Analgesic onset and efficacy of a fast-acting formulation of acetaminophen in a postoperative dental impaction pain model

Abstract

Objectives

Speed of onset can be critical to an analgesic’s efficacy treating acute pain. To enhance onset, a new oral acetaminophen formulation intended to be fast acting was developed. Two studies evaluated the analgesic onset, efficacy, and safety of this fast-acting acetaminophen (FA-acetaminophen) tablet relative to commercial acetaminophen caplets (ES-acetaminophen) and commercial ibuprofen liquid-filled gelatin capsules (LG-ibuprofen).

Methods

Two single-center, single-dose, inpatient, randomized, double-blind, triple-dummy, placebo-controlled, parallel group design clinical trials were conducted using the postoperative dental impaction pain model. Subjects were healthy men and women aged 17–50 years experiencing moderate-to-severe pain after surgical extraction of at least three impacted third molars. In both studies, four treatment groups were evaluated: 1,000 mg acetaminophen as two 500 mg FA-acetaminophen tablets, 1,000 mg as two 500 mg ES-acetaminophen caplets, 400 mg ibuprofen as two 200 mg LG-ibuprofen capsules, and placebo. To maintain blinding, each subject received six units of study medication. Times to confirmed perceptible pain relief (TCPR) and meaningful pain relief (TMPR) were obtained using the double-stopwatch method. Pain intensity and relief were measured over 6 h following drug administration using a 0–10 numerical rating scale. Time to use of rescue medication (naproxen sodium) and subject global evaluations of study medications at 6 h were collected. Pharmacokinetic blood sampling and safety assessments were performed.

Results

Studies 1 and 2 enrolled 240 and 420 subjects, respectively. No clinically important differences among treatment groups were observed for any demographic or baseline characteristics. Efficacy results showed all active treatments statistically superior to placebo. In Study 1, TCPR was statistically significantly shorter for FA-acetaminophen compared to ES-acetaminophen and LG-ibuprofen. In Study 2, no statistically significant differences in TCPR were noted across the active treatment groups. In Study 1, FA-acetaminophen 1,000 mg provided significantly shorter TMPR compared with LG-ibuprofen but not compared with ES-acetaminophen. In Study 2, no significant differences in TMPR were noted across the active treatment groups. In both Study 1 and 2 at 15 min after administration of study drug, PID and PAR scores were greater for FA-acetaminophen than LG-ibuprofen.

Conclusions

Both studies suggested FA-acetaminophen had faster onset of action compared to ES-acetaminophen and LG-Ibuprofen. In light of the difference in TCPR and TMPR results between Study 1 and 2, an additional study is needed to further investigate time to analgesic onset of FA-acetaminophen compared with ES-acetaminophen and LG-Ibuprofen.

Study registry numbers

Study 1: NCT02735122; Study 2: NCT03224403

Keywords:

• Acetaminophen
• fast-acting formulation
• analgesic onset
• pain relief

This article is related to:

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Introduction

Speed of onset can be a critical attribute to an analgesic’s efficacy in the treatment of acute pain. Interview responses from adults who had a history of using over-the-counter (OTC) analgesics to treat non-specific daily headaches revealed that they considered onset of pain relief within 30 min as fast acting¹. Moreover, these adults identified an earlier onset of relief of at least 5 min as the indicator qualifying an analgesic as providing faster relief than other analgesics.

Acetaminophen is a non-opiate, para-aminophenol derivative with a well-established history of analgesic and antipyretic properties^2,3. In vivo rodent models suggest acetaminophen may exert analgesic effects through cyclooxygenase (COX) enzymes, serotonin receptors, transient receptor potential ion channels, and endocannabinoid transporters^3–8. Although the exact mechanism of action for acetaminophen is not fully known, it is thought to act primarily in the central nervous system to elevate the pain threshold^9–12. Numerous studies confirm the effectiveness of acetaminophen in the relief of mild-to-moderate pain related to osteoarthritis¹³, headache^14,15, muscle aches and pains^16,17, and postoperative pain^18–21 and Cochrane reviews address the effectiveness and safety of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) in these pain states^22–24. Standard formulations of acetaminophen dosed at 650 mg and 1,000 mg typically provide an onset of perceptible pain relief in less than 30 min and meaningful pain relief in less than 1 h with pain relief persisting for 4 to 6 h^{14,15,18,19,21}. Recognizing that fast onset of pain relief is an important attribute for consumers using an OTC pain reliever and can be critical to an analgesic’s efficacy in the treatment of acute pain, a new fast-acting oral acetaminophen formulation (FA-acetaminophen tablets) was developed. It contains a blend of excipients thought to result in faster dissolution and absorption of acetaminophen.

