This study tested the prophylactic and therapeutic efficacy of memantine (1-amino-3,5-dimethyl-amandate), a clinically tested N-methyl-D-aspartate (NMDA) antagonist on thermal hyperalgesia in a rat model of painful mononeuropathy. Persistent hyperalgesia induced by chronic constrictive injury (CCI) to the sciatic nerve was significantly reduced for up to 14 days by prophylactic administration of memantine (3.0 mg/kg) via i.p. implanted osmotic micropumps for a period of 7 days. Therapeutic i.p. injections of memantine (10 mg/kg) given on post-injury days 7 and 14 completely reversed existing hyperalgesia for a short period of 1 h. These results provide evidence that memantine produces long-term prophylactic and short-term therapeutic effects on thermal hyperalgesia in a model of painful mononeuropathy.