Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

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.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

To the Editor: A recent article by Baron et al.1 reports the results of a clinical trial (CT) to compare the effectiveness of tapentadol with oxycodone/naloxone (Ox/Nal) for the treatment of chronic low back pain of neuropathic origin. This study is a remarkable attempt to progress in this area. We argue, however, that it contains several drawbacks that leave open ground for further trials with more stringent methodological controls. The double-blind design: The preventive effect of double-blinding against the effects of placebo and nocebo has been extensively documented in the literature. The decision to perform an open-label trial runs contrary to the basic rules of CTs. The use of pickup arms: Using “pickup or rescue arms” prevents the evaluation of the superiority of one treatment over another. In the reviewed trial, there are other reasons that render the use of a rescue arm doubly questionable: The first is the asymmetry which allows to use tapentadol under some subjective conditions of lack of efficacy of Ox/Nal, but not the other way around; the second is that the use of this “rescue arm” is combined with the open-label design and prior information to the patient. This leads to unmanageable biases when combined with the use of prior treatments without full equipoise. Dynamics of titration: In CTs aimed at comparing drugs, it is essential to consider pharmacokinetic characteristics of the drugs. In the evaluated study, the comparison was not performed according to this principle because the administration of Ox/Nal did not comply with the established guidelines neither in dose titration nor in titration intervals. They were however adapted to tapentadol guidelines. Criteria for continuation or discontinuation during titration period: The literature favors the use of validated numerical scales sensitive to changes in chronic pain intensity.2, 3 The use of these scales requires a rigorous control of reproducibility. In the reviewed study, two alternative criteria were formulated to enter the maintenance period, which are based essentially on the same metric, although with different cutoff points. In any case, it is essential to report the quantitative pain reduction achieved up to that point in each trial arm. On the inclusion criteria: The selection of patients not previously exposed (naïve) to the use of opioids is a logical criterion. On the same ground, we wonder why the protocol allowed to select patients under treatment with co-analgesics, with lower levels of pain than the rest of patients and with a negative score in the scale painDETECT. The use of the last observation carried forward (LOCF) for imputing the missing data: This method is based on the assumption that the time series is stationary, which does not appear to be a realistic assumption in this trial because it entails the assumption that the patient's perception of change remains constant. The evidence derived from this trial supports the feasibility of the use of both drugs, but is so far insufficient for an excluding preference for one or the other. This letter was written by the authors on a proposal from Mundipharma Spain; Mundipharma did not participate in the preparation of the letter. To the Editor: In response to the Letter to the Editor, we will substantiate point-by-point why our study is appropriate and supportive of the favorable efficacy and tolerability profile of tapentadol prolonged release (TAP). Our study was designed to test the hypotheses of noninferiority (followed by superiority) for TAP vs. oxycodone/naloxone PR (OXN) in a preplanned, 2-step statistical testing procedure for two co-primary endpoints.1, 2 The study hypotheses assumed an efficacy of OXN comparable to that of oxycodone CR (OXY)3 and a difference in tolerability of OXN vs. OXY related to naloxone's (nonsystemic) effect on opioid-induced constipation. As per relevant EMA guideline,4 the criteria for switching between noninferiority and superiority were met (lower boundary of the 97.5% RCI of the difference not including zero). As a result, the trial provided confirmatory evidence of superiority of TAP vs. OXN. We maintain that this trial taken together with other data available on TAP supports its favorable efficacy and tolerability profile.

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.

ObjectiveTo evaluate the effectiveness and tolerability of tapentadol prolonged release (PR) for severe, chronic low back pain with a neuropathic component in a subpopulation that achieved adequate pain relief with tapentadol PR 300mg/day in a randomized, double-blind, phase 3b study.MethodsPatients with painDETECT unclear or positive ratings and pain intensity 6 (11-point NRS-3 [average 3-day pain intensity]) were titrated to tapentadol PR 300mg/day over 3weeks. A subpopulation with pain intensity <4 continued receiving tapentadol PR 300mg/day during an 8-week, open-label continuation arm. For the primary study population, patients with 1-point decrease from baseline and pain intensity 4 were randomized to tapentadol PR 500mg/day or tapentadol PR 300mg/day plus pregabalin 300mg/day during a concurrent 8-week, double-blind comparative period.ResultsFrom baseline to end of titration and to final evaluation, significant improvements were observed in pain intensity (mean [SD] changes from baseline to: end of titration; -5.3 [1.78]; final evaluation; -5.2 [2.39]; both P<0.0001), neuropathic pain symptoms, and quality-of-life measures in the open-label continuation arm, with greater improvements in this selected subpopulation than in either group in the primary study population. A favorable tolerability profile was observed, with incidences of all individual treatment-emergent adverse events5.1% during the continuation period.ConclusionsA subpopulation of patients with low back pain with a neuropathic component responded very well to tapentadol PR 300mg/day, with significant improvements in pain intensity, neuropathic pain-related symptoms, and quality of life. Further research is needed to identify factors associated with a very positive treatment response.

