A New Transmucous-Buccal Formulation of Acetaminophen for Acute Traumatic Pain: A Non-inferiority, Randomized, Double-Blind, Clinical Trial

Abstract

Background: Acetaminophen (APAP) consumption is large and sometimes excessive, and guidelines suggest to diminish the dosage prescription. In emergency situations of mild/moderate pain intravenous (iv) APAP is recommended, but the route of administration is invasive. Objective: To determine the efficacy of a new transmucous-buccal (B) pharmaceutical form of 125mg-APAP in patients. To confirm the findings obtained in 2 previous clinical trials in healthy volunteers. Study Design: A randomized, double-blind, non-inferiority, clinical trial (NCT01586143) was carried out from 03/05/2012 to 13/05/2013. Setting: The study took place in the Emergency Department of the University Hospital, ClermontFd, France. Methods: Forty-three patients were included and 40 analyzed. Patients were eligible if they had leg or arm traumatic pain of moderate intensity. Pain intensity was measured using a numerical scale (0 – 10) at regular times for 120 minutes and the main endpoint was at 30 minutes. The hypothesis of non-inferiority was formulated from previous works with healthy volunteers. After pain assessment, patients received at baseline 1 g-iv-APAP or saline and concomitantly, 125 mg APAP in 1 mL hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Non-inferiority of the primary outcome was assessed by one-sided 2 group t-test of equivalence in means with equal variances with a non-inferiority limit difference of 1. Other tests were two-sided, with a type I error set at α = 0.05. Results: Intention-to-treat analysis shows that pain intensity of B-APAP and iv-APAP groups were not significantly different at t30 minutes (3 ± 1.3 vs 2.7 ± 1.2, P = 0.23, one-sided Student t-test), and at any other times for 120 minutes. The difference of pain intensity between groups was 0.30 with 2-sided IC90% = [-0.38 – 0.98], not including the non-inferiority margin (∆ = 1). Time to exhibit a statistical significance in pain relief from baseline was reached at t10 for B-APAP (P = 0.03) and iv-APAP (P < 0.001). Patients preferred the buccal rather than the iv route of administration. Limitations: Small population study with limited doses. Conclusions: For acute traumatic pain of moderate intensity, B-APAP has a non-inferior analgesic effect compared to iv-APAP for 2 hours. Such a pharmaceutical form would be useful in emergency situations and breakthrough moderate pain episodes. It would diminish APAP consumption per dosage unit, limit the risk of adverse events and toxicity, and adhere to actual guidelines of APAP prescription. It must be now studied in a larger population and with repeated doses. Key words: Transmucosal delivery, pain, trauma