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.

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).

Physicians' beliefs and likelihood of prescribing opioid tamper-resistant formulations for chronic noncancer pain patients.

BACKGROUND: Tamper-resistant opioid formulations (TRFs) have recently been the target of active development in an effort to deter opioid misuse and abuse. OBJECTIVE: To understand factors that are predictive of physicians' likelihoods of prescribing TRFs to patients with chronic noncancer pain (CNCP). DESIGN: A cross-sectional survey was conducted, utilizing a questionnaire of clinicians' attitudes and opinions about opioids for CNCP (Clinicians' Attitudes about Opioids Scale) to explore beliefs about and likelihood of prescribing TRFs. SUBJECTS: A nationally representative sample of 1,535 practicing physicians throughout the United States. METHODS: A stepwise hierarchical multiple linear regression analysis was conducted to estimate if physician characteristics, opinions, or geographic region categorized according to state rates of mortality by drug overdose and milligrams of opioids prescribed by state were predictive of the likelihood of prescribing TRFs. RESULTS: Board certification in Pain Medicine and prescribing opioids to a higher volume of CNCP patients were significantly predictive of a reported likelihood of prescribing TRFs, in addition to concerns about possible misuse and abuse of opioids, beliefs in the effectiveness of opioids for CNCP, and greater satisfaction with education and training in pain management this set of factors accounted for 21% of the model variance. Rates of mortality by drug overdose and opioid prescription volume by location were not predictive of TRF usage. CONCLUSIONS: Reducing physician concerns about potential misuse and abuse of opioids through additional education in pain management and dissemination of information about the potential benefits and availability of TRFs should influence physicians' attitudes about and the adoption of TRFs.

Immediate-release tapentadol or oxycodone for treatment of acute postoperative pain after elective arthroscopic shoulder surgery: a randomized, phase IIIb study.

OBJECTIVE: Arthroscopic shoulder surgery can result in substantial postoperative pain. This study evaluated the efficacy and safety of tapentadol immediate release (IR) or oxycodone IR in this setting for the treatment of acute pain. DESIGN: Subjects received tapentadol IR 50 or 100 mg or oxycodone IR 5 or 10 mg every 4-6 hours as needed for pain up to 7 days after arthroscopic shoulder surgery. Twice daily, subjects recorded pain intensity from 0 (no pain) to 10 (pain as bad as you can imagine) and pain relief from 0 (none) to 5 (complete). Final assessments included patient and clinician global impression of change and subject satisfaction with treatment. The primary efficacy endpoint was the sum of pain intensity differences (SPID) over 3 days. RESULTS: Of 378 subjects (192 tapentadol IR, 186 oxycodone IR) who took study medication, 312 (158 tapentadol IR, 154 oxycodone IR) had pain intensity ≥4 before the first dose and were evaluated for efficacy. Mean SPID scores over 3 days were 32.1 and 41.1 in the tapentadol IR and oxycodone IR groups, respectively (least-squares mean difference [95% confidence interval], 9.0 [-18.9, 36.9]; p = 0.527). Secondary analyses of pain intensity, pain relief, and subject satisfaction were similar between groups. Subjects and clinicians reported significantly better global impression of change for tapentadol IR. Adverse events were consistent with established safety profiles for IR opioids. CONCLUSIONS: Tapentadol IR and oxycodone IR had similar efficacy for pain after arthroscopic shoulder surgery, but subjects and clinicians reported greater overall improvement with tapentadol IR.

Tapentadol immediate release versus oxycodone immediate release for treatment of acute low back pain.

