Clinical Immunogenicity Evaluation of Eptinezumab, a Therapeutic Humanized Monoclonal Antibody Targeting Calcitonin Gene-Related Peptide (CGRP) for the Preventive Treatment of Migraine.

Background: Eptinezumab is a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and is indicated for the preventive treatment of migraine in adults. This analysis characterizes the immunogenic profile of eptinezumab using data from clinical trials of eptinezumab for migraine prevention. Methods: Immunogenicity data were collected from five studies that included 2076 patients with episodic or chronic migraine treated with eptinezumab at dose levels ranging from 10 to 1000 mg, administered intravenously for up to 4 doses at 12-week intervals. Anti-drug antibody (ADA) results were available from 2074 of these patients. Four studies were randomized, double-blind, placebo-controlled trials with ADA monitoring for up to 56 weeks; one was a 2-year, open-label, phase 3 safety study with ADA monitoring for 104 weeks. Patients who had a confirmed ADA-positive result at the end-of-study visit were monitored for up to 6 additional months. Development of ADA and neutralizing antibodies (NAbs) were evaluated to explore three key areas of potential impact: pharmacokinetic exposure profile (eptinezumab trough plasma concentrations), efficacy (change in monthly migraine days), and safety (rates of treatment-emergent adverse events). These studies included methods designed to capture the dynamics of a potential humoral immune response to eptinezumab treatment, and descriptive analyses were applied to interpret the relationship of ADA signals to drug exposure, efficacy, and safety. Results: Pooled across the five clinical trials, treatment-emergent ADAs and NAbs occurred in 15.8 and 6.2% of eptinezumab-treated patients, respectively. Highly consistent profiles were observed across all studies, with initial onset of detectable ADA observed at the week 8 measurement and maximal ADA frequency and titer observed at week 24, regardless of eptinezumab dose level or number of doses. After 24 weeks, the ADA and NAb titers steadily declined despite additional doses of eptinezumab. Interpretation: Collectively, these integrated analyses did not demonstrate any clinically meaningful impact from ADA occurring after treatment with eptinezumab. The ADA profiles were low titer and transient, with the incidence and magnitude of ADA or NAb responses declining after week 24. Development of ADAs and NAbs did not impact the efficacy and safety profiles of eptinezumab.

Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy-2) study.

BACKGROUND: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment. METHODS: Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32). RESULTS: A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, - 7.7 days; 300 mg, - 8.2 days; placebo, - 5.6 days) was further decreased after an additional dose (100 mg, - 8.2 days; 300 mg, - 8.8 days; placebo, - 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13-24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13-24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events. CONCLUSION: Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02974153 ). Registered November 23, 2016.

Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2.

OBJECTIVE: To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of chronic migraine (CM). METHODS: The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with CM were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12. RESULTS: Among treated participants (n = 1,072), baseline mean number of MMDs was ≈16.1 across groups. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1 to 12 compared with placebo (placebo -5.6, 100 mg -7.7, p < 0.0001 vs placebo; 300 mg -8.2, p < 0.0001 vs placebo). Treatment-emergent adverse events (TEAEs) were reported by 43.5% (100 mg), 52.0% (300 mg), and 46.7% (placebo) of patients. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab-treated patients at an incidence of >2% over placebo; it occurred in the 300 mg eptinezumab arm (eptinezumab 9.4%, placebo 6.0%). CONCLUSION: In patients with CM, eptinezumab 100 and 300 mg was associated with a significant reduction in MMDs from the day after IV administration through week 12, was well tolerated, and demonstrated an acceptable safety profile. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with CM, a single dose of eptinezumab reduces MMDs over 12 weeks of treatment. CLINICALTRIALSGOV IDENTIFIER: NCT02974153.

Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1).

