Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain

Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the μ-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6 mg/kg) and methadone (3 mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5 h post-injection (P<0.05); codeine (30 mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6 mg/kg) and methadone (0.5-3 mg/kg) robustly attenuated mechanical and cold allodynia for at least 2 h post-injection (P<0.05). Codeine (10 and 30 mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3 h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of μ-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.