Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing.
Traditional and COX-2 selective non-steroidal anti-inflammatory drug (NSAID) treatment inhibits fracture healing in animal models. This indicates that either the inflammatory phase following a bone fracture is necessary for efficient or sufficient bone regeneration to heal the fracture or COX-2 may have a specific function during bone regeneration unrelated to inflammation. These observations also indicate that NSAID use during fracture healing may be contra-indicated. Thus, identification of different analgesics for fracture pain or other orthopaedic surgical procedures would be of significant clinical benefit. Inhibitors of p38 kinase also have significant analgesic properties. However, p38 kinase is a critical regulator of inflammation. To assess the potential use of p38 kinase inhibition as a therapeutic strategy to manage fracture pain, the analgesic properties of SCIO-469, a p38alpha kinase inhibitor, were assessed in a rat fracture model and compared to other common analgesics. In addition, the effects of SCIO-469 treatment on ultimate fracture healing outcomes were measured by radiography and torsional mechanical testing. The data indicate that SCIO-469 was an effective analgesic. No adverse events related to fracture healing were observed in rats treated with SCIO-469. Immunohistochemistry showed that p38 kinase is activated primarily in the first days following a fracture. These observations suggest that p38alpha kinase inhibition may be an effective therapeutic strategy to manage orthopaedic-related pain. These observations also indicate that COX-2 has a specific function during bone regeneration other than promoting inflammation.
Cottrell
Jessica A
JA
Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School & Graduate School of Biomedical Sciences, MSB E659, 185 S. Orange Avenue, Newark, NJ, USA.
Meyenhofer
Markus
M
Medicherla
Satyanarayana
S
Higgins
Linda
L
O'Connor
J Patrick
JP
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D001703:Biophysics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D011859:Radiography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D054159:Torsion, Mechanical; D016474:Weight-Bearing / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000700:Analgesics; D004791:Enzyme Inhibitors; D007211:Indoles; C499748:SCIO-469; D048051:p38 Mitogen-Activated Protein Kinases