Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study.

BACKGROUND: Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). METHODS: To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI ≥ 15 vs < 15). The primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. RESULTS: Mixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥ 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: -4.9 (-8.98; -0.80) and -0.7 (-5.16; 3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea. CONCLUSIONS: A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥ 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified. REGISTRATION: ClinicalTrials.gov Identifier: NCT03227224. PREVIOUS PRESENTATION: Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.

Treatment patterns and sequences of pharmacotherapy for patients diagnosed with depression in the United States: 2014 through 2019.

BACKGROUND: Understanding how patients are treated in the real-world is vital to identifying potential gaps in care. We describe the current pharmacologic treatment patterns for the treatment of depression. METHODS: Patients with depression were identified from four large national claims databases during 1/1/2014-1/31/2019. Patients had ≥2 diagnoses for depression or an inpatient hospitalization with a diagnosis of depression. Patients were required to have enrollment in the database ≥1 year prior to and 3 years following their first depression diagnosis. Treatment patterns were captured at the class level and included selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, and antipsychotics. Treatment patterns were captured during all available follow-up. RESULTS: We identified 269,668 patients diagnosed with depression. The proportion not receiving any pharmacological treatment during follow-up ranged from 29 to 52%. Of the treated, approximately half received ≥2 different classes of therapy, a quarter received ≥3 classes and more than 10% received 4 or more. SSRIs were the most common first-line treatment; however, many patients received an anxiolytic, hypnotic/sedative, or antipsychotic prior to any antidepressive treatment. Treatment with a combination of classes ranged from approximately 20% of first-line therapies to 40% of fourth-line. CONCLUSIONS: Many patients diagnosed with depression go untreated and many others receive a non-antidepressant medication class as their first treatment. More than half of patients received more than one type of treatment class during the study follow up, suggesting that the first treatment received may not be optimal for most patients.

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.

Validation of a bowel function diary for assessing opioid-induced constipation.

OBJECTIVES: Validated tools to assess opioid-induced constipation (OIC) are needed. The aim of this study was to validate a Bowel Function Diary (BF-Diary) that includes patient-reported outcomes (PROs) associated with OIC. METHODS: In a multicenter, observational study, opioid-naive or recently untreated (≥ 14 days) adults with nonmalignant, chronic pain who were prescribed oral opioid and usual care completed an electronic diary daily for 2 weeks. Test-retest reliability was assessed. Validity was evaluated for two composite end points--number of spontaneous bowel movements (SBM) and complete SBMs (SCBM)--and for other relevant PROs. RESULTS: Of 238 patients (mean age 54 years, 58% women), 63% reported constipation. The intraclass correlation coefficient for numbers of SBM and SCBM, and other BF-Diary PROs was ≥ 0.71 for all items except stool consistency. Mean (s.d.) number of SBM per week was significantly less in each week for patients with vs. without constipation (5.6 ± 4.3 and 7.3 ± 3.6, respectively over week 1, P=0.0012; similarly, P=0.0096 over week 2). Validity of individual items in the BF-Diary was supported (P<0.05, stool consistency; P<0.0001, all others). CONCLUSIONS: BF-Diary items are generally reliable and valid assessments for OIC research. Specifically, number of SBM is a valid measure for differentiating opioid-treated patients with and without constipation.

Characteristics of patients with major depressive disorder switching SSRI/SNRI therapy compared with those augmenting with an atypical antipsychotic in a real-world setting.

BACKGROUND: Following a partial response of first-line antidepressant therapy for the treatment of major depressive disorder (MDD), there is a choice to augment treatment with another agent or switch to a different antidepressant. OBJECTIVE: To report the prevalence and compare the characteristics of patients switching from their initial selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) to a new SSRI/SNRI versus those augmenting SSRI/SNRI therapy with a second-generation antipsychotic (SGA). METHODS: MDD patients receiving first-line SSRI/SNRI treatment were identified from a large US-based claims database during 2000-2019. Patients augmenting therapy with an SGA were compared with those who switched to a new SSRI/SNRI. The date of the treatment change was the index date. Previously diagnosed comorbid conditions, medication use and demographics were captured. Treatment patterns following the index date were also captured. Standardized differences (StdDiff) were used to quantify dissimilarities between the two groups. RESULTS: There were 4572 SGA add-on and 24,409 switching patients identified. SGA augmentation patients had more severe disease (diagnosed severe recurrent major depression: 24.7% vs. 9.5%, StdDiff = 0.41) and more diagnosed psychiatric conditions, including: suicidal thoughts (10.7% vs. 3.2%, StdDiff = 0.29), post-traumatic stress disorder (6.1% vs. 2.6%, StdDiff = 0.17) and alcohol abuse (5.4% vs. 2.7%, StdDiff = 0.14). SGA augmentation patients had higher rates of prior use of anxiolytics (37.4% vs. 28.2%, StdDiff = 0.20) and anticonvulsants (26.0% vs. 13.1%, StdDiff = 0.33). CONCLUSIONS: Patients adding an SGA to their SSRI/SNRI therapy appeared to have more severe depression and comorbid psychiatric profile than those switching their SSRI/SNRI. These differences are important to consider and adequately control for in any future comparative outcome research between these two groups.

