Background & Aims

Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line analgesics for most patients undergoing third molar extraction surgery (1). However, there is considerable variability in the analgesic response to NSAIDs, with 20-30% of patients requiring opioids in addition to an optimal NSAID-based analgesic regimen (2,3). Understanding the mechanisms that contribute to heterogeneity in analgesic response to NSAIDs will enable the application of precision medicine approaches to optimize pain management after third molar extraction. Our prior study suggested that the analgesic response to ibuprofen was associated with the degree of cyclooxygenase pathway activation (4). The aim of this study was to compare the acute inflammatory response in patients who required opioids in addition to NSAIDs to those who did not after third molar extraction, to identify biomarkers that are predictive of analgesic response to NSAIDs.

Methods

Healthy adults (N=85, 18-37 years) underwent surgical extraction of partial or full bony impacted mandibular third molars. While local anesthesia dissipated, patients were evaluated for pain intensity, employing a numeric rating scale (0=no pain; 10=worst imaginable). When pain intensity was ?4/10, patients were given solubilized ibuprofen (400 mg) or placebo (3:1) in a randomized, double-blind design. Following the initial 4-hour evaluation period, all patients transitioned to open-label ibuprofen 400 mg plus acetaminophen 500 mg (IBU/APAP) taken every 4 hours around-the-clock for 48 hours, then as needed for up to 7 days. Patients were provided with eight oxycodone 5 mg tablets for breakthrough pain. Inflammatory profiles were evaluated at baseline, prior to treatment (t=0), and 4h, 24h, and Day 7 after treatment by complete blood count, serum C-reactive protein (CRP) concentration, and plasma proteomics using the Olink Target 96 Inflammation panel.

Results

Ibuprofen was significantly more effective than placebo, with a median pain intensity difference of 4 (IQR: 3?4) in the ibuprofen group, compared to -0.5 (IQR: -1-0) in the placebo group (p<0.05). After discharge, IBU/APAP provided adequate analgesia in most patients, with only 16 patients (18.6%) using oxycodone during the open-label phase. Patients who used oxycodone in addition to IBU/APAP had significantly lower neutrophil counts prior to surgery (2.5 (1.8-3.0) vs. 3.3 (2.5-4.2) x 103/µl; p<0.05). Serum CRP increased 24h after surgery in both groups (opioid users: 1.5 (0.6-2.9) vs. opioid non-users: 1.3 (0.8-2.3) mg/dl; p=0.62) but remained elevated at Day 7 in opioid users (0.8 (0.3-1.3) mg/dl) compared to non-users (0.3 (0.2-0.7) mg/dl; p<0.05). Several inflammatory plasma proteins, including SLAMF1, TNF-?, CD5, CX3CL1, CDCP1, and CD6, were significantly higher in opioid users at baseline and following third molar extraction.

Conclusions

IBU/APAP provided effective analgesia for the treatment of moderate-to-severe pain in most dental impaction surgery patients. The need for opioid rescue medication was associated with differences in the inflammatory profile at baseline and after third molar extraction. Future studies are necessary to elucidate the molecular mechanisms underlying these differences in the inflammatory profiles, as well as validate their utility as predictive biomarkers of analgesic response to NSAIDs.

References

1. Hersh, E.V., et al. Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain. J Dent Res 99, 777-786 (2020).
2. Hersh, E.V., et al. Ibuprofen liquigel for oral surgery pain. Clin Ther 22, 1306-1318 (2000).
3. Hersh, E.V., et al. Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain. Clin Ther 26, 1215-1227 (2004).
4. Theken, K.N., et al. Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain. Clin Pharmacol Ther 106, 632-641 (2019).

Presenting Author

Katherine Theken

Poster Authors

Katherine Theken

PhD

University of Pennsylvania

Lead Author

E-mail

Elliot Hersh

DMD

University of Pennsylvania

Lead Author

E-mail

Stacey Secreto

University of Pennsylvania

Lead Author

E-mail

Fabian Banze

University of Bielefeld

Lead Author

E-mail

Truongan Pham

University of Pennsylvania

Lead Author

E-mail

Gaurav Gupta

University of Pennsylvania

Lead Author

E-mail

Perla Cherfane

University of Pennsylvania

Lead Author

E-mail

Sydney Juska

University of Pennsylvania

Lead Author

E-mail

Steven Wang

DMD

University of Pennsylvania

Lead Author

E-mail

Neeraj Panchal

MD

University of Pennsylvania

Lead Author

E-mail

Rania Habib

MD

University of Pennsylvania

Lead Author

E-mail

Brian Ford

DMD

University of Pennsylvania

Lead Author

E-mail

Claire Mitchell

PhD

University of Pennsylvania

Lead Author

E-mail

John Farrar

Univ of PA

Lead Author

E-mail

Tilo Grosser

MD

University of Bielefeld

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Acute Pain and Nociceptive Pain