BACKGROUND: Tapentadol has demonstrated analgesic efficacy across a range of pain conditions. OBJECTIVE: In a head-to-head study of up to 10 days in duration, the analgesic efficacy and tolerability of tapentadol immediate release (IR) versus oxycodone IR using a flexible dosing regimen were compared in patients with acute low back pain (LBP) and associated radicular leg pain. STUDY DESIGN: Randomized (1: 1), double-blind, parallel-group study (NCT00986180). Independent Ethics Committee/Institutional Review Board approval of the protocol was obtained. SETTING: Ninety US outpatient treatment centers. METHODS: Patients with moderate to severe, acute LBP received tapentadol IR (50, 75, or 100 mg) or oxycodone HCl IR (5, 10, or 15 mg) every 4 to 6 hours as needed for pain for up to 10 days. Patients reported current pain intensity twice daily (11-point numerical rating scale). The primary efficacy endpoint was the sum of pain intensity differences (SPID) over 120 hours for LBP. Tapentadol IR was considered non-inferior to oxycodone IR if the upper bound of the 95% confidence interval (CI) for the least-squares mean (LSM) difference in SPID120 was less than 120. Secondary efficacy endpoints included 2-, 3-, and 10-day SPID for LBP; 2-, 3-, 5-, and 10-day SPID for index leg pain; 30% and 50% responder rates; patient and clinician global impressions of change; and patient satisfaction. RESULTS: The safety population included 645 patients, and the modified intent-to-treat population included 585 patients. In the tapentadol IR and oxycodone IR groups, respectively, 86.3% (277/321) and 82.7% (268/324) of patients completed the study. The most common reason for study withdrawal in both treatment groups was adverse events (tapentadol IR, 6.5% [21/321]; oxycodone IR, 7.1% [23/324]). The LSM (standard error) SPID120 for LBP was 264.6 (11.43) for tapentadol IR (n = 287) and 264.0 (11.22) for oxycodone IR (n = 298). The 95% CI for the LSM difference was -32.1 to 30.9; therefore, tapentadol IR was non-inferior to oxycodone IR for relief of LBP. No significant differences were observed between tapentadol IR and oxycodone IR for other SPID endpoints or for responder rates. At the end of the study, in the tapentadol IR and oxycodone IR treatment groups, respectively, approximately two-thirds of patients (66.2% vs 66.2%) and clinicians (67.9% vs 66.6%) rated patients' overall condition as "very much improved" or "much improved," and more than 75% of patients (79.3% vs 78.9%) were "very satisfied" or "somewhat satisfied" with their treatment. In the tapentadol IR and oxycodone IR groups, respectively, 52.3% (168/321) and 58.0% (188/324) of patients reported at least one treatment-emergent adverse event (TEAE); the most common (≥ 10%) TEAEs were vomiting (15.9% vs 24.7%), nausea (15.9% vs 20.7%), and dizziness (11.8% vs 10.5%). Vomiting (odds ratio [95% CI], 1.74 [1.17 - 2.57]) and constipation (3.43 [1.45 - 8.11]) were significantly more likely to occur in the oxycodone IR treatment group. Two (0.6%) patients in the tapentadol IR group and 3 (0.9%) patients in the oxycodone IR group experienced treatment-emergent serious adverse events. LIMITATIONS: Strict patient monitoring is generally not representative of real-world medical practice; consequently, higher incidences of TEAEs may have been reported than would be expected in a typical practice setting; it is anticipated that this bias would be similar for both treatment groups. CONCLUSIONS: This head-to-head study demonstrated that tapentadol IR had comparable analgesic efficacy and overall safety to that of oxycodone IR for the relief of moderate to severe, acute LBP and associated radicular leg pain when using flexible dosing regimens that reflect typical use in clinical practice; however, tapentadol IR demonstrated a better gastrointestinal tolerability profile, particularly for the common opioid-related TEAEs of vomiting and constipation. CLINICAL TRIAL REGISTRATION: NCT00986180.

Clinicians' attitudes and beliefs about opioids survey (CAOS): instrument development and results of a national physician survey.

UNLABELLED: Beliefs surrounding the use of opioids for chronic noncancer pain have vacillated over time. Concerns regarding long-term efficacy and adverse effects of opioids, along with increases in opioid prescribing, have contributed to many political, regulatory, and clinical responses. The present study was designed to (1) develop a reliable and valid measure (Clinicians' Attitudes about Opioids Scale [CAOS]) to assess current and evolving beliefs regarding opioids and opioid use in patients with chronic pain; and (2) survey these beliefs in a nationally representative sample of providers from multiple medical specialties throughout the United States. We developed the questionnaire in 3 phases: (1) focus groups and content development; (2) pilot testing and subsequent revisions; and (3) formal survey (N = 1,535) and assessment of stability (N = 251). The resulting 38-item measure assessed 5 domains: (1) Impediments and Concerns; (2) Perceived Effectiveness; (3) Schedule II versus III Opioids; (4) Medical Education; and (5) Tamper Resistant Formulations. No significant differences were identified among geographical regions; however, several differences were observed among medical specialties. Orthopedists were most troubled by impediments/concerns from long-term opioid use and had the least confidence in opioid efficacy, whereas Pain Medicine specialists and Physical Medicine and Rehabilitation specialists were the most confident in efficacy. PERSPECTIVE: This article presents the psychometric properties of a new measure of clinicians' beliefs surrounding opioid use for chronic pain. Using this measure, beliefs and behaviors of physicians across medical specialties and geographic regions using a nationally representative sample are presented, updating findings from a similar survey conducted 20 years ago.

Tapentadol, oxycodone or placebo for acute pain of vertebral compression fractures: a randomized Phase IIIb study.

