Analgesic efficacy and safety of naproxen sodium versus hydrocodone / acetaminophen in acute postsurgical dental pain: a randomized, double-blind, placebo-controlled trial
Stephen A. Cooper (1), Paul J. Desjardins (2), Todd Bertoch (3), Engy Mikhail (4), Sistine Jarvis (4), Azita Tajaddini (4)

Background
We compared a non-prescription, maximum single dose of naproxen sodium (NapS) with the most prescribed oral opioid combination pain medication in the US, hydrocodone plus acetaminophen (HYD+APAP) in the dental impaction pain model. The study objective was to compare the efficacy and safety of a single oral dose of NapS 440 mg, HYD+APAP 10/650 mg or placebo (PBO) in patients experiencing moderate to severe pain after surgical extraction of impacted molars.

This study is important because the relative efficacy of these two commonly used pain medications has not been directly compared in a validated acute pain model. Furthermore, this study is timely because options for reducing the use of opioids to control postoperative pain are highly desired and can provide clinicians with important alternatives when recommending appropriate analgesics.

Methods
We conducted a 12-hour, single-dose, single center, randomized, double-blind, parallel, placebo-controlled study (ClinicalTrials.gov Identifier: NCT04307940). Healthy male and non-pregnant females, 18-40 years old, who had undergone surgical removal of 3 or 4 third molars, 2 of which had to be mandibular partial or full bony impactions, were eligible to participate if they had ‘moderate’ or ‘severe’ postsurgical pain and a score of ≥5 on the 0–10 pain intensity Numerical Rating Scale (NRS) within 4.5 hours after surgery.

The study took place at JBR Clinical Research (Salt Lake City, UT, USA) and consisted of a prescreening telephone call, a screening visit, a one-day treatment period, and a postoperative visit. Patients remained onsite throughout the 12-hour observation period for efficacy and safety evaluations.

Treatments: Naproxen sodium (440 mg) (NapS); Hydrocodone (10 mg) plus acetaminophen (650 mg) (HYD+APAP); Placebo.

Patient Demographics

Results

* Two-sided test with alpha 0.05 considered statistically significant (bold)). a ANCOVA model, with SPID0-12, TOTPAR or SPID (as appropriate) as the dependent variable, treatment as the main effect and baseline pain intensity as the covariate. b For patients who used rescue medication, their post-rescue medication assessment of efficacy endpoints was replaced by c the worse of the baseline or the score assessed immediately before taking rescue medication or d ‘No relief’ or e the time was censored at the time of the last pain intensity score assessment. f Estimated using Kaplan-Meier methods. CI, confidence interval; HYD+APAP, hydrocodone (10 mg) + acetaminophen (650 mg); LS, least square; NapS, naproxen sodium (440 mg); NE, not estimable (<50% of patients required rescue medication during the 12-hour follow-up); PBO, placebo; SE, standard error; SPID, summed pain intensity difference over time (pain intensity assessed using the numerical rating scale, from 0=no pain to 10=worst pain imaginable); TOTPAR, total pain relief (Pain Relief Score assessed on a categorical scale from 0 = No Relief to 4 = Complete Relief).

Conclusions
This study contributes to the growing body of evidence that NSAIDs relieve acute pain more effectively than an opioid-containing medication. In moderate or severe dental pain, a single dose of naproxen sodium was at least as effective in the early hours and significantly more effective over 12 hours than hydrocodone plus acetaminophen at reducing pain intensity and providing greater pain relief. Naproxen sodium was better tolerated than the opioid combination. When not contraindicated, NapS should be considered as a superior alternative to prescribing opioid combinations for the management of acute pain.

Funding: This study was sponsored by Bayer HealthCare, LLC, Consumer Health,, USA
1 Stephen A. Cooper, LLC, 2 Desjardins Associates LLC, 3 CenExel, 4 Bayer HealthCare LLC