Temporal summation of second pain at least partly reflects temporal summation of dorsal horn neuronal responses, and both have been termed windup (WU), a form of nociception-dependent central sensitization. Animal and human experiments have shown that both forms of WU depend on N-methyl-D-aspartate (NMDA) and substance P receptor systems. WU of second pain (WU(SP)) in patients with fibromyalgia (FM) is enhanced compared with normal control (NC) subjects and is followed by exaggerated WU(SP) aftersensations and prolonged WU(SP) maintenance at low stimulus frequencies. Because the enhanced WU(SP) of FM patients could be related to abnormal endogenous modulation of NDMA receptors, we tested the effects of the NMDA receptor antagonist dextromethorphan (DEX) on WU(SP) in FM and NC subjects in a double-blind, placebo-controlled, crossover study. WU(SP) was elicited by trains of 0.7-second duration thermal pulses applied to the glabrous surface of the hands or by 1-second mechanical stimuli to the adductor pollicis muscle of the hands at a frequency of 0.33 Hz. In comparison to baseline and placebo conditions, single oral doses of DEX 60 and 90 mg reduced thermal and mechanical WU(SP) in NC and FM subjects, with DEX 90 mg being most effective. These effects did not differ for male and female NC subjects. FM subjects required less thermal and mechanical stimulus intensity than NC to achieve maximal WU(SP), but the extent of WU(SP) reduction by DEX did not statistically differ between NC and FM subjects for all study conditions. Thus, central pain processing of FM subjects is not different from NC in at least one important aspect, namely their NMDA receptor system responsiveness to pharmacologic inhibition by DEX.
Perspective: Results of this study demonstrate that FM patients show abnormal WU(SP) during thermal and mechanical stimulation compared with NC. Because oral doses of the NMDA receptor antagonist DEX attenuated thermal and mechanical WU(SP) similarly in FM patients and NC, other mechanisms than WU(SP) need to be considered for the widespread pain of FM patients. These mechanisms might include tonic nociceptive input from peripheral tissues and/or enhanced descending facilitation.