An essential component of the interpretation of results of randomized clinical trials of treatments for chronic pain involves the determination of their clinical importance or meaningfulness. This ...involves two distinct processes--interpreting the clinical importance of individual patient improvements and the clinical importance of group differences--which are frequently misunderstood. In this article, we first describe the essential differences between the interpretation of the clinical importance of patient improvements and of group differences. We then discuss the factors to consider when evaluating the clinical importance of group differences, which include the results of responder analyses of the primary outcome measure, the treatment effect size compared to available therapies, analyses of secondary efficacy endpoints, the safety and tolerability of treatment, the rapidity of onset and durability of the treatment benefit, convenience, cost, limitations of existing treatments, and other factors. The clinical importance of individual patient improvements can be determined by assessing what patients themselves consider meaningful improvement using well-described methods. In contrast, the clinical meaningfulness of group differences must be determined by a multi-factorial evaluation of the benefits and risks of the treatment and of other available treatments for the condition in light of the primary goals of therapy. Such determinations must be conducted on a case-by-case basis, and are ideally informed by patients and their significant others, clinicians, researchers, statisticians, and representatives of society at large.
To evaluate the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain.
Patients (N = 981) were randomized 1:1:1 to receive tapentadol ...ER 100 - 250 mg b.i.d., oxycodone HCl controlled release (CR) 20 - 50 mg b.i.d., or placebo over 15 weeks (3-week titration period, 12-week maintenance period).
Efficacy was assessed as change from baseline in average pain intensity (11-point NRS) at week 12 of the maintenance period and throughout the maintenance period; last observation carried forward was used to impute missing pain scores. Adverse events (AEs) were monitored throughout the study.
Tapentadol ER significantly reduced average pain intensity versus placebo at week 12 (least squares mean difference vs placebo 95% confidence interval, -0.8 -1.22, -0.47; p < 0.001) and throughout the maintenance period (-0.7 -1.06,-0.35; p < 0.001). Oxycodone CR significantly reduced average pain intensity versus placebo at week 12 (-0.9 -1.24,-0.49; p < 0.001) and throughout the maintenance period (-0.8 -1.16,-0.46; p < 0.001). Tapentadol ER was associated with a lower incidence of treatment-emergent AEs (TEAEs) than oxycodone CR. Gastrointestinal TEAEs, including constipation, nausea, and vomiting, were among the most commonly reported TEAEs (placebo, 26.3%; tapentadol ER, 43.7%; oxycodone CR, 61.9%). The odds of experiencing constipation or the composite of nausea and/or vomiting were significantly lower with tapentadol ER than with oxycodone CR (both p < 0.001).
Tapentadol ER (100 - 250 mg b.i.d.) effectively relieved moderate to severe chronic low back pain over 15 weeks and had better gastrointestinal tolerability than oxycodone HCl CR (20 - 50 mg b.i.d.).
Abstract 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.)
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.
Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of ...preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.
This study evaluated the efficacy and tolerability of tapentadol extended release (ER) for the management of chronic pain associated with diabetic peripheral neuropathy (DPN).
Adults with moderate to ...severe DPN pain were titrated to tapentadol ER 100-250 mg bid during a 3-week open-label period; patients with ≥1-point reduction in pain intensity (11-point numerical rating scale) at end of titration were randomized to receive placebo or tapentadol ER (optimal dose from titration) for 12 weeks (double-blind, fixed-dose maintenance phase). The primary end point was mean change in average pain intensity from the start to week 12 (last observation carried forward LOCF) of the double-blind maintenance phase.
A total of 358 patients completed the titration period; 318 patients (placebo, n = 152; tapentadol ER, n = 166) were randomized and received one or more doses of double-blind study medication. Mean (SD) pain intensity (observed case) was 7.33 (1.30) at the start and 4.16 (2.12) at week 3 of the open-label titration period (mean SD change, -3.22 1.97). The mean (SD) change in pain intensity (LOCF) from start of double-blind treatment to week 12 was as follows: placebo, 1.30 (2.43); tapentadol ER, 0.28 (2.04; least squares mean difference, -0.95 95% CI -1.42 to -0.49; P < 0.001). Treatment-emergent adverse events (≥10%) in the tapentadol ER group during the double-blind maintenance phase were nausea (21.1%) and vomiting (12.7%).
Tapentadol ER (100-250 mg bid) was effective and well tolerated for the management of moderate to severe chronic pain associated with DPN.
ABSTRACT
Objective: Tapentadol is a novel, centrally acting analgesic with two mechanisms of action, μ-opioid receptor agonism and norepinephrine reuptake inhibition, in a single molecule. This phase ...III, randomized, double-blind, active-controlled study evaluated the tolerability of tapentadol immediate release (IR) and oxycodone IR for low back pain or osteoarthritis pain (hip or knee), using flexible dosing over 90 days.
Methods: Patients (N = 878) were randomly assigned (4:1 ratio) to receive tapentadol IR (50 or 100 mg, q4-6h, p.o.) or oxycodone IR (10 or 15 mg, q4-6h, p.o.). Tapentadol IR was evaluated for tolerability over 90 days, tolerability relative to oxycodone IR, withdrawal symptoms, and pain intensity. This study was not placebo-controlled, which limited efficacy evaluations.
Results: In total, 849 intent-to-treat patients received tapentadol IR (n = 679) or oxycodone IR (n = 170), and among these, 391 patients (57.6%) in the tapentadol IR group and 86 patients (50.6%) in the oxycodone IR group completed the study. Gastrointestinal events, including nausea (18.4% vs 29.4%), vomiting (16.9% vs 30.0%), and constipation (12.8% vs 27.1%), were reported by 44.2% of patients receiving tapentadol IR and 63.5% of patients receiving oxycodone IR, respectively. Nervous system events, including dizziness (18.1% vs 17.1%), headache (11.5% vs 10.0%), and somnolence (10.2% vs 9.4%), were reported by 36.7% of patients receiving tapentadol and 37.1% of patients receiving oxycodone, respectively. Odds ratios (tapentadol:oxycodone) showed that the incidences of somnolence and dizziness were similar; however, nausea, vomiting, and constipation were significantly less likely with tapentadol IR compared with oxycodone IR. The pattern of withdrawal symptoms suggests that drug tapering may not be necessary after tapentadol IR treatment of this duration. Pain intensity measurements showed similar efficacy for tapentadol and oxycodone.
Conclusion: During this 90-day study, tapentadol IR was associated with improved gastrointestinal tolerability compared with oxycodone IR while providing similar pain relief.
Trial registration information: NCT00364546.
Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of ...preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.
Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The ...goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of ...treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed.
Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.
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