Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects.
Intradermal (ID) capsaicin injection in humans induces spontaneous pain, flare, primary hyperalgesia, secondary hyperalgesia, and allodynia. Secondary hyperalgesia and allodynia are a reflection of central sensitization. The effect of treatment of single doses of (1) pregabalin, 300 mg single oral dose, and (2) morphine, 10 mg IV, on the area of secondary hyperalgesia induced by ID capsaicin injection was studied by using a randomized, double-blinded, placebo-controlled, 4-period, cross-over design in 20 healthy men. Compared with active placebo diphenhydramine (50 mg oral dose), pregabalin and morphine significantly reduced the area of secondary hyperalgesia over 15 to 240 minutes after capsaicin injection (approximately 25%, P = .002 and approximately 33%, P < .001, respectively). A smaller reduction was observed when pregabalin and morphine were compared with true placebo (approximately 13%, P = .081 and approximately 24%, P = .009, respectively). Diphenhydramine, on the other hand, increased the area of secondary hyperalgesia in comparison with true placebo (approximately 16%, P = .061). The relationship between the baseline area of hyperalgesia and assay sensitivity suggests that establishing minimum entry criteria for the baseline area of hyperalgesia requirement increases the sensitivity of the assay.


CONCLUSIONS
These results suggest that the minimally invasive intradermal capsaicin model, when it is compared with true placebo, can potentially be used for an early assessment of relevant pharmacology of novel analgesic compounds in healthy subjects. This platform may provide a means to rapidly assess new analgesics and enhance dose selection and decision-making during clinical development.
Wang
Hao
H
Department of Experimental Medicine, Merck Research Laboratories, North Wales, PA 19454-2505, USA. hao_wang2@merck.com
Bolognese
James
J
Calder
Nicole
N
Baxendale
Jane
J
Kehler
Andrea
A
Cummings
Corrine
C
Connell
John
J
Herman
Gary
G
D000293:Adolescent; D000328:Adult; D000470:Alkaloids; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use; D000704:Analysis of Variance; D002211:Capsaicin; D018592:Cross-Over Studies; D004155:Diphenhydramine / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004333:Drug Administration Routes; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000627:therapeutic use; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D010919:Placebos; D000069583:Pregabalin; D016896:Treatment Outcome; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000470:Alkaloids; D000700:Analgesics; D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D010919:Placebos; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D004155:Diphenhydramine; D002211:Capsaicin