OBJECTIVE: To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of episodic migraine. METHODS: The PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy-1 (PROMISE-1) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with episodic migraine were randomized to eptinezumab 30 mg, 100 mg, 300 mg, or placebo for up to four intravenous (IV) doses administered every 12 weeks. The primary endpoint was change from baseline in monthly migraine days (MMDs) over weeks 1-12. RESULTS: A total of 888 patients received treatment across 84 study sites. Mean MMDs at baseline was ∼8.6 across treatment groups. Eptinezumab 100 mg and 300 mg met the primary endpoint, significantly reducing MMDs across weeks 1-12 compared with placebo (30 mg, -4.0; 100 mg, -3.9, p = 0.0182; 300 mg, -4.3; placebo, -3.2, p = 0.0001). Treatment-emergent adverse events were reported by 58.4% (30 mg), 63.2% (100 mg), 57.6% (300 mg), and 59.5% (placebo) of patients. Treatment-emergent adverse events reported by ≥2% of eptinezumab-treated patients at an incidence greater than placebo included: upper respiratory tract infection (30 mg, 11.4%; 100 mg, 9.9%; 300 mg, 10.3%; placebo, 7.2%), and fatigue (30 mg, 2.3%; 100 mg, 3.6%; 300 mg, 3.6%; placebo, <1%). CONCLUSION: Eptinezumab (100 mg or 300 mg) significantly reduced migraine frequency, was well tolerated, and had an acceptable safety profile when used for the preventive treatment of migraine in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.

Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial.

BACKGROUND: Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. OBJECTIVE: To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. METHODS: This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18-55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1-12 compared with the 28-day screening period. RESULTS: The ≥75% migraine responder rates over weeks 1-12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo (p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. CONCLUSIONS: The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02275117.

The Research and Evaluation of Antipsychotic Treatment in Community Behavioral Health Organizations, Outcomes (REACH-OUT) study: real-world clinical practice in schizophrenia.

BACKGROUND: Outpatient facilities, such as community behavioral health organizations (CBHOs), play a critical role in the care of patients with serious mental illness, but there is a paucity of "real-world" patient outcomes data from this health care setting. Therefore, we conducted The Research and Evaluation of Antipsychotic Treatment in Community Behavioral Health Organizations, Outcomes (REACH-OUT) trial, a real-world, prospective, noninterventional observational study of patients with mental illness treated at CBHOs across the United States. We describe demographic and clinical characteristics, antipsychotic therapy (APT) treatment patterns, and health care resource utilization in patients with schizophrenia undergoing medical care as usual. METHODS: This study enrolled adults with schizophrenia or bipolar I disorder who initiated APT treatment at various time points: 1) within 8 weeks of initiating risperidone long-acting injectables (RLAIs) or other APTs except paliperidone palmitate (PP), 2) after more than 24 weeks of continuous RLAI treatment, or 3) at any time after initiating PP LAI treatment (schizophrenia only). Study assessments were performed via participant interview, medical chart abstraction, and clinical survey at enrollment and at month 12. RESULTS: A total of 1065 patients from 46 CBHOs were enrolled. Of these, 944 (88.6%) had a diagnosis of schizophrenia and 121 (11.4%) had bipolar I disorder. At enrollment, 599 (63.5%) of patients with schizophrenia were receiving RLAIs or PP LAI, 281 (29.8%) were receiving oral APTs, and 64 (6.8%) were receiving other injectable APTs. A number of differences in patient characteristics and outcomes were observed between patients in the LAI APT cohort and the oral APT cohort. CONCLUSION: Descriptive analyses from this observational study suggest differences in the patient characteristics, treatment patterns, and clinical and economic outcomes among those with schizophrenia treated at CBHOs with LAI APT or oral APTs. Additional analyses will be conducted to delineate the impact of LAI APT versus oral APTs on patient outcomes. TRIAL REGISTRATION: Clinical Trial Registry: NCT01181960 . Registered 12 August 2010.

VISTA: A µ-Thermogravimeter for Investigation of Volatile Compounds in Planetary Environments.

This paper presents the VISTA (Volatile In Situ Thermogravimetry Analyser) instrument, conceived to perform planetary in-situ measurements. VISTA can detect and quantify the presence of volatile compounds of astrobiological interest, such as water and organics, in planetary samples. These measurements can be particularly relevant when performed on primitive asteroids or comets, or on targets of potential astrobiological interest such as Mars or Jupiter's satellite Europa. VISTA is based on a micro-thermogravimetry technique, widely used in different environments to study absorption and sublimation processes. The instrument core is a piezoelectric crystal microbalance, whose frequency variations are affected by variations of the mass of the deposited sample, due to chemical processes such as sublimation, condensation or absorption/desorption. The low mass (i.e. 40 g), the low volume (less than 10 cm(3)) and the low power (less than 1 W) required makes this kind of instrument very suitable for space missions. This paper discusses the planetary applications of VISTA, and shows the calibration operations performed on the breadboard, as well as the performance tests which demonstrate the capability of the breadboard to characterize volatile compounds of planetary interests.

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.

Validation of the Hospital Anxiety and Depression Scale in Patients With Acute Low Back Pain.

UNLABELLED: The Hospital Anxiety and Depression Scale (HADS) is a self-report instrument used to evaluate depression and anxiety in clinical research. The HADS has advantages over other assessments of anxiety and depression; it is efficient in assessing both anxiety and depression with a total of 14 items, and it was originally developed on a general medical rather than psychiatric sample. However, the HADS has not been evaluated specifically for use in clinical trials of acute pain. Validation analyses were conducted on data from a randomized, double-blind, parallel-group study of tapentadol immediate release vs oxycodone immediate release for acute low back pain (N = 666). Analyses of psychometric properties, internal consistency, convergent validity, assessments of bias, and confirmatory factor analysis were conducted on pretreatment data. Additional analyses were performed to test the responsiveness and predictive validity of the HADS. Both the Anxiety and Depression subscales (1) showed good psychometric properties, (2) had high internal consistency, (3) displayed good convergent validity, (4) had no unexpected biases, (5) fit the a priori factor structure, and (6) were highly sensitive to changes as a result of analgesic treatment. We conclude that the HADS is a valid instrument for efficient, low-burden assessment of anxiety and depression in clinical trials with an acute low back pain population. PERSPECTIVE: Considered together with the results of other recent studies, the data suggest that the HADS can provide a valid, responsive, and efficient assessment of anxiety and depression in acute low back pain for clinical trials and other clinical research examining acute pain populations.

Validation of the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) in acute low back pain.

UNLABELLED: The Short-form McGill Pain Questionnaire (SF-MPQ-2) assesses the major symptoms of both neuropathic and nonneuropathic pain and can be used in studies of epidemiology, natural history, pathophysiologic mechanisms, and treatment response. Previous research has demonstrated its reliability, validity, and responsiveness in diverse samples of patients with chronic pain. However, the SF-MPQ-2 has not been evaluated for use in patients with acute pain. Data were examined from a double-blind, randomized clinical trial of immediate-release tapentadol versus immediate-release oxycodone in patients with acute low back and associated radicular leg pain (N = 666). Analyses of internal consistency, convergent validity, and confirmatory factor structure were conducted using baseline data, and analyses of responsiveness were conducted using baseline and endpoint data. The SF-MPQ-2 total score and its 4 subscale scores (continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors) generally showed good psychometric properties and 1) were internally consistent, 2) displayed good convergent validity, 3) fit the a priori factor structure, and 4) were highly responsive to analgesic treatment. These data extend previous evidence of the reliability, validity, and responsiveness of the SF-MPQ-2 in patients with chronic pain to those with acute low back and associated radicular leg pain. PERSPECTIVE: Considered together with the results of other recent studies, the data suggest that the SF-MPQ-2 can provide a valid, responsive, and efficient assessment of both neuropathic and nonneuropathic pain qualities for clinical trials and other clinical research examining patients with various acute and chronic pain conditions.

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).

Economic burden of back and neck pain: effect of a neuropathic component.

