{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T09:39:31Z","timestamp":1783762771725,"version":"3.55.0"},"reference-count":32,"publisher":"American Veterinary Medical Association (AVMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ajvr"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:sec id=\"s001\">\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>To assess the pharmacokinetics and opioid effects of methadone after administration of multiple doses by means of 2 dosing regimens of methadone-fluconazole-naltrexone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s002\">\n<jats:title>ANIMALS<\/jats:title>\n<jats:p>12 healthy Beagles.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s003\">\n<jats:title>PROCEDURES<\/jats:title>\n<jats:p>Dogs were randomly allocated (6 dogs\/group) to receive 1 of 2 oral dosing regimens of methadone-fluconazole-naltrexone. Treatment 1 doses were administered at 0 (methadone-to-fluconazole-to-naltrexone ratio of 1:5:0.25 mg\/kg), 14 (1:5:0.25), 24 (0.5:2.5:0.125), and 38 (0.5:2.5:0.125) hours. Treatment 2 doses were administered at 0 (1:5:0.25), 4 (0.5:2.5:0.125), 10 (0.5:2.5:0.125), and 24 (0.5:2.5:0.125) hours. Blood samples, rectal temperatures, and von Frey antinociceptive measurements were obtained at designated times.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s004\">\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Compared with baseline, temperatures significantly decreased for treatment 1 group dogs at 2 to \u2265 4 hours and from 16 to \u2265 50 hours (12 hours after last dose) and for treatment 2 group dogs at 2 to \u2265 36 hours (12 hours after last dose), when trough methadone concentrations were \u2265 21.3 ng\/mL. Antinociception occurred after the first dose but was not maintained throughout the study. Lesions were noted in some dogs at the application site of the von Frey device. Naltrexone and \u03b2-naltrexol were sporadically detected in plasma, and naltrexone glucuronide was consistently detected.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"s005\">\n<jats:title>CONCLUSIONS AND CLINICAL RELEVANCE<\/jats:title>\n<jats:p>Opioid effects were noted after oral administration of the first dose, and data suggested that administering a second dose 6 hours later and every 12 hours thereafter was necessary to maintain opioid effects. Antinociception may have been lost because dogs became averse or hyperalgesic to the von Frey device, such that the antinociception model used here may not be robust for repeated measurements in dogs.<\/jats:p>\n<\/jats:sec>","DOI":"10.2460\/ajvr.82.3.171","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T16:51:37Z","timestamp":1614271897000},"page":"171-180","source":"Crossref","is-referenced-by-count":5,"title":["Multiple-dose pharmacokinetics and opioid effects of a novel analgesic with a deterrent to human opioid abuse (methadone-fluconazole-naltrexone) after oral administration in dogs"],"prefix":"10.2460","volume":"82","author":[{"given":"Butch","family":"KuKanich","sequence":"first","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"KuKanich","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles W.","family":"Locuson","sequence":"additional","affiliation":[{"name":"Vanderbilt University Center for Neuroscience Drug Discovery, Cool Springs Life Sciences Center, Nashville, TN 37240."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Rankin","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyson H.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa S.","family":"Komp","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1272","reference":[{"key":"ref1","series-title":"Vet Clin North Am Small Anim Pract","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/j.cvsm.2013.04.007","article-title":"Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: an evidence-based approach","volume":"43","author":"KuKanich B","year":"2013","unstructured":"KuKanich B. 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