Submucosal diclofenac for acute postoperative pain in third molar surgery: a randomized, controlled clinical trial

Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) for relief of inflammatory pain. A recent formulation combines this drug with hydroxypropyl-β-cyclodextrin (HPβCD) to improve its solubility and to enable subcutaneous administration. Previous studies confirmed the efficacy of this combination. This study’s aim was to evaluate the efficacy, safety, and local tolerability of diclofenac HPβCD administered as a local submucosal injection prior to lower third molar surgery. We conducted a prospective, randomized, double-blind, placebo-controlled, parallel-group phase II single-center study. Seventy-five patients requiring mandibular third molar surgery were randomized into 1 of 5 groups: 5 mg/1 mL diclofenac HPβCD, 12.5 mg/1 mL diclofenac HPβCD, 25 mg/1 mL diclofenac HPβCD, 50 mg/1 mL diclofenac HPβCD, or 1 mL placebo. The respective study drug was injected into the mucosal tissue surrounding the surgical site prior to surgery following achievement of local anesthesia. The primary outcome measure was the area under the curve (AUC) of cumulative pain scores from end of surgery to 6 h postsurgery. This demonstrated a global treatment effect between the active groups and placebo, hence confirming the study drug’s efficacy (P = 0.0126). Secondary outcome measures included the time until onset of pain and the time until patients required rescue medication, both showing statistical significance of the study drug compared to placebo (P < 0.0161 and P < 0.0001, respectively). The time until rescue medication ranged between 7.8 h (for 25 mg/1 mL diclofenac HPβCD) and 16 h (for 50 mg/1 mL diclofenac HPβCD). Interestingly, the 5-mg/1-mL solution appeared superior to the 12.5-mg/1-mL and 25-mg/1-mL solutions (time until rescue medication = 12.44 h). A total of 14% of patients experienced minor adverse drug reactions (ADRs), of which 2 cases demonstrated flap necrosis. These resolved without further intervention. The study results overall indicate efficacy, safety, and relative tolerability of diclofenac HPβCD used locally as a submucosal injection prior to third molar surgery (ClinicalTrials.gov NCT01706588).