The importance of N-methyl-D-aspartate (NMDA) receptor-mediated sensitization of central nervous system (CNS) neurons is well established in animal models of acute and chronic pain. A human model of central sensitization would be useful in screening new NMDA antagonists and establishing dose regimens for clinical trials in patients with pain related to sensitization of CNS neurons. We used this model to examine the effects of intravenous infusions of two centrally acting analgesics, the NMDA receptor antagonist ketamine and the morphine-like opioid agonist alfentanil. Twelve normal subjects completed a 3-session, randomized, double-blind, crossover study. From 25 to 60 min after capsaicin injection, subjects were given intravenous infusions of ketamine (mean dose: 32 mg), alfentanil (mean dose: 3075 micrograms), or saline placebo. Both drugs significantly reduced ongoing pain and pinprick-evoked hyperalgesia during the infusion. The reduction in allodynia evoked by light stroking was statistically significant only for alfentanil. Mean reduction +/- SEM relative to placebo were for ongoing pain: ketamine, 36 +/- 9%; alfentanil, 51 +/- 5%; area of pinprick hyperalgesia: ketamine, 34 +/- 7%; alfentanil, 35 +/- 7%; and area of mechanical allodynia: ketamine, 52 +/- 20%; alfentanil, 70 +/- 12%. Because the drugs were given systemically and produced side effects in all subjects, we cannot specify the site or sites of action nor conclusively rule out a non-specific 'active placebo' response as the cause for reduction of symptoms. Arguing against an 'active placebo' response, however, was the lack of analgesic effect of intravenous midazolam (mean dose; 3.4 mg, titrated to produce side effects of similar magnitude to ketamine and alfentanil) given at 145 min after capsaicin in 9 subjects who had received saline from 25 to 60 min. The results of this study suggest that neural systems sensitive to NMDA receptor antagonists and opioids participate in capsaicin-evoked pain phenomena, and support the feasibility of pharmacological studies using the intradermal capsaicin model.