Increased Purinergic Signaling in Human Dental Pulps With Inflammatory Pain is Sex-Dependent.

An enhanced understanding of neurotransmitter systems contributing to pain transmission aids in drug development, while the identification of biological variables like age and sex helps in the development of personalized pain management and effective clinical trial design. This study identified enhanced expression of purinergic signaling components specifically in painful inflammation, with levels increased more in women as compared to men. Inflammatory dental pain is common and potentially debilitating; as inflammation of the dental pulp can occur with or without pain, it provides a powerful model to examine distinct pain pathways in humans. In control tissues, P2X3 and P2X2 receptors colocalized with PGP9.5-positive nerves. Expression of the ecto-nucleotidase NTPDase1 (CD39) increased with exposure to extracellular adenosine triphosphate (ATP), implying CD39 acted as a marker for sustained elevation of extracellular ATP. Both immunohistochemistry and immunoblots showed P2X2, P2X3, and CD39 increased in symptomatic pulpitis, suggesting receptors and the ATP agonist were elevated in patients with increased pain. The increased expression of P2X3 and CD39 was more frequently observed in women than men. In summary, this study identifies CD39 as a marker for chronic elevation of extracellular ATP in fixed human tissue. It supports a role for increased purinergic signaling in humans with inflammatory dental pain and suggests the contribution of purines shows sexual dimorphism. This highlights the potential for P2X antagonists to treat pain in humans and stresses the need to consider sex in clinical trials that target pain and purinergic pathways. PERSPECTIVE: This article demonstrates an elevation of ATP-marker CD39 and of ATP receptors P2X2 and P2X3 with inflammatory pain and suggests the rise is greater in women. This highlights the potential for P2X antagonists to treat pain and stresses the consideration of sexual dimorphism in studies of purines and pain.

A randomized, double-blind pilot study of analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen following dental implant placement surgery.

Introduction: Post-surgical pain following dental implant placement surgery is typically managed with non-opioid analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. However, the comparative analgesic efficacy of over-the-counter doses of non-steroidal anti-inflammatory drugs and acetaminophen in implant patients is unknown. Therefore, we compared the analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen after surgical placement of one or two dental implants. Methods: Adult patients were treated with naproxen sodium (440 mg loading dose +220 mg q8h, n = 15) or acetaminophen (1,000 mg q6h-max daily dose 3,000 mg, n = 15) for 3 days after implant placement in a randomized, double-blind design. Pain was assessed on a 0-10 scale every 20 min for 6 h after study medication treatment. Tramadol (50 mg) was available as a rescue medication. Plasma and gingival crevicular fluid (GCF) were collected prior to the surgery and 0, 1, 2, 4, 6, 24, and 72 h after surgery for quantification of interleukin (IL)-6, IL-8, and IL-1ß levels. Results: Pain scores were significantly lower in patients treated with naproxen sodium compared to those treated with acetaminophen. Inflammatory mediator levels in plasma and gingival crevicular fluid increased after surgery and returned to near baseline levels by 72 h. Plasma IL-6 levels were significantly lower 6 h after surgery in patients treated with naproxen sodium compared to acetaminophen. No differences in inflammatory mediator concentrations in gingival crevicular fluid were observed between the treatment groups. The number of implants placed and body mass index (BMI) influenced inflammatory mediator concentrations in plasma and gingival crevicular fluid, respectively. Discussion: Naproxen sodium was more effective than acetaminophen in reducing post-operative pain and systemic inflammation following surgical placement of one or two dental implants. Further studies are needed to determine whether these findings are applicable to more complex implant cases and how they affect clinical outcomes following implant placement. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04694300.