Correlation of Pain Reduction with fMRI BOLD Response in Osteoarthritis Patients Treated with Paracetamol: Randomized, Double-Blind, Crossover Clinical Efficacy Study.

Objective: To assess the relationship between the analgesic efficacy of extended-release paracetamol (ER-APAP) and brain blood oxygen level-dependent (BOLD) signal activation in response to painful stimulation measured by functional magnetic resonance imaging (fMRI) in patients with osteoarthritis of the knee. Methods: This placebo-controlled, double-blind, crossover, randomized trial (N = 25) comprised three treatment periods in which patients received four doses of an eight-hour ER-APAP caplet (2 x 665 mg), four doses of matched placebo, and no treatment. Pain intensity of the knee was measured before and after painful stimulation at the knee with osteoarthritis and before and after fMRI. Results: ER-APAP significantly reduced prestimulation osteoarthritis knee joint pain compared with baseline (P < 0.003) and placebo (P < 0.004). ER-APAP and placebo significantly reduced knee joint pain after stimulation (P = 0.014 and P = 0.032, respectively); however, pain reduction with ER-APAP was 35% greater than placebo. ER-APAP was associated with significant reductions in BOLD signal activation after stimulation compared with control in the sensory cortex (P = 0.002) and supramarginal gyrus (P = 0.003). Reduction in BOLD signal activation after stimulation for placebo was significantly greater than control in the subgenual prefrontal cortex (P < 0.001), frontal cortex (P < 0.001), insula (P < 0.003), and sensory cortex (P < 0.001). Conclusions: ER-APAP had a significantly greater effect than placebo and no treatment in reducing knee pain, which was associated with reduced BOLD signal activations in pain pathways, including the sensory cortex and supramarginal gyrus. BOLD observations after placebo treatment may shed light on the role of the brain regions potentially involved in placebo response in clinical trials investigating pain therapies.

Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation.

OBJECTIVE: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2x1,000 mg) with those of immediate-release (IR) paracetamol (2x500 mg) and existing extended-release (ER) paracetamol (2x665 mg). METHODS: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. RESULTS: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86-0.96) for the fasted state and 99% (0.95-1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96-1.03) in the fasted state and 98% (0.95-1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p<0.0001) and 0.77 (p<0.0001) in study I and II, respectively. CONCLUSIONS: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.

A new rapidly absorbed paediatric paracetamol suspension. A six-way crossover pharmacokinetic study comparingthe rate and extent of paracetamol absorption from a new paracetamol suspension with two marketed paediatric formulations.

The objective of this study was to compare the rate and extent of paracetamol absorption from the new Paracetamol pediatric suspension (PPS) with two marketed paracetamol suspensions: Children's panadol (CP) and Panodil baby & infant (PBI). The study also assessed the effect on paracetamol absorption of light-calorie, low-fat food consumed 2 h before dosing. Twenty eight male adult volunteers received a single oral dose of 1000 mg of paracetamol from each of three treatments, in both fasted and fed states according to a randomized, single-center, open-label, six-way crossover study design. PPS was bioequivalent to both CP and PBI for AUC(0-10 h), AUC(0-inf) and C(max) in both fasted and fed state. However, PPS had greater rate of paracetamol absorption and a faster speed of onset. T(max) for PPS was significantly shorter than for PBI in both fasted (p = 0.0005) and fed state (p = 0.0001). Median T(max) for PPS was also 10 min shorter than CP in fasted state. Time to reach minimum effective concentration (MEC) for PPS was significantly shorter than CP and PBI. Early paracetamol exposure of PPS was significantly higher than that of the two existing paracetamol products. Food had a significant effect in the early exposure and onset of therapeutic level of paracetamol from PPS. AUC(0-30 min) was significantly higher and time to reach plasma paracetamol at MEC level was significantly shorter than in the fasted state.

Mogamulizumab in Combination with Nivolumab in a Phase I/II Study of Patients with Locally Advanced or Metastatic Solid Tumors.

PURPOSE: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. PATIENTS AND METHODS: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. RESULTS: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6-17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3-3.1) months, and median overall survival was 9.5 (95% CI, 5.9-13.5) months. CONCLUSIONS: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-C-C chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or tremelimumab. PATIENTS AND METHODS: This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg in patients with advanced pancreatic cancer. RESULTS: Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%-26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4+ eTregs or with baseline degree of CCR4+ expression. CONCLUSIONS: Mogamulizumab in combination with durvalumab or tremelimumab did not result in potent antitumor efficacy in patients with advanced solid tumors. Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or tremelimumab 10 mg/kg was acceptable.

Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers.

Twice-daily sustained-release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3-day dosing period) the pharmacokinetics, bioequivalence, and safety of twice-daily SR paracetamol compared with extended-release (ER) and immediate-release (IR) paracetamol. In this open-label, randomized, multidose, 3-way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice-daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0-t , 0.973-1.033; AUC0-24 , 0.974-1.034; AUC0-∞ , 0.948-1.011; Cmax , 1.082-1.212; Cav , 1.011-1.106) and SR/IR paracetamol (AUC0-t , 0.969-1.029; AUC0-24 , 0.968-1.027; AUC0-∞ , 0.963-1.026; Cmax , 0.902-1.010; Cav , 1.004-1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 µg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax , a longer half-life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.

Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single-dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 µg/mL (TC≥4µg/mL ). Key secondary outcomes were area under the plasma concentration-time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC0-t ), AUC from 0 to infinity (AUC0-inf ), and maximum plasma acetaminophen concentration (Cmax ). TC≥4µg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas TC≥4µg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC0-12 , AUC0-t , and AUC0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen.

Efficacy and safety of twice daily sustained-release paracetamol formulation for osteoarthritis pain of the knee or hip: a randomized, double-blind, placebo-controlled, twelve-week study.

OBJECTIVE: Evaluate efficacy and safety of an investigational, twice daily sustained-release (SR) paracetamol formulation in subjects with knee or hip osteoarthritis (OA). METHODS: In this multicenter, double-blind, parallel study (NCT02311881), subjects with hip or knee OA were randomly assigned to SR paracetamol 2 × 1000 mg BID, extended-release (ER) paracetamol 2 × 665 mg TID or placebo for 12 weeks. Primary endpoint was mean change from baseline through 12 weeks in WOMAC Osteoarthritis Index pain. Secondary efficacy endpoints included other WOMAC categories, Global Patient Assessment of Osteoarthritis (GPAOA), Patient Global Assessment of Response to Therapy (PGART) and responder rate. RESULTS: A total of 676 subjects were included in the analysis population (mITT). Mean change from baseline in WOMAC pain subscale was not significantly greater with SR paracetamol BID versus placebo (LS mean [SE]: -28.25 [1.697] vs. -25.74 [1.713]; p = .163). Reduction in WOMAC physical function and stiffness subscales with SR paracetamol BID was not significantly greater than with placebo (p = .089 and .054, respectively). Significant improvement over placebo was observed for GPAOA (p = .043), PGART (p = .012), and proportion of high-improvement responders (p = .015). Safety and tolerability were consistent with the known profile of paracetamol. CONCLUSIONS: Improvement in WOMAC pain, physical function and stiffness subscales from treatment with SR paracetamol BID versus placebo in subjects with knee or hip OA was not significant. SR paracetamol BID demonstrated significant improvements in GPAOA, PGART, and high-responder rate. High placebo response may have contributed to lack of statistical separation on some outcomes. All interventions were generally well tolerated.

Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo-controlled, 4-way crossover clinical trial.

