Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain

We examined the role of N-methyl-D-aspartate (NMDA) receptors in chronic (p athological) pain in humans by using the NMDA receptor antagonist ketamine as a probe. Thirty patients with neuropathic pain in the trigeminal area we re given an i.m. injection of ketamine 0.4 mg/kg combined with midazolam 0. 05 mg/kg. Pethidine 1.0 mg/kg served as a control. Three different response patterns were observed. Ketamine caused a longterm (6-24 h) analgesic effe ct partly dissociated from the mental side effects in 8 of the 26 patients who completed the study; these patients also had a slight analgesic effect of pethidine. In nine patients, ketamine caused a short-lasting (<2 h) anal gesic effect closely associated with the mental side effects, whereas pethi dine caused little or no analgesia. The remaining nine patients did not exp erience any reduction of pain after either drug in spite of characteristic side effects. One week after the i.m. challenge the patients received eithe r 4.0 mg/kg ketamine hydrochloride or placebo capsules to be taken orally a s a nightly dose for three consecutive nights. Five of the eight patients w ho had a long-term analgesic effect of the i.m. challenge reported decrease d pain on days after ketamine. None of the others reported an analgesic eff ect. The phenomenon of long-term depression of pain in a subgroup of patien ts was thus confirmed when ketamine was given p.o. These findings indicate that NMDA receptors are involved in the perception and maintenance of patho logical pain in some patients. In others, pain appears to be mediated by NM DA receptor-independent mechanisms. We suggest that NMDA receptor-independe nt transmission in central pain pathways may contribute to the reduced effi ciency of analgesic drugs often seen in chronic pain states.