This was a retrospective database analysis (2001-2009) of employees' medical, prescription drug, and absence costs and days from sick leave, short- and long-term disability, and workers' compensation. Employees with an ICD-9 diagnostic code for back or neck pain and an ICD-9 for a back- or neck-related neuropathic condition (eg, myelopathy, compression of the spinal cord, neuritis, radiculitis) or radiculopathy were considered to have nociceptive back or neck pain with a neuropathic component. Employees with an ICD-9 for back pain or neck pain and no ICD-9 for a back- or neck-related neuropathic condition or radiculopathy were defined to have nociceptive back or neck pain. Patients with nociceptive back or neck pain with a neuropathic component were classified as having or not having prior nociceptive pain. Annual costs (medical and prescription drug costs and absence costs) and days from sick leave, short- and long-term disability, and workers' compensation were evaluated. Mean annual total costs were highest ($8512) for nociceptive pain with a neuropathic component with prior nociceptive pain (n=9162 employees), $7126 for nociceptive pain with a neuropathic component with no prior nociceptive pain (n=5172), $5574 for nociceptive pain only (n=35,347), and $3017 for control employees with no back or neck pain diagnosis (n=226,683). Medical, short-term disability, and prescription drugs yielded the highest incremental costs compared to controls. Mean total absence days/year were 8.26, 7.86, 5.70, and 3.44, respectively. The economic burden of back pain or neck pain is increased when associated with a neuropathic component.

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.

Risk assessment and counseling behaviors of healthcare professionals managing patients with chronic pain: a national multifaceted assessment of physicians, pharmacists, and their patients.

INTRODUCTION: Due to the significant and increasing problem of chronic pain in the United States, pain management is a frequent need in many healthcare settings. At the same time, there has been rising concern with the abuse/misuse and potential for addiction to opioid therapies. This study was conducted to better understand healthcare professionals' current knowledge, perceptions, and clinical practice patterns regarding prescribing of extended-release or long-acting opioid therapy to patients with chronic pain. METHODS: This study was conducted from March 2011 to May 2011; it utilized a nationally distributed case vignette survey of primary care physicians (PCPs), pain specialists, and pharmacists, along with nested chart reviews and surveys of patients with chronic pain. RESULTS: Many PCPs are inadequately performing opioid risk assessments and there is variability in interpreting a patient's opioid risk, resulting in misestimated risk. Physicians underutilize urine drug screens and written opioid use agreements when initiating opioid therapy in patients. Physicians and pharmacists often omit key messages during patient counseling about safe use of opioids and safe medication storage. Among pharmacists, safety counseling is generally limited to alerting patients to potential side effects. For most PCPs, difficulty managing patients with risk factors for opioid use and uncertainty about managing first line opioid efficacy failure are significant barriers to effective management of chronic pain. CONCLUSIONS: Patients having chronic pain and concomitant risk factors for opioid abuse, misuse, and diversion are prevalent, yet many physicians, especially PCPs, are uncomfortable managing opioid therapy in such patients. Education on best practices for risk assessment, patient monitoring during treatment, strategies for more effective counseling, patient chart documentation, and management strategies to enhance effective treatment of chronic pain are essential to ensure that PCPs and specialists maximize effective and safe use of opioid medications. Pharmacists could be a valuable member of this interdisciplinary team and should be involved in patient counseling and monitoring for aberrant behavior.

Economic study on the impact of side effects in patients taking oxycodone controlled-release for noncancer pain.

