degree of analgesia. It is recommended that cattle are fasted before systemic administration of higher doses of xylazine to reduce the risk of rumen tympany and aspiration of rumen contents. Xylazine epidural has been shown to produce greater perineal analgesia than xylazine given intramuscularly.62 Xylazine epidural has been proposed as a method of providing sedation and analgesia to facilitate castration in mature bulls.63 The onset of analgesia following administration of xylazine alone was found to be significantly longer (11.7 ± 1 minute) than the combination of xylazine and lidocaine (5.1 ± 0.9 minutes) and lidocaine alone (4.8 ± 1.0 minutes).64 The combination of lidocaine and xylazine produced analgesia of significantly longer duration (302.8 ± 11.0 minutes) than xylazine alone (252.9 ± 18.9 minutes) or lidocaine alone (81.8 ± 11.8 minutes). Xylazine induced mild to moderate sedation and ataxia. Ataxia was also noted in cattle receiving lidocaine alone. N-METHYL D-ASPARTATE RECEPTOR ANTAGONISTS. Ketamine is an Wmethyl D-aspartate (NMDA)-receptor antagonist that produces analgesia and dissociative anesthetic effects when administered at a dose of 2 to 4 mg/kg IV to calves.65 Ketamine and its active metabolite, norketamine, also bind μ and κ opioid receptors producing analgesia. Data from rats suggest that norketamine contributes to the analgesic effect of ketamine, with a potency that is one third of the parent drug. Subanesthetic ketamine administered at 0.1 to 1 mg/kg as an IV bolus is effective in managing acute postoperative pain in human medicine. In humans, plasma ketamine concentrations above 4 to 5 μmolZL (1000 ng/mL) are required to produce anesthetic effects, while analgesic effects are associated with plasma concentrations below 1 μmoVL (275 ng/mL) or X0th to ⅛th of the anesthetic dose. Plasma ketamine concentrations ranging from 40 to 150 ng/mL were associated with analgesia in humans. Our group previously demonstrated that mean plasma ketamine and norketamine concentrations in cattle decreased to below 40 ng/mL and 10 ng/mL after 30 and 60 minutes, respectively, after administration of a subanesthetic combination of xylazine (0.05 mg/kg) and ketamine (0.1 mg/ kg).66 NMDA receptor antagonists are designated as Schedule 3 drugs and are subject to regulation by the DEA.
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