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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

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  • 1 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502.
  • | 2 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502.
  • | 3 Vanderbilt University Center for Neuroscience Drug Discovery, Cool Springs Life Sciences Center, Nashville, TN 37240.

Abstract

OBJECTIVE

To assess the pharmacokinetics and opioid effects of methadone after administration of multiple doses by means of 2 dosing regimens of methadone-fluconazole-naltrexone.

ANIMALS

12 healthy Beagles.

PROCEDURES

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.

RESULTS

Compared with baseline, temperatures significantly decreased for treatment 1 group dogs at 2 to ≥ 4 hours and from 16 to ≥ 50 hours (12 hours after last dose) and for treatment 2 group dogs at 2 to ≥ 36 hours (12 hours after last dose), when trough methadone concentrations were ≥ 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 β-naltrexol were sporadically detected in plasma, and naltrexone glucuronide was consistently detected.

CONCLUSIONS AND CLINICAL RELEVANCE

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.

Abstract

OBJECTIVE

To assess the pharmacokinetics and opioid effects of methadone after administration of multiple doses by means of 2 dosing regimens of methadone-fluconazole-naltrexone.

ANIMALS

12 healthy Beagles.

PROCEDURES

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.

RESULTS

Compared with baseline, temperatures significantly decreased for treatment 1 group dogs at 2 to ≥ 4 hours and from 16 to ≥ 50 hours (12 hours after last dose) and for treatment 2 group dogs at 2 to ≥ 36 hours (12 hours after last dose), when trough methadone concentrations were ≥ 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 β-naltrexol were sporadically detected in plasma, and naltrexone glucuronide was consistently detected.

CONCLUSIONS AND CLINICAL RELEVANCE

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.

Supplementary Materials

    • Supplementary Table S1 (PDF 49 kb)
    • Supplementary Table S2 (PDF 48 kb)
    • Supplementary Table S3 (PDF 63 kb)

Contributor Notes

Dr. Locuson's present address is Agios Pharmaceuticals, Cambridge, MA 02139.

Dr. Cho's present address is the VCA Veterinary Care Animal Hospital and Referral Center, Albuquerque, NM 87111.

Address correspondence to Dr. Butch KuKanich (kukanich@ksu.edu).