Model of methadone-induced hyperalgesia in rats and effect of memantine

Methadone used for opioid dependence therapy is associated with increased pain sensitivity. This study aimed to investigate whether methadone administration lowers nociceptive threshold in adult male Sprague-Dawley (SD) rats, and if this threshold could be altered by the NMDA receptor antagonist memantine. Rats were implanted with osmotic pumps delivering 1 mg/kg/day methadone (n = 6), or saline placebo (n = 6) (0.51 μl/h). A separate cohort of rats received either methadone 1 mg/kg/day (n = 8) or methadone 1 mg/kg/day with 20 mg/kg/day memantine (n = 8). Nociception was measured by the Hargreave's paw withdrawal test. Baseline nociception was measured on day 0 prior to osmotic pump implantation and was measured daily for the following 21 days. Osmotic pumps were removed following nociceptive testing on day 14. Methadone only treated rats had a mean paw withdrawal latency significantly lower than the corresponding values for saline on days 8, 9, 10, 11, 12, 14, and 17 (P < 0.05). At all other time points the mean paw withdrawal latency was not significantly different from saline (P > 0.05). Paw withdrawal latency of rats treated with methadone co-administered with memantine did not differ significantly compared to methadone only (P > 0.05). This demonstrates that methadone induces hyperalgesia in the SD rat yet this hyperalgesia resolves following discontinuation of methadone administration. Furthermore, memantine does not alter the development of methadone-induced hyperalgesia.