BACKGROUND: While gastrointestinal (GI) effects of standard ibuprofen and N-acetyl-p-aminophenol (APAP) have been reported, upper GI injury following treatment with fast-dissolving (FD) formulations of these analgesics has not been investigated. We evaluated upper GI effects of over-the-counter doses of 2 FD ibuprofen products and 1 FD-APAP product. METHODS: In a randomized, placebo-controlled, endoscopist-blinded, 4-way crossover study, 28 healthy subjects received FD ibuprofen 2×200 mg liquid capsules 3 times daily (TID), ibuprofen 2×200 mg tablets TID, FD-APAP 2×500 mg tablets 4 times daily (QID), and placebo 2×500 mg tablets QID for 7 days. The primary end point was gastric mucosal damage assessed by endoscopy using the Lanza scale: 0=normal stomach or proximal duodenum, 1=mucosal hemorrhages only, 2=1 or 2 erosions, 3=numerous (3-10) erosions, and 4=large number of erosions (>10) or ulcer. Secondary end points included duodenal mucosal damage (Lanza scale); gastroduodenal mucosal injury, classified as present (gastric and/or duodenal endoscopy score ≥2) or absent (gastric and/or duodenal endoscopy score <2); and number of hemorrhages, erosions, and ulcers counted separately in the stomach and duodenum. RESULTS: Significantly greater gastric mucosal injury was observed after treatment with both ibuprofen products vs FD-APAP (p<0.0001 and p=0.0095, respectively). FD-APAP showed no difference from placebo (p=0.4794). The odds of having an incidence of gastroduodenal mucosal injury were over 6 times greater from FD ibuprofen liquid capsule treatment (odds ratio [OR]=6.19, 95% confidence interval [CI]: 1.60, 23.97) and over 3 times greater from ibuprofen tablet treatment (OR=3.19, 95% CI: 0.8, 12.74) vs FD-APAP. CONCLUSION: Treatment with 2 ibuprofen products was associated with significant gastric mucosal injury. Of the 4 treatments studied, FD ibuprofen liquid capsules had the highest risk of incidence of gastroduodenal mucosal injury. Treatment with FD-APAP did not induce any clinically or statistically significant gastroduodenal mucosal injury.

Efficacy and safety of topical diclofenac/menthol gel for ankle sprain: A randomized, double-blind, placebo- and active-controlled trial.

Purpose This study was performed to evaluate topical 1% diclofenac/3% menthol gel in treating ankle sprain. Design In this randomized, double-blind, placebo-controlled trial, adolescents and adults with acute ankle sprain (N = 385) applied 4 g of gel containing 1% diclofenac/3% menthol (n = 117), 1% diclofenac (n = 112), 3% menthol (n = 77), or placebo (n = 75) four times daily. The primary outcome was the area under the curve of pain intensity (PI) on movement [0 (no pain) to 10 (extreme pain)] from 24 to 72 hours post-application (AUC1-3 days). Secondary outcomes included pain relief (PR); PI; time to onset of PR, meaningful PR, cooling, and complete recovery; PI difference; sum of PI difference; total PR; reduction in ankle swelling; and the patient's global assessment of response to treatment. Results There were no statistically significant differences in AUC1-3 between 1% diclofenac/3% menthol and placebo, diclofenac, or menthol gels and no meaningful advantages of 1% diclofenac/3% menthol for any secondary outcome. There was a higher incidence of skin and application-site events with 1% diclofenac/3% menthol than with placebo or 1% diclofenac. Conclusion No significant improvement was observed with topical 1% diclofenac/3% menthol gel compared with placebo, 1% diclofenac, or 3% menthol gel in treating pain from ankle sprain. ClinicalTrials.Gov Identifier: NCT02100670.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

BACKGROUND/OBJECTIVE: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. METHODS: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. RESULTS: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. CONCLUSION: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

Skin Irritation and Sensitization Potential of Fixed-Dose Combination of Diclofenac 1% and Menthol 3% Topical Gel: Results of Two Phase I Patch Studies.

Phase I, randomized, controlled patch studies were conducted to evaluate skin sensitization and irritation potential of a new gel formulation containing 1% diclofenac and 3% menthol as a fixed-combination product.In study A, healthy volunteers were exposed to 4 test patches containing 1% diclofenac+3% menthol, diclofenac, menthol, or placebo gels during an induction (nine 48 to 72-h applications) and challenge phase (one 48-h application). Some subjects were re-challenged to evaluate suspected sensitization. Study B participants underwent 21 consecutive 24-h patch applications of the 4 treatments from study A, 0.2% sodium lauryl sulfate (positive control), 0.9% saline, and a marketed gel (1% diclofenac, Voltaren). Application sites were visually scored by blinded observers for skin sensitization/irritation.In study A, 77% of participants showed minimal erythema and signs of glazing and peeling with 1% diclofenac+3% menthol by the end of the induction phase, which diminished during the challenge phase. Similar patterns were seen with menthol gel. Only 1 subject exhibited possible sensitization to 1% diclofenac+3% menthol. In study B, mean cumulative irritation score with 1% diclofenac+3% menthol was significantly higher (P<0.0001) vs. reference treatments; however, the positive control failed to produce the expected level of irritation. No treatment-related adverse events were reported.The sensitization and irritation potential of 1% diclofenac+3% menthol was greater than with the reference treatments. Comparison with positive control was not possible because it did not produce irritation under semiocclusive patch conditions.

