Pooled Phase III safety analysis of sufentanil sublingual tablets for short-term treatment of moderate-to-severe acute pain.

Aim: To evaluate the pooled safety of sufentanil sublingual tablets (SSTs) administered at 30-mcg dose equivalents over ≤72 h for moderate-to-severe acute pain management in medically supervised settings. Patients & methods: Safety data from SST 30 mcg Phase III studies were pooled with an additional patient subset from studies in which two SST 15 mcg were self-administered within 20-25 min (30-mcg dose-equivalent). Results: Analyses included 804 patients. Median (range) SST 30-mcg dosing over 24 h was 7.0 (1-15) tablets. Adverse events (AEs) were experienced by 60.5% (SST) and 61.4% (placebo) and treatment-related AEs by 43.8% (SST) and 33.5% (placebo; 10.3% difference; 95% CI: 2.0-18.6) of patients. No dose-dependent increase in oxygen desaturation was observed with SST. Conclusion: SST was well-tolerated, with most AEs considered mild or moderate in severity.

Sufentanil sublingual tablet system for the management of postoperative pain following open abdominal surgery: a randomized, placebo-controlled study.

BACKGROUND AND OBJECTIVES: This study evaluates the efficacy and safety of a sufentanil sublingual tablet system (SSTS) for the management of postoperative pain following open abdominal surgery. METHODS: At 13 hospital sites in the United States, patients following surgery with pain intensity of greater than 4 on an 11-point numerical rating scale were randomized to receive SSTS dispensing a 15-µg sufentanil tablet sublingually with a 20-minute lockout or an identical system dispensing a placebo tablet sublingually. Pain intensity scores were recorded at baseline and for up to 72 hours after starting study drug. The primary end point was time-weighted summed pain intensity difference (SPID) over 48 hours. Secondary end points included SPID and total pain relief (TOTPAR) for up to 72 hours and patient and health care provider global assessments of the method of pain control. RESULTS: Summed pain intensity difference over 48 hours was significantly higher in the SSTS group than in the placebo group (least squares mean [SEM], 105.60 [10.14] vs 55.58 [13.11]; P = 0.001). Mean SPID and TOTPAR scores were significantly higher in the SSTS group at all time points from 1 hour (SPID) or 2 hours (TOTPAR) until 72 hours (P < 0.05). In the SSTS group, patient global assessment and health care provider global assessment ratings of good or excellent were greater than placebo at all time points (P < 0.01). Safety parameters, including adverse events and vital signs, were similar for SSTS and placebo. CONCLUSIONS: These results suggest that SSTS is effective and safe for the management of postoperative pain in patients following open abdominal surgery.

Pharmacokinetic properties of single- and repeated-dose sufentanil sublingual tablets in healthy volunteers.

PURPOSE: Sufentanil is a µ-opioid agonist with a high therapeutic index in preclinical studies and no active metabolites, and it is highly lipophilic, thereby enabling a transmucosal route of administration. Rapid distribution from the plasma after IV sufentanil administration results in a short duration of action requiring excessive repeated dosing if used for postoperative analgesia. The sufentanil sublingual tablet system (SSTS) is a handheld, preprogrammed, patient-controlled analgesia system designed to allow patients to self-administer sufentanil 15-µg tablets under their tongue with a 20-minute lockout. The pharmacokinetic (PK) characteristics of sufentanil, administered by different routes of delivery and after single and repeated sublingual (SL) administration, were examined in 2 studies. METHODS: A randomized, open-label, crossover study in healthy subjects evaluated the PK profile of sufentanil 15 µg administered by different routes: IV, SL, buccal (BU), and PO. A second open-label, crossover study in healthy subjects evaluated the PK parameters after single and repeated doses (full SSTS drug cartridge of 40 consecutive SL doses administered every 20 minutes) of a sufentanil 15-µg SL tablet. Doses were self-administered using the SSTS. FINDINGS: In the route of administration study (n = 25), mean Cmax values were highest with IV administration, and bioavailability values were: SL, 59%; BU, 78%; and PO, 9%. The absorption across the oral mucosa was associated with a median plasma half-time (time from Cmax to 50% of Cmax) that was 25-fold longer (2.5 hours) with SL versus IV administration (0.1 hours). In the single- and repeated-dose study (n = 38), mean AUC0-∞ was 125.5 h · pg/mL, and Cmax was 35.0 pg/mL, with a median Tmax of 0.8 hours after the administration of a single sufentanil SL tablet. With 40 consecutive doses, Cmax was 8-fold higher compared with that of a single dose, and steady state was achieved after the 13th dose. Median plasma half-time after the 40th dose was not statistically longer than that after a single dose (2.7 vs 2.2 hours, respectively), and the median Tmax was 0.3 hours after the last repeated dose. IMPLICATIONS: These study results support the viability of the SSTS for use in patient-controlled analgesia. The wide range of mean drug concentrations achieved after repeated dosing at 20-minute intervals compared with those with a single dose suggests the flexibility of patient-controlled dosing to meet individual analgesic requirements. The prolonged plasma half-time with SL administration is expected to provide a more appropriate duration of analgesia compared with that of IV administration, and the PK properties of repeated-dose administration support a 20-minute lockout interval.

Sufentanil sublingual tablet system vs. intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, active-comparator trial.

BACKGROUND: Problems with intravenous patient-controlled analgesia (IV PCA) are well known, including invasive route of delivery and pump programming errors. The primary objective of this study was to evaluate patient satisfaction with a novel sublingual sufentanil PCA system (sufentanil sublingual tablet system 15 mcg with a 20-minute lockout interval; SSTS) to IV PCA morphine sulfate 1 mg with a 6-minute lockout interval (IV PCA MS) for the management of acute postoperative pain. METHODS: This was a randomized, open-label, 48-hour non-inferiority study with optional extension to 72 hours at 26 U.S. sites enrolling patients scheduled for elective major open abdominal or orthopedic (hip or knee replacement) surgery. The primary outcome measure was the proportion of patients who responded "good" or "excellent" (collectively "success") at the 48-hour timepoint on the Patient Global Assessment of method of pain control (PGA48). RESULTS: A total of 357 patients received study drug and 78.5% vs. 65.6% of patients achieved PGA48 "success" for SSTS vs. IV PCA MS, respectively, demonstrating non-inferiority (P < 0.001 using the one-side Z-test against the non-inferiority margin) as well as statistical superiority for treatment effect (P = 0.007). Patients using SSTS reported more rapid onset of analgesia and patient and nurse ease of care and satisfaction scores were higher than IV PCA MS. Adverse events were similar between the 2 groups; however, SSTS had fewer patients experiencing oxygen desaturations below 95% compared to IV PCA MS (P = 0.028). CONCLUSIONS: Sufentanil sublingual tablet system is a promising new analgesic technology that may address some of the concerns with IV PCA.

Pharmacokinetics of sublingual sufentanil tablets and efficacy and safety in the management of postoperative pain.

BACKGROUND AND OBJECTIVES: A sublingual sufentanil tablet is being developed as a potential alternative to intravenous (IV) opioids for the management of postoperative pain. The objective of these studies was to evaluate the pharmacokinetics, efficacy, and safety of sublingual sufentanil tablets for postoperative pain management. METHODS: The pharmacokinetics of sublingual sufentanil 10 and 80 µg were compared with IV sufentanil in 12 subjects in a phase 1 study. The safety and efficacy of sublingual sufentanil (5-15 µg) were evaluated in double-blind, randomized, placebo-controlled phase 2 studies in patients undergoing knee replacement surgery (n = 101) or open abdominal (ABD) surgery (n = 94). The primary efficacy measurement was the summed pain intensity difference compared with baseline over 12 hours (SPID-12). RESULTS: Sublingual sufentanil pharmacokinetics were dose proportional following single doses of 10 and 80 µg. Plasma half-time (time from peak plasma concentration to 50% of peak concentration) was 80 to 90 minutes for sublingual sufentanil compared with 15 minutes or less for IV sufentanil. In the phase 2 studies, greater SPID-12 scores (ie, lower pain intensity) compared with placebo were observed for sublingual sufentanil 15 µg in the knee replacement study (P < 0.05) and for 10 and 15 µg in the ABD study (P < 0.01). All doses of sublingual sufentanil were well tolerated, and the incidence of adverse events was similar between the sublingual sufentanil and placebo groups. CONCLUSIONS: Sufentanil formulated as a sublingual solid dosage form provides a duration of action that allows effective analgesia for postoperative patients in a medically supervised setting.

Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia.

OBJECTIVE: To replicate and extend previous research concerning the validity and utility of using pain quality measures in clinical trials. METHODS: One hundred fifty-eight patients with moderate-to-severe postherpetic neuralgia were randomly assigned to 1 of 3 treatment conditions: (1) extended release gabapentin (G-ER) 1800 mg once-daily administered in the evening; (2) G-ER 1800 mg asymmetric divided dose (600 mg AM and 1200 mg PM); or (3) placebo G-ER. A measure of different pain qualities, the Neuropathic Pain Scale, was administered as a secondary measure in this study before, during, and after the treatment. RESULTS: The results suggest that G-ER, especially when administered twice-daily, have the greatest effects on sharp, dull, sensitive, and itchy pain. Few between-condition effects were found for the global ratings of intensity or unpleasantness, and for hot, cold, deep, or surface pain qualities. CONCLUSIONS: The results provide further support for the importance of assessing specific pain qualities as outcomes in clinical trials. The findings may also be used by clinicians for identifying those patients for whom G-ER may be particularly effective; that is, patients with postherpetic neuralgia presenting with pain described as sharp, dull, sensitive, or itchy.

Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To determine the efficacy and safety of a gastric-retentive, extended-release gabapentin (gabapentin ER) taken once or twice daily for treatment of postherpetic neuralgia. METHODS: Using an enrichment design, a randomized, double-blind, placebo-controlled study was conducted in 158 patients who had experienced pain for at least 3 months after healing of acute herpes zoster skin rash and who had a baseline average daily pain (ADP) score of > or =4 on a 0 to 10 Numerical Rating Scale. Patients received gabapentin ER either once daily (1800 mg PM) or twice daily (600 mg AM, 1200 mg PM) or placebo for 4 weeks. Efficacy measures included changes from baseline to end point in ADP score and average daily sleep interference score. RESULTS: Mean (SEM) changes for ADP score were -1.93 (0.28), -2.24 (0.29), and -1.29 (0.29) in the gabapentin ER once daily, twice daily, and placebo groups, respectively (P=0.089 and 0.014 for gabapentin ER once daily and twice daily, respectively, vs. placebo), with 25.5%, 28.8%, and 11.8% of patients, respectively, reporting > or =50% decrease from baseline in ADP score. Mean (SEM) changes in sleep interference scores were -1.94 (0.30), -2.28 (0.30), and -1.16 (0.30), respectively (P=0.048 and 0.006 for gabapentin ER once daily and twice daily, respectively, vs. placebo). Common adverse events in the gabapentin ER once daily, twice daily, and placebo groups, respectively, were dizziness (22.2%, 11.3%, and 9.8%) and somnolence (9.3%, 7.5%, and 7.8%). CONCLUSIONS: Gabapentin ER administered twice daily is effective and safe for the treatment of pain associated with postherpetic neuralgia.

Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. RESULTS: Significant decreases (P < 0.001) in mean HbA(1c) (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.

Efficacy and safety of a novel once-daily extended-release ciprofloxacin tablet formulation for treatment of uncomplicated urinary tract infection in women.

The efficacy and safety of a novel once-daily extended-release ciprofloxacin (ciprofloxacin ER) 500-mg dose were compared with those of an immediate-release ciprofloxacin (ciprofloxacin IR) 250-mg twice-daily dose, each administered orally for 3 days in the treatment of acute uncomplicated urinary tract infection (uUTI) in women. Adult female outpatients (mean age, 39 years) with clinical signs and symptoms of acute uUTI and a positive pretreatment urine culture (> or =10(5) CFU/ml) were enrolled in a multicenter, randomized, double-blind, noninferiority trial. Patients were assessed at a test-of-cure visit (4 to 11 days posttreatment) and a late-posttreatment visit (4 to 6 weeks posttreatment) for microbiological and clinical outcomes and safety. The primary efficacy endpoint and microbiological eradication rate at the test-of-cure visit in the ciprofloxacin ER group (254/272; 93.4%) were noninferior to those in the ciprofloxacin IR group (225/251; 89.6%) (95% confidence interval [CI] of difference, -0.99%, 8.59%). Clinical-cure rates at the test-of-cure visit were 85.7% (233/272) for ciprofloxacin ER and 86.1% (216/251) for ciprofloxacin IR (95% CI of difference, -6.37%, 5.57%). At the late-posttreatment visit, microbiological and clinical outcomes were similar for the two treatments and consistent with test-of-cure results. Both treatments were well tolerated, but the frequencies of nausea and diarrhea were lower in the ciprofloxacin ER group than in the ciprofloxacin IR group (nausea, ER, 0.6%; IR, 2.2%; P = 0.033; diarrhea, ER, 0.2%; IR, 1.4%; P = 0.037). Once-daily ciprofloxacin ER was safe, effective, and noninferior to twice-daily ciprofloxacin IR in the treatment of acute uUTI. Additionally, ciprofloxacin ER was associated with significantly reduced frequencies of nausea and diarrhea.

Real-world efficacy of prescription and over-the-counter nicotine replacement therapy.

AIMS: To assess smoking cessation rates achieved with nicotine gum and patch in simulated over-the-counter (OTC) and actual prescription (Rx) settings. DESIGN: Separate open-label studies with gum and patch in OTC and Rx settings. PARTICIPANTS: There were multiple samples: OTC gum: 2981 smokers; OTC patch: 2367; Rx gum: 324; Rx patch: 669. INTERVENTIONS: All smokers received active nicotine replacement. In the OTC setting, smokers self-selected doses of nicotine gum (2 or 4 mg Nicorette) or patch (21, 14 or 7 mg NicoDerm CQ). No intervention was provided. In the Rx setting, smokers were prescribed gum or patch by their physician. MEASUREMENTS: Biochemically verified continuous smoking abstinence was assessed at 6 weeks (28-day abstinence) and 6 months. FINDINGS: OTC success rates were consistently higher than Rx rates: differences were significant at 6 weeks for both patch [OR = 1.45 (1.05-1.98)] and gum [OR 2.92 (1.58-5.40)], and remained significant at 6 months for patch [OR = 3.63: (1.74-7.61)] but not gum [OR = 1.37: (0.73-2.58)]. Among OTC gum users. 16.1% were abstinent at 6 weeks and 8.4% at 6 months. For Rx gum users, abstinence rates were 7.7% at 6 weeks and 7.7% at 6 months. With OTC patch, 19.0% were abstinent at 6 weeks and 9.2% at 6 months. With Rx patch. abstinence rates were 16.0% at 6 weeks and 3.0% at 6 months. CONCLUSIONS: Smoking cessation rates achieved with nicotine gum and patch under OTC conditions were as good as those under real-world prescribing conditions.