BACKGROUND: Chronic pain is a prevalent condition in the United States. Musculoskeletal pain, including joint and back pain, is the most common type of chronic pain, and many patients with back pain have a neuropathic component. Pain has direct economic consequences. While oxycodone controlled-release (CR) is one of the most widely used oral long-acting opioids for pain, including pain with a neuropathic component, it is often associated with bothersome side effects, resulting in additional medical resource use (MRU) and costs. OBJECTIVE: To examine the impact on MRU and costs to payers of side effects in patients taking oxycodone CR alone or in combination with other pain medications for noncancer pain (including those with neuropathic pain symptoms). METHODS: A nationwide convenience sample of adults in the United States, who participated in a survey research panel and reported current use of oxycodone CR for noncancer pain, completed an online survey between November 2, 2010, and December 13, 2010. Respondents were excluded if they reported current use of other extended-release or long-acting opioid prescription medications. The survey consisted of questions on demographics, clinical characteristics, pain characteristics, experience with pain medication, and MRU associated with side effects. Payer costs were calculated based on the MRU reported by the respondents multiplied by Medicare reimbursement rates for hospitalizations and outpatient visits and average wholesale price (AWP) minus 20% for medications. A subgroup of patients who reported neuropathic pain symptoms also was examined. RESULTS: After applying the exclusion criteria, 432 respondents completed the survey. Approximately half of the respondents (n = 219; 50.7%) reported neuropathic pain symptoms. The majority of respondents were Caucasian (88.4%) and female (63.7%) with an average age of 41.8 years (14.89). Respondents most frequently reported low back pain (41.2%), followed by osteoarthritis/rheumatoid arthritis (20.4%), neuropathic pain (10.6%), and fibromyalgia (9.0%). Respondents reported having their pain condition for an average of 5.4 (7.42) years. On days when taken, respondents reported a mean oxycodone CR daily dose of 83.3 mg (126.93) taken in an average of 2 doses. Most respondents (82.4%) reported experiencing at least 1 side effect with 77.5% being bothered by at least 1 side effect. The most frequently reported side effects ( greater than 25%) were drowsiness (41.4%), constipation (37.0%), fatigue or daytime sleepiness (36.6%), and dizziness (27.1%). Among respondents who reported being bothered by one or more side effects in the previous month, MRU associated with side effects was reported by 39.1% of respondents and significantly increased as the level of side-effect bother increased from 19.8% among those "A little bit bothered" to 38.4% among those "Bothered" to 61.0% among those "Extremely bothered" (P less than 0.001). Additionally, total average payer costs (in 2010 dollars) per respondent in the previous month associated with side effects were $238 ($1,159) and also significantly increased as the level of side-effect bother increased from $61 ($512) among those "A little bit bothered" to $238 ($1,160) among those "Bothered" to $425 ($1,561) among those "Extremely bothered" (P less than 0.001). Results reported in the neuropathic pain subgroup were similar to results reported in the total study sample. CONCLUSIONS: Among adults taking oxycodone CR for chronic noncancer pain (with or without a neuropathic pain component), over three-fourths reported being bothered by side effects. Respondents who reported higher levels of side-effect bother also reported greater MRU, resulting in increased payer costs. The results of this study provide further support of the econo-mic burden to payers associated with opioid-related side effects in patients with chronic noncancer pain, with and without neuropathic pain.

Imputing at-work productivity loss using results of a randomized controlled trial comparing tapentadol extended release and oxycodone controlled release for osteoarthritis pain.

OBJECTIVE: : To determine the impact of tapentadol extended release (ER) versus placebo or oxycodone controlled release (CR) on the work productivity of adults with chronic moderate to severe knee osteoarthritis pain. METHODS: : Using clinical trial data on pain outcomes, a validated methodology imputed treatment group differences in at-work productivity and associated differences in productivity costs (assuming a $100,000 annual salary per participant). RESULTS: : Imputed improvements in at-work productivity were significantly greater for tapentadol ER compared with either placebo (mean, 1.96% vs 1.51%; P = 0.001) or oxycodone CR (mean, 1.96% vs 1.40%; P < 0.001). Mean net savings per participant were $450 (P < 0.01) for tapentadol ER versus placebo and $560 (P = 0.001) for tapentadol ER versus oxycodone CR. CONCLUSION: : Effective osteoarthritis pain treatment also may help employees to function better at work and reduce their employers' productivity costs.

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.

Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study.