UNLABELLED: SUMMARY  AIM: Tapentadol is a centrally acting analgesic that combines µ-opioid receptor agonism with norepinephrine reuptake inhibition. This study evaluated the efficacy and safety of tapentadol immediate-release (IR), oxycodone IR or placebo in subjects with acute pain from vertebral compression fracture (VCF) associated with osteoporosis. PATIENTS & METHODS: Study patients were adults with new onset of pain or acute exacerbation of previous pain from VCF associated with osteoporosis, radiographic confirmation of VCF and back pain intensity of 5 or greater on an 11-point scale from 0 (no pain) to 10 (pain as bad as you can imagine). Patients were randomized to treatment with tapentadol IR (50 mg, then 50 or 75 mg), oxycodone IR (5 mg, then 5 or 10 mg) or placebo every 4-6 h as needed for pain, for up to 10 days. Twice daily, subjects recorded pain intensity on the 11-point scale (numeric rating scale), pain relief on a 5-point scale from 0 (none) to 4 (complete), sleep assessments (morning assessment only) and any episodes of vomiting (evening assessment only). RESULTS: The study was designed to include 625 subjects, but was stopped after 14 months due to slow enrollment (44 tapentadol IR, 43 oxycodone IR and 21 placebo subjects) and had insufficient statistical power for comparative efficacy analyses. Discontinuation rates in the tapentadol IR, oxycodone IR and placebo groups were 18.2, 27.9 and 9.5%, respectively, often due to adverse events (4.5, 18.6 and 4.8%, respectively). Treatment-emergent adverse-event rates were 63.6, 81.4 and 38.1%, respectively. CONCLUSION: In this prematurely terminated study in adults with painful VCF, trends suggested that tapentadol IR was tolerated better than oxycodone IR.

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.

Analgesic treatment for moderate-to-severe acute pain in the United States: patients' perspectives in the Physicians Partnering Against Pain (P3) survey.

OBJECTIVES: To evaluate patients' perceptions of the adequacy of analgesia for moderate-to-severe acute pain and the influence of opioid-related side effects in outpatient pain management. SETTING: The Physicians Partnering Against Pain (P3) survey of analgesic treatment for moderate-to-severe acute pain in the United States. PATIENTS: Adults with moderate-to-severe acute pain at their first analgesic followup visit. MAIN OUTCOME MEASURES: Analgesic level was determined from the World Health Organization'spain ladder (0 = none; 1 = nonopioid; 2 = weak opioid; 3 = strong opioid). Pain intensity was derived from numeric rating scale (NRS) scores (0 = none [NRS = 0]; 1 = mild [NRS = 1-3]; 2 = moderate [NRS = 4-7]; 3 = severe [NRS = 8-10). Pain management index scores were calculated as the analgesic level minus the pain intensity. Opioid recipients responded to questions on the P3 survey regarding side effects and their management. RESULTS: Of the 50,869 patients with complete data for analysis, 22,267 (44 percent) had received potentially inadequate analgesia, including 43, 46, and 52 percent of patients aged < 65, 65-74, and > or = 75 years, respectively. Of the 39,6 75 patients treated with an opioid, 10,925 (28 percent) experienced at least one gastrointestinal side effect (nausea, vomiting or constipation). Many of these patients stopped taking the medication (13 percent) or reduced their dose (16 percent) to manage gastrointestinal side effects. CONCLUSIONS: In the P3 study, one of the largest outpatient surveys conducted in pain management, moderate-to-severe acute pain continued to be widely undertreated in outpatient settings in the United States, particularly among older patients. Opioids with improved tolerability profiles might help to alleviate this undertreatment of moderate-to-severe acute pain.

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.

Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol.

OBJECTIVE: Extended-release tramadol (tramadol ER) is a once-daily formulation of tramadol approved in the United States for moderate to moderately severe chronic pain in adults. This modeling and simulation analysis was conducted to support dosing recommendations for switching patients receiving immediate-release tramadol (tramadol IR) to tramadol ER. RESEARCH DESIGN AND METHODS: Monte Carlo simulations based on steady-state data from three Phase 1 studies predicted minimum plasma concentration (C(min)), maximum plasma concentration (C(max)), and area under the plasma-concentration-versus-time curve (AUC). MAIN OUTCOME MEASURES: Pharmacokinetic parameters were compared between 100-mg daily increments of tramadol ER every 24 h (Q24H) and corresponding 25-mg increments of tramadol IR every 6 h (Q6H), such as tramadol ER 200 mg Q24H versus tramadol IR 200, 225, 250, and 275 mg daily. RESULTS: Tramadol ER and IR were predicted to provide similar exposure (AUC) at a total daily dose of 100, 200, or 300 mg. Estimated exposure was comparable between tramadol IR 125-, 225-, and 325-mg and tramadol ER 100-, 200-, and 300-mg, respectively. Estimated exposure was 30-41% lower with tramadol ER 100 mg versus tramadol IR 150 and 175 mg daily, 15-26% lower with tramadol ER 200 mg versus tramadol IR 250 and 275 mg daily, and 8-19% lower with tramadol ER 300 mg versus tramadol IR 350 and 375 mg daily. CONCLUSIONS: This pharmacokinetic analysis supports switching patients from a total daily dose of tramadol IR 200 or 300 mg directly to tramadol ER 200 and 300 mg once daily, respectively. Patients who take other doses of tramadol IR may switch to the next lower 100-mg increment of tramadol ER (e.g., from tramadol IR 225, 250, or 275 mg daily in divided doses to tramadol ER 200 mg once daily). Confirmation of these findings would require clinical studies comparing the systemic exposure of tramadol upon switching from the IR to the ER formulation.