Tramadol Hydrochloride at Steady State Lacks Clinically Relevant QTc Interval Increases in Healthy Adults.

We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18-55 years) in a randomized, phase I, double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover study. Participants were randomized to receive 1 of 4 treatments (A-D), 1 each in 4 treatment periods (1-4), separated by a washout period (7-15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin-matched placebo on day 4, and placebo on all 4 days. Treatment B comprised tramadol 600 mg (supratherapeutic dose) on days 1 through 3, and tramadol 150 mg and moxifloxacin-matched placebo on day 4. Treatment C comprised placebo on days 1 through 4 and moxifloxacin-matched placebo on day 4. Treatment D comprised placebo on days 1 through 4 and moxifloxacin 400 mg on day 4. Of 68 participants enrolled, 57 (83.8%) completed the study. Both therapeutic and supratherapeutic doses of tramadol were shown to be noninferior to placebo regarding their effect on QTc prolongation. Sixty-one of 68 (89.7%) participants reported at least 1 treatment-emergent adverse event (mild); nausea was the most frequently reported treatment-emergent adverse event. Summarizing, tramadol at doses up to 600 mg/day did not cause clinically relevant QTc interval prolongation in healthy adults.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

On-demand proton pump inhibitory treatment in overweight/obese patients with gastroesophageal reflux disease: are there pharmacodynamic arguments for using higher doses?

BACKGROUND: Increased body mass index (BMI) is associated with a higher risk of gastroesophageal reflux disease (GORD). AIM: To investigate whether overweight/obesity affects proton pump inhibitor pharmacodynamics when used in a single dose in patients with GORD. METHODS: Post hoc analyses by patient BMI were performed on data from two single-center, double-blind, single-dose, crossover studies comparing the pharmacodynamics of rabeprazole 20 mg and pantoprazole 40 mg in GORD patients with a history of nocturnal heartburn. The primary endpoint was the mean percentage of time with intragastric pH >4 between lean and overweight/obese patients (BMI <25 and ≥25). RESULTS: 24 h baseline intragastric pH values were not different between BMI groups. The pharmacodynamic effects of both proton pump inhibitors were not significantly different between BMI groups, and no evidence was found for an interaction between BMI and treatment. As compared with pantoprazole, rabeprazole showed a significantly greater effect on the antisecretory response for both BMI groups. CONCLUSIONS: Overweight/obesity in GORD patients does not appear to affect the antisecretory efficacy of a single dose of rabeprazole and pantoprazole. These data do not support adapting the dosage of rabeprazole and pantoprazole according to BMI in GORD patients when administered as an on-demand therapy schedule.

Does BMI affect the clinical efficacy of proton pump inhibitor therapy in GERD? The case for rabeprazole.

BACKGROUND: Increased BMI is associated with a higher risk of gastroesophageal reflux disease. AIMS: To investigate whether overweight/obesity (BMI≥25 kg/m(2)) affects rabeprazole clinical efficacy versus omeprazole in patients with erosive esophagitis (EE). PATIENTS AND METHODS: Post-hoc analysis of EE healing rate and symptom response stratified by patient BMI was performed on data from a multicenter, double-blind, randomized, 4-to-8-week trial comparing EE healing with rabeprazole (20 mg daily) and omeprazole (20 mg daily). Analysis of variance, two-sample t-test, Blackwelder's test for equivalence, log-rank, and Cochran-Mantel-Haenszel tests were used to analyze comparisons. RESULTS: In the two BMI groups (<25 kg/m(2) and ≥25 kg/m(2) respectively), rabeprazole and omeprazole were equally effective for mucosal healing regardless of patient's BMI (N=542, P>0.05). However, in overweight/obese patients, rabeprazole was significantly faster than omeprazole in inducing heartburn relief during the first treatment week (P<0.0001). CONCLUSIONS: Results of this study show that the clinical efficacy of rabeprazole is maintained in overweight/obese patients with gastroesophageal reflux disease and suggest that this subgroup of patients may derive, from rabeprazole, even greater benefit than lean patients.

Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial.

This 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial evaluated tramadol ER (extended-release tramadol) in the management of osteoarthritis pain. Adults with knee and/or hip osteoarthritis and baseline pain intensity of ≥40 on a 100-mm visual analog scale (0 = no pain, 100 = extreme pain) received once-daily tramadol ER 100 mg (n = 201), 200 mg (n = 199), or 300 mg (n = 199), celecoxib 200 mg (n = 202; to test model sensitivity), or placebo (n = 200). Coprimary efficacy variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and patient global assessment of disease activity. Tramadol ER 300 mg significantly improved patient global assessment scores compared with placebo (P ≤ 0.05), but not the other 2 coprimary efficacy variables. Tramadol ER 200 and 100 mg were not significantly different from placebo for the coprimary efficacy variables. Daily diary arthritis pain intensity scores improved significantly for tramadol ER 300 and 200 mg compared with placebo. WOMAC joint stiffness subscale, physician's global assessment, arthritis pain intensity in index and nonindex joints, and overall sleep quality scores improved significantly for tramadol ER 300 mg compared with placebo. Significant differences in efficacy between celecoxib and placebo validated the model sensitivity. Adverse events occurred more frequently with tramadol ER than placebo in the gastrointestinal (nausea, constipation, diarrhea) and central nervous (dizziness, headache) systems. In this study, tramadol ER 300 mg was effective in the management of moderate to severe painful osteoarthritis of the hip or knee. A large, increasing placebo response during the study may have contributed to the lack of statistical separation between tramadol ER 200 or 100 mg and placebo.

Rabeprazole 20 mg for erosive esophagitis-associated symptoms in a large, community-based study: additional results.

PURPOSE: To provide additional efficacy data in patients treated with rabeprazole through week 4, and to validate sustained relief of gastroesophageal reflux disease symptoms through week 8 as well as to further analyze rabeprazole safety in patients with wide-ranging demographic and clinical characteristics. RESULTS: Patients in this study (N = 2,449) demonstrated significant overall improvement versus baseline (P < 0.001). Substantial symptom relief was seen throughout 8 weeks of treatment. By week 4, complete relief of daytime and nighttime heartburn, belching, regurgitation, and dysphagia was observed in 87.5, 90.7, 50.7, 77.6, and 75.1% of patients, respectively. Improvements were seen in rabeprazole-treated patients (<65 or >or=65 years) with a range of baseline symptom severities and across different racial groups. Rabeprazole was well tolerated. CONCLUSIONS: In patients with endoscopy-confirmed erosive esophagitis treated with once-daily rabeprazole 20 mg, prompt and continuing improvements were seen in daytime and nighttime heartburn, belching, regurgitation, and dysphagia.