Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats

Emerging evidence suggests the potential utility of combining opioids with imidazoline I-2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear. This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I-2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment. Von Frey filament test was used to examine the anti-hyperalgesic effect of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain or chronic constriction injury (CCI)-induced neuropathic pain in rats. Twice-daily treatment with oxycodone and phenyzoline, alone or in combination, was continued until the development of significant tolerance (oxycodone) or as long as 19 days passed (phenyzoline). In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 x ED50 dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice-daily treatment with 2 x ED50 dose of phenyzoline for 19 days led to significant antinociceptive tolerance to phenyzoline but not cross-tolerance to oxycodone. Twice-daily treatment with the combined oxycodone and phenyzoline using different ratios (1:3, 1:1 and 3: 1) at the doses that were functionally equivalent to the treatment doses of oxycodone and phenyzoline for 13-19 days generally led to delayed antinociceptive tolerance. Combination therapy with oxycodone and I-2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.