Mechanisms of Variability in the Analgesic Response to Ibuprofen Following Third Molar Extraction

PROJECT SUMMARY/ABSTRACT Nonopioid analgesics are highly effective for pain management following most dental procedures, but data suggest that prescription of opioids by dental clinicians is excessive. Prescription opioid misuse remains a significant public health concern in the US, and ongoing opioid crisis has highlighted the need to optimize pain management with non-addictive analgesics, with non-steroidal anti-inflammatory drugs (NSAIDs) at the forefront. Numerous clinical trials have shown that NSAIDs are effective in the treatment of post-surgical pain following third molar extraction. However, there is substantial inter-individual variability in the analgesic response, with 20-30% of patients requiring opioids in addition to NSAIDs to achieve adequate pain relief. The use of precision medicine approaches to tailor analgesic therapy would enable oral surgeons to rationally prescribe opioids to only those patients who require them and avoid unnecessary opioid prescriptions in those patients who can achieve adequate pain relief with NSAIDs alone. However, the factors that contribute to heterogeneity in analgesic response to NSAIDs and need for opioid rescue medication have not been well-studied, and there is limited evidence to inform which patients should receive opioid prescriptions and how much should be prescribed. The work proposed in this application will identify individual host factors associated with need for opioid analgesics, in addition to NSAIDs, following third molar extraction. We will specifically investigate the role of inter-individual differences in regulation of the acute inflammatory response to surgical trauma and seek to identify an inflammatory response signature associated with need for opioid following third molar extraction. We will also investigate the role of neutrophil subtypes in mediating heterogeneity in analgesic efficacy of NSAIDs. Elucidation of the molecular mechanisms underlying inter-individual variability in analgesic efficacy of NSAIDs may allow the identification of biomarkers that are predictive of response, thereby facilitating a precision medicine approach to pain management. This work will provide a foundation for future clinical interventions to better manage pain following third molar extraction, with the goal to limit opioid prescriptions to only those patients not likely to respond adequately to NSAIDs.