The two studies described in this paper were designed to assess if this new oral formulation of acetaminophen tablets had a faster onset of action than selected commercially available OTC fast-acting analgesics in a third molar extraction model.

Subjects and methods

Both Studies 1 and 2 had a single-center, single-dose, inpatient, randomized, double-blind, triple-dummy, placebo-controlled, parallel design. Study 1 was conducted between November 2014 and April 2015; Study 2 was conducted between April and October 2016. Both studies were conducted at JBR Clinical Research (Salt Lake City, UT, USA). The studies complied with International Conference on Harmonization and Good Clinical Practice guidelines and were approved by Aspire Institutional Review Board (Santee, CA, USA). All subjects and, where applicable, the parents or legally authorized representative of subjects, provided written informed consent on a form which complied with the requirements of the Health Insurance Portability and Accountability Act. Written assent was obtained from prospective subjects who were below the age of legal consent yet old enough to understand the details of the study. The subset of subjects included in the pharmacokinetic analysis were also asked to consent to the collection of blood samples. The studies were registered at ClinicalTrials.gov: Study 1: NCT02735122; Study 2: NCT03224403.

The data sharing policy of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

Inclusion criteria were similar for Studies 1 and 2. Eligible subjects were healthy men and women aged 17–50 years. In Study 1, ≥25% of subjects were required to be male; in Study 2, no less than approximately 30% of randomized subjects could be either male or female, and no more than 30% could be 17 years of age at the time of surgery. Subjects had to have a body mass index of 18–30 kg/m² at screening and required surgical removal of a minimum of three impacted third molars, of which two had to be mandibular impactions. Mandibular extractions met one of the following scenarios without resulting in a surgical trauma rating of severe on a mild, moderate, or severe scale: two full bony impactions; two partial bony impactions; or one full bony impaction in combination with one partial bony impaction. Maxillary third molars could be removed regardless of impaction level. Surgical trauma was determined postoperatively by the surgeon based on the degree of tissue trauma associated with the third molar extraction. Subjects who were classified as having had severe surgical trauma were excluded from randomization. If within 4.5 h of surgery, subjects experienced at least moderate postsurgical pain on a categorical scale of (0) none, (1) mild, (2) moderate, or (3) severe and at least a score of 5 on the 11-point pain intensity numerical rating scale (PI-NRS), they were randomized to treatment.

Subjects had to agree to follow specified contraceptive requirements. In both studies, subjects were excluded from the study if they had any existing or previous history of a potentially confounding medical condition or were taking any drug that could have interfered with the evaluation of the study medications.

Four treatment groups were evaluated in both studies: 1,000 mg acetaminophen as two 500 mg FA-acetaminophen tablets (Patheon), 1,000 mg acetaminophen as two Tylenol® Extra Strength Caplets (Johnson and Johnson Consumer, Inc; JJCI), 400 mg ibuprofen as two 200 mg Advil^® Liqui-gels (Pfizer Inc), and placebo (Piramal: placebo to match FA-acetaminophen; Catalent: placebos to match LG-ibuprofen and ES-acetaminophen). The FA-acetaminophen formulations in Studies 1 and 2 varied slightly in excipient type; however, these changes were shown in vitro and in human pharmacokinetic studies not to result in any relevant difference in dissolution or absorption. All study medications and a computer-generated randomization schedule were provided by JJCI. In Study 1, subjects were randomized to one of the four treatments in a 1:1:1:1 ratio and stratified by baseline pain level (moderate or severe). In Study 2, subjects were randomized in a 2:2:2:1 ratio active to placebo and stratified according to sex and baseline pain rating (moderate or severe). A triple-dummy method was used to maintain blinding in both studies. Each dose was supplied in a blister card containing six units: two tablets, two caplets, and two liquid filled capsules. The card included either two active units and four placebo units, or six placebo units. Each subject swallowed the six units with 180 mL water.

