Bowel function after tapentadol and oxycodone immediate release (IR) treatment in patients with low back or osteoarthritis pain.

OBJECTIVES: Constipation is a common side effect of opioid therapy. Tapentadol immediate release (IR) was better tolerated than oxycodone IR in 2 clinical trials involving patients with low back or osteoarthritis pain. The objective of this study was to examine patient-reported bowel function during those trials. METHODS: Bowel function was assessed during secondary post hoc analyses using: the bowel movement questionnaire (BMQ; 10-d trial); the Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM; 90-day trial); and laxative use (both trials). Random effects maximum likelihood regressions were run to examine PAC-SYM data. BMQ data were analyzed using 1-way analyses of variance and a multinomial logistic regression. Rates of laxative use were compared using χ(2) statistics. RESULTS: The 10- and 90-day trials consistently showed that tapentadol IR caused less impairment of bowel function than oxycodone IR. BMQ data were comparable between patients receiving tapentadol IR and placebo, and better versus oxycodone IR including: lower proportion of days where bowel movement was absent (P<0.05); lower risks of reporting hard stools (P<0.001); and moderate or severe straining (P<0.001). All PAC-SYM summary scores (abdominal, rectal, stool, overall) indicated fewer symptoms among patients receiving tapentadol IR versus oxycodone IR (P<0.001). In both trials, rates of laxative use was lower for tapentadol IR treatment groups versus oxycodone IR (P<0.001). DISCUSSION: Patient-reported bowel function associated with tapentadol IR treatment was similar to that associated with placebo (10-d trial) and significantly better than that associated with oxycodone IR treatment (10- and 90-d trials).

Pain relief and tolerability balance of immediate release tapentadol or oxycodone treatment for patients with moderate to severe osteoarthritis or low back pain.

PURPOSE: Opioid treatment effectiveness may be best compared using definitions of treatment response, which combine measures assessing pain reduction and the occurrence of adverse events (AEs). This analysis of data from two phase III clinical trials was conducted to examine the pain relief and tolerability (PRT) balance of immediate release (IR) tapentadol and oxycodone in patients with moderate to severe osteoarthritis (OA) or low back pain. METHODS: This was a post hoc analysis of two multicenter, randomized, double-blind studies (10-day and 90-day) that evaluated the efficacy and safety of tapentadol IR in patients with moderate-severe OA pain. PRT was defined as adequate pain reduction (30% or 50% pain intensity improvement from baseline) and no gastrointestinal AE or other type of treatment-emergent AE. The percentage of patients and mean number of days per patient meeting the PRT criteria were summarized. RESULTS: In the 10-day trial, the percentages of patients meeting PRT criteria (30% reduction) for both tapentadol groups were consistently above that for oxycodone 10 mg, although only significantly different for the 50 mg formulation. The mean number of days per patient meeting the PRT criteria was 3.7, 3.2, and 2.3 days for tapentadol 50 mg, 75 mg and oxycodone 10 mg, respectively. No significant difference between the groups was observed using the 50% pain reduction criterion. For the 90-day trial, using multiple definitions, tapentadol IR showed a significantly higher proportion of days meeting PRT criteria. CONCLUSION: Pain reduction and tolerability are both important attributes of an effective analgesic treatment. Based on data from two trials, tapentadol IR produced an improved PRT balance compared with oxycodone IR.

Dose-response relationship after single oral dose administrations of morphine and oxycodone using laser-evoked potentials on UVB- and capsaicin-irritated skin in healthy male subjects.

The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of ≥ 2.5 µV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids.

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

PURPOSE: To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models. METHODS: The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models. RESULTS: Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3-4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios. CONCLUSIONS: This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.

Post hoc analyses of data from a 90-day clinical trial evaluating the tolerability and efficacy of tapentadol immediate release and oxycodone immediate release for the relief of moderate to severe pain in elderly and nonelderly patients.

OBJECTIVE: To evaluate the tolerability and efficacy of tapentadol immediate release (IR) and oxycodone IR for relief of moderate to severe pain in elderly and nonelderly patients. METHODS: Post hoc data analyses were conducted on a 90-day randomized, phase 3, double-blind, flexible-dose study (ClinicalTrials.gov: NCT00364546) of adults with moderate to severe lower back pain or osteoarthritis pain who received tapentadol IR 50 mg or 100 mg, or oxycodone HCl IR 10 mg or 15 mg every 4 h to 6 h as needed for pain relief. Treatment-emergent adverse events and study discontinuations were recorded. RESULTS: Data from 849 patients randomly assigned (4:1 ratio) to treatment with a study drug (tapentadol IR [n=679] or oxycodone IR [n=170]) were analyzed according to age (younger than 65 years of age [nonelderly], or 65 years of age or older [elderly]) and treatment group. Among elderly patients, incidences of constipation (19.0% versus 35.6%) and nausea or vomiting (30.4% versus 51.1%) were significantly lower with tapentadol IR versus oxycodone IR (all P<0.05). Initial onsets of nausea and constipation occurred significantly later with tapentadol IR versus oxycodone IR (both P<=0.031). Tapentadol IR-treated elderly patients had a lower percentage of days with constipation than oxycodone IR-treated patients (P=0.020). For tapentadol IR- and oxycodone IR-treated elderly patients, respectively, incidences of study discontinuation due to gastrointestinal treatment-emergent adverse events were 15.8% and 24.4% (P=0.190). Tapentadol IR and oxycodone IR provided similar pain relief, with no overall age-dependent efficacy differences (mean pain scores [11-point numerical rating scale] decreased from 7.0 and 7.2 at baseline, to 4.9 and 5.2 at end point, respectively). CONCLUSIONS: Tapentadol IR was safe and effective for the relief of lower back pain and osteoarthritis pain in elderly patients, and was associated with a better gastrointestinal tolerability profile than oxycodone IR.

Evaluation of study discontinuations with tapentadol inmmediate release and oxycodone immediate release in patients with low back or osteoarthritis pain.

OBJECTIVE: To examine discontinuations due to nausea and/or vomiting or constipation with tapentadol immediate release (IR) or oxycodone IR treatment. DESIGN: Post hoc analyses of a 90-day, phase 3, randomized, double-blind, flexible-dose study. SETTING: United States, Canada, United Kingdom. PATIENTS: Adults with moderate to severe low back or osteoarthritis (OA) pain for > or =3 months. INTERVENTIONS: Tapentadol IR 50 or 100 mg or oxycodone HCI IR 10 or 15 mg every 4-6 hours as needed. MAIN OUTCOME MEASURES: Adverse events and discontinuations were recorded. RESULTS: Post hoc analyses included data from 679 patients receiving tapentadol IR and 170 receiving oxycodone IR (4:1 randomization). Tapentadol IR 50 or 100 mg and oxycodone HCI IR 10 or 15 mg provided similar levels of pain relief Overall, 21.2 percent of patients receiving tapentadol IR discontinued treatment for adverse events versus 31.2 percent of patients receiving oxycodone IR. The percentage of patients who discontinued for nausea and/or vomiting was significantly lower with tapentadol IR (5.9 percent) than oxycodone IR (14.7 percent; p = 0.0003); patients treated with oxycodone IR discontinued because of nausea and/or vomiting significantly earlier than with tapentadol IR (p < 0.0001). The percentage of patients who discontinued because of constipation was significantly lower with tapentadol IR (1.5 percent) than with oxycodone IR (5.9 percent; p = 0.0023); patients treated with oxycodone IR discontinued because of constipation significantly earlier versus tapentadol IR (p = 0.0003). CONCLUSIONS: A lower percentage of patients discontinued because of nausea and/or vomiting or constipation with tapentadol IR versus oxycodone IR while receiving comparable pain relief suggesting tapentadol may improve the management of low back and OA pain.

