Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats

Objectives To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects. Methods Twelve healthy adult domestic shorthair cats (6.0 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate. Results Baseline TT was 47.6 +/- 4.1 degrees C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1-30 h post-treatment. The time to maximum effect (T-max) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (C-max) were 1.01-1.72 ng/ml after the 0.02 mg/kg dose, 1.4-4.9 ng/ml after the 0.06 mg/kg dose, 4.6-51.4 ng/ml after the 0.12 mg/kg dose and 5.3-22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35-5.33 h; 0.06 mg/kg = 16.1-31.2 h; 0.12 mg/kg = 10.1-34.0 h; and 0.24 = mg/kg 16.1-31.6 h. The mean plasma concentration for the offset of analgesia' was 2.3 +/- 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects. Conclusions and relevance Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.