title: Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats.
abstract: OBJECTIVE
  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°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 (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) 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
  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.
authors.affiliation: Taylor Monroe, Ely, UK polly@taylormonroe.co.uk.
authors.forename: Polly M
authors.initials: PM
authors.lastname: Taylor
authors.affiliation: Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Carmela H
authors.initials: CH
authors.lastname: Luangdilok
authors.affiliation: University of Oxford, Oxford, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Sear
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D002047:Buprenorphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002371:Cat Diseases / Q000188:drug therapy*; D002415:Cats; D007279:Injections, Subcutaneous; D010146:Pain / Q000188:drug therapy / Q000662:veterinary*; D010147:Pain Measurement / Q000662:veterinary
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine