{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T21:14:40Z","timestamp":1787174080717,"version":"build-2736575974"},"reference-count":21,"publisher":"American Veterinary Medical Association (AVMA)","issue":"8","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ajvr"],"published-print":{"date-parts":[[2022,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>To assess the pharmacokinetics, clinical efficacy, and adverse effects of injectable methadone with the pharmacokinetic enhancer fluconazole (methadone-fluconazole), compared with the standard formulation of injectable methadone, in dogs after ovariohysterectomy. We hypothesized that 2 doses of methadone-fluconazole would provide 24 hours of postoperative analgesia.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>ANIMALS<\/jats:title>\n<jats:p>3 purpose-bred dogs (pharmacokinetic preliminary study) and 42 female dogs from local shelters (clinical trial) were included.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>PROCEDURES<\/jats:title>\n<jats:p>Pharmacokinetics were preliminarily determined. Clinical trial client-owned dogs were blocked by body weight into treatment groups: standard methadone group (methadone standard formulation, 0.5 mg\/kg, SC, q 4 h; n = 20) or methadone-fluconazole group (0.5 mg\/kg methadone with 2.5 mg\/kg fluconazole, SC, repeated once at 6 h; n = 22). All dogs also received acepromazine, propofol, and isoflurane. Surgeries were performed by experienced surgeons, and dogs were monitored perioperatively using the Glasgow Composite Measure Pain Scale\u2013Short Form (CMPS-SF) and sedation scales. Evaluators were masked to treatment.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Findings from pharmacokinetic preliminary studies supported that 2 doses of methadone-fluconazole provide 24 hours of drug exposure. The clinical trial had no significant differences in treatment failures or postoperative CMPS-SF scores between treatments. One dog (methadone-fluconazole group) had CMPS-SF &gt; 6 and received rescue analgesia. All dogs had moderate sedation or less by 1 hour (methadone-fluconazole group) or 4 hours (standard methadone group) postoperatively. Sedation was completely resolved in all dogs the day after surgery.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CLINICAL RELEVANCE<\/jats:title>\n<jats:p>Methadone-fluconazole with twice-daily administration was well tolerated and provided effective postoperative analgesia for dogs undergoing ovariohysterectomy. Clinical compliance and postoperative pain control may improve with an effective twice-daily formulation.<\/jats:p>\n<\/jats:sec>","DOI":"10.2460\/ajvr.22.01.0014","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T12:42:32Z","timestamp":1654778552000},"source":"Crossref","is-referenced-by-count":8,"title":["Long-acting injectable methadone (methadone-fluconazole) provides safe and effective postoperative analgesia in a randomized clinical trial for dogs undergoing soft tissue surgery"],"prefix":"10.2460","volume":"83","author":[{"given":"Zackery D.","family":"Bieberly","sequence":"first","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Butch","family":"KuKanich","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate S.","family":"KuKanich","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara A.","family":"Berke","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily E.","family":"Klocke","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Upchurch","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa J.","family":"Comroe","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Jugan","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane E.","family":"Mason","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron J.","family":"Orchard","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshuah B.","family":"Klutzke","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallie","family":"Woodruff","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1272","reference":[{"issue":"5","key":"B1","series-title":"J Vet Pharmacol Ther","first-page":"461","article-title":"The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs","volume":"28","year":"2005","unstructured":"KuKanich B, Lascelles BD, Aman AM, Mealey KL, Papich MG. The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs. J Vet Pharmacol Ther. 2005;28(5):461\u2013466.16207309"},{"issue":"11","key":"B2","series-title":"Am J Vet Res","first-page":"1968","article-title":"Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs","volume":"66","year":"2005","unstructured":"KuKanich B, Lascelles BD, Papich MG. Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs. Am J Vet Res. 2005;66(11):1968\u20131974."},{"issue":"3","key":"B3","series-title":"Vet Anaesth Analg","first-page":"242","article-title":"The disposition and behavioral effects of methadone in Greyhounds","volume":"35","year":"2008","unstructured":"KuKanich B, Borum SL. The disposition and behavioral effects of methadone in Greyhounds. Vet Anaesth Analg. 2008;35(3):242\u2013248.18282261"},{"issue":"6","key":"B4","series-title":"J Vet Pharmacol Ther","first-page":"580","article-title":"Pharmacokinetics and behavioral effects of oxymorphone after intravenous and subcutaneous administration to healthy dogs","volume":"31","year":"2008","unstructured":"KuKanich B, Schmidt BK, Krugner-Higby LA, Toerber S, Smith LJ. Pharmacokinetics and behavioral effects of oxymorphone after intravenous and subcutaneous administration to healthy dogs. J Vet Pharmacol Ther. 2008;31(6):580\u2013583.19000282"},{"issue":"5","key":"B5","series-title":"Am J Vet Res","first-page":"664","article-title":"Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds","volume":"69","year":"2008","unstructured":"KuKanich B, Borum SL. Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. Am J Vet Res. 2008;69(5):664\u2013669.18447799"},{"issue":"3","key":"B6","series-title":"Vet Anaesth Analg","first-page":"256","article-title":"Pharmacokinetics of hydromorphone hydrochloride in healthy dogs","volume":"35","year":"2008","unstructured":"KuKanich B, Hogan BK, Krugner-Higby LA, Smith LJ. Pharmacokinetics of hydromorphone hydrochloride in healthy dogs. Vet Anaesth Analg. 2008;35(3):256\u2013264.18282253"},{"issue":"4","key":"B7","series-title":"Vet Anaesth Analg","first-page":"501","article-title":"The effect of fluconazole on oral methadone in dogs","volume":"46","year":"2019","unstructured":"KuKanich B, KuKanich K, Rankin D, Locuson CW. The effect of fluconazole on oral methadone in dogs. Vet Anaesth Analg. 2019;46(4):501\u2013509.30982709"},{"issue":"6","key":"B8","series-title":"Vet Anaesth Analg","first-page":"597","article-title":"Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs","volume":"42","year":"2015","unstructured":"KuKanich B, KuKanich K. Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs. Vet Anaesth Analg. 2015;42(6):597\u2013607.25733012"},{"issue":"3","key":"B9","series-title":"Am J Vet Res","first-page":"171","article-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","volume":"82","year":"2021","unstructured":"KuKanich B, KuKanich K, Locuson CW, Rankin DC, Fitzgerald AH, Cho P, Komp MS. 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. Am J Vet Res. 2021;82(3):171\u2013180.33629900"},{"issue":"8","key":"B10","series-title":"Am J Vet Res","first-page":"656","article-title":"Pharmacokinetics and pharmacodynamics of a novel analgesic with a deterrent to human opioid abuse (methadone-fluconazole-naltrexone) after oral administration in dogs","volume":"81","year":"2020","unstructured":"KuKanich B, KuKanich K, Rankin DC, Locuson CW, Joo H. Pharmacokinetics and pharmacodynamics of a novel analgesic with a deterrent to human opioid abuse (methadone-fluconazole-naltrexone) after oral administration in dogs. Am J Vet Res. 2020;81(8):656\u2013664.32700999"},{"issue":"9","key":"B11","series-title":"Am J Vet Res","first-page":"699","article-title":"Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy","volume":"81","year":"2020","unstructured":"KuKanich B, KuKanich K, Rankin DC, Upchurch DA, Comroe A, Crauer B, Berke K, Klocke EE, Gonzalez SE, Mason D, Jensen G, Orchard R, Fitzgerald AH, Cho P, Komp M. Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. Am J Vet Res. 2020;81(9):699\u2013707.33112167"},{"issue":"3","key":"B12","series-title":"J Vet Intern Med","first-page":"832","article-title":"Efficacy and safety of injectable robenacoxib for the treatment of pain associated with soft tissue surgery in dogs","volume":"31","year":"2017","unstructured":"Friton G, Thompson C, Karadzovska D, King S, King JN. Efficacy and safety of injectable robenacoxib for the treatment of pain associated with soft tissue surgery in dogs. J Vet Intern Med. 2017;31(3):832\u2013841.28514527"},{"issue":"1","key":"B13","series-title":"BMC Vet Res","first-page":"197","article-title":"Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs","volume":"13","year":"2017","unstructured":"Friton G, Thompson CM, Karadzovska D, King S, King JN. Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs. BMC Vet Res. 2017;13(1):197.28651573"},{"key":"B14","series-title":"Anim Welf","first-page":"97","article-title":"Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score","volume":"16S","year":"2007","unstructured":"Reid J, Nolan AM, Hughes JML, Lascelles BD, Pawson P, Scott EM. Development of the short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score. Anim Welf. 2007;16S:97\u2013104."},{"issue":"4","key":"B15","series-title":"J Vet Pharmacol Ther","first-page":"394","article-title":"The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study","volume":"37","year":"2014","unstructured":"Martinez SA, Wilson MG, Linton DD, Newbound GC, Freise KJ, Lin TL, Clark TP. The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study. J Vet Pharmacol Ther. 2014;37(4):394\u2013405.24344787"},{"issue":"2","key":"B16","series-title":"J Pharmacol Exp Ther","first-page":"833","article-title":"l-alpha-Acetylmethadol, l-alpha-acetyl-N-normethadol and l-alpha-acetyl-N, N-dinormethadol: comparisons with morphine and methadone in suppression of the opioid withdrawal syndrome in the dog","volume":"283","year":"1997","unstructured":"Vaupel DB, Jasinski DR. l-alpha-Acetylmethadol, l-alpha-acetyl-N-normethadol and l-alpha-acetyl-N, N-dinormethadol: comparisons with morphine and methadone in suppression of the opioid withdrawal syndrome in the dog. J Pharmacol Exp Ther. 1997;283(2):833\u2013842.9353405"},{"key":"B17","article-title":"Plumb\u2019s veterinary drugs: vital parameters appendix","unstructured":"Plumb\u2019s. Plumb\u2019s veterinary drugs: vital parameters appendix. Accessed January 5, 2022. https:\/\/app-plumbs-com.er.lib.k-state.edu\/"},{"issue":"1","key":"B18","series-title":"BMC Vet Res","first-page":"35","article-title":"Plasma levels of a methadone constant rate infusion and their corresponding effects on thermal and mechanical nociceptive thresholds in dogs","volume":"17","year":"2021","unstructured":"Amon T, K\u00e4stner SBR, Kietzmann M, T\u00fcnsmeyer J. Plasma levels of a methadone constant rate infusion and their corresponding effects on thermal and mechanical nociceptive thresholds in dogs. BMC Vet Res. 2021;17(1):35.33461553"},{"issue":"7","key":"B19","series-title":"Am J Vet Res","first-page":"969","article-title":"Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication","volume":"63","year":"2002","unstructured":"V\u00e4is\u00e4nen M, Raekallio M, Kuusela E, Huttunen P, Lepp\u00e4luoto J, Kirves P, Vainio O. Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication. Am J Vet Res. 2002;63(7):969\u201375.12118677"},{"key":"B20","article-title":"Comfortan\u00ae 10 mg\/mL solution for injection for dogs and cats","unstructured":"NOAH. Comfortan\u00ae 10 mg\/mL solution for injection for dogs and cats. Accessed January 15, 2022. https:\/\/www.noahcompendium.co.uk\/?id=-475541"},{"issue":"3","key":"B21","series-title":"Vet Surg","first-page":"336","article-title":"Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs","volume":"41","year":"2012","unstructured":"Bienhoff SE, Smith ES, Roycroft LM, Roberts ES. Efficacy and safety of deracoxib for control of postoperative pain and inflammation associated with soft tissue surgery in dogs. Vet Surg. 2012;41(3):336\u2013344.22225463"}],"container-title":["American Journal of Veterinary Research"],"original-title":[],"link":[{"URL":"https:\/\/avmajournals.avma.org\/view\/journals\/ajvr\/83\/8\/ajvr.22.01.0014.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/avmajournals.avma.org\/view\/journals\/ajvr\/83\/8\/ajvr.22.01.0014.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/avmajournals.avma.org\/view\/journals\/ajvr\/83\/8\/ajvr.22.01.0014.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T21:03:37Z","timestamp":1696539817000},"score":1,"resource":{"primary":{"URL":"https:\/\/avmajournals.avma.org\/view\/journals\/ajvr\/83\/8\/ajvr.22.01.0014.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,1]]},"references-count":21,"journal-issue":{"issue":"8"},"URL":"https:\/\/doi.org\/10.2460\/ajvr.22.01.0014","relation":{},"ISSN":["0002-9645"],"issn-type":[{"value":"0002-9645","type":"print"}],"subject":[],"published":{"date-parts":[[2022,8,1]]}}}