Surgical anesthesia consisted of a short-acting local anesthetic (lidocaine) with epinephrine and the optional use of nitrous oxide during dental surgery with no other perioperative sedatives or analgesics. Topical benzocaine was allowed prior to the injection of the local anesthetic. The use of ice packs was prohibited during the postsurgical observation period until the subject completed the analgesic evaluations. Subjects were encouraged, but not required, to wait at least 1.5 h before taking a rescue analgesic. Subjects fasted prior to their surgical procedure; postoperatively, subjects were allowed only clear, non-caffeinated liquids until 2 h following administration of the investigational product at which time they were allowed to have soft foods. Naproxen sodium at labeled dosing recommendations was allowed as rescue therapy if the severity of the subject’s pain increased to an intolerable level.

Measures

Upon ingestion of the study medication, time to perceptible pain relief (TPPR) and time to meaningful pain relief (TMPR) were collected using two separate stopwatches. Subjects were asked to stop the first stopwatch when they began to feel any pain relief compared to pain at baseline and to stop the second stopwatch when pain relief was meaningful to them. Time to confirmed perceptible pain relief (TCPR) was calculated as the time (in minutes) to perceptible relief as indicated on the first stopwatch, provided that the subject also stopped the second stopwatch indicating meaningful pain relief. Pain intensity and pain relief were assessed at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, and 6 h after dose administration and at the time of rescue in Studies 1 and 2 and at TMPR in Study 2. Both pain intensity and pain relief were measured using a 0–10 Numerical Rating Scale (NRS). At the end of the 6-h assessment or at the time of rescue, whichever came first, subject global evaluation (SGE) of the study medication was collected. SGE was measured using a categorical scale of poor (0), fair (1), good (2), very good (3), or excellent (4).

In Study 1, all subjects had blood drawn for determination of study drug plasma concentrations; whereas, in Study 2 only the first 140 subjects had blood drawn. To determine drug concentrations, 3 mL blood samples were collected by direct venipuncture into Vacutainers containing sodium heparin or equivalent at 10, 20, 40, 90, 240, and 360 min after dosing. Plasma was harvested and stored frozen until assay for acetaminophen and ibuprofen using validated analytical methods (Frontage Laboratories, Inc, Exton, PA).

The efficacy endpoints for Study 1 were TCPR, time weighted sum of pain intensity difference from 0 to 4 and 0 to 6 h (SPID 0–4, SPID 0–6); TMPR; TPPR; time weighted sum of pain relief from 0 to 4 and 0 to 6 h (TOTPAR 0–4, TOTPAR 0–6); duration of relief after dosing (calculated as the time to rescue analgesic); proportion of subjects taking a rescue analgesic by 6 h; pain relief (PAR) and pain intensity difference (PID) scores at individual time points; and SGE. Exploratory endpoints were the proportion of subjects achieving meaningful pain relief within 30, 60, and 90 min of dosing; the proportion of subjects with perceptible relief within 15, 30, and 45 min of dosing (results not presented); the proportion of subjects with confirmed perceptible relief within 15, 30, and 45 min of dosing. TPPR endpoints and sum of pain intensity differences and pain relief scores from 0 to 4 h are not presented.

For Study 2, the primary endpoint was TCPR. Secondary efficacy measures were the percentage of subjects with confirmed perceptible relief from 0–30 min, 0–29 min, etc to successively earlier minutes in one-minute increments (FA-acetaminophen versus placebo); risk ratios of confirmed perceptible relief by 10, 15, and 20 min (1,000 mg FA-acetaminophen incidence divided by 400 mg LG-ibuprofen incidence); the percentage of subjects with meaningful relief by 30 min; and TMPR. Tertiary efficacy measures were time-weighted SPID 0–6; time-weighted TOTPAR 0–6; PAR and PID scores at individual time points; time to rescue analgesic; and SGE.

Spontaneous adverse events (AEs) reported by subjects were collected throughout the study. No vital signs or laboratory assessments were made after screening and baseline visits. Normal consequences of dental surgery, such as pain, swelling, and bruising at the surgical site, were not recorded as AEs unless, in the opinion of the investigator, the conditions were aggravated or worsened after administration of the study medication. A follow-up phone call 1 week after dental surgery was used to monitor changes in health and concomitant therapies. AEs with a suspected causal relationship to the study drug were followed until the event or its sequelae resolved or stabilized. Spontaneous reports of serious AEs (SAEs) were collected through and including 30 calendar days after administration of study drug. AEs were coded using Medical Dictionary for Regulatory Activities version 16.1 for Study 1, Version 18 for Study 2.

Safety endpoints were as follows: percentage of subjects experiencing AEs, discontinuing the study due to an AE or experiencing an SAE; percentage of subjects experiencing treatment-related AEs (possible, probable, very likely, or unknown); percentage of subjects with AEs by severity and relationship to treatment.

Statistical methods

In Study 1, a sample size of 60 subjects per treatment group was planned to provide reliable estimates of the outcome measures for future research. In Study 2, 120 subjects per group for the active treatment arms was chosen based on simulations using pharmacokinetic/pharmacodynamic models based on TCPR, TMPR, and pharmacokinetic data from Study 1, and pharmacokinetic models based on data from Study 1 and other pharmacokinetic studies. Each simulated study produced a Wilcoxon test result (statistically significant or not at alpha < 0.05, two-sided), with 94% of the simulated studies showing significance for FA-acetaminophen versus LG-ibuprofen in TCPR and 87% for the same comparison in TMPR.

All efficacy analyses were based on the intent-to-treat (ITT) analysis set which consisted of all subjects who were randomized. Safety analyses included all subjects who received study medication.

TCPR and TMPR (and TPPR in Study 1) were each compared using the generalized Wilcoxon test. Subjects who did not have relief by 6 h, or who took rescue medication before having relief had their time of relief set to 6 h and were censored at 6 h. Fisher’s Exact test was used to analyze the proportion of subjects experiencing relief by specified time points and the proportion taking rescue analgesic by 6 h. Time to rescue was analyzed using the log-rank test. Subjects not using rescue medication had their time to rescue set to 6 h and were censored at 6 h. SPID, TOTPAR, PID, PAR, and SGE were analyzed with an analysis of variance (ANOVA) with factors of baseline pain and treatment. For subjects who used rescue medication, the last reported pain score before use of rescue or the baseline pain score, whichever was worse, was carried forward to the remaining time points; pain relief scores after rescue were set to zero. Median time to rescue was set to not estimable if fewer than 50% of subjects rescued. Similarly, time to pain relief (TPPR, TCPR, and TMPR), and median time to pain relief was set to not estimable if fewer than 50% of subjects reported obtaining pain relief. Comparisons for efficacy variables were tested at the 0.05 significance level, two-sided.

In Study 2, to control the Type I error rate at 0.05, a sequential testing method was used to assess TCPR; testing continued until statistical significance was no longer achieved at alpha = 0.05.

1. FA-acetaminophen vs placebo on TCPR.

2. FA-acetaminophen vs LG-ibuprofen on TCPR.

3. FA-acetaminophen vs placebo on TMPR.

4. FA-acetaminophen vs placebo on percentage of subjects with meaningful relief at 30 minutes.

5. FA-acetaminophen vs LG-ibuprofen on percentage of subjects with meaningful relief at 30 minutes.

6. FA-acetaminophen vs placebo on percentage of subjects with confirmed perceptible relief by 30 minutes, then 29 minutes, 28 minutes and successively earlier minutes until p >.05.

In Study 2, the earliest statistical separation of FA-acetaminophen from placebo in confirmed perceptible pain relief was determined using the percentage of subjects achieving confirmed perceptible pain relief within 30 min followed by successively earlier intervals in 1-min increments.

Plasma concentrations are presented by treatment group and time. Due to sparse sampling, pharmacokinetic parameters were not determined.

Results

Subject population

Figure 1 summarizes the status of all randomized subjects by treatment group. In each study, one subject withdrew from treatment. Overall demographic and baseline characteristics of the subjects were similar across treatment groups in each study (Supplementary Table). More females were enrolled in Study 1 than Study 2 and more subjects were ≥18 years of age in Study 1 than Study 2. In both studies, the proportions of subjects with moderate and severe baseline pain were similar.

Figure 1. Patient disposition for Studies 1 and 2.

Treatment comparisons

All active treatments were statistically superior to placebo for TCPR, TMPR, time to rescue, use of rescue analgesic, SPID 0–6, TOTPAR 0–6, and SGE in Studies 1 and 2.

Onset of pain relief: confirmed perceptible pain relief

In Study 1, TCPR was statistically significantly shorter for FA-acetaminophen compared to ES-acetaminophen and LG-ibuprofen. In Study 2, no statistically significant differences in TCPR were noted across the active treatment groups (Table 1). The cumulative percentage of subjects with confirmed perceptible pain relief over time is shown in Figure 2 for both studies.

Figure 2. Kaplan-Meier plots of time to confirmed perceptible pain relief in Study 1 (a) and Study 2 (b).

Table 1. Summary of pain relief, pain intensity differences, use of rescue medication, and subject global evaluation during the 6 h treatment period.

Endpoint	Placebo	FA-Acetaminophen 1,000 mg	ES-Acetaminophen 1,000 mg	LG-Ibuprofen 400 mg
Number of Subjects
Study 1	60	59	60	61
Study 2	60	122	118	120
Median TCPR (min) (95% CI)
Study 1	NE	15.2 (13.6–17.6)^a	21.6 (16.6–26.5)^a^,^b	27.5 (24.3–31.7)^a^,^c
Study 2	NE	18.8 (15.8–22.5)^a	22.5 (16.9–26.4)^a	24.5 (21.3–27.0)^a
Median TMPR (min) (95% CI)
Study 1	NE	33.2 (27.1–49.5)^a	50.5 (38.4–66.8)^a	56.3 (46.1–64.9)^a^,^c
Study 2	NE	42.6 (38.5–53.2)^a	52.8 (45.9–68.6)^a	43.6 (38.8–56.5)^a
% Rescuing by 6 h
Study 1	83.3%	32.2%^a	46.7%^a	29.5%^a
Study 2^d	71.2%	25.4%	26.3%	10.0%
Median Time to Rescue (min)
Study 1	105.0	NE^a	NE^a	NE^a
Study 2	102.0	NE^a	NE^a	NE^a^,^c
SPID 0–6 LS Mean (SE)
Study 1	−1.01 (1.82)	20.53 (1.84)^a	16.05 (1.82)^a	23.40 (1.81)^a
Study 2	3.66 (1.83)	22.06 (1.28)^a	22.46 (1.30)^a	28.20 (1.30)^a^,^c
TOTPAR 0–6 LS Mean (SE)
Study 1	5.94 (2.20)	28.53 (2.21)^a	24.00 (2.20)^a	32.32 (2.18)^a
Study 2	11.01 (2.24)	30.96 (1.57)^a	31.14 (1.60)^a	38.86 (1.58)^a^,^c
Mean SGE LS Mean (SE)
Study 1	0.5 (0.13)	2.4 (0.13)^a	2.1 (0.13)^a	2.7 (0.13)^a
Study 2	0.8 (0.14)	2.3 (0.10)^a	2.4 (0.10)^a	2.8 (0.10)^a^,^c

^a p < .001 treatment vs placebo.

^b p < .05 FA-Acetaminophen vs ES-Acetaminophen.

^c p < .05 FA-Acetaminophen vs LG-Ibuprofen (superiority of treatment varies by endpoint).

^d No statistical comparisons performed for this variable in Study 2.

Abbreviations: CI, confidence interval; LS Mean, least squares mean; NE, not estimable, <50% subjects achieved endpoint; TCPR, time to confirmed perceptible pain relief; TMPR, time to meaningful pain relief; SPID, summary of pain intensity differences; TOTPAR, time weighted sum of pain relief scores; SE, standard error; SGE, subject global evaluation.

In Study 2, the earliest separation in confirmed perceptible pain relief occurred at 13 min when 23.0% of FA-acetaminophen and 8.3% of placebo (p = .023) subjects achieved confirmed perceptible pain relief.

Onset of pain relief: meaningful pain relief

In Study 1, FA-acetaminophen 1,000 mg provided significantly shorter TMPR compared with LG-ibuprofen but not compared with ES-acetaminophen (Table 1). In Study 2, no significant differences in TMPR were noted across the active treatment groups. The cumulative percentage of subjects with meaningful pain relief over time is shown in Figure 3 for both studies. In Study 1 at 30 min, significantly more FA-acetaminophen subjects achieved meaningful pain relief than ES-acetaminophen and LG-ibuprofen subjects. In Study 2 at 30 min, similar percentages of subjects in the active treatment groups achieved meaningful pain relief.

Figure 3. Kaplan-Meier plots of time to meaningful pain relief in Study 1 (A) and Study 2 (B).

Onset and duration of pain relief: analgesia: pain intensity difference and pain relief

The time course of mean PID scores is shown in Figure 4 for both studies, whereas the time course of mean PAR scores is shown in the Supplementary Figure. At early time points in Study 1, PID and PAR scores for FA-acetaminophen were significantly greater than for ES-acetaminophen (0.25 h, 0.5 h) and LG-ibuprofen (0.25 h, 0.5 h, 0.75 h). At early time points in Study 2, PID and PAR scores for FA-acetaminophen and ES-acetaminophen were similar while FA-acetaminophen had significantly greater PID and PAR scores than LG-ibuprofen at 0.25 h. LG-ibuprofen had significantly greater PID scores than FA-acetaminophen from 1.25 to 6 h and greater PAR scores than FA-acetaminophen from 1 through 6 h.

Figure 4. Time course of pain intensity difference (PID) scores for each treatment in Study 1 (A) and Study 2 (B). Data presented as least squares mean (LSMean) ± standard error (SE).

Duration of pain relief: time to rescue

In Studies 1 and 2, median time to rescue for each active treatment group was not estimable, as fewer than 50% of the subjects received rescue. In Study 1, no significant differences between FA-acetaminophen and ES-acetaminophen or LG-ibuprofen were detected in time to rescue or the percentage of subjects rescuing by 6 h. In Study 2, time to rescue was similar for ES-acetaminophen and significantly longer for LG-ibuprofen compared to FA-acetaminophen (Table 1).

Summed pain intensity difference and total pain relief

For SPID 0–6 and TOTPAR 0–6 in Study 1, there were no significant differences among active treatments. In Study 2 there were no significant differences between FA-acetaminophen and ES-acetaminophen while LG-ibuprofen had significantly better SPID 0–6 and TOTPAR 0–6 scores than FA-acetaminophen (p <.001) (Table 1).

Subject global evaluation

For SGE, no statistically significant differences in mean ratings were noted between FA-acetaminophen and the other active treatment groups in Study 1. In Study 2, while no statistically significant differences in mean ratings were observed between FA-acetaminophen and ES-acetaminophen, ratings were significantly higher for LG-ibuprofen compared with FA-acetaminophen (Table 1).

Subgroup analyses

Pairwise comparison of treatments by gender and baseline pain (moderate or severe) are presented in the Supplementary Materials. For Studies 1 and 2, pairwise comparison of treatments by gender and baseline pain (moderate or severe) for onset of analgesia endpoints showed results roughly consistent with the ITT analyses. In Study 2, TCPR was similar between male and female subjects and between subjects with moderate and severe baseline.

Safety and tolerability

During Studies 1 and 2, 22.1% and 11.2% of subjects reported AEs, respectively; no SAEs were reported and no subject was discontinued from either study due to an AE. Similar numbers and percentages of subjects in each treatment group reported AEs in both studies. The most commonly reported AEs were nausea and vomiting. The severity of all AEs was rated as mild or moderate by the investigator in both studies, except for two AEs rated as severe: syncope and loss of consciousness that were reported by two subjects receiving placebo in Study 1. Treatment-related AEs were reported by three (1.3%) subjects in Study 1 and two subjects (0.5%) in Study 2. The reported AEs did not suggest any new safety signals for any of the active treatments under study.

Plasma concentrations

In Studies 1 and 2, mean acetaminophen plasma concentrations for a 1,000 mg dose of FA-acetaminophen were higher at 10, 20, and 40 min after dosing compared with a 1,000 mg dose of ES-acetaminophen (Table 2). Thereafter, plasma concentrations for FA-acetaminophen and ES-acetaminophen were similar. Mean ibuprofen plasma concentrations following a 400 mg dose of LG-ibuprofen were negligible at 10 min. These observations are consistent with the numerically faster median times to confirmed perceptible relief for FA-acetaminophen compared with ES-acetaminophen and LG-ibuprofen.

Table 2. Plasma concentrations (μg/mL) following a single oral dose of study drug.

Mean plasma concentrations	FA-acetaminophen 1,000 mg Study 1 (N = 59) Study 2 (N = 40)	ES-Acetaminophen 1,000 mg Study 1 (N = 60) Study 2 (N = 40)	LG-Ibuprofen 400 mg Study 1 (N = 61) Study 2 (N = 40)
10 min
Study 1	2.57 ± 4.52	0.51 ± 2.08	0.12 ± 0.20^a
Study 2	2.48 ± 3.70	0.71 ± 2.57	0.54 ± 1.13
20 min
Study 1	12.22 ± 7.95^b	5.18 ± 7.03	9.49 ± 15.50
Study 2	8.51 ± 6.61	4.41 ± 5.67	12.55 ± 15.81
40 min
Study 1	15.10 ± 5.04	12.16 ± 6.82^c	32.52 ± 16.15^a
Study 2	12.29 ± 5.21	8.83 ± 5.86	35.40 ± 13.77
90 min
Study 1	12.41 ± 3.00^b	13.71 ± 3.47^c	33.24 ± 8.35
Study 2	11.42 ± 3.35	11.19 ± 3.96	34.49 ± 6.66
240 min
Study 1	6.00 ± 2.01	6.68 ± 2.25	12.96 ± 4.12
Study 2	6.08 ± 1.78	5.83 ± 2.19	11.73 ± 3.93
360 min
Study 1	3.47 ± 1.42	3.68 ± 1.56	6.36 ± 2.70
Study 2	3.57 ± 1.33	3.32 ± 1.49	5.65 ± 2.86

^a N = 60.

^b N = 58.

^c N = 59.

Discussion

The novel, fast-acting oral acetaminophen formulation (FA-acetaminophen) provided rapid and effective pain relief among individuals who experienced moderate-to-severe dental pain following third molar extractions. In both studies, FA-acetaminophen, OTC ES-acetaminophen, and OTC LG-ibuprofen were well tolerated.

The dental impaction pain model, a validated model of acute pain and one of the most widely used to study analgesic onset and efficacy, has been used to evaluate various analgesics, including OTC formulations of acetaminophen and ibuprofen^25–27. For moderate acute dental pain, the American Dental Association (ADA) recommends oral NSAIDs such as ibuprofen 400–800 mg every 6 h or oral acetaminophen 500–650 mg every 6 h or 1,000 mg every 8 h. The doses of acetaminophen and ibuprofen used in these studies were consistent with ADA recommendations. With a higher likelihood of adverse effects compared to other non-opioid analgesics, opioids are not recommended for mild-to-moderate acute dental pain.

Standard formulations of oral acetaminophen (500 mg, 650 mg, or 1,000 mg) show onset of action to be 20 min to 30 min^18,19,28. Research shows that consumers clearly prefer analgesics with more rapid onset of pain relief (preferably within 15 to 20 min) and that consumers perceive a drug (or formulation) to be faster acting when comparative times to onset are reduced by at least 5 min¹. The TCPR results in these studies for FA-acetaminophen suggest that it will meet consumer expectations for a more rapid onset of pain relief. Recently, Yue and associates reported the results of two clinical studies evaluating a 1,000 mg dose of a fast-dissolving (FD) formulation of acetaminophen versus 500 mg FD acetaminophen, 650 mg standard formulation acetaminophen and placebo¹⁹. Similar to the results found in the two studies reported herein, the 1,000 mg dose of FD acetaminophen in the Yue studies provided an onset of pain relief at 15 min. In both our and Yue’s studies, acetaminophen 1,000 mg fast acting/dissolving formulations were effective up to 6 h. However, in contrast to Yue’s studies, the two studies reported herein compared 1,000 mg FA-acetaminophen, 1,000 mg ES-acetaminophen and placebo. Durability of analgesia with 1,000 mg FA-acetaminophen was confirmed by similar times to rescue and PID and PAR profiles from 1 to 6 h for 1,000 mg FA-acetaminophen and 1,000 mg ES-acetaminophen. In a dental pain study with subject population, design, and endpoints similar to the current studies, Moller and associates determined that the onset of analgesia was significantly faster for commercially available effervescent acetaminophen 1,000 mg (20 min) compared with a non-effervescent tablet acetaminophen 1,000 mg (45 min)²⁹. Likewise, TMPR was significantly shorter for effervescent acetaminophen (45 min) compared with non-effervescent tablet acetaminophen (60 min). Although the effervescent formulation provided faster pain relief, subjects ranked the two formulations as equally effective.

Time to confirmed perceptible relief and pain relief and pain intensity profiles in Study 1 demonstrated that a single dose of 1,000 mg FA-acetaminophen provided greater initial pain relief and faster analgesic onset than 1,000 mg ES-acetaminophen and 400 mg LG-ibuprofen. Analysis of plasma samples confirmed that acetaminophen concentrations for FA-acetaminophen increased more rapidly than ES-acetaminophen and that ibuprofen concentrations for LG-ibuprofen were essentially negligible at 10 min after the dose. These results suggest that the initial surge in acetaminophen concentrations for FA-acetaminophen is associated with perceiving pain relief more quickly than either ES-acetaminophen or LG-ibuprofen. Study 2 again demonstrated the rapid onset of action for 1,000 mg FA-acetaminophen; FA-acetaminophen provided greater improvements in reducing pain intensity and increasing pain relief than 400 mg LG-ibuprofen at 15 min and plasma concentration-time data were consistent with numerically faster onset of analgesic effect of 1,000 mg FA-acetaminophen compared with 1,000 mg ES-acetaminophen and 400 mg LG-ibuprofen. When considering these data and PID and PAR profiles, FA-acetaminophen provided clinically effective pain relief faster than ES-acetaminophen but with similar durability.

Studies 1 and 2 were conducted at the same clinical center using the same pain model and methodology and had subject populations with overall similar demographic characteristics and proportions of subjects reporting moderate and severe baseline pain. Despite the similarities in design and conduct, variations in the clinical outcomes in the two studies for speed of onset were observed even though the time course of measured drug plasma concentrations for each formulation were reproduced showing the initial surge after dosing with FA-acetaminophen and lag with LG-ibuprofen. Potential factors that may have introduced variability into the study results are discussed below.

Use of triple-dummy blinding may have affected the onset of pain relief. Subjects were required to swallow six dosage units over a short period (two units for each active treatment); theoretically, ingestion of six dosage units at one time may have potential effects on the rates of gastric emptying, dissolution, and absorption which may influence the onset of pain relief. Secondly, a post-hoc subgroup analysis suggested that the collection of blood samples for determination of drug concentrations may have potentially confounded the measurement of early analgesic onset for some subjects by distracting them or inducing additional pain stimulus at 10, 20, and 40 min when subjects were otherwise focused on reporting the potential improvement in their dental pain.

An additional dental pain study is warranted to confirm the faster onset of pain relief associated with the new fast-acting oral acetaminophen tablet. Eliminating the collection of pharmacokinetic blood samples and incorporating a blind-fold technique to enable subjects to receive only their assigned treatment (two rather than six dosage units) are design modifications that may mitigate some variability.

Conclusions

The efficacy results for Studies 1 and 2 suggest that the new oral formulation of FA-acetaminophen shortens the onset of analgesic efficacy compared to OTC ES-acetaminophen and has a faster onset of pain relief than OTC LG-ibuprofen. An additional study with design modification is warranted to confirm these results.

Transparency

Declaration of funding

This study was sponsored by Johnson & Johnson Consumer Inc which was responsible for study design and collection, analysis, and interpretation of the data. All authors were employees of or consultants to Johnson & Johnson at the time the study was conducted.

Declaration of financial/other relationships

AM, CG, AZ, BZ, AS, and DQ were employees of Johnson & Johnson Consumer Inc at the time the research was conducted. SAC is a consultant to Johnson & Johnson Consumer Inc. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Andrew Myers: resources, writing – original draft, writing – review and editing, visualization, supervision, project administration, funding acquisition. Cathy Gelotte: conceptualization, methodology, resources, writing – review and editing, visualization, supervision, project administration. Annette Zuckerman: resources, writing – original draft, writing – review and editing, supervision, project administration. Brenda Zimmerman: conceptualization, methodology, software, resources, formal analysis, data curation, writing – review and editing, visualization, supervision, project administration. Ami Shenoy: resources, writing – review and editing, supervision, project administration. Dan Qi: conceptualization, methodology, resources, writing – review and editing, visualization, supervision, project administration, funding acquisition. Stephen Cooper: conceptualization, methodology, writing – review and editing, visualization, supervision.

Acknowledgements

The authors thank the subjects of this clinical study. The authors thank Kathleen Boyle, PhD, CMPP of 4 Learning Group, LLC (Exton, PA, USA) who, under the direction of the authors, supported manuscript preparation and managed the review process.