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To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. NCT03224403 [ABSTRACT FROM AUTHOR]

Objectives: Opioid/acetaminophen combinations may be overly prescribed in many post-surgical situations where a non-steroidal anti-inflammatory drug with equal or greater efficacy, fewer central nervous system side effects, and no risk for opioid abuse could be substituted. We compared a single, non-prescription dose of naproxen sodium 440 mg (NapS) against hydrocodone plus acetaminophen 10/650 mg (HYD+APAP) in post-impaction surgery pain.Methods: Single-center, randomized, double-blind, placebo-controlled study in moderate-severe pain after surgical removal of impacted third molars (ClinicalTrials.gov: NCT04307940). Patients (n = 212) received NapS, HYD+APAP, or placebo and were assessed over 12 hours. Primary endpoint: summed pain intensity difference from 0 to 12 hours (SPID0-12). Secondary endpoints: pain intensity, pain relief, time to rescue medication, duration of pain at least half gone. Others: onset of pain relief, global assessment of treatment, adverse events.Results: All 221 randomized patients formed the safety population and were included in the intention-to-treat sensitivity analysis. Nine patients discontinued treatment or had protocol violations, and 212 patients were included in the per-protocol, primary efficacy population. Both active treatments were significantly more effective than placebo. NapS was significantly more effective than HYD+APAP regarding SPID0-12 (p = 0.01; primary endpoint), total pain relief (0-6 and 0-12 hours; p < 0.05), time to rescue medication (p < 0.001), and duration of pain at least half gone (p < 0.001). HYD+APAP was not statistically superior to NapS for any endpoint. More adverse events were reported with HYD+APAP (n = 63) than NapS (n = 2) and placebo (n = 20), including nausea, vomiting, and dizziness.Conclusion: In moderate-to-severe postsurgical dental pain, a single dose of NapS was at least as effective as HYD+APAP in the early hours, significantly more effective at reducing pain intensity and providing greater pain relief over 12 hours, and was better tolerated. When not contraindicated, NapS should be considered a preferred alternative to opioid combinations for acute pain. (ClinicalTrials.gov, Identifier: NCT04307940; https://clinicaltrials.gov/ct2/show/NCT04307940). [ABSTRACT FROM AUTHOR]

Abstract: The analgesic efficacy and safety of DFN-15, a new oral liquid formulation of celecoxib with more rapid absorption than the capsule, were evaluated in the treatment of acute pain in adult patients after dental surgery. In this randomized, double-blind, placebo-controlled, dose-ranging study, 120 otherwise healthy adults who underwent the extraction of bilateral impacted mandibular third molar teeth and experienced moderate to severe pain postsurgery were randomly assigned, in a 1:1:1:1 ratio, to receive one dose of either placebo or DFN-15 at 3 doses: 62.5, 125, and 250 mg. Participants were evaluated at prespecified time points over 8 hours after study drug administration, using several instruments, including the 11-point Numerical Pain Rating Scale, 5-point Pain Relief Scale, and 5-point Treatment Satisfaction Scale. Rescue analgesic (oxycodone / acetaminophen) was permitted. The primary endpoint was the summed pain intensity difference (SPID) over the 6-hour postdose period (SPID6), which was compared between each DFN-15 dose and placebo using analysis of covariance. Other assessments of pain relief, use of rescue medication, and safety were also analyzed. All 3 doses of DFN-15 were significantly superior to placebo in SPID6 (least square mean difference over placebo: -756.6, -1120.7, and -1355.1, P < 0.0001 for all comparisons). In addition, DFN-15 was generally superior to placebo in other endpoints, including reduction of pain intensity, speed and magnitude of pain relief, treatment satisfaction, and rescue medication use. DFN-15 was similar to placebo in the incidence of adverse events with no apparent dose-related effects. [ABSTRACT FROM AUTHOR]

Background: The Na V 1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na V 1.8, on control of acute pain is being studied., Methods: After establishing the selectivity of VX-548 for Na V 1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo., Results: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548., Conclusions: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.)., (Copyright © 2023 Massachusetts Medical Society.)