HuiChu Lin Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA Increased effort to manage pain has become standard practice in small animal medicine in recent years, but advances in pain mitigation in livestock species have been slower. Factors contributing to the slow progress are lack of analgesic drugs specifically approved for ameliorating pain of farm animals, known adverse effects, including excitation and decreased gastrointestinal (GI) motility caused by opioids or GI ulcer and impairment of renal function associated with nonsteroidal anti‐inflammatory drugs (NSAIDs), fear that loss of pain prompts further damage to the injured tissue, requirement of record keeping by the Drug Enforcement Administration (DEA) when using scheduled drugs, inconvenient timing to administer the drugs for effective pain relief, the need for trained personnel to administer the drug via a specified route such as intravenous (IV) injection, and the increased cost to owners for analgesic drugs and their administration [1]. Untreated pain can delay wound healing and cause significant patient discomfort, stress, depression, and inappetence. When pain is severe and prolonged, the immune system can become impaired. A goal for appropriate patient care is restoration of normal physiological functions. Judicious use of analgesic drugs should be an essential part of the treatment plan to provide adequate pain relief and ensure comfort so that normal physiological functions are not impaired or are allowed to return. It should be kept in mind that pain is easier to treat before perception of pain actually occurs (preemptive analgesia) [2]. Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in term of such damage.” Perception of pain involves transmission of electrical impulses in response to noxious stimuli received at the peripheral nociceptors located at the site of insult, which are Aδ or C fibers; transduction of the impulses through the spinothalamic tract to the dorsal horn of the spinal cord, modification of these impulses by releasing central nervous system (CNS) neurotransmitters, for example substance P, neurokinin A, and brain‐derived neurotrophic factor (glutamate), and activation of N‐methyl‐D‐aspartate (NMDA) receptors. Projection of these neurotransmitters is mediated through specific pathways to the thalamus (neospinothalamic and paleospinothalamic tract neurons) and the limbic system (thalamocortical tract neurons). As a result, generation and awareness of the perception or emotion of pain occur [3, 4]. The initial response to acute pain tends to be well localized, short‐lived, and proportional to the intensity of the insult. This response is usually a protective mechanism with the subject moving away from the insult. Unlike acute pain, chronic pain is usually diffuse and persistent, and is often associated with hypersensitivity of the neural cells in the spinal cord and brain. Chronic pain may not involve in injury to the tissue, but rather is often the result of inflammation associated with disease [4]. Hypersensitivity in the neural cells of the spinal cord and brain is reflected in the progression to central sensitization with increased sensitization of excitable nerve cells as evidenced by a disproportionally painful response to a normally mild noxious stimulation (wind‐up syndrome) or greater perception of pain to a previously nonpainful stimulation (allodynia) [4, 5]. Surgery‐induced pain often begins as acute pain but can progress to chronic pain as a result of prolonged inflammation. Pain experienced by farm animals is often difficult to recognize due to their stoic temperament and the natural instinct of prey animals not to attract the attention of predators when injured. Behavioral indications of a farm animal in pain may include one or more of the following clinical signs: excessive grunting and bellowing (vocalization), lowering of the head, rigid posture, tail swishing, limping, kicking, or stomping of feet, teeth grinding, excessive licking on the affected area, reluctance to move or lay down, depression, decreased interest in surroundings, and inappetence. Physiological changes associated with pain include increased respiration, heart rate, body temperature, and pupil size. However, these physiological responses to pain can be misinterpreted since vital signs are often influenced by stress or other endogenous as well as exogenous factors [6]. Therefore, close observation and monitoring of the animal by regular caretakers or a veterinarian on‐site are required for objective and unbiased judgment to institute appropriate and timely administration of pain‐relieving treatment. Inadequate pain management in young livestock undergoing castration surgery was evident in a survey of Canadian veterinarians in 2004 and 2005, which showed that less than 0.001% in piglets, 6.9% in beef calves, and 18.7% in dairy calves received perioperative analgesics [7]. A similar survey done in the UK showed that only 57% of adult cattle that underwent cesarean section and laparotomy received epidural anesthesia and/or postoperative analgesics [8]. A web‐based survey of members of American Association of Bovine Practitioners and Academy of Veterinary Consultants of the United States was conducted regarding castration methods, adverse events, and husbandry procedures [9]. The survey results indicated that only one of five surveyed participants provided an analgesic or local anesthetic at the time of castration [9]. In 2013, a survey of Brazilian large animal veterinarians indicated that 84% of them believed their knowledge of recognition and treatment of pain to be insufficient, and only 58.5% of the cattle they treated received preoperative analgesics for laparotomy as compared to the 72.9% for their equine patients [10]. Bradbury et al. [11] reviewed 233 papers on pain management in pigs undergoing experimental surgery, which would later transition to apply to human medicine due to the similarities of the physiology between pigs and humans. A total of 193 of the 233 papers described the use of drugs with analgesic effects but only 87 papers described the use of analgesics postoperatively. None of the papers described the justification for the analgesic chosen and only 23 papers provided an assessment of postoperative pain management. The authors concluded that postoperative pain management in pigs was either under‐reported or underused even though the surgical procedures performed would have very likely caused a similar degree of pain in humans. Furthermore, the description of analgesics used, when given, were too limited to provide useful information to other researchers or veterinarians performing similar procedures [11]. In a recent report, multiple professional organizations and beef and dairy producers in the USA indicated via online survey that the frequency of use of analgesics increased as cattle age