The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone

No abstract

Many clinicians hoped that the completion of the Human Genome Project would result in "individualized drug therapy," i.e., determining the right medication at the right dose 100% of the time based upon the individual's genetics. The pharmacogenomic prediction of drug efficacy and safety has not become a reality due to continuing realization of the complexity dictating the human-drug interaction. New methods of metabolomics, proteomics, and transcriptomics that account for this complexity hold promise for translational researchers hoping to increase drug efficacy and decrease drug toxicity.

Objective: Opioids are often combined with adjuvants to treat symptoms that accompany pain and with adjuvant analgesics to treat neuropathic pain. Herein, we aim to investigate the analgesic and anti-inflammatory effects of oxycodone and selected adjuvants in rats.Methods: Analgesic and anti-inflammatory effects of oxycodone were assessed after single subcutaneous (SC) (0.56 mg/kg) injections in rats, with the following drugs: midazolam (0.3 mg/kg), haloperidol (0.45 mg/kg), ketamine (0.3 mg/kg), hyoscine butylbromide (1.7 mg/kg), levomepromazine (0.35 mg/kg), and metoclopramide (1.0 mg/kg). Analgesia was assessed by the tail flick test. Anti-inflammatory activity was evaluated using a plethysmometer after carrageenan-induced edema. For neuropathic pain, analgesia was explored using the tail flick and von Frey tests. Neuropathic pain was induced by vincristine (0.1 mg/kg, i.p.) in male Wistar rats.Results: All tested combinations of oxycodone with particular adjuvants showed increased analgesia in comparison to oxycodone alone. Compared to oxycodone alone, combinations with midazolam, haloperidol, hyoscine butylbromide, and levomepromazine prolonged analgesia. Anti-inflammatory activities were observed after coadministration of oxycodone paired with haloperidol and ketamine, which is a new aspect of the pharmacological profile of oxycodone. In the neuropathic pain model, vincristine lowered pain threshold in rats and inhibited growth of normal rat body weight. Oxycodone in combination with adjuvant analgesics showed more potent analgesia than oxycodone alone, especially in the tail-flick test. In most cases, the maximum effects were observed for 15-30 min since combined SC administration.Conclusions: Analgesic and anti-inflammatory effects were observed in oxycodone combined with selected adjuvants in rats; although the mechanism of these interactions is not yet well understood. Further studies should test these combinations after chronic administration and assess the benefits and risks associated with the use of the tested combinations in humans.