David A Thorn1, Yanan Zhang2, Jun-Xu Li3,4. 1. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA. 2. Research Triangle Institute, Research Triangle Park, NC, USA. 3. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA. junxuli@buffalo.edu. 4. Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NC, USA. junxuli@buffalo.edu.
Abstract
RATIONALE: Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear. OBJECTIVE: This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment. METHODS: 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). RESULTS: In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × 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 × 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. CONCLUSIONS: Combination therapy with oxycodone and I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.
RATIONALE: Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear. OBJECTIVE: This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment. METHODS: 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). RESULTS: In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × 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 × 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. CONCLUSIONS: Combination therapy with oxycodone and I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.
Authors: Sofia Ramiro; Helga Radner; Désirée van der Heijde; Astrid van Tubergen; Rachelle Buchbinder; Daniel Aletaha; Robert Bm Landewé Journal: Cochrane Database Syst Rev Date: 2011-10-05
Authors: A L Hudson; R Gough; R Tyacke; L Lione; M Lalies; J Lewis; S Husbands; P Knight; F Murray; P Hutson; D J Nutt Journal: Ann N Y Acad Sci Date: 1999-06-21 Impact factor: 5.691
Authors: Jun-Xu Li; Alison Unzeitig; Martin A Javors; Kenner C Rice; Wouter Koek; Charles P France Journal: J Pharmacol Exp Ther Date: 2009-08-17 Impact factor: 4.030