Dose patterns in commercially insured subjects chronically exposed to opioids: a large cohort study in the United States.

BACKGROUND: Little data exist on how opioid doses vary with the length of exposure among chronic opioid users. METHODS: To characterize the change in the dosage of opioids over time, a retrospective cohort study using the PharMetrics database for the years 1999 through 2008 was conducted. Individuals exposed to opioids in 2000 who had 2 opioid dispensings at least 6 months apart and were opioid naive (did not receive any opioid 6 month before their exposure in 2000) were included. The date of the first dispensing in 2000 was defined as the index date and the dispensing had to be for a strong and full agonist opioid. All opioid doses were converted to oral morphine equivalent doses. Exposure was classified as continuous or intermittent. Mean, median, interquartile range, and 95th percentile of opioid dose over 6-month periods, as well as the percentage of subjects who ever received a high or very high opioid dose, were calculated. RESULTS: Among the 48,986 subjects, the mean age was 44.5 years and 54.5% were women. Intermittent exposure was observed in 99% of subjects; continuous exposure was observed in 1% of subjects. The mean duration of exposure for the subjects who were continuously exposed to opioids was 477 days. In subjects with no cancer diagnosis who were continuously exposed to opioids, the mean, 25th, 50th, and 75th percentile of dose was stable during the first 2 years of use, but the 95th percentile increased. Seven percent of them were exposed to doses of 180 mg or more of morphine at some point. CONCLUSIONS: Dose escalation is uncommon in subjects with intermittent exposure to opioids. For subjects with continuous exposure to opioids who have cancer, doses rise substantially with time. For those without cancer, doses remain relatively stable for the first 2 years of use, but subsequently increase. Seven percent of subjects with no cancer diagnosis will be exposed to daily doses of 180 mg or more of morphine equivalent at some point.

Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.

BACKGROUND: Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity. OBJECTIVE: to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. METHODS: this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. RESULTS: efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). CONCLUSION: treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.

Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.

BACKGROUND: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain. METHODS: Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study. RESULTS: A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients. CONCLUSION: Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.

First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18.

BACKGROUND: This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents. PATIENTS AND METHODS: This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised. Adverse events were monitored throughout the trial. RESULTS: Forty-four patients who received a single dose of 1 mg/kg tapentadol OS were included in this investigation. Maximum serum concentrations of tapentadol (111 ng/mL) and tapentadol-O-glucuronide (2,400 ng/mL) observed in this trial were within the range of individual maximum concentrations observed in healthy adults administered a comparable dose (range for tapentadol 23.2-129 ng/mL, for tapentadol-O-glucuronide 1,040-4,070 ng/mL). Following tapentadol administration, pain intensity scores improved from baseline at all timepoints. Treatment-emergent adverse events, none of which were serious, were experienced by 45.5% of the patients; the most commonly reported were vomiting (29.5%) and nausea (9.1%). CONCLUSIONS: Tapentadol OS administered as a single dose of 1 mg/kg in children aged 6 to <18 years was generally well tolerated and produced similar serum concentrations as administration of 50-100 mg tapentadol immediate-release tablets in adults. A decrease in postsurgical pain was observed using exploratory subject-reported pain assessments. Tapentadol OS may provide a new treatment option in the management of moderate to severe acute pain in children and adolescents.

Quantifying the Exposure of Tapentadol Extended Release in Japanese Patients with Cancer Pain and Bridging Tapentadol Pharmacokinetics Across Populations Using a Modeling Approach.

BACKGROUND AND OBJECTIVES: Tapentadol extended release (ER) is approved for the management of chronic and acute pain in adults. There has been no report of tapentadol ER pharmacokinetics in subjects with cancer pain. This analysis investigated tapentadol ER pharmacokinetics in Japanese patients with cancer pain and bridged it with the pharmacokinetics in Japanese healthy subjects and Caucasian patients with cancer pain. METHODS: Nonlinear mixed-effect pharmacokinetic modeling was conducted based on pooled tapentadol ER concentration data collected in five Phase 1 studies from 138 Japanese and Korean healthy subjects and in two Phase 3 studies from 215 Japanese and Korean subjects with cancer pain. Expected tapentadol exposure in subjects with different characteristics was assessed via simulation. Tapentadol ER exposures in Caucasian populations were compared with those in corresponding Japanese populations. RESULTS: Tapentadol ER pharmacokinetics in Japanese cancer-pain patients were adequately described by a time-invariant, one-compartment disposition model with two input functions and first-order elimination. Weight, age, and albumin were identified as statistically significant covariates, but do not warrant dose adjustment. Comparable pharmacokinetics were shown between Japanese healthy and Caucasian healthy subjects, and between Japanese cancer-pain patients and Caucasian cancer-pain patients. CONCLUSION: The apparent differences in the estimated individual pharmacokinetic parameters in Japanese healthy subjects and Japanese cancer-pain patients taking tapentadol ER were explained by covariates incorporated in a unified pharmacokinetic model. Population modeling was essential in this cross-population bridging analysis.

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Tolerability and efficacy of tapentadol extended release in elderly patients ≥ 75 years of age with chronic osteoarthritis knee or low back pain.

OBJECTIVE: Management of chronic pain in elderly adult patients is often complicated by analgesic medication-related side effects. This post hoc analysis of pooled data evaluated the tolerability and analgesic efficacy of tapentadol extended release (ER) compared with oxycodone controlled release (CR) in elderly adult patients (≥ 75 years of age) with moderate to severe, chronic osteoarthritis knee or low back pain. METHODS: Data were pooled from three similarly designed, randomized, doubleblind, placebo- and active-controlled, phase 3 studies of tapentadol ER for moderate to severe, chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain, and data for patients ≥ 75 years of age were evaluated. Each study consisted of a 3-week titration and 12-week maintenance period. Patients received placebo, tapentadol ER (100-250 mg bid), or oxycodone HCl CR (20-50 mg bid). Tolerability was evaluated using adverse event reporting. Efficacy was evaluated using pain intensity ratings (11-point numerical rating scale). RESULTS: For patients ≥ 75 years of age (n = 210), incidences of gastrointestinal treatment-emergent adverse events (TEAEs) overall and TEAEs of vomiting and the composite of nausea and/or vomiting were significantly lower in the tapentadol ER group compared with the oxycodone CR group (all p ≤ 0.0206). Tapentadol ER treatment was associated with significant reductions in pain intensity from baseline to week 15 compared with placebo (p = 0.0075); differences between the oxycodone CR and placebo groups failed to reach statistical significance (p = 0.1195), likely related to a higher treatment discontinuation rate in the oxycodone CR group. No significant differences were observed between the tapentadol ER and oxycodone CR groups in the change in pain intensity from baseline to week 15 (p = 0.2135). CONCLUSIONS: In elderly adult patients ≥ 75 years of age with moderate to severe, chronic osteoarthritis knee or low back pain, tapentadol ER (100-250 mg bid) provided significant pain relief compared with placebo and had a better overall gastrointestinal tolerability profile than oxycodone CR.

Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency.

OBJECTIVES: Opioid-induced androgen deficiency (OPIAD) affects patients treated with opioid analgesics. The norepinephrine reuptake inhibitor (NRI) and µ-opioid receptor (MOR) agonist activities of tapentadol may result in tapentadol having less effect on serum androgen concentrations than analgesics acting through the MOR alone, such as morphine and oxycodone. The objectives of this publication are to 1) evaluate the effects of tapentadol (NUCYNTA and NUCYNTA extended release [ER]) on sex hormone concentrations in healthy male volunteers (vs placebo and morphine) and patients with osteoarthritis (vs placebo and oxycodone), and 2) present a mechanistic hypothesis explaining how the combined MOR agonist and NRI activities of tapentadol may result in less impact on androgen concentrations. METHODS: Three clinical studies were conducted: study 1 (single-dose comparison study vs morphine in healthy volunteers), study 2 (single-dose-escalation study in healthy volunteers without an active comparator), and study 3 (multiple-dose study vs oxycodone in patients with osteoarthritis). Studies 1 and 2 were conducted at medical research centers in Germany and the United Kingdom; study 3 was conducted at primary and secondary care centers and medical research centers in the United States. All three studies were randomized, double blind, and placebo controlled. Concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH; study 3 only) were evaluated at 6 and 24 hours postdose in studies 1 and 2, respectively, and at varying time points postdose in study 3. RESULTS: In study 1, mean serum total testosterone concentrations in healthy male volunteers were similar at baseline for all treatment periods; 6 hours after dosing, mean concentrations were comparable between placebo (8.6 nmol/L) and tapentadol immediate release (IR; 43 mg, 8.8 nmol/L; 86 mg, 9.3 nmol/L), but were lower following administration of morphine IR 30 mg (5.4 nmol/L). In study 2, there were no or minimal changes in testosterone in the therapeutic dose range with tapentadol IR (75-100 mg), and there was a modest decrease that appeared to level off in the supratherapeutic range (125-175 mg); mean testosterone and LH concentrations with all doses remained within normal ranges (testosterone, 4.56-28.2 nmol/L; LH, 2.9-4.6 U/L). In study 3, the decrease in the mean [standard deviation] testosterone concentration from baseline to endpoint for male patients receiving tapentadol ER (100 mg, -1.9 [0.71] nmol/L; 200 mg, -2.1 [0.93] nmol/L) was numerically smaller compared to oxycodone CR (20 mg, -2.7 [0.93] nmol/L), but higher compared to placebo (-0.3 [1.62] nmol/L). CONCLUSIONS: These results suggest that tapentadol, which has combined MOR and NRI activities, may have a lower impact on sex hormone concentrations than pure opioid analgesics, such as morphine or oxycodone. The data and mechanistic rationale presented herein provide a justification for conducting additional hypothesis testing studies, and are not intended to be used as a basis for clinical decision making. Future studies may help elucidate whether the observed trends are clinically significant and would translate into a reduced incidence of OPIAD.

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PURPOSE: Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. METHODS: Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. FINDINGS: Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. IMPLICATIONS: Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.).

A pooled analysis evaluating the efficacy and tolerability of tapentadol extended release for chronic, painful diabetic peripheral neuropathy.

BACKGROUND AND OBJECTIVE: Data from two similarly designed studies of tapentadol extended release (ER) for managing neuropathic pain associated with diabetic peripheral neuropathy (DPN; NCT00455520, NCT01041859) in adults were pooled for this analysis, allowing a detailed evaluation of efficacy in patient subgroups and secondary endpoints. METHODS: In each study, patients were titrated to their optimal dose of open-label tapentadol ER [100-250 mg twice daily (bid)] over 3 weeks. Patients with ≥1-point improvement in average pain intensity [11-point numerical rating scale (NRS)] were randomized (1:1) to receive placebo or tapentadol ER during a 12-week, double-blind maintenance period. RESULTS: Mean (standard deviation [SD]) changes in pain intensity from baseline to week 12 of maintenance in the placebo (n = 343) and tapentadol ER (n = 360) groups, respectively, were 1.28 (2.41) and 0.08 (1.87) [least squares mean difference (LSMD): -1.14 (95 % confidence interval [CI]: -1.435, -0.838); P < 0.001, in favour of tapentadol ER]. Significant between-group differences were also observed in changes from the start of the double-blind treatment period to the double-blind endpoint for the Short Form-36 physical functioning, role-physical, bodily pain, social functioning and role-emotional subscale and physical component summary scores, and the EuroQol 5-Dimension health status index (all P < 0.05, in favour of tapentadol ER). No clinically relevant differences were observed in the efficacy of tapentadol ER across patient subgroups divided by age, sex, race, opioid experience and pain intensity. Incidences of treatment-emergent adverse events were 56.0 % (192/343) with placebo and 74.7 % (269/360) with tapentadol ER during maintenance. CONCLUSION: Results of this pooled analysis indicate that tapentadol ER was effective for managing DPN-related pain, and provided consistent analgesic efficacy across different patient subgroups.

Evaluation of blood pressure and heart rate in patients with hypertension who received tapentadol extended release for chronic pain: a post hoc, pooled data analysis.