Tapentadol immediate release: a new treatment option for acute pain management.

The undertreatment of acute pain is common in many health care settings. Insufficient management of acute pain may lead to poor patient outcomes and potentially life-threatening complications. Opioids provide relief of moderate to severe acute pain; however, therapy with pure µ-opioid agonists is often limited by the prevalence of side effects, particularly opioid-induced nausea and vomiting. Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action, µ-opioid receptor agonism and norepinephrine reuptake inhibition. The analgesic effects of tapentadol are independent of metabolic activation and tapentadol has no active metabolites; therefore, in theory, tapentadol may be associated with a low potential for interindividual efficacy variations and drug-drug interactions. Previous phase 3 trials in patients with various types of moderate to severe acute pain have shown that tapentadol immediate release (IR; 50 to 100 mg every 4 to 6 hours) provides analgesia comparable to that provided by the pure µ-opioid agonist comparator, oxycodone HCl IR (10 or 15 mg every 4 to 6 hours), with a lower incidence of nausea, vomiting, and constipation. Findings suggest tapentadol may represent an improved treatment option for acute pain.

Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies.

STUDY OBJECTIVE: To evaluate the effects of acetaminophen, naproxen, and acetylsalicylic acid on the pharmacokinetics of the centrally acting analgesic tapentadol in healthy subjects. DESIGN: Two randomized, open-label, crossover, drug-drug interaction studies. SETTING: Clinical research facilities in the United States and Belgium. PARTICIPANTS: Twenty-four healthy adults (2-way crossover study) and 38 healthy adults (3-way crossover study). INTERVENTIONS: In both studies, tapentadol immediate release (IR) 80 mg was administered as a single oral dose alone. In the 2-way crossover study, tapentadol IR was also given with the fifth of seven doses of acetaminophen 1000 mg; in the 3-way crossover study, tapentadol IR was also given with the third of four doses of naproxen 500 mg and the second of two doses of acetylsalicylic acid 325 mg. All treatments were separated by a washout period of 7-14 days. MEASUREMENTS AND MAIN RESULTS: Overall, mean serum concentrations were similar after administration of tapentadol IR alone and after coadministration with acetaminophen or acetylsalicylic acid, and the 90% confidence intervals (CIs) for the ratios of the mean area under the serum concentration-time curve (AUC) from time zero to time of the last measurable concentration (AUC(0-t)) and from time zero extrapolated to infinity (AUC(0-infinity)) and the maximum serum concentration (C(max)) of the combined treatments to those parameters of tapentadol alone were well within 80-125%, representing the accepted range for bioequivalence. Coadministration of naproxen did not significantly alter the C(max) of tapentadol, although a slightly higher serum tapentadol exposure relative to tapentadol alone was observed. Coadministration of naproxen resulted in a mean increase of 17% in AUCs, and the upper limits of the 90% CIs for the ratios of the mean AUC(0-t) and AUC(0-infinity) were slightly outside the upper limit of bioequivalence range of 80-125%(126.47%AUC(0-t) and 126.14%AUC(0-infinity)). CONCLUSION: No clinically relevant changes were noted in the serum concentrations of tapentadol, and accordingly, no dosage adjustments with respect to the investigated pharmacokinetic mechanism of interaction are warranted for the administration of tapentadol given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid.

Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.

Tapentadol exerts its analgesic effects through micro opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Preclinical studies demonstrated that tapentadol is effective in a broad range of pain models, including nociceptive, inflammatory, visceral, mono- and polyneuropathic models. Moreover, clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings. In addition, it was reported to be associated with significantly fewer treatment discontinuations due to a significantly lower incidence of gastrointestinal-related adverse events compared with equivalent doses of oxycodone. The combination of these reduced treatment discontinuation rates and tapentadol efficacy for the relief of moderate to severe nociceptive and neuropathic pain may offer an improvement in pain therapy by increasing patient compliance with their treatment regimen.

A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain.

OBJECTIVE: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy). METHODS: Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4-6 h over a 72-h period following surgery. Acetaminophen (< or =2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting). RESULTS: Statistically significantly higher mean SPID(48) values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non-inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups. CONCLUSIONS: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID(48) and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg.

Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study.

OBJECTIVES: The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. METHODS: This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). RESULTS: Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference [LSMD] = 101.2 [95% CI, 54.58- 147.89]; tapentadol IR 75 mg: LSMD = 97.5 [95% CI, 51.81-143.26]) or oxycodone HCl IR (LSMD = 111.9 [95% CI, 66.49-157.38]) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg (P < 0.001). CONCLUSIONS: In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability.

Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study.

OBJECTIVE: Tapentadol is a novel, centrally acting analgesic with two mechanisms of action, mu-opioid receptor agonism and norepinephrine reuptake inhibition, in a single molecule. This phase III, randomized, double-blind, active-controlled study evaluated the tolerability of tapentadol immediate release (IR) and oxycodone IR for low back pain or osteoarthritis pain (hip or knee), using flexible dosing over 90 days. METHODS: Patients (N = 878) were randomly assigned (4:1 ratio) to receive tapentadol IR (50 or 100 mg, q4-6h, p.o.) or oxycodone IR (10 or 15 mg, q4-6h, p.o.). Tapentadol IR was evaluated for tolerability over 90 days, tolerability relative to oxycodone IR, withdrawal symptoms, and pain intensity. This study was not placebo-controlled, which limited efficacy evaluations. RESULTS: In total, 849 intent-to-treat patients received tapentadol IR (n = 679) or oxycodone IR (n = 170), and among these, 391 patients (57.6%) in the tapentadol IR group and 86 patients (50.6%) in the oxycodone IR group completed the study. Gastrointestinal events, including nausea (18.4% vs 29.4%), vomiting (16.9% vs 30.0%), and constipation (12.8% vs 27.1%), were reported by 44.2% of patients receiving tapentadol IR and 63.5% of patients receiving oxycodone IR, respectively. Nervous system events, including dizziness (18.1% vs 17.1%), headache (11.5% vs 10.0%), and somnolence (10.2% vs 9.4%), were reported by 36.7% of patients receiving tapentadol and 37.1% of patients receiving oxycodone, respectively. Odds ratios (tapentadol:oxycodone) showed that the incidences of somnolence and dizziness were similar; however, nausea, vomiting, and constipation were significantly less likely with tapentadol IR compared with oxycodone IR. The pattern of withdrawal symptoms suggests that drug tapering may not be necessary after tapentadol IR treatment of this duration. Pain intensity measurements showed similar efficacy for tapentadol and oxycodone. CONCLUSION: During this 90-day study, tapentadol IR was associated with improved gastrointestinal tolerability compared with oxycodone IR while providing similar pain relief. Trial registration information: NCT00364546.

A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain.

OBJECTIVE: This study evaluated tapentadol immediate release (IR) for pain relief following orthopedic bunionectomy surgery. METHODS: This randomized, double-blind, placebo- and active-controlled, phase III study included patients with moderate-to-severe pain following bunionectomy. Randomized patients (N = 603) received tapentadol IR 50, 75, or 100 mg; oxycodone HCl IR 15 mg; or placebo orally every 4-6 hours over a 72-hour period following bunionectomy. The primary endpoint was the sum of pain intensity difference (SPID) over 48 hours. Secondary endpoints included SPID over 12, 24, and 72 hours; total pain relief, and sum of total pain relief and sum of pain intensity difference (SPRID) over 12, 24, 48, and 72 hours; use of rescue medication; patient global impression of change; and onset of action assessment. Possible limitations of this study were that the intense dose monitoring and thorough nursing care were unlikely to represent actual use situations and could introduce similar bias across all treatment groups. CLINICAL TRIAL REGISTRATION: NCT00364247. RESULTS: Mean SPID(48) values were significantly higher for tapentadol IR (50, 75, and 100 mg) and oxycodone HCl IR 15 mg compared with placebo (all p

The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunionectomy) surgery .

