Quantification of observable behaviors following oral administration of oxycodone and nalfurafine in male rhesus monkeys

Background: Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. Methods: Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8 mg/kg), nalfurafine (0.001-0.0056 mg/kg), or mixtures (1.0 mg/kg oxycodone/0.001-0.0056 mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320 min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. Results: Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001 mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056 mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). Conclusions: Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain.