Thomas Passler Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA Veterinarians and animal owners who are involved in the production of animals for human consumption are charged with providing healthy, wholesome, and safe products. Consumers demonstrate an increased interest in the origin of their food and demand that it is produced under standards that ensure the well‐being of food‐producing animals and prevent contamination of food with harmful microorganisms or residues. While much misconception about the use of pharmaceuticals in food‐producing animals exists in the general public, ensuring that edible animal products are free from harmful residues is the legal and moral obligation of producers and veterinarians. To achieve this goal, labels for all drugs approved for use in food‐producing animals must provide a withdrawal time for meat, milk, and/or eggs, and animal products cannot be harvested until this time has elapsed. In the USA, this requirement is the result of amendments to the federal Food, Drug, and Cosmetics Act of 1906s, including the Delaney Clause of 1958 and the Kefauver‐Harris Drug Amendments of 1962, which imposed that drugs must be safe and efficacious and must not leave unsafe residues in edible animal products [1]. Similarly, the directive 2001/82/EC has regulated the use of veterinary medicinal products in the European Union and created the legal framework for establishment of withdrawal periods following drug administration to food‐producing animals. Directive 2001/82/EC has been repealed and replaced by Regulation (EU) 2019/6 with the goal of harmonizing and enhancing the regulatory framework among member countries [2]. In the USA, to achieve approval for marketing of a new animal drug, the sponsor must file a New Animal Drug Application (NADA) with the US Food and Drug Administration (FDA). The sponsor then must demonstrate in studies that the new drug is safe and efficacious in the target animal species, is safe for the environment, and can be manufactured to uniform standards of purity, strength, and identity. In addition, for food‐producing animals, the sponsor must demonstrate that food products derived from treated animals are safe for human consumption. The goal of human food safety studies is a risk standard of “reasonable certainty of no harm,” which is assessed in toxicity and residue chemistry studies [3]. Toxicity studies are performed to assess the toxic hazard of a drug and its metabolites resulting from consumption of products from treated animals, and include genetic toxicity studies, 90‐day feeding studies, and a two‐generation reproduction study to assess the cross‐generational toxicity and teratogenic potential of a new drug [3]. Residue and metabolism studies are performed to describe the fate of a drug following administration to the target species. For drugs demonstrated to require a withdrawal time, residue depletion studies are performed. The drug is administered at the largest label dose for the longest label duration to evaluate residue depletion to below a tolerated concentration (tolerance). For withdrawal time calculations, the FDA, using parametric statistical methods, determines 99% tolerance limits with 95% confidence, indicating that there is only a 5% chance that 1 of 100 animals treated in accordance with label directions has tissue residues that exceed the tolerance value [3]. While similar in approach, the European Committee for Veterinary Medicinal Products (CVMP) determines withdrawal periods using differing statistical methods and suggests that 95% tolerance limits are more appropriate [4]. Support and criticism exist for these methods, and alternative statistical procedures have been proposed, including nonparametric methods that do not require the satisfaction of assumptions of parametric methods to estimate withdrawal times [5–8]. Additional concerns have also been expressed concerning withdrawal time calculations for injection sites, from which residues deplete extremely slowly and erratically [9, 10]. Various factors influence the metabolism and degradation of injectable pharmaceuticals at the injection site, which can result in differing residue depletion profiles as compared to other tissues [11]. In different countries, varying assessments are used by licensing authorities to evaluate the food safety implications of injection site residues, and the necessity for an internationally harmonized approach has been emphasized [11]. Veterinarians are commonly faced with the need to administer medications in a fashion or to a species that is not in accordance with label directions. When using pharmaceuticals in an extralabel fashion, the veterinarian assumes the legal responsibility of ensuring that the product is safe, efficacious, and will not leave harmful residues in animal products intended for human consumption. The Animal Drug Use Clarification Act (AMDUCA) of 1994 amended the Federal Food, Drug and Cosmetics Act to allow veterinarians to prescribe approved animal drugs in an extralabel fashion, but also defined several conditions and stipulations, including the following [12]: The effects of antimicrobial use in food animals and resulting residues in animal products have received much attention, but human safety concerns unique to residues associated with anesthetic drugs exist. At least four idiosyncratic or allergic responses related to anesthetic or anesthetic adjuncts can occur in people, including malignant hyperthermia, halothane hepatitis, porphyria, and allergic reactions [1]. Violative residues of anesthetics are much less frequently detected than those of antimicrobials or anthelmintics, and adverse reactions in people exposed to anesthetic residues are not reported. While sensitive detection methods exist, the infrequency of detecting anesthetic residues in food animal tissues may in part result from paucity of routine testing. Additional factors that decrease the risk of anesthetic residues include (i) short‐term use for single procedures reduce the risk of accumulation, (ii) short half‐life (t½) of most anesthetics, (iii) common intravenous (IV) or inhalant administration results in more rapid absorption as compared to other routes of administration, (iv) potency of current anesthetics results in low doses, and (v) unlike many other drugs, anesthetics are usually used under direct veterinary supervision [13]. Following the use of an anesthetic for surgery, sufficient time for drug elimination usually elapses until slaughter; however, risk of violative residues exists when fractious animals are tranquilized for transport to slaughter or show animals are sedated in shows preceding sale. As most anesthetic or anesthetic adjunct drugs are not approved for food animals, their use commonly falls under the regulations of AMDUCA. Considerable heterogeneity exists in the metabolism and excretion of pharmaceuticals within and especially between species, limiting the ability to extrapolate residue information from one species to another. Therefore, an extended withdrawal time should be considered when using a drug approved for one food animal species in another. The primary resource for information for veterinarians using pharmaceuticals in an extralabel fashion is the Food Animal Residue Avoidance Databank (FARAD), which was established as part of the USDA FSIS Residue Avoidance Program of 1982 [14, 15]. On its webpage, veterinarians can search the database for approved food animal drugs and find recommended withdrawal times for extralabel use of some drugs. In addition, veterinarians can contact FARAD by email, or in emergencies by phone, and FARAD personnel will recommend an appropriate withdrawal interval according to the individual features of each case. Recommendations are based on available pharmacokinetic studies, and members of FARAD have developed an Extended Withdrawal Interval Estimator (EWE) algorithm that facilitates the calculation of extended withdrawal times in a repeatable and scientifically valid fashion [16]. The accuracy of the recommended withdrawal times is dependent on available pharmacokinetic data, and more conservative estimates are provided when little data is available. When tissue residue depletion data are not available, the plasma t½ can be used to calculate withdrawal times, and this approach is a viable alternative for many drugs [17, 18]. For other drugs, such as those that concentrate in target tissues or that have metabolites that are excreted at a slower rate than the parent drug, plasma t½‐derived estimates of withdrawal time may be too short. Furthermore, pharmacokinetic studies are performed in healthy animals, and drug elimination in sick animals with compromised kidney or liver function may be prolonged [13]. The animal groups in which violative residues are most often reported are veal calves and culled dairy cows, in which elimination kinetics are often altered due to disease and reduced excretory function [19]. Considering the various factors that can influence drug elimination, adding a safety margin to the withdrawal time in sick and debilitated animals is prudent. Some general rules apply when extrapolating withdrawal times in the absence of available information from FARAD [19, 20]: With some exceptions, most