OBJECTIVE: The study sought to evaluate whether topiramate prevents development of chronic daily headache (CDH, ≥15 headache days per month) in adult subjects with high-frequency episodic migraine (HFEM, 9-14 migraine headache days/month). A secondary objective was to assess the efficacy of topiramate as preventive migraine treatment in this population. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study comparing topiramate 100 mg/day and placebo for 26 weeks. The primary efficacy variable was new-onset CDH at month 6. Secondary efficacy measures included migraine and headache days. Adverse events (AEs) were evaluated. RESULTS: A total of 159 topiramate subjects and 171 placebo subjects were efficacy-evaluable. At month 6, 1.4% of topiramate subjects versus 2.3% of placebo subjects had CDH (p = .589). Compared with placebo, topiramate treatment was associated with statistically significant reductions in mean number of migraine days (6.6 vs. 5.3/28 days; p = .001) and headache days (6.6 vs 5.3/28 days; p = .001). Most commonly reported AEs in the topiramate versus placebo group included paresthesia (32.4% vs. 7.0%), fatigue (14.8% vs. 8.6%), dizziness (11.4% vs. 7.6%) and nausea (10.8% vs. 9.2%). CONCLUSION: Topiramate 100 mg/day did not prevent the development of CDH at six months in subjects with HFEM. Topiramate was effective in reducing headache days and migraine headache days and generally well tolerated.

Long-term, open-label safety study of oral almotriptan 12.5 mg for the acute treatment of migraine in adolescents.

OBJECTIVES: This study evaluated the long-term safety of oral almotriptan 12.5 mg for the treatment of multiple migraine episodes in adolescents over a 12-month period. Efficacy outcomes were assessed as a secondary objective. METHODS: Adolescent migraineurs aged 12-17 years were enrolled in this 12-month, open-label study (Study ID CR002827). Patients were instructed to record their assessments on paper headache records whenever they experienced a migraine headache that they treated with study medication. Safety was assessed descriptively and assessments included adverse event (AE) recording, change in laboratory values, vital signs, and electrocardiogram parameters. Efficacy outcomes were assessed descriptively and outcomes included rates for 2- and 24-hour pain relief and sustained pain relief, 2- and 24-hour pain-free and sustained pain-free, and presence of migraine-associated symptoms of photophobia, phonophobia, nausea and vomiting. RESULTS: Overall, 67.1% of patients reported >or=1 AE over the course of the trial, 7.6% had an AE judged by the study investigator to be related to treatment with almotriptan, 2.4% discontinued because of an AE, and 1.9% reported serious AEs. The most commonly reported treatment-related AEs (occurring in >or=1% of patients) were nausea (1.4%) and somnolence (1.4%). Pain relief responses for treated migraines of moderate or severe intensity at baseline were 61.7% and 68.6%, at 2 and 24 hours, respectively; the sustained pain relief rate was 55.5%. Pain-free responses were reported for 40.5% of all treated migraines at 2 hours and 65.9% of treated migraines at 24 hours; the sustained pain-free rate was 38.4%. The proportion of migraines that achieved the pain relief, sustained pain relief, pain-free and sustained pain-free endpoints were similar in the 12- to 14-year and 15- to 17-year age groups. Treating with almotriptan 12.5 mg when headache pain was mild was associated with higher rates of pain relief and pain-free at 2 and 24 hours, and sustained pain relief and sustained pain-free, compared with treatment initiated when pain was severe. CONCLUSIONS: Almotriptan 12.5 mg was well tolerated in this adolescent population over a 12-month period. No unexpected safety or tolerability concerns were revealed over the course of this study. The results are consistent with almotriptan 12.5 mg being effective for the acute treatment of pain and symptoms associated with migraine in both younger and older adolescents.

Carisbamate in essential tremor: brief report of a proof of concept study.

The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double-blind, cross-over, placebo-controlled study of essential tremor. Sixty-two patients (intent-to-treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21-day treatment periods. The Fahn-Tolosa-Marín Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo.