Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30 mg, PO, QID) for two weeks and received placebo ibudilast (0 mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N = 10/group) were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50 mg/70 kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4 degrees C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40 mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p <= 0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p <= 0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.