NMDA-receptors are a major target in the prevention and treatment of hyperalgesic pain states in neuropathic pain. However, previous studies revealed equivocal results depending on study design and efficacy parameters. We tested the analgesic (generalized reduction of generation and processing of nociceptive signalling) and anti-hyperalgesic (prevention of central sensitization) properties of the NMDA-receptor antagonist neramexane and the potassium channel opener flupirtine in the intradermal capsaicin injection model. Furthermore, we tested the effect on pain summation (wind up). Eighteen healthy subjects received either a single dose of neramexane (40 mg p.o.), flupirtine (100 mg) or placebo in a double-blind, randomized, cross-over study. Pain evoked by intradermal capsaicin injection as well as pain evoked by pinpricks was significantly reduced by neramexane (-22% to -30% vs. placebo) in the non-sensitized skin indicating a marked analgesic effect. Moreover, dynamic mechanical allodynia (pain to light touch) was also significantly attenuated by neramexane (-28% vs. placebo). However, static secondary hyperalgesia to pinprick stimuli after capsaicin injection was not significantly reduced (-9% vs. placebo). Flupirtine showed no analgesic or anti-hyperalgesic effect. Mechanically-evoked wind up of pain sensation was not affected by any treatment. The results suggests that in a human surrogate model of neurogenic hyperalgesia a single low-dose of neramexane had a marked analgesic effect in the sensitized and in the non-sensitized state and thus may be a useful drug to treat the enhanced pain sensitivity in neuropathic pain patients. Its efficacy may be based on analgesia rather than anti-hyperalgesia or anti-windup. In contrast, flupirtine showed neither an analgesic nor an anti-hyperalgesic effect at a dose used for the treatment of postoperative pain.