Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.

the effect of application site on a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 27-33. Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg ⁄ kg (50 lL ⁄ kg) dose of a novel, long-acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng ⁄ mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (C max ) and the area under the curve (AUC) were not contained within the 80-125% interval. The C max was 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng ⁄ mL for the ventral and dorsal application groups, respectively. The terminal elimination half-lives (t 1 ⁄ 2 ) for both groups were similar with values of 137 ± 58.9 and 117 ± 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of ‡2 lg AE kg ⁄ h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2-4 h prior to surgery with analgesia lasting a minimum of 4 days.(Paper

Buprenorphine is effective for the control of postoperative pain in cats (Steagall, Monteiro-Steagall, and Taylor 2014). Two pharmaceutical buprenorphine formulations have been approved for use in cats. The first, a low concentration buprenorphine solution (0.3 mg/ ml) was approved for use as intramuscular (IM) and intravenous (IV) injection (0.01-0.02 mg/kg) in 1995 in the United Kingdom (UK) ("Vetergesic; Ceva Animal Health 1995") and later in several other regulatory jurisdictions. It has not been approved in the United States (US) to date. In thermal threshold antinociceptive studies with the labeled dose of the low concentration buprenorphine solution, IV and IM injections to cats have a duration-of-action ranging from

dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 21-26.A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg ⁄ kg (100 lL ⁄ kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t lag ) of 0.333 h in the 1.3 mg ⁄ kg group and 0 in the other two groups. The mean C max increased with dose and were 2.28, 2.67, and 4.71 ng ⁄ mL in the 1.3, 2.6 and 5.2 mg ⁄ kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg ⁄ kg dose groups, respectively. The mean AUC 0-LLOQ from lowest to highest dose groups were 157, 268, and 645 ngAEh ⁄ mL and were dose proportional with a R 2 value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg ⁄ kg (50 lL ⁄ kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg ⁄ kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg ⁄ kg group.

The effectiveness of a long-acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 53-64.A prospective, double-blinded, positive-controlled, multicenter, noninferiority clinical study was conducted to evaluate the safety and effectiveness of a longacting transdermal fentanyl solution (TFS) for the control of postoperative pain. Four hundred forty-five client-owned dogs of various breeds were randomly assigned to receive a single dose of TFS (2.6 mg ⁄ kg [50 lL ⁄ kg]) (N = 223) applied 2-4 h prior to surgery or buprenorphine (20 lg ⁄ kg) (N = 222) administered intramuscularly 2-4 h prior to surgery and every 6 h through 90 h. There were 159 (35.7%) males and 286 (64.3%) females ranging from 0.5 to 16 years of age and 3 to 98.5 kg enrolled. Pain was scored using the modified Glasgow Composite Pain Scale with an a priori dropout criteria of ‡8 (20 maximum score). The one-sided upper 95% confidence interval of the mean difference between fentanyl and buprenorphine treatment failures was 5.6%, which was not greater than the a priori selected margin difference of 15%. Adverse events attributed to either treatment were minimal in impact and were approximately equal between groups. Sustained plasma fentanyl concentrations provided by a single pre-emptive dose of TFS are safe and effective and are noninferior to repeated injections of buprenorphine in controlling postoperative pain over 4 days. This long-acting fentanyl formulation provides veterinarians with a novel, registered option for the control of postoperative pain in dogs that improves dosing compliance and potentially mitigates the disadvantages of oral, parenteral, and patch delivered opioids.

The alpha2-adrenergic receptor antagonists, yohimbine, atipamezole and tolazoline, are used in veterinary medicine as reversal agents for the sedative/hypnotic effects of alpha2-agonists. Ruminants have increased sensitivity to the sedative/hypnotic effects of alpha2-agonists compared to other species. The receptors mediating the sedative effects of alpha2-agonists are located primarily on locus coeruleus neurons in the pons of the lower brainstem. Four pharmacological subtypes of the alpha2-adrenergic receptor (A,B, C and D) have been identified based on differences in ligand affinity. The aim of this study was to: 1) determine the pharmacological profile of atipamezole, yohimbine and tolazoline at the four alpha2-adrenergic receptor subtypes and; 2) determine whether these agents differ in their affinities at the alpha2-adrenergic receptor present in the sheep brainstem. In inhibition binding studies against the selective alpha2-adrenergic receptor ligand [3H]-MK-912, tolazoline showed the lowest affinity for all four alpha2-adrenergic receptor subtypes compared to yohimbine and atipamezole. The affinities of yohimbine and atipamezole were similar at the alpha2A-, alpha2B- and alpha2C-adrenergic receptors but differed by approximately 100 fold at the alpha2D-adrenergic receptor. Atipamezole had a 100 fold higher affinity at the alpha2D-adrenergic receptor when compared to yohimbine. To determine the ligand binding characteristics of these agents at the alpha2-adrenergic receptor in sheep brainstem, membranes were labelled with [3H]-MK-912 and inhibition competition curves were performed. Atipamezole showed approximately a 100 fold higher affinity for the sheep brainstem alpha2-adrenergic receptor compared to yohimbine which was similar to what was observed for the alpha2D-adrenergic receptor in PC12 cells transfected with RG-20. The results from these studies suggest that atipamezole has a high affinity for the alpha2D-adrenergic receptor that appears to be the receptor subtype in sheep brainstem.

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Urine cortisokcreatinine ratios (UCCR) were determined from single urine samples obtained by cystocentesis in 47 cats allotted into 2 groups: 31 healthy cats and 16 sick, hospitalized cats with assorted clinical illnesses. The mean ( 2 standard deviation) UCCR for healthy cats was 5.9 2 7.0 (median, 3.2; range, 0.6 to 27.8). Age or gonadal status had no significant effect on the magnitude of UCCR within this group. However, sick cats had significantly higher UCCR ( P wareness of disorders of the hypothalamo-pituitary-