increased, regardless of the procedure or disease [12]. Veterinarians were more likely to administer analgesics, either locally or systemically, than producers for routine procedures such as surgical castration and dehorning. While all respondents recognized the long‐term benefits of using analgesics in cattle, perceived federal regulations, lack of trained personnel to administer analgesics, and cost of the analgesics continue to be the limiting factors for routine pain management in cattle [12]. Apparently, there is a need for animal caretakers, producers, and veterinarians to better recognize pain associated with disease and to promote pain management. Awareness of the need for proper pain management of farm animals has prompted researchers worldwide to promote studies of objective methods to recognize and evaluate pain responses, and develop effective and safe analgesics. Analgesics commonly used in veterinary practice today include local anesthetics, α2 agonists, NSAIDs, opioids, and NMDA antagonists. These analgesics can be administered alone or in combination. The advantage of combining different classes of analgesics is the potentiation of each drug’s analgesic effect (synergism). Combining different classes of analgesics allows reduction of the dose requirement of each drug to produce effective analgesia, which then reduces the potential for side effects of each drug. Pain perception and its signal transmission occur at different levels, that is, peripheral nociceptor site, spinal dorsal horn, and central thalamic and limbic regions. Therefore, combining analgesics acting on different mechanisms and/or receptors maximizes analgesia (multimodal analgesia). A combination of local or regional anesthesia, NSAIDs, and low doses of an opioid and/or an α2 agonist is the most commonly practiced multimodal treatment for intra‐and postoperative pain management in farm animals [13]. Pain management should be included in the context of overall case management to optimize the patient’s quality of life and early return of normal physiological functions. Although analgesics may be effective in relieving pain caused by disease, they do not cure the cause of pathological tissue damage resulting from the disease. Therefore, it is imperative that the disease causing pain be appropriately treated by medication and/or surgery to remove the origin of the pain. Currently, no medications are approved by the US Food and Drug Administration (FDA) specifically for alleviation of pain in farm animals. Flunixin meglumine is approved for use in cattle only for treatment of pyrexia and inflammation [14]. Recently, transdermal flunixin meglumine was approved by the FDA for pain control in cattle, making it the only NSAID approved for pain control in cattle. Administering a drug not approved by FDA for pain relief is considered extralabel use [14]. Under the guidelines of the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) [15], extralabel drug use is permitted for relief of suffering of pain in food animals as long as the following specific conditions are met: (i) extralabel drug use is allowed only by or under the supervision of a licensed veterinarian; (ii) extralabel drug use is allowed only for FDA‐approved animal and human drugs; (iii) extralabel drug use is permitted only when the health of the animal is threatened and not for production purposes; (iv) extralabel drug use in feed is prohibited; and (v) extralabel drug use is not permitted if it results in a violative drug residue in food intended for human consumption. Therefore, pain management using analgesics not approved by the FDA can be instituted to minimize pain and suffering of farm animals only as long as the aforementioned conditions are observed. Fortunately, analgesics used today, with the exception of phenylbutazone, are short‐acting, but often require repeat dosing for long‐term treatment. Thus, their administrations can be terminated accordingly to avoid violative residues and to ensure protection of animal and human health [6, 16]. Local anesthetics, particularly lidocaine, can be administered locally or intravenously to produce pain relief. These drugs produce their anesthetic effects by blocking the propagation of action potentials along nerve axons via the reversible blockade of Na+ channels. These anesthetics can be injected into the tissue at the surgical site to produce local anesthesia, or they can be administered in the perineural area of major nerves to produce regional anesthesia. Local anesthetics block nerve fibers in the order β fibers (motor, touch) > nonmyelinated C fibers (pain, temperature) > A fibers (motor, proprioception), with the intensity of perception diminishing in the order of pain > cold > warmth > touch > deep pressure [17]. In domestic ruminants, many surgical procedures are performed safely and painlessly under local or regional anesthesia. All local anesthetics have similar physical properties and molecular structures. Most of these drugs are weakly basic tertiary amines, and they are generally available as acid solutions of the water‐soluble salts. The acid salt is neutralized in the tissue, liberating the basic drug form, which then penetrates the cell membrane and interrupts the propagation of the action potential. Therefore, local anesthetics are less effective in inflamed tissue with lower pH because less liberation of the basic form of the drug occurs [18]. A painful, stinging sensation on injection has been reported due to the acid nature of local anesthetics. This stinging sensation can be ameliorated by adding 5 ml of 8.5% sodium bicarbonate to 50 ml of 2% lidocaine solution (1 : 10 ratio) [19]. There are two types of local anesthetics: ester local anesthetics (e.g. procaine, tetracaine) and amide local anesthetics (e.g. lidocaine, mepivacaine, bupivacaine, ropivacaine). Amide local anesthetics are the most commonly used. Administration of local anesthetics prior to castration in young calves was shown to have beneficial effects such as reduced distress and improved incisional healing, though no significant improvement of average daily gain was observed [20–23]. Lidocaine in 2% injectable solution is the only local anesthetic approved by the FDA for use in cattle. It is approved for epidural administration with a maximal volume of 15 ml or for nerve blocks for volume up to 20 ml [16]. Lidocaine is the most popular local anesthetic, with onset of effect occurring within 5 minutes and a duration of 0.75–2 hours. Epinephrine induces vasoconstriction in the tissue surrounding the injected area and can be used with lidocaine to prolong the anesthetic duration of lidocaine by reducing absorption and removal of the drug by the blood circulation from the injection site. Epinephrine (1 : 200000–1 : 50000) at concentrations of 5–20 μg/ml can be added to lidocaine solutions [24, 25]. For sheep, the maximum concentration of epinephrine that can be added to lidocaine is 12.5 μg/ml of total solution [26]. However, potential side effects associated with addition of epinephrine to lidocaine include lack of revascularization of the wound edge and tissue necrosis when injected subcutaneously, and possible spinal cord ischemia when administered intrathecally or epidurally [27, 28]. When administered at 1.5 mg/kg intravenously to adult beef cows, lidocaine has a plasma half‐life (t½) of 1.06 ± 0.70 hours, a volume distribution of 4.6 ± 2.1 l/kg, and an elimination t½ of 1.52 ± 0.94 hours. When 100 ml of lidocaine was infiltrated subcutaneously for inverted‐L nerve blocks to Holstein cows, the maximum plasma concentration was reached at 0.52 ± 0.23 hours with a significant longer elimination t½, compared to that when the drug was administered intravenously (4.2 ± 1.7 hours) [29]. Other amide local anesthetics such as mepivacaine (5 mg/kg, 1.5–3 hours) and bupivacaine (2 mg/kg, 4–8 hours) can be used for procedures that require a longer duration of local anesthesia [30]. Bupivacaine is believed to have greater cardiotoxicity than lidocaine and mepivacaine [31]. Bupivacaine is not recommended for routine clinical use in cattle because the drug is reported to be toxic to cattle, particularly in cases of accidental IV administration [19]. Administration of a large single dose or repeated small doses of local anesthetics can result in toxicity, particularly in neonates and young patients. Clinical signs of toxicity include nystagmus, muscle fasciculation, CNS stimulation progressing to opisthotonos and convulsions, hypotension, respiratory arrest, circulatory collapse, and death [18]. The maximum calculated safe dose of lidocaine was reported to be 13 mg/kg in one study [32]. In another study, accumulated IV doses of 5.8, 18, and 42 mg/kg induced signs of toxicity in adult, neonatal, and fetal sheep, respectively [33]. IV infusion of mepivacaine in sheep induced convulsions at doses of 7.5–7.9 mg/kg and cardiovascular collapse at doses as high as 52–69 mg/kg [34]. Bupivacaine is approximately four times more potent than lidocaine. Therefore, a 0.5% solution of bupivacaine produces the same degree of neuronal blockade as a 2% solution of lidocaine. Anderson and Edmondson [19] recommended a lower maximum safe lidocaine dose of 10 mg/kg for cows undergoing cesarean section since a large volume of lidocaine is required to produce effective infiltration nerve blocks. Because small ruminants appear to be more likely to experience lidocaine toxicity, a maximum safe dose of 4 mg/kg is recommended [19]. Ewing [35] suggested a maximum dose of 6 mg/kg for lidocaine and mepivacaine, and 2 mg/kg for bupivacaine for small ruminants. With the maximum safe dose in mind, veterinarians should dilute lidocaine and mepivacaine solutions to 1 and 0.5%, respectively, to prevent overdosing in lambs and kids [35]. Diazepam (0.1–0.5 mg/kg IV) should be administered if seizure activity or convulsions caused by accidental overdose persist longer than 1–2 minutes [31, 36]. Ropivacaine is a newer local anesthetic with a duration of effect similar to bupivacaine (6‐8 hours) but lower risk of cardiotoxicity than bupivacaine and less vasodilation than lidocaine [18]. Please refer to Chapter 12 for withdrawal times for lidocaine. Opioid analgesics such as morphine, meperidine, fentanyl, buprenorphine, and butorphanol have been used for pain management in farm animal species. These drugs bind to μ, κ, or δ (OP3, OP1, or OP2) opioid receptors located on neuronal cell membranes. Binding of an opioid to these receptors triggers cellular changes that hyperpolarize the cell membrane and inhibit spinal pain transmission. Activation of μ receptors results in depletion of intraneuronal substance P, which reduces overall inflammation and neural pain transmission. There are opioid receptors located centrally in the hypothalamus, brain stem and spinal cord, and, peripherally, in joints and the cornea. Therefore, opioid analgesics can be administered either systemically for action on the brain or they can be deposited close to the site of action and produce their effects at all levels of pain pathways. For example, parenteral administration of an opioid provides analgesia at the central supraspinal level, intra‐articular injection relieves joint pain, and epidural administration provides pain relief at the level of the spinal cord. Side effects of opioid analgesics such as respiratory depression, decreased GI motility and increased GI emptying time, increased appetite, sedation, euphoria, and nausea are also associated with activation of μ receptors [37]. Tachycardia and hyperexcitability develop occasionally when high doses of opioids are administered to farm animal species. Interestingly, hyperexcitability, though commonly observed in other species, does not occur as frequently in ruminants when administered at the recommended dose [38]. Most opioids used in veterinary practice are classified as either pure μ agonists (morphine, meperidine, and fentanyl), partial μ agonists (buprenorphine), or agonist/antagonist (butorphanol). Butorphanol is classified as agonist/antagonist because it possesses agonistic effects on κ receptors but antagonistic effects on μ receptors. Thus, butorphanol should not be administered at the same time as a pure μ agonist such as morphine because these two drugs compete for binding at μ receptor sites and butorphanol can antagonize the pharmacological effects of morphine, including analgesia. Unlike in other species, opioids have not been commonly prescribed for analgesia in farm animal species due to their controlled substance status and questionable effectiveness, although they have proven to provide effective pain relief in response to thermal and pressure stimulations [39–43]. Morphine, a pure μ opioid agonist, is effective in relieving mild pain in ruminants. Good analgesia only occurred in one‐third of the farm animals receiving morphine [2]. Morphine should be administered parenterally, not orally, to ruminants because the drug is inactivated by the ruminal microflora. Doses of 0.05–0.5 mg/kg every 4–6 hours by IV, intramuscular (IM), or subcutaneous (SC) route are recommended [38, 44]. Superior analgesia produced by morphine was reported when administered at doses as high as 10 mg/kg to goats [38], even though 0.5 mg/kg IM is the dose recommended for use in goats [45]. Due to the slow onset of analgesic effect of morphine as a result of low lipid solubility (10 minutes IV, 20 minutes IM), an initial IV administration of the drug is recommended when significant pain is expected after surgery and maintenance of analgesia can be continued with IM administration or constant rate infusion (CRI) of a low IV dose of morphine. Large IV doses of morphine have been reported to cause a reduction of ruminoreticular contractions for up to 20 minutes [46]. However, GI side effects were not observed when morphine was administered intravenously at 0.1 mg/kg to cattle [46]. A low‐dose CRI of morphine maintains constant effective blood level but minimizes the risk of inhibition of ruminoreticular contraction [44]. Please refer to Chapter 12 for withdrawal times for morphine. Meperidine hydrochloride is a synthetic opioid with an analgesic potency only 10–50% of that of morphine. Meperidine produces mild sedation and analgesia. Its administration has been associated with histamine release [47]. In yearling goats, meperidine (10 mg/kg IM) can be used as a preanesthetic analgesic given 10 minutes before induction of anesthesia with thiopental. After intubation, this combination provides 20 minutes of surgical anesthesia with complete recovery occurring in 90 minutes [48]. Fentanyl is a pure μ agonist similar to morphine with a potency that is approximately 75–100 times that of morphine. Fentanyl can be administered parenterally or transdermally. When administered parenterally, fentanyl induces analgesia within 5 minutes with a short duration of 20 minutes [38]. IV administration of fentanyl has been associated with abnormal behaviors and adverse effects such as pica, stall pacing, nystagmus, hyperexcitability, mania, ataxia, sedation, bradycardia, and respiratory depression [38, 49]. Transdermal patches are available at 0.025, 0.05, 0.075, and 0.1 mg/hour doses. A 0.05 mg/hour patch is an appropriate dose for a 30–50‐kg (66–110‐lb) goat [49]. Onset of analgesia is observed 18–24 hours after placement, and each patch lasts approximately 3 days. A new patch should be placed 48 hours after the first one has been applied. Variable absorption of fentanyl from the patch limits its clinical usefulness [49]. Contrary to the report in goats, transdermal fentanyl produced superior analgesia to intermittent administration of IM buprenorphine in sheep [50]. Maximum plasma concentration was reached at 12 hours following the placement of the patch with the concentration maintained above 0.5 ng/ml for 40 hours. In addition to effective analgesia, fentanyl‐treated sheep required less preanesthetic sedation to allow for tracheal intubation [50, 51]. When compared to intermittent IM administration of buprenorphine (0.01 mg/kg every 8 hours), transdermal fentanyl (2 μg/kg/hour) applied 24 hours prior to surgery in pregnant ewes produced more profound analgesia and a shorter anesthesia recovery time [52]. However, signs of excitement such as vocalizing, paddling, head jerking, and multiple unsuccessful attempts to stand were observed during the recovery period with fentanyl treatment but light manual restraint was sufficient to prevent the ewes from injuring themselves until signs of excitement subsided [52]. In cattle, application of 0.05–0.1 μg/kg of fentanyl patch for pain relief was shown to be clinically beneficial [19]. Consistent skin absorption from fentanyl patches has also been reported when placed on the medial antebrachium in llamas [53]. In swine, a fentanyl 75–100 μg/hour patch can be applied to the interscapular region to provide analgesia in 20–40‐kg (44–88‐lb) pigs postoperatively [38]. Effective plasma concentrations of 0.5 and 2 ng/ml can be achieved within 24 hours following application of the transdermal patch [38]. A fast‐acting analgesic should be given to provide pain relief due to slow absorption of fentanyl from a transdermal patch [2]. It is very important that the hair on the area intended for placement of the patch be clipped and the skin cleaned completely to ensure secure adherence of the patch. Excessive hair, dirty skin, or insecure adherence of the patch may result in inconsistent and unreliable absorption of the drug and subsequently suboptimal analgesic effect. Keep in mind that rumenosalivary recycling may result in bioavailability exceeding 100% and thus prolong the effects of fentanyl. This may pose a problem in establishing accurate withdrawal times [49]. Tramadol is a synthetic analog of codeine and morphine [54]. Tramadol produces analgesia by its action through central opioid, adrenergic, and serotoninergic receptors [55]. It is classified as scheduled IV drug in 2014. Tramadol offers advantages over other opioids. It causes less respiratory depression and has low potential for human abuse [54, 56]. Furthermore, tramadol is reported to produce less CNS excitation in horses [57].Tramadol has been shown to be effective in treating moderate to more severe postoperative pain in humans and dogs [58, 59]. However, clinical experience of this author indicated that only minimal analgesia was observed when tramadol was administered to dogs. Tramadol has low affinity for opiate μ receptors, and its dose requirement to produce similar degree of analgesia for moderate pain is 10 times that of morphine [60]. For more severe pain, tramadol administered at the same dose ratio is less effective than morphine [61]. One of the metabolites of tramadol, O‐desmethyltramadol, is reported to be six times more potent in analgesic effect and 200 times more potent in binding ability to μ receptors than tramadol [62]. In calves undergoing a disbudding procedure, either IV tramadol (4 mg/kg) or rectal suppositories [200 mg/50–60 kg (110–132 lb)] provided effective analgesia to prevent head shaking, ear flicking, and head rubbing, indicators of pain from the application of caustic paste following disbudding [63]. Orally administered tramadol is well absorbed in humans, dogs, and cats with bioavailabilities of 70%, 65%, and 93%, respectively [64–66]. Lower absorption with a bioavailability of 23–37% and 5.9–19.1%, respectively, was reported following a single oral dose of 2 mg/kg in goats and 11 mg/kg in alpacas [67, 68]. A large volume‐to‐surface ratio, constantly high content of solid matter, and complex microflora and microfauna in the rumen were suggested to be the causes for the lower oral absorption of tramadol in goats and alpacas [67, 68]. A higher gastric pH of 6.8 in the rumen [69] as opposed to pH of 1.0–2.0 in the monogastric stomach [70] in the presence of a pK a value of 9.41 of tramadol results in a greater percentage of nonionized tramadol in plasma and enterohepatic recycling in ruminants, which increase absorption of the drug and are believed to be the primary factors responsible for the high plasma tramadol concentrations in goats (542.9 ± 219.5 ng/ml) and alpacas (1202 ± 1319 ng/ml) [67, 68]. In humans, plasma concentrations of 100–150 ng/ml are recommended as the minimum effective concentration of tramadol in relieving mild to moderate pain [58, 64]. The elimination t½ following oral administration was 2.67 ± 0.54 hours in goats, which is shorter than that of humans [56] but longer than that of horses and alpacas [57, 68]. However, IV administration of tramadol at 2 mg/kg to these goats did not provide effective pain relief as the plasma concentration rapidly declined below minimum effective concentrations [67]. Adverse effects such as hyperexcitability, hyperesthesia, tremors, and ataxia occurred soon after the start of IV administration of tramadol over a period of 5 minutes, but side effects quickly dissipated 15 minutes after the termination of IV infusion to alpacas [68]. These adverse effects were not observed following oral administration or slower IV administration over a period of 10 minutes. In alpacas, two of the metabolites, O‐desmethyltramadol and N‐desmethyltramadol, have slightly longer plasma t½, 1.53 ± 0.68 and 1.38 ± 0.48 hours, respectively, than tramadol itself (0.849 ± 0.463 hours) [68]. Tramadol is capable of crossing the placenta and appears in the fetal circulation, and low concentrations of the parent drug and its active metabolites were also detected in human breast milk within 16 hours after administration [56]. A milk or meat withdrawal time for tramadol has not been established at this time. In pigs anesthetized with xylazine (2.5 mg/kg IM) and ketamine (25 mg/kg IM), adding tramadol (5 mg/kg IM) to the anesthetic combination improved the quality of anesthesia and prolonged the duration of analgesia (43.7 ± 15.5 minutes vs. 32 ± 13.3 minutes) without alteration of physiologic parameters and prolongation of recovery from anesthesia [71]. Tramadol (1.6 mg/kg IM) has also been combined with xylazine (1.2 mg/kg IM) and telazol (3 mg/kg IM) to produce general anesthesia with excellent muscle relaxation and analgesia for approximately 80 minutes in pigs [72]. Buprenorphine is classified as a partial μ agonist with an analgesic potency that is 25 times that of morphine. Buprenorphine is poorly absorbed from the GI tract. Due to its high affinity and low specificity for the μ receptors, opioid antagonists are ineffective in reversing buprenorphine’s effects. Onset of analgesia occurs in 45 minutes with a duration of 240 minutes following IM administration of buprenorphine (0.005–0.01 mg/kg). Propulsive walking, rapid and frequent head movements, chewing, and hypersensitivity to auditory and visual stimuli were observed in sheep receiving buprenorphine [39]. This author (Lin) has used IM buprenorphine at 0.01 mg/kg administered to goats every 6 hours following orthopedic surgery and observed satisfactory analgesia. No signs of CNS excitation as described in sheep were observed in the goats. A 3‐day meat withdrawal is suggested for buprenorphine [38]. The recommended dose of buprenorphine in pigs is 0.01–0.05 mg/kg IM or IV every 6–12 hours [73]. When compared to etorphine (0.003 mg/kg IM) and pethidine (20 mg/kg IM), buprenorphine (0.12 mg/kg IM) produced longer duration of analgesia (7–24 hours) in pigs [74]. The analgesic effect of buprenorphine is deemed better than that of pethidine but not as good as etorphine [74]. Buprenorphine has been used in pigs following thoracotomy surgery at 0.01–0.04 mg/kg administered intramuscularly to provide adequate pain relief (Lin, personal observation). Butorphanol is a κ agonist and μ antagonist with an analgesic potency approximately three to five times that of morphine. Butorphanol has a unique “ceiling effect”, that is, after effective action has been attained further increases in doses do not increase or enhance the degree of desirable pharmacologic effect [75]. Butorphanol may cause slight CNS stimulation in farm animal species, especially when administered to animals that are not in pain. Twitching of the facial muscles, lips, and head may occur. Butorphanol is the most frequently used opioids in farm animals. The recommended dose of butorphanol is 0.02–0.05 mg/kg IV or SC every 4–6 hours. Jones (2008) [2] commented that butorphanol is the best analgesic for ameliorating established pain and is capable of providing excellent visceral analgesia in 80% of the ruminant patients. Butorphanol can be given alone in sheep and goats to produce light sedation. No behavioral effects were observed when butorphanol was administered intravenously at 0.05 mg/kg in sheep, but ataxia was observed at 0.4 mg/kg while excitement occurred at 0.1–0.2 mg/kg [42, 76, 77]. In cattle, tremor and propulsive walking occurred following IV administration of butorphanol, but the signs disappeared within 30 minutes [38]. Butorphanol is frequently used in combination with a sedative or a tranquilizer to produce standing sedation and analgesia for minor surgery and diagnostic procedures. It can also be administered postoperatively for pain relief. In sheep and goats, xylazine and butorphanol can be administered simultaneously to produce deep sedation and recumbency lasting for as long as 60 minutes. In dairy cows, the t½ of 0.25 mg/kg IV is reported to be 82 minutes [78]. Adding xylazine (0.05 mg/kg) and ketamine (0.1 mg/kg) to butorphanol (0.025 mg/kg) did not affect the elimination t½ of butorphanol (71.28 ± 7.64 minutes) when the combination was administered intramuscularly to Holstein calves immediately prior to castration and dehorning [79]. This combination has been used successfully to provide analgesia for surgical procedures on very fractious cattle and also in cattle suffering extreme pain caused by disease [19]. Interestingly, when IV butorphanol (0.07 mg/kg) and xylazine (0.02 mg/kg) were administered to weanling bulls at the time of castration, the treatment did not offer significant beneficial effects in reducing distress and improving growth performance after surgery [80]. In pigs, butorphanol is recommended at 0.1–0.3 mg/kg IV or IM every 4 hours, doses slightly higher than for other farm animal species [73]. Please refer to Chapter 12 for withdrawal times for butorphanol. NSAIDs are used for their analgesic, antipyretic, and anti‐inflammatory properties through inhibition on cyclooxygenase (COX), lipoxygenase, and thromboxane enzymes. The COX acts on arachidonic acid to release prostaglandins and other mediators of inflammation, and thus COX inhibitors like NSAIDs prevent the production of these mediators. There is evidence indicating NSAIDs may produce analgesia by central inhibition of pain response involving α2 and μ receptors. There are two COX isoforms, COX‐1 and COX‐2. The COX‐1 isoform is present in normal peripheral tissues and CNS. Its expression is enhanced by pain and inflammatory mediators. The COX‐2 isoform is expressed in the CNS but only becomes the major enzyme for prostaglandin synthesis after induction by factors released from cell damage and death. Maximal COX‐2 mRNA expression occurs in peripheral tissues 2–8 hours after induction [81]. NSAIDs appear to have differential activity according to their affinity for the two COX isoforms. For example, flunixin meglumine, ketoprofen, and phenylbutazone are nonspecific COX inhibitors, whereas etodolac and carprofen are selective COX‐2 inhibitors. Flunixin meglumine is an excellent visceral analgesic, and phenylbutazone is very effective in relieving musculoskeletal pain. Clinical observation suggests specific COX‐2 inhibitors are not effective analgesics in ruminants [2, 82]. NSAIDs are available in oral formulation, making oral administration an alternative route to provide pain relief. However, there are significant differences in the clearance of these drugs between animal species and age groups. Also, some of the NSAIDs have a narrow margin of safety in that therapeutic indexes are relatively close to their toxic indexes. Therefore, extrapolation of alternative NSAID dosing regimens from one species to another is extremely dangerous and not recommended [83]. Aspirin (acetylsalicylic acid) and sodium salicylate are both salicylic acid derivatives and were the first NSAIDs used for their analgesic, antipyretic, and anti‐inflammatory effects. Though neither drug has been approved for use in food animals by the FDA, aspirin is frequently administered at 100 mg/kg, twice daily orally, for treatment of fever and minor joint and muscle pain. Aspirin ionized extensively in the rumen pH with an ionized‐to‐nonionized ratio of 1000 : 1, indicating a low oral bioavailability and slow absorption of the drug following oral administration in ruminants [84, 85]. It is believed that the rumen serves as a slow‐release reservoir for oral aspirin absorption, reflecting the longer elimination t½ of 3.70 ± 0.44 hours following oral administration of salicylic acid as compared to 0.54 ± 0.04 hours following IV administration of sodium salicylate to adult dairy cows [84, 86]. In humans, minimum effective serum concentration of salicylic acid to relieve mild pain resulting from headaches, aches, and pain is 30 μg/ml, but 100 μg/ml is required to relive pain caused by arthritis. In cattle, only oral administration of 100 mg/kg of aspirin resulted in a serum concentration above 30 μg/ml while 50 mg/kg did not. Therefore, 100 mg/kg of sodium salicylate is recommended to maintain serum concentration above 30 μg/ml. However, conflicting reports showed that sodium salicylate relieved pain caused by nonsuppurative tarsitis in two cows but did not relieve pain in a bull suffering suppurative tarsitis [84]. There is no report on salicylic acid‐induced clotting deficit in cattle [87]. For pigs, aspirin is recommended at a dose range of 10–20 mg/kg administered orally every 4–6 hours [73]. Please refer to Chapter 12 for withdrawal times for aspirin. Flunixin meglumine (banamine) is a COX‐1 inhibitor. It is approved by the FDA for use in beef and lactating dairy cattle for fever and inflammation associated with respiratory diseases, endotoxemia, and acute bovine mastitis [14]. Recently, transdermal flunixin meglumine was approved by the FDA for pain control in cattle, making it the only NSAID approved for pain control in cattle. Flunixin meglumine is approved for IV administration at a dose of 1.1 mg/kg BID or 2.2 mg/kg SID, and this dosing regimen may produce analgesia for 6–12 hours. This dose can be repeated for up to 3 days. In calves undergoing castration with a Burdizzo clamp or surgical removal, effective pain relief was produced by flunixin meglumine administered IV along with epidural lidocaine. The report showed a significant decrease (50%) in plasma cortisol concentration and that the calves receiving flunixin meglumine had better steps and stride 6–8 hours into the postoperative period compared to the nontreated calves [88, 89]. Flunixin meglumine alone (2.2 mg/kg IV) administrated 20 minutes before castration resulted in a mild decrease (20%) in plasma cortisol concentration. Several studies showed that concurrent administration of epidural lidocaine or xylazine enhanced the analgesic effect of flunixin meglumine [88–91]. Nonetheless, significantly better appetite, defecation, and milk production have been observed in cows receiving flunixin meglumine 24 hours before and after surgical correction of a left displaced abomasum [92]. In cattle, significant myonecrosis and prolonged tissue residues have been reported when flunixin meglumine is administered intramuscularly [14] (refer to Chapter 12 for drug withdrawal times). Thus, the drug should only be administered intravenously in cattle. However, this route of administration not only causes stress to the animal but also requires special training for personnel performing the task. Transdermal flunixin meglumine is given as a pour‐on for transdermal absorption. It is reportedly to have a bioavailability of 37–48% and a plasma t½ of 6.42–7.16 hours in calves without painful stimulations [93, 94]. In dehorning calves, Kleinhenz et al. [94] demonstrated that pain‐induced sympathetic nervous stimulation with subsequent vasoconstriction caused a reduction of blood flow to the skin surrounding the horns. As a result, blood perfusion to the tissues surrounding the base of the horns decreased, which in turn decreased the absorption and bioavailability of the transdermal flunixin meglumine [94]. Furthermore, evaluation of pain biomarkers following dehorning indicated that transdermal flunixin meglumine alone did not provide effective analgesia to dairy calves either intraoperatively or postoperatively, as indicated by the lack of significant difference in the mechanical nociceptive threshold and plasma concentrations of cortisol and substance P [95]. However, local anesthetic blockade was not performed prior to dehorning in these two studies, as the intent of the studies was to assess the response of the biomarkers and the impact of pain on the pharmacokinetics of transdermally administered flunixin meglumine [94, 95]. Concurrent use of local anesthetic blockade and transdermal flunixin meglumine provided perioperative multimodal analgesia. The ease of administration and FDA‐approved transdermal flunixin meglumine allows producers to formulate a method that does not require using a needle to provide analgesia without additional personnel training. Flunixin meglumine has become the second most common residue violation (the first being penicillin) in cull dairy cows. Veterinarians should address and emphasize the importance of following label instruction of the drug to farm personnel [96]. Doses of 2–4 mg/kg IV or SC once daily for flunixin meglumine are recommended for use in pigs [73]. However, 1–4 mg/kg IV, IM, or SC every 12 hours is recommended for pet pigs [97]. Please refer to Chapter 12 for withdrawal times for flunixin meglumine. Phenylbutazone is clinically more effective in relieving pain associated with musculoskeletal injuries and chronic osteoarthritis than flunixin meglumine. Phenylbutazone is a drug with high level of regulatory concern due to lack of predictable withdrawal times. The drug is highly protein‐bound with a very long elimination t½ in cattle (30–80 hours) and sheep and goats (15–20 hours) when compared to that of other large animal species. When administered to cattle at a loading