BACKGROUND AND OBJECTIVES: Hypertension is one of the most common co-existing conditions in patients with chronic pain, and the potential effects of an analgesic on heart rate and blood pressure are of particular concern for patients with hypertension. The purpose of this analysis was to evaluate changes in blood pressure and heart rate with tapentadol extended release (ER) treatment in patients with hypertension. METHODS: We performed a post hoc analysis of data pooled from three randomized, placebo- and active-controlled, phase III studies of tapentadol ER for managing chronic osteoarthritis knee (NCT00421928, NCT00486811) or low back (NCT00449176) pain (15-week, double-blind treatment period). Data were independently analyzed for patients with a listed medical history of hypertension at baseline and patients with at least one listed concomitant antihypertensive medication at baseline. Heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured at each visit. RESULTS: In patients with a listed medical history of hypertension (n = 1,464), least-squares mean (LSM [standard error (SE)]) changes from baseline to endpoint with placebo, tapentadol ER, and oxycodone HCl controlled release (CR), respectively, were -0.7 (0.44), 0.2 (0.43), and -0.9 (0.45) beats per minute (bpm) for heart rate; -2.4 (0.64), -2.7 (0.64), and -3.7 (0.67) mmHg for SBP; and -1.0 (0.39), -1.3 (0.39), and -2.3 (0.41) mmHg for DBP; in patients with at least one listed concomitant antihypertensive medication (n = 1,376), the LSM (SE) changes from baseline to endpoint were -0.6 (0.45), 0.1 (0.44), and -0.7 (0.47) bpm for heart rate; -1.8 (0.66), -3.3 (0.65), and -3.7 (0.69) mmHg for SBP; and -0.7 (0.40), -1.4 (0.40), and -2.3 (0.42) mmHg for DBP. CONCLUSION: No clinically meaningful mean changes in heart rate or blood pressure were observed for the evaluated cohorts of patients with hypertension who were treated with tapentadol ER (100-250 mg twice daily).

Safety and tolerability of tapentadol extended release in moderate to severe chronic osteoarthritis or low back pain management: pooled analysis of randomized controlled trials.

INTRODUCTION: This analysis of pooled data from four randomized, controlled-dose adjustment, phase 3 studies (three 15-week, double-blind, placebo- and active-controlled studies and a 1-year, open-label, active-controlled safety study) in patients with chronic osteoarthritis hip or knee pain or low back pain evaluated the safety and tolerability of tapentadol extended release (ER) for the management of moderate to severe, chronic pain. METHODS: In the three 15-week studies, patients were randomized (1:1:1) to twice-daily (bid) doses of placebo, tapentadol ER (100-250 mg), or oxycodone hydrochloride (HCl) controlled release (CR; 20-50 mg). In the 1-year safety study, patients were randomized (4:1) to tapentadol ER (100-250 mg bid) or oxycodone HCl CR (20-50 mg bid). Adverse events (AEs) and discontinuations were recorded in each study; pooled results were analyzed by treatment group. RESULTS: In the placebo (n = 993), tapentadol ER (n = 1,874), and oxycodone CR (n = 1,224) groups, respectively, 40.7%, 48.4%, and 62.3% of patients discontinued treatment prematurely and 58.7%, 79.0%, and 86.6% of patients experienced ≥ 1 treatment-emergent AE (TEAE). Incidences of gastrointestinal TEAEs in the placebo, tapentadol ER, and oxycodone CR groups, respectively, were 26.6%, 47.3%, and 65.4%; incidences of nervous system TEAEs were 22.5%, 42.6%, and 45.1%, respectively. Moderate or severe gastrointestinal TEAEs were reported for 10.9% of patients who received placebo, 25.3% of patients who received tapentadol ER, and 42.3% of patients who received oxycodone CR, and moderate or severe nervous system TEAEs were reported for 10.6%, 22.1%, and 25.2% of patients, respectively. In the placebo, tapentadol ER, and oxycodone CR groups, respectively, incidences of gastrointestinal TEAEs leading to study discontinuation were 2.1%, 8.3%, and 24.1%; incidences of nervous system TEAEs leading to discontinuation were 1.4%, 7.9%, and 16.3%, respectively. CONCLUSION: Results from this large patient population showed that tapentadol ER (100-250 mg bid) had improved gastrointestinal tolerability compared with oxycodone CR, based on the overall incidence of gastrointestinal TEAEs, the incidence of moderate or severe gastrointestinal TEAEs, and the incidence of gastrointestinal TEAEs leading to discontinuation.

Evaluation of the tamper-resistant properties of tapentadol extended-release tablets: results of in vitro laboratory analyses.

OBJECTIVE: To evaluate tamper-resistant properties of tapentadol tablets formulated with polyethylene oxide (PEO) matrix. DESIGN: Analytical and physical tests to characterize tablets. INTERVENTIONS: Tapentadol extended release (ER) 50, 100, 150, 200, and 250 mg. MAIN OUTCOME MEASURE(S): Mechanical resistance of tapentadol ER tablets to crushing (all doses), in vitro drug-release profiles of intact and tampered 50- and 250-mg tablets, and resistance to extraction of 250-mg tablets subjected to hammering. RESULTS: Crush resistance testing showed no deformation of tablets with two metal spoons, minimal deformation (no pulverization/breakage) with a pill crusher, slight deformation with a standardized pharmacopeia breaking force tester, and flattening (no pulverization/breakage) with a standardized hammer instrument. Mean in vitro release profiles in quality control medium (0.050 M phosphate buffer, pH 6.8) were similar with intact and tampered (pill crusher) tablets; the release profile was faster for hammered than intact tablets, with 30 percent of the drug released after 30 minutes (slightly higher than maximum release allowed per drug product specifications). Intact tablets were completely resistant to extraction in most organic solvents tested; in aqueous solvents, the amount of drug extracted increased with time. Hammered tablets were less resistant to extraction but required vigorous shaking over extended periods of time to release >50 percent of active ingredient. CONCLUSIONS: In vitro results from tampering attempts presented herein demonstrate that tapentadol ER tablets were resistant to these forms of physical manipulation. Tapentadol ER tablets were also generally resistant to dissolution in most solvents. Developing tamper-resistant formulations is an important step in strategies to mitigate opioid abuse.

Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor-related pain on other opioids to tapentadol extended release.

BACKGROUND AND OBJECTIVES: The effectiveness and tolerability of tapentadol extended release (ER), a centrally acting analgesic with µ-opioid receptor agonist and norepinephrine (noradrenaline) reuptake inhibitor activities, have been demonstrated in patients with chronic pain, including those switching directly from prior opioid therapy. The objective of the current study was to evaluate the effectiveness and safety of conversion to oral tapentadol ER (50-250 mg twice daily) from previous around-the-clock strong opioid therapy in patients with moderate to severe, chronic malignant tumor-related cancer pain that was well-controlled. METHODS: This randomized, open-label, phase III study, which was conducted in Japan, included a 1- to 2-week screening period (on previous opioid) and an 8-week, open-label treatment period. Eligible patients, who were taking a strong opioid analgesic and had a mean pain intensity score <4 during the 3 days prior to randomization (adequate pain control on previous strong opioid), were randomized (1:1) to receive twice-daily treatment with tapentadol ER (100-500 mg/day) or morphine sustained release (SR; 20-140 mg/day; reference for assay sensitivity). Initial doses were estimated based on the conversion ratio of tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. The primary effectiveness endpoint was the proportion of patients who maintained pain control [change from baseline in mean pain intensity (11-point numerical rating scale) less than +1.5 for 3 consecutive days and no more than two doses of rescue medication per day for 3 consecutive days) during the first week of open-label treatment. RESULTS: In the tapentadol ER group (n = 50), 84.0 % of patients (42/50; 95 % CI, 70.89-92.83) maintained pain control during Week 1. On the Patient Global Impression of Change, 2.1 % (1/48), 2.1 % (1/48), 22.9 % (11/48), and 50.0 % (24/48) of patients in the tapentadol ER group reported that their overall condition was "very much improved," "much improved," "minimally improved," and "not changed," respectively, at Week 1 compared with 0 %, 10.7 % (3/28), 28.6 % (8/28), and 53.6 % (15/28) reporting these ratings at Week 8. The sensitivity of effectiveness analyses was validated based on results using morphine SR; 98.0 % (49/50; 95 % CI, 89.35-99.95) of patients in the morphine SR group maintained pain control after 1 week of treatment. The overall safety profile was similar to that demonstrated in previous studies; tapentadol ER was associated with a lower incidence of gastrointestinal treatment-emergent adverse events than morphine SR [38.0 % (19/50) vs. 54.0 % (27/50)], including constipation [12.0 % (6/50) vs. 20.0 % (10/50)] and vomiting [6.0 % (3/50) vs. 26.0 % (13/50)]. CONCLUSIONS: Overall, results indicate that conversion from previous strong opioids to tapentadol ER (50-250 mg twice daily) was successful and resulted in safe and effective pain control with improved gastrointestinal tolerability versus morphine SR in patients with moderate to severe cancer-related pain that was well-controlled on their previous opioid.