anesthetics and anesthetic adjuncts have very short elimination t½ and should be largely cleared from the body after 48–96 hours [13]. Alpha‐2 agonists include xylazine, detomidine, and medetomidine, which induce sedation and analgesia. While xylazine and detomidine are commonly used in all farm animals, in the USA xylazine is approved only for horses and cervids, and detomidine is approved only for horses. In contrast to the USA, detomidine and xylazine are approved for use in food animals in various countries, and recommended withdrawal times vary (Table 12.1). Cattle and small ruminants are very sensitive to the effects of xylazine. For systemic administration of xylazine, typical doses range from 0.05 to 0.3 mg/kg in cattle and 0.05 to 0.2 mg/kg in small ruminants. The pharmacokinetics profile of xylazine is best described by a two‐compartment model with a rapid distribution phase and a large volume of distribution [21]. Following IV administration, the t½ of distribution was 1.2 minutes in cattle and 1.9 minutes in sheep [22]. The elimination t½ of xylazine following IV administration in cattle is 36 and 23 minutes in sheep, and is very similar when the drug is administered intramuscularly. Xylazine is rapidly metabolized to inactive compounds, and elimination occurs mainly by urinary excretion of these metabolites. In cattle, the primary metabolite of xylazine is 2,6‐dimethylaniline, a toxic substance demonstrated to be carcinogenic in rats [21]. The toxicity of 2,6‐dimethylaniline, which is used for many industrial manufacturing processes, has been extensively studied and its genotoxic and carcinogenic properties have prevented the FDA from establishing an acceptable daily intake (ADI) [21, 23]. However, there is currently no evidence that xylazine has carcinogenic potential for livestock at tranquilizing doses, and ingestion of edible tissues from xylazine‐treated animals appears to pose an extremely low risk [24, 25]. Table 12.1 Examples of anesthetics and anesthetic adjuncts approved for use in farm animals outside of the USA (note that recommended withdrawal times can vary widely between countries). FARAD has updated its previous recommendations for xylazine withdrawal times (Table 12.2) based on approval of the drug for cattle in New Zealand [26]. In that study, a single intramuscular (IM) dose of 0.35 mg/kg of xylazine followed by 4 mg/kg of IV tolazoline were administered, and concentrations of xylazine and 2,6‐dimethylaniline were below the limit of detection (10 μg/kg) by 72 hours in tissues and 12 hours in milk [27]. Currently, a withdrawal time of 4 days for meat and 24 hours for milk is recommended for doses of 0.05–0.3 mg/kg by IM administration [26]. For larger doses of xylazine (0.3–2.0 mg/kg) given intramuscularly, the recommended meat withdrawal time is 10 days and milk withdrawal time is 120 hours. For IV administration of 0.016–0.1 mg/kg of xylazine, recommended withdrawal times are 5 days for meat and 72 hours for milk. These recommendations pertain to single and multiple doses and are identical to those for sheep and goats [28]. For swine, a withdrawal time of 18 days is recommended for a single IM xylazine administration of up to 2.2 mg/kg [29]. For cervidae, including elk, fallow deer, mule deer, sika deer, and white‐tailed deer, species‐specific IM doses are provided. Xylazine should not be administered 15 days before or during the hunting season, and a minimum withdrawal time of 14 days is recommended [28]. In an emergency, xylazine is approved for use in organic livestock production, which requires a meat withdrawal time of 8 days and a milk discard period of 4 days [30]. The newer α2 agonist detomidine has similar effects as xylazine, but, in contrast to xylazine treatment, animals usually remain standing after an IV dose of detomidine [24]. When intramuscularly administered at 50 μg/kg to facilitate castration of rams and bucks, detomidine affected body temperature, heart and respiratory rates, and blood pressure similarly, but provided superior analgesia to xylazine administered at 200 μg/kg [31]. Detomidine is labeled for IV or IM use in horses, but IV use has been recommended for most clinical scenarios [24]. An IV dose of 0.01 mg/kg is commonly used at a referral hospital [24]. A detomidine gel formulation approved for sublingual administration in horses was demonstrated to result in similarly deep sedation and approximately 34% bioavailability when administered to calves at 0.08 mg/kg sublingually as compared to IV detomidine administered at 0.03 mg/kg [32]. In goats, 0.01 mg/kg of detomidine produced sedation only when administered