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

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.

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 margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 35-43. Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1·, 3·, or 5· multiple of the dose of 2.6 mg ⁄ kg (50 lL ⁄ kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1· group were transient and included a low prevalence ( £ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3· and 5· groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1· dose and describe the outcome of an overdose of up to 5· dose in the absence of opioid reversal.(Paper

Freise, K. J., Newbound, G. C., Tudan, C., Clark, T. P. Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 45-51.Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg ⁄ kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 lg ⁄ kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 lg ⁄ kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 lg ⁄ kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 lg ⁄ kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 lg ⁄ kg i.m. naloxone administered at hourly intervals.(Paper