OBJECTIVE: Tapentadol is a new, centrally acting analgesic with two mechanisms of action, combining µ-opioid agonism and norepinephrine reuptake inhibition in a single molecule. This study assessed tapentadol immediate release (IR) in patients with postsurgical orthopedic pain. METHODS: This randomized, double-blind, phase II study involved patients with moderate-to-severe pain after bunionectomy surgery (first metatarsal with osteotomy). Patients (N = 269) were randomly assigned to receive tapentadol IR 50 or 100 mg, oxycodone HCl IR 10 mg, or placebo; the study drug was taken every 4-6 h, over a 72-h period starting 1 day after surgery (Evaluation Day 2). The primary endpoint was the sum of pain intensity over 24 h (SPI-24) on the second day after randomization (Evaluation Day 3). Potential limitations of this study included the use of rescue medication and the fact that it was not powered to statistically compare between-group differences in tolerability measures. RESULTS: Mean (standard deviation [SD]) SPI-24 values on Evaluation Day 3 were significantly lower for tapentadol IR (50 mg: 33.6 [19.7], p = 0.0133; 100 mg: 29.2 [15.2], p = 0.0001) and oxycodone HCl IR 10 mg (35.7 [17.2]; nominal p = 0.0365) compared with placebo (41.9 [17.7]). The most common treatment-emergent adverse events for all treatment groups were characteristic of drugs with µ-opioid agonist activity. While providing similar analgesic efficacy, tapentadol IR 50 mg was associated with lower rates of nausea (46.3% vs. 71.6% for oxycodone HCl IR 10 mg), dizziness (32.8% vs. 56.7%), vomiting (16.4% vs. 38.8%), and constipation (6.0% vs. 17.9%), and a similar rate of somnolence (28.4% vs. 26.9%) compared with oxycodone HCl IR 10 mg. CONCLUSIONS: Tapentadol IR 50 and 100 mg and oxycodone HCl IR 10 mg were effective in this study for the relief of acute postoperative pain following bunionectomy. The study results suggest improved gastrointestinal tolerability of tapentadol IR 50 mg compared with oxycodone at a dose showing comparable efficacy.

Bioavailability study of a 1200 mg miconazole nitrate vaginal ovule in healthy female adults.

This study was undertaken to determine the bioavailabilityof a 1200 mg miconazole nitrate vaginal ovule in 20 healthy premenopausal females following a single application (Day 1, Group 1) and two applications, 48 hours apart (Day 1 and Day 3, Group 2). In Dose Group 1 (n = 10), the mean Cmax of 10.7 ng/ml occurred at 18.4 hours. The average plasma miconazole concentration was calculated to be 5.7 ng/ml during the 4- to 96-hour time interval. In Dose Group 2 (n = 10), mean Cmax values were 10.8 ng/ml and 12.0 ng/ml and occurred at 18.4 hours (Day 1) and 16.0 hours (Day 3), respectively. Comparing AUC0-48 on Days 1 and 3 (338 vs. 408 ng x h/ml) indicated small accumulation of plasma miconazole, while AUC0-48 obtained from Dose Group 2, Day 1 was similar to that of Dose Group 1 (338 vs. 329 ng x h/ml, respectively). Plasma miconazole profiles were best described by a monoexponential equation with zero-order input. Pharmacokinetic simulations performed on the pooled data from two dose groups (n = 20) suggest a steady-state accumulation after five doses administered daily or three doses taken once every other day. Drug exposure was similar to that of the marketed formulation (MONISTAT 7 vaginal cream), applied once daily for 7 days and more than 100-fold less than that reported when given intravenously or orally.