intravenously, and this dose does not result in observable analgesia. In contrast, doses of 0.02 or 0.04 mg/kg produced effective sedation and moderate analgesia by IV or IM routes, and ataxia and sternal recumbency were observed in all goats that were given 0.04 mg/kg [33]. In cattle, detomidine is characterized by rapid distribution and elimination, with elimination t½ of 1.32 hours after IV administration and 2.56 hours after IM administration [34]. Excretion of detomidine in milk is very low, and concentrations of 0.4 ng/g were present at the first milking 11 hours after dosing, and no detectable amounts were present at 23 hours following administration [34]. Recommended withdrawal times for single or multiple IM or IV doses of up to 0.08 mg/kg are 3 days for meat and 72 hours for milk for cattle and small ruminants [28]. The pharmacologic effects of α2 agonists are commonly reversed using the α2 antagonist tolazoline, which is generally administered at 2–4 mg/kg by slow IV infusion. In 13 steers and 10 lactating dairy cows, tolazoline was administered 10 minutes after sedation with xylazine, and tissue and milk concentrations were evaluated [27]. Concentrations of tolazoline were below the limit of quantification (10 μg/kg) by 96 hours in tissues and 48 hours in milk. These data served as the basis for current FARAD withdrawal time recommendations, which are 8 days for meat and 48 hours for milk following a single IV dose of 2–4 mg/kg [26]. While demonstrated to be less effective than tolazoline or atipamezole [35–37], yohimbine can be used to reverse the effects of α2 agonists. Relatively little pharmacokinetic data are available for yohimbine, and FARAD recommends a conservative withdrawal time of 7 days for meat and 48 hours for milk for cattle and small ruminants [15]. In organic livestock production, tolazoline can be utilized for the reversal of xylazine, and withdrawal periods of 8 days for meat and 4 days for milk are required [30]. Table 12.2 Recommended withdrawal times for anesthetics and anesthetic adjuncts in farm animals in the USA. IM, intramuscular; IV, intravenous; PO, per os; q24 hours, every 24 hours; SC, subcutaneous.Further information and sources of recommendations are detailed in the text. The short‐acting barbiturate thialbarbitone and ultra‐short‐acting barbiturate thiamylal are approved for food animal use, but are, like thiopental, not currently available. The short duration of narcosis following single IV infusion of N‐methyl‐barbiturates and thiobarbiturates is not a result of rapid metabolism but of redistribution to less vascularized tissues. After administration, the short‐acting barbiturates almost instantly enter the brain and other organs that receive large proportions of the cardiac output. Subsequently, redistribution to larger, less vascularized tissues occurs and results in loss of narcosis. A large proportion of short‐acting barbiturates can redistribute to adipose tissues, depending on the amount of body fat, and accumulation in adipose tissues can occur with repeated administration. FARAD has established withdrawal times of 1 day for meat and 24 hours for milk after administration of the ultra‐short‐acting barbiturates thiamylal (up to 5.5 mg/kg) and thialbarbitone (up to 9.4 mg/kg) [28]. In small ruminants, recommended withdrawal times for a single IV dose of up to 5 mg/kg of thiopental are 1 day for meat and 24 hours for milk [38]. Ultra‐short‐acting barbiturates are most commonly used for induction of anesthesia. For this purpose, they may be replaced by other injectable anesthetics such as propofol, which is discussed in section 12.9. The minor tranquilizers diazepam and midazolam are used for their anxiolytic, anticonvulsant, and centrally muscle‐relaxing effects. They can be suitable for sedation or, in combination with another agent such as ketamine, for induction of anesthesia. Benzodiazepines can be especially useful for use in high‐risk animals, such as geriatric or debilitated livestock, because of their minimal cardiovascular and pulmonary effects. Additionally, benzodiazepines have a short‐lived appetite‐stimulating effect, and an injectable formulation containing brotizolam (Mederantil®) is commercially available for the approved use of appetite‐stimulation in cattle in some European countries. Benzodiazepines rapidly penetrate the blood–brain barrier, and maximal brain concentrations are achieved within a minute of IV administration [39]. In sheep, diazepam reaches maximal serum concentrations in 14.6 ± 7.2 minutes following IM administration, which is much more rapid than in people [40]. Diazepam and midazolam are metabolized by the liver, and high concentrations of active diazepam metabolites are present in the bloodstream following administration. Elimination kinetics and other pharmacokinetic characteristics vary greatly between species [41], making the extrapolation of appropriate withdrawal times from other species difficult. The prevention of benzodiazepine residues in tissues of farm animals is critical because a variety of adverse effects can occur in people [13]. Pharmacokinetic and residue studies guiding withdrawal time recommendations for benzodiazepines in food‐producing animals are currently lacking. Therefore, a conservative withdrawal time estimate of 30 days for meat should be used [13]. For IV doses of diazepam of up to 0.1 mg/kg in cattle and small ruminants, FARAD recommends a withdrawal of 10 days [29]. Benzodiazepines should not be used in lactating dairy cattle [13]. Dissociative anesthesia differs from narcosis induced by other drugs, as in addition to the depressive components such as unconsciousness and analgesia, catalepsy and spasms are also induced. The mechanism of action is understood to be a noncompetitive blockade of glutamate at the N‐methyl‐D‐aspartate (NMDA) receptor. Only two dissociative anesthetics are used in veterinary medicine, ketamine and tiletamine. Ketamine is usually administered in combination with other anesthetics and can be used in anesthesia induction and maintenance protocols. Tiletamine is available only in combination with the benzodiazepine‐derivative zolazepam, and this combination (Telazol®) is widely used for immobilization and anesthesia in various species. While tissue‐residue data for ketamine are not available, the European Committee for Veterinary Medicinal Products concluded that a maximum residue limit
12
Regulatory and Legal Considerations of Anesthetics and Analgesics Used in Food‐producing Animals
12.1 Alpha‐2 Agonists and Antagonists
Drug name
Country
Species
Withdrawal time
Acepromazine
Canada
Cattle, sheep, goats, pigs
Meat 7 days, milk 48 hours
Detomidine
Europe
Cattle
Meat 2 days, milk 12 hours
Ketamine
Europe
Cattle, sheep, goats, pigs
Meat 1 day, milk 0 hours
Meloxicam
Australia,
New Zealand
Cattle, sheep, pigs
Injectable formulation:
meat (cattle, pigs, sheep) 10 days, 3 days, 11 days
milk (cattle, sheep) 84 hours, 11 days
Canada
Cattle, sheep, pigs
Injectable formulation:
meat (cattle, pigs, sheep) 20 days, 5 days, 11 days
milk (cattle, sheep) 96 hours, 11 days
Canada
Cattle (not in lactating
animals)
Oral formulation:
meat 35 days
Europe
Cattle, pigs
Meat (cattle) 15 days
Milk 5 days
Meat (pigs) 5 days
Xylazine
Europe
Cattle
Meat 1 days, milk 0 days
New Zealand
Cattle
Milk 3 days, milk 0 days
Drug class
Drug name
Cattle
Small ruminants
Swine
Meat
Milk
Dose
Meat
Milk
Dose
Meat
Dose
Alpha‐2 Agonists
Detomidine
3 days
72 hours
≤0.08 mg/kg IV or IM
3 days
72 hours
≤0.08 mg/kg IV or IM
Xylazine
5 days
72 hours
0.016–0.1 mg/kg IV
5 days
72 hours
0.016–0.1 mg/kg IV
18 days
2.2 mg/kg IM
4 days
24 hours
0.05–0.3 mg/kg IM
4 days
24 hours
0.05–0.3 mg/kg IM
10 days
120 hours
0.3–2.0 mg/kg IM
10 days
120 hours
0.3–2.0 mg/kg IM
Alpha‐2
Antagonists
Tolazoline
8 days
48 hours
2–4 mg/kg IV
Yohimbine
7 days
72 hours
≤0.3 mg/kg
7 days
72 hours
≤0.3 mg/kg
Barbiturates
Thiopental
1 day
24 hours
≤9.4 mg/kg IV
1 days
24 hours
≤5.0 mg/kg IV
Benzodiazepines
Diazepam
10 days
≤0.1 mg/kg IV
10 days
≤0.1 mg/kg IV
Dissociative Anesthetics
Ketamine
3 days
48 hours
≤10 mg/kg IM
3 days
48 hours
≤10 mg/kg IM
2 days
10 mg/kg IM
3 days
48 hours
≤2 mg/kg IV
3 days
48 hours
≤2 mg/kg IV
4 days
20 mg/kg
Telazol®
30 days
≤2 mg/kg
Local anesthetics
Lidocaine
1 day
24 hours
≤15 ml epidurally
4 days
72 hours
≤100 ml SC
Opioids
Morphine
14 days
48 hours
0.1 mg/kg once IV, IM, epidurally
14 days
48 hours
0.1 mg/kg once IV, IM, epidurally
Butorphanol
5 days
72 hours
Non‐steroidal anti‐inflammatory drugs
Flunixin
4 days
36 hours
≤2.2 mg/kg IV, q24 hours for ≤3 days (label)
12 days
2.2 mg/kg IM
7 days
84 hours
≤2.2 mg/kg IV, once
13–15 days
2.2 mg/kg IM, if product not labeled for swine
10 days
96 hours
≤2.2 mg/kg IM, SC, PO once
21 days
2.2 mg/kg, IV or PO, ≥1 dose
≤60 days
≤2.2 mg/kg IM, SC, PO multiple doses
Meloxicam
21 days
0.5–1 mg/kg PO single dose
15 days
1 mg/kg PO, single dose
30 days
≤1 mg/kg PO, multiple doses
Phenothiazine Derivatives
Ace‐promazine
7 days
48 hours
≤0.13 mg/kg IV
7 days
48 hours
≤0.13 mg/kg IV
7 days
≤0.055 mg/kg IV
7 days
48 hours
≤0.44 mg/kg IM
7 days
48 hours
≤0.44 mg/kg IM
7 days
≤0.44 mg/kg IM
12.2 Barbiturates
12.3 Benzodiazepines
12.4 Dissociative Anesthetics
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