[Abstract Title]. - Society for Neuroscience

267. Pain: Pain Models II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 267.9/FF15
Topic: D.08.j. Pain models
Title: Uv-induced heat pain thresholds: a translational preclinical/clinical biomarker model for
pain research
Authors: *L. CORRADINI 1 , T. PITCHER 1 , N. BENSON 1 , H. MANSIKKA 2 , J. G.
WHEELER 1 , B. TRAN 1 , F. KHEDACHE 1 , I. MACHIN 1 , K. TAN 1 , M. J. FIELD 1 ;
1 Discovery Biol., Pfizer Ltd, Sandwich, United Kingdom; 2 Cambridge science park,
Mundipharma Res. Ltd, Cambridge, United Kingdom
Abstract: UltraViolet (UV) irradiation of the skin results in an inflammatory reaction
characterised by erythema and hypersensitivity to noxious and non noxious stimuli (i.e.
hyperalgesia and allodynia) in rats and humans (Bishop et al, 2007; Davies et al, 2005; Gustorff
et al, 2004; Harrison et al, 2004; Hamilton et al, 1999). We have pharmacologically characterised
thermal endpoints in both human and rat UV models using ibuprofen and oxycodone.
The aim of this study was to explore the preclinical/clinical PK/PD translation of this model.
To generate the model, the plantar surface of the rat hind paw exposed to UV light source (300
mJ/cm2). Oxycodone (1-0.3 mg/kg, SC) and Ibuprofen (30-300 mg/kg, PO) were administered 2
days post UV irradiation and thermal hypersensitivity assessed at various time pre- and postdose.
All experiments were randomized by treatment and days, and conducted accordingly to a
fully blind protocol.
Clinically, we conducted a double-blind, placebo-controlled, randomised, 4-way crossover. All
subjects were white male (mean age: 40.7 years). A minimum erythema dose (MED) was
determined during training session and 3xMED applied during the study periods. Subjects were
randomised to receive 20 mg oral oxycodone CR formulation, ibuprofen 800 mg IR, or placebo.
Heat pain perception threshold (HPPT) and heat pain tolerance threshold (HPTT) were assessed
in the area of erythema at 24 hours following UV irradiation (predose: baseline measurement)
and 2, 4 and 6 hours post dose in the area of erythema and in the control site (on the opposite
leg).
Ibuprofen and Oxycodone significantly reversed thermal hyperalgesia in a dose dependent
manner in rats and demonstrated a significant reversal of HPPT and HPTT in man (p≤0.05).
Oxycodone, but not ibuprofen, had a frank analgesic effect on heat pain measures on nonirraditated
control sites in both species.
PK/PD analysis of ibuprofen and oxycodone multi dose experiments in the rat UV model showed
that the data could be described by a direct Emax model, affording EC50 as a summary parameter
for efficacy. These values were compared to the reported EC50 in man for ibuprofen (Kowalski et
al, 2007), or in the case of oxycodone to the known exposure profile at a commonly given
clinical efficacious dose (Bensinger et al, 1997). This analysis of data suggested that the potency
of these two compounds appears to be approximately 10-20 fold lower in the rat than man.
In conclusion, using UV-induced heat hypersensitivity model and PKPD methodology, a