A genome-wide linkage scan for dietary energy and nutrient intakes: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study.

BACKGROUND: A poor diet is a risk factor for chronic diseases such as obesity, cardiovascular disease, hypertension, and some cancers. Twin and family studies suggest that genetic factors potentially influence energy and nutrient intakes. OBJECTIVE: We sought to identify genomic regions harboring genes affecting total energy, carbohydrate, protein, and fat intakes. DESIGN: We performed a genomic scan in 347 white sibling pairs and 99 black sibling pairs. Dietary energy and nutrient intakes were assessed by using Willett's food-frequency questionnaire. Single-point and multipoint Haseman-Elston regression techniques were used to test for linkage. These subjects were part of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a multicenter project undertaken by 5 laboratories. RESULTS: In the whites, the strongest evidence of linkage appeared for dietary energy and nutrient intakes on chromosomes 1p21.2 (P = 0.0002) and 20q13.13 (P = 0.00007), and that for fat intake appeared on chromosome 12q14.1 (P = 0.0013). The linkage evidence on chromosomes 1 and 20 related to total energy intake rather than to the intake of specific macronutrients. In the blacks, promising linkages for macronutrient intakes occurred on chromosomes 12q23-q24.21, 1q32.1, and 7q11.1. Several potential candidate genes are encoded in and around the linkage regions on chromosomes 1p21.2, 12q14.1, and 20q13.13. CONCLUSIONS: These are the first reported human quantitative trait loci for dietary energy and macronutrient intakes. Further study may refine these quantitative trait loci to identify potential candidate genes for energy and specific macronutrient intakes that would be amenable to more detailed molecular studies.

Efficacy and speed of onset of pain relief of fast-dissolving paracetamol on postsurgical dental pain: two randomized, single-dose, double-blind, placebo-controlled clinical studies.

BACKGROUND: Paracetamol (APAP), also known as acetaminophen, is the most commonly used over-the-counter analgesic for the treatment of mild-to-moderate pain. However, the speed of onset of pain relief is limited mainly to the standard, immediate-release formulation. Efficacy and speed of onset of pain relief are critical in acute pain situations such as postsurgical dental pain, because reducing pain can improve clinical outcome and reduce the risk of transition from acute pain to more chronic pain. Efficacy and rapid onset also reduce the risk of excessive dosing with the analgesic. OBJECTIVE: We sought to investigate the dose-response efficacy and speed of onset of pain relief of a fast-dissolving APAP formulation compared with lower doses of APAP and placebo in dental patients after impacted third molar extraction. METHODS: Two single-center, single-dose, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies (Study I and Study II) were conducted to evaluate the efficacy and speed of onset of pain relief of different doses of a fast-dissolving APAP tablet (FD-APAP), standard APAP, and placebo in patients with postsurgical dental pain following third molar extraction. In Study I, a single dose of FD-APAP 1000 mg, FD-APAP 500 mg, or placebo was given to 300 patients; in Study II, a single dose of FD-APAP 1000 mg, standard APAP 650 mg, or placebo was given to 401 patients. All 701 patients from both studies were included in the analysis and safety assessment. RESULTS: FD-APAP 1000 mg demonstrated significantly greater effect compared with FD-APAP 500 mg, APAP 650 mg, and placebo for all efficacy measurements, including sum of pain relief and pain intensity difference, total pain relief, sum of pain intensity difference, pain intensity difference, and pain relief score during 6 hours after the dose. Onset of confirmed first perceptible relief in subjects treated with FD-APAP 1000 mg was 15 minutes, which was 32% and 25% significantly shorter than onset of pain relief of FD-APAP 500 mg (22 minutes) and standard APAP 650 mg (20 minutes), respectively. FD-APAP 500 mg and APAP 650 mg demonstrated efficacy over placebo for most of the measurements; however, their effects were significantly lower and lasted for a shorter period of time than for FD-APAP 1000 mg. All study treatments were well tolerated. CONCLUSIONS: FD-APAP 1000 mg tablets demonstrated efficacy over placebo. Also, FD-APAP 1000 mg had significantly superior effect, faster onset, and longer duration of pain relief compared with FD-APAP 500 mg and APAP 650 mg tablets.