Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers.
BACKGROUND
Central sensitization is an important mechanism of neuropathic pain; its human models could be useful for early detection of efficacy of novel treatments. The electrical hyperalgesia model invokes central sensitization by repetitive stimulation of the skin. To assess its predictive value, we have investigated pregabalin, a standard neuropathic pain treatment, and aprepitant, an NK(1) antagonist, as an example of a drug class active in animal models but not in neuropathic pain patients. Furthermore, we explored if combinations of either of these drugs with the COX-2 inhibitor parecoxib could improve its efficacy.


METHODS
This was a double-blind, two-period, placebo-controlled study using incomplete block design. Thirty-two healthy volunteers received either oral pregabalin (titrated to 300 mg) or aprepitant (titrated to 320 mg), or matching placebo over 6 days before testing. Sensitization was assessed over 3 h; at 2 h, subjects received either parecoxib (40 mg) or saline i.v.


RESULTS
Pregabalin significantly reduced the areas of punctate mechanical hyperalgesia and dynamic touch allodynia vs placebo (both P < 0.0001); no significant reduction in the area of hyperalgesia or allodynia vs placebo was observed with aprepitant. In the pregabalin + parecoxib treated group, the area of allodynia was significantly reduced (P < 0.0001) and the area of hyperalgesia insignificantly attenuated (P = 0.09) vs placebo + parecoxib; no efficacy improvement was observed with aprepitant + parecoxib.


CONCLUSIONS
The model can serve to predict analgesic efficacy in early human development and investigate the mechanism of action. The model could also be used to explore efficacy of analgesic combinations to provide a rationale for patient studies.
Chizh
B A
BA
Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2GG, UK. boris_a_chizh@gsk.com
Göhring
M
M
Tröster
A
A
Quartey
G K
GK
Schmelz
M
M
Koppert
W
W
D000284:Administration, Oral; D000328:Adult; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use*; D000077608:Aprepitant; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use*; D010147:Pain Measurement; D000069583:Pregabalin; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000700:Analgesics; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D009025:Morpholines; D000077608:Aprepitant; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; C409945:parecoxib