Development and validation of a human bio-marker for cutaneous inflammatory pain (the UVB-model): - a methodological study in healthy volunteers

Abstract

Baggrund: Humane eksperimentelle smerte modeller er et vigtigt redskab i den tidlige kliniske udvikling hvor de smertestillende medikamenter efficacy bestemmes. Ultraviolet-B smerte modellen anvendes til fremkaldelse af en lokal kutan inflammation med primær hyperalgesi (øget sensibilisering overfor smertefulde stimuli)i et afgrænset område i huden. UVB- bestråling kan muligvis også fremkalde et areal i huden, omkring det bestrålede område, med sekundær hyperalgesi (sAREA). Formål: At undersøge de potentielle effekter UVB- bestråling medfører i denne smertemodel. At undersøge UVB-modellens reliabilitet ved at finde den inter- og intra- individelle variation for denne model. At udforme en tabel med sample size beregninger for både et parallelt og et Cross over studie design. Metoder: Inflammatoriske hyperalgesi fremkaldes på overarmen af 15 raske mandlige forsøgsdeltagere, et cirkulært areal (5 cm diameter) bestråles med tre gange den minimal erythma dose (MED). Det inflammatoriske respons bedømmes ved måling af erythema, den overfladiske blodgennemstrømning og temperaturen i huden. De sensoriske test inkluderede børste induceret allodyni, stimulering med von Frey filament og pinprick, smertetærsklen for tryk og smertetærsklen for varme. Alle målinger blev fortaget før bestrålingen (baseline), 24t, 48t og 72t efter bestrålingen, proceduren blev gentaget på den modsatte arm med et to ugers interval. Efter UVB-bestrålingen blev sAREA bestemt med von Frey filament og pinprick stimuli. Resultater: En signifikant stigning blev fundet for erythema, den gennemsnitlige overfladiske blodgennemstrømning og hud temperaturen (P <0,001 for alle), der var ingen signifikant ændring i den overfladiske blodgennemstrømning i det sAREA (P=0,664). Børste induceret allodyni blev fundet 48t efter bestrålingen (P=0,02). Der var ingen signifikant stigning i den primære hyperalgesi for von Frey filament eller pinprick (P=0,124). En signifikant stigning blev fundet for pinprick induceret primær hyperalgesi (P=0.001) og der var en signifikant forskel mellem størrelsen på pinen (P<0,001). Smertetærsklerne for både tryk (PPT) og varme (HPT) var signifikant sænket efter UVB-bestrålingen (P<0.001 for begge), men PPT faldt ikke med samme grad på begge arme (P<0,001). Konklusion: Dette studie konkluderede at UVB-smerte modellen var succesfuldt i at fremkalde en lokal kutan inflammatorisk reaktion i et afgrænset område i huden, da både ændringer i den overfladiske blodgennemstrømning og synligt erythema blev observeret. Ydermere blev en signifikant stigning i både temperatur og erythema også fundet. Dette studie konkluderede at pinprick stimuli var den bedste metode til fremkaldelse af primær hyperalgesi, i forholde til von Frey filamenter. Påvisningen af smertetærsklen for varmepåvirkning ved UVB stimulering blev vurderet til a at være en test med høj pålidelighed. Påvisningen af smertetærsklen for tryk påvirkning ved UVB stimulering var kun pålidelig på den dominante side. Arealet for sekundær hyperalgesi blev påvist ved både von Frey filament og pinprick stimulering, begge test syntes at være pålidelige, men problematikker om hvorvidt hvilken test bør foretrækkes kræver yderligere udredninger.

Background: In the early clinical trials, human experimental pain models are important tools for defining the analgesic efficacy of drugs. The Ultraviolet-B (UVB) pain model is used for the induction of a local cutaneous inflammation in a circumscribed skin area with primary hyperalgesia (increased sensitivity to painful stimuli) and possible area of secondary hyperalgesia (sAREA). Aim: To investigate the potential effect of the UVB-irradiation in this pain model and the reliability of this model by detecting the inter- and intra- individual variations in this model and to produce sample size estimates for a parallel and a cross over study design. Methods: Inflammatory hyperalgesia was induced on the upper arms of 15 healthy male volunteers by irradiating a circular spot (5 cm diameter) with three times minimal erythema dose (MED) of the UVB-irradiation. The inflammatory response assessed by measures of erythema, superficial blood flow and skin temperature. The sensory tests including the brush induced allodynia, von Frey and pinprick stimuli, pressure pain threshold (PPT) and heat pain threshold (HPT), all measurements were performed at baseline, 24h, 48h and 72h after the irradiation, the whole procedure was repeated on the opposite arm with a two week’s interval. sAREA was assessed to both von Frey filament and pinprick after the UVB-exposure. Results: A significant increase in the erythema, mean blood flow (BF) and skin temperature was detected after the irradiation (P <0.001 in all three cases), but no changes in the BF in the sAREA was detected (P=0.664). Brush induced allodynia was detected 48h after the irradiation (P=0.02). No significant increase was detected in primary hyperalgesia to von Frey filament (P=0.124). A significant increase in the pinprick induced primary hyperalgesia was detected (P<0.001) and a significant difference between the pin sizes (P<0.001). Both heat pain threshold (HPT) and pressure pain threshold (PPT) significantly decreased after the irradiation (P<0.001 in both cases), but the PPT decreased differently in both arms (P<0.001). Conclusion: The present study concluded that the UVB-pain model was successful in inducing a local cutaneous inflammation in a circumscribed skin area, as both alteration in the BF and visually erythema was noticed. Furthermore, significantly increase in both skin temperature and erythema were detected. For detection of mechanical induced primary hyperalgesia the present study concluded that the pinprick was the most suitable test in comparison to von Frey filaments. Detection of the heat pain threshold was found to be a highly reliable test in the UVB-pain model. PPT only seemed to be reliable on the dominant side. Area of secondary hyperalgesai was detected to both von Frey filament and pinprick stimuli and both test seemed to be reliable, the issues of which test should be preferred need to be addressed further.

A master thesis from Aalborg University

Development and validation of a human bio-marker for cutaneous inflammatory pain (the UVB-model): - a methodological study in healthy volunteers