dose of 24 mg/kg followed by a single daily dose of 12 mg/kg, the drug was still detectable in milk 82 hours after administration. At this time, the use of phenylbutazone in female dairy cattle older than 20 months of age is strictly prohibited, and its use in other milk‐ and meat‐producing animals is strongly discouraged due to the concern over human consumption [98]. Phenylbutazone is capable of crossing the blood–placenta barrier, and concentration of the drug can be detected in calves born to treated cows. Continued exposure through the milk may lead to detectable plasma concentration in newborn calves with an elimination t½ as long as 4 days [99]. In addition, the elimination t½ of phenylbutazone has been reported to be age dependent, and it is twice as long in 1‐month‐old calves compared to 3‐month‐old calves [100]. Thus, the administration of phenylbutazone in very young calves is also discouraged. Phenylbutazone is believed to be a carcinogen and has been reported to cause blood dyscrasias (e.g. aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenia), and the death rate in humans that develop aplastic anemia can be as high as 94% [101]. There are reports indicating that an idiosyncratic serum sickness, a type III hypersensitivity reaction, results from exposure to food residue of phenylbutazone, but no threshold concentration of phenylbutazone has been established [102]. Extralabel use of phenylbutazone is not justifiable under the AMDUCA guidelines because another NSAID (flunixin meglumine) is available and approved for use in food animals. It is recommended that phenylbutazone be reserved for valuable beef breeding stock with severe chronic disease when slaughter is not an option but temporary relief of pain is necessary for embryo or semen collection followed by euthanasia. A meat withdrawal time of a minimum of 45 days for the first dose of phenylbutazone with another 5 days added to each additional day of therapy beyond the first is recommended with a duration of up to 6–8 months if needed [2, 14, 83]. Although there are no NSAIDs approved for use in small ruminants, flunixin meglumine is labeled for use in food animals and should be used preferentially over phenylbutazone. Ketoprofen is not approved by the FDA for use in food‐producing animals. In Canada and European countries, ketoprofen is approved for use in alleviation of inflammation and pain associated with arthritis and traumatic musculoskeletal injuries, and also as adjunctive treatment for pain, fever, and inflammation associated with acute mastitis [103]. Compared to other NSAIDs, ketoprofen has a short plasma t½ (30 minutes) and a small volume of distribution (0.2 l/kg), with 80% of the parent drugs eliminated in urine within 24 hours [103, 104]. Ketoprofen comes as a racemic combination of 50 : 50 ratio of R(−) and S(+) enantiomeric forms in the commercial formulation. It is reported that the S(+) isoform is approximately 250 times more potent than the R(−) isoform in its ability to inhibit prostaglandin E2 (PGE2). Approximately 31% of the R(−) isoform is converted to the S(+) isoform following IV administration in calves [105]. In sheep, the inhibition of PGE2 by the S(+) isoform lasts four times longer than that of the R(−) isoform [106]. The concentration of ketoprofen in milk, even at peak plasma concentration, was below the sensitivity level of the analytical test, suggesting that the drug can be used safely in milk‐producing ruminants with a short and predictable milk withdrawal time. The Food Animal Residue Avoidance Databank (FARAD) recommends a 24‐hour and 7‐day milk and meat withdrawal times, respectively [107]. Some clinicians believe that ketoprofen does not have any advantage over flunixin meglumine for treatment of inflammatory diseases in ruminants [83]. However, if the criteria for extralabel use can be met, ketoprofen can be administered at 3.3 mg/kg SID for up to 3 days. In 4‐ to 8‐week‐old calves, ketoprofen (3 mg/kg per os [PO]) has been shown to reduce pain‐related behaviors when administered prior to and at 2–7 hours post the hot‐iron dehorning procedure [108]. Combining ketoprofen and a cornual nerve block with or without xylazine greatly reduced the distress associated with dehorning and disbudding in calves as indicated by the reduction of the cortisol response to the surgery [109, 110]. Comparing intratesticular lidocaine alone to the combined technique of ketoprofen with intratesticular lidocaine for castration in calves less than 4 months old, the combined technique completely inhibited cortisol response to the surgery, while lidocaine alone did not inhibit cortisol response [111]. In pigs, 1–3 mg/kg IV, IM, or PO of ketoprofen every 12 hours is recommended [73, 97]. Carprofen has greater potency and lower ulcerogenicity than phenylbutazone or aspirin [112]. Carprofen is approved in European countries for use as an adjunct treatment to antimicrobial therapy to reduce clinical signs in acute infectious respiratory disease and acute mastitis in cattle [113]. Similar to ketoprofen, carprofen has two enantiomer isoforms with the S(+) isoform approximately 100 times more potent than the R(−) isoform in inhibiting COX‐2 enzyme in a canine study [114]. However, the effect of carprofen on both COX‐1 and COX‐2 enzyme activities is considered poor [112]. In sheep, the elimination t½ of carprofen was 26.1 and 33.7 hours when administered intravenously at 0.7 and 4 mg/kg. Plasma concentration greater than 1.5 μg/ml corresponded to the effective analgesic effect of carprofen. When administered at 4 mg/kg IV, carprofen maintained therapeutic plasma concentrations for longer than 72 hours [115, 116]. Measurable amounts of carprofen were detected in the milk of cattle with mastitis following a single IV dose of 0.7 mg/kg [117]. In another study, no measurable milk concentrations of greater than 25 μg/ml were detected when carprofen was administered at 1.4 mg/kg IV to healthy cows. No milk withdrawal time for carprofen is needed in European countries. Based on a maximum residue level of carprofen of 500 μg/kg in muscle and 1000 μg/kg in liver and kidney, a meat withdrawal time of 21 days is recommended following a single injection of 1.4 mg/kg IV in European countries [118]. In calves, carprofen (1.4 mg/kg IV) alone administered 20 minutes before castration using a Burdizzo clamp technique decreased plasma cortisol concentration by 19% [119], but a 59% reduction was observed when carprofen was combined with epidural lidocaine [88]. Similar to ketoprofen, carprofen is believed not to have any advantage over flunixin meglumine, and its use in food‐producing animals is not recommended due to its prolonged clearance time and detectable milk distribution. Doses of 2–4 mg/kg IV or SC once daily are recommended for administration of carprofen in pigs [73]. Wolff [97] suggested that administration of carprofen at 2–3 mg/kg IM, SC, or PO every 12 hours is appropriate for treatment of pigs. Carprofen administered orally at 2 mg/kg every 12 hours for 3 days provided effective analgesia in a pig suffering severe joint pain (Lin, personal observation). Meloxicam preferentially, though not specifically, inhibits COX‐2 enzymes. Meloxicam (0.5 mg/kg IM or SC) is approved as adjunct treatment of cattle with acute respiratory diseases, acute mastitis, or diarrhea in several European countries and the UK [120]. A small animal formulation is approved and marketed in the USA. Meloxicam has been proven to effectively relieve pain in calves resulting from castration, dehorning, and diarrhea [121–123]. Good oral bioavailability with maximum plasma concentration occurred at 10–12 hours with an elimination t½ of 27.5 hours after oral administration of meloxicam at 1 mg/kg to 3‐month‐old Holstein calves [124]. Other evidence supporting the effectiveness of meloxicam (0.5 mg/kg IV) in ameliorating pain includes reduced heart rate and respiratory rate, and improved weight gain in treated calves when compared to untreated calves following dehorning and castration procedures [125–127]. In lactating goats, the elimination t½ following IV and IM administration of 0.5 mg/kg of meloxicam was reported to be 9.96 and 10.83 hours, respectively. The study also showed complete absorption of the drug, as reflected in 105% bioavailability following IM administration [128]. The authors suggested that once‐a‐day dosing at 0.5 mg/kg may be sufficient to sustain long duration of analgesia based on the high IM bioavailability, long elimination t½, and a mean plasma concentration at the steady state above the values of average therapeutic concentrations [128]. It is believed that meloxicam may be useful for sustained pain relief of greater than 3 days at 0.5–1 mg/kg orally every 24–48 hours [19]. A possible fatal anaphylactoid reaction in an Ayrshire cow to IV meloxicam was reported [129]. The cow appeared agitated and had profuse lacrimation, bilateral periocular edema, and chemosis within 10 minutes after IV administration. She became markedly ataxic and assumed a recumbent position. Hyperventilation rapidly progressed to blood‐tinted foaming at the mouth, tachypnea, and then dyspnea with cyanotic oral, nasal, and vulvar mucous membrane. The cow was euthanized due to the severity of the clinical signs [129]. Although manufacturers reported that the anaphylactoid reaction to NSAIDs is extremely rare with possibility incidence of less than 1 per 30 000 administrations, veterinarians should be aware of this possible reaction and be prepared to institute emergency treatment when an incident occurs [129]. Preemptive administration of meloxicam (0.4 mg/kg IM) to pigs not only reduces stress prior to castration but also provides analgesia following surgery [130]. Similar analgesic effects evaluated by vocal characteristics and cortisol response to castration was reported in piglets when meloxicam (0.4 mg/kg IM) with or without lidocaine local anesthesia was administered 15 minutes prior to surgery [131]. Meloxicam appeared to have wide margin of safety as evidenced by administration of five times the recommended dose (2 mg/kg) for 6 consecutive days to 5‐ to 6‐month‐old pigs with no lasting adverse effects observed [132]. Please refer to Chapter 12 for withdrawal times for meloxicam. Diclofenac, a newly introduced NSAID, is an effective analgesic for post‐traumatic pain, postoperative wound hyperalgesia, pain associated with movement and swelling, and joint pain resulting from lameness in horses [133–136]. Diclofenac was reported to be an effective analgesic for treatment of acute aseptic arthritis and myositis in cattle and buffalos [136, 137], and in relieving pain caused by castration in lambs [138, 139]. In sheep, diclofenac is proven to be effective against Brucella species and schistosomiasis when used in combination with streptomycin, rifampicin, or tetracycline [138, 140]. The elimination t½ of diclofenac following 1 mg/kg IV and IM administration to sheep were 2.84 ± 1.94 and 2.12 ± 1.60 hours, respectively. Therefore, twice or three times daily doses will be ideal to maintain an effective plasma concentration of the drug [141]. Tolfenamic acid is an anthranilic acid class of NSAIDs. The drug is approved in European countries and Canada for use in cattle for treatment of acute mastitis and respiratory tract diseases. Although there are no proven data indicating any advantage of tolfenamic acid over flunixin meglumine, it has been occasionally used extralabelly. The pharmacokinetic study in cattle showed that tolfenamic acid has a large volume of distribution (1 l/kg) and a long elimination t½ (8–10 hours) [16]. Prolonged, sustained therapeutic plasma concentration of tolfenamic acid following a single injection has been attributed to the unique enterohepatic recirculation in this species. Tolfenamic acid, when administered at the recommended dose of 4 mg/kg IV, has a milk withdrawal time of 24 hours [16]. The maximum residue levels of the drug in milk and muscle, kidneys, and liver have been set at 50, 100, and 400 μg/kg, respectively. Therefore, a meat withdrawal time of 7 days for a single IV injection of 2 mg/kg in beef cattle is recommended where the drug is approved [16, 142]. Metamizole, a pyrazolone derivative, is classified as a nonacid antipyretic analgesic. It is licensed for use in cattle in European countries. When administered at 40 mg/kg IV prior to umbilical surgery in calves, evidence of analgesia was supported by significantly lower heart rate and plasma cortisol concentrations for at least 150 minutes following skin incision into the postoperative period. Repeat dosing may be required if longer duration of pain relief is needed [143]. α2 agonists such as xylazine, detomidine, medetomidine, dexmedetomidine, and romifidine have been shown to produce good visceral analgesia. These drugs produce analgesic effects via their actions on the peripheral and central α2 receptors. There are α2 receptors located in the dorsal horn of the spinal cord, whereas stimulation of the α2 receptors located at the periaqueductal gray area of the midbrain (site of origin of the descending inhibitory pain pathways) is responsible for the release of norepinephrine and modulation of pain at the spinal level. In sheep, it was shown that approximately 60% of analgesia produced by IV xylazine is mediated via spinal α2 receptors and this was supported by the evidence of prior intrathecal administration of α2 antagonists, idazoxan or RX811059A, which resulted in a reduction of IV xylazine‐induced analgesia [144]. Therefore, α2
10
Pain Management for Farm Animals
10.1 Local Anesthetics
10.2 Systemic Pain Management
10.2.1 Opioid Analgesics
10.2.2 Nonsteroidal Anti‐inflammatory Drugs
10.2.3 Alpha‐2 Agonists
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