Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.
OBJECTIVE
The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers.


METHODS
The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.


RESULTS
Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively.


CONCLUSIONS
Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
Hughes
A M
AM
Experimental Medicine, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, SK10 4TG, UK. andrew.hughes@astrazeneca.com
Rhodes
J
J
Fisher
G
G
Sellers
M
M
Growcott
J W
JW
D000208:Acute Disease; D000328:Adult; D000700:Analgesics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003917:Dextrorphan / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007649:Ketamine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000700:Analgesics; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D007649:Ketamine; D003915:Dextromethorphan