PurposeChronic pain is often challenging to address appropriately. Although patients with severe chronic pain may respond to treatment with an opioid analgesic, opioids are often associated with adverse effects that may lead patients to disrupt or discontinue therapy. In addition, opioid analgesics alone may not be effective for all types of chronic pain, including neuropathic pain. Tapentadol prolonged release (PR), a centrally acting analgesic with 2 mechanisms of action (μ-opioid receptor agonism and noradrenaline reuptake inhibition), provides strong and reliable analgesia across a range of indications, including nociceptive, neuropathic, and mixed types of chronic pain, and is associated with an improved tolerability profile relative to classic opioid analgesics. The purpose of this article was to review the recent literature on different aspects related to the clinical use of tapentadol PR.MethodsA review was conducted of the current literature and relevant unpublished data on initiation and titration of tapentadol PR, switching from classic strong opioids, risk of withdrawal after discontinuation, long-term treatment, coadministration with other medications, and risk of abuse and diversion.FindingsTapentadol PR may provide clinically meaningful benefits over classic opioid analgesics, including ease of initiating and titrating tapentadol PR treatment in opioid-naive and opioid-experienced patients, low risk of withdrawal after cessation of tapentadol PR therapy, a favorable pharmacokinetic profile (allowing for coadministration with other medications) of tapentadol PR, and low potential for tapentadol PR abuse.ImplicationsThe broad analgesic efficacy of tapentadol PR may simplify chronic pain management by allowing for the treatment of different types of pain with a single analgesic. In addition, tapentadol is associated with a low risk of pharmacokinetic interactions, which permits its use in patients taking multiple medications. Furthermore, the favorable tolerability profile of tapentadol PR may result in improved patient compliance and allow for easy titration and rotation from previous strong opioids.

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. (C) 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Tapentadol prolonged release (PR; 100–250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment.

This open-label, phase 3b study evaluated the effectiveness and tolerability of oral tapentadol prolonged release (PR; 50–250 mg twice daily [b.i.d.]) for managing severe, chronic low back pain in patients responding to World Health Organization (WHO) step III opioids but tolerating treatment poorly. Equianalgesic ratios for tapentadol to prior strong opioids were calculated.

Objective:This open-label, phase 3b study evaluated the effectiveness and tolerability of tapentadol prolonged release and tapentadol immediate release (for acute pain episodes) for severe, chronic low back pain with or without a neuropathic pain component that was inadequately managed in patients taking World Health Organization (WHO) Step I or II analgesics or who were not regularly treated with analgesics.Research design and methods:Average baseline pain intensity was greater than 5 (11-point numerical rating scale-3 [NRS-3; 3-day average pain intensity]) with WHO Step I or II analgesics and greater than 6 with no regular analgesic regimen. WHO Step II analgesics were discontinued before starting study treatment; WHO Step I analgesics or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration and 7-week maintenance period. Tapentadol immediate release was permitted for acute pain episodes (tapentadol prolonged release and immediate release maximum combined dose, <= 500 mg/day). The painDETECT questionnaire was used to define subsets of patients based on the probability of a neuropathic pain component to their low back pain as 'negative', 'unclear', or 'positive'.Clinical trial registration: NCT00983385.Main outcome measure:The primary endpoint was the change from baseline to week 6 in average pain intensity (NRS-3), using the last observation carried forward to impute missing scores.Results:In the painDETECT negative (n = 49) and unclear/positive (n = 126) subsets, respectively, mean (SD) changes in pain intensity from baseline to week 6 were -2.4 (2.18) and -3.0 (2.07; both p<0.0001). Among patients who had not received prior WHO Step II treatment, lower doses of tapentadol prolonged release were generally required with increasing likelihood of a neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic Pain Symptom Inventory (NPSI), tapentadol prolonged release treatment was also associated with significant improvements in neuropathic pain symptoms, with decreases in the number of pain attacks and the duration of spontaneous pain in the last 24 hours in patients with low back pain with a neuropathic pain component (painDETECT unclear or positive score at baseline or screening). The most common treatment-emergent adverse events (incidence >= 10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea, nasopharyngitis, and somnolence.Conclusions:Tapentadol prolonged release was well tolerated and effective for managing severe, chronic low back pain with or without a neuropathic pain component.

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

This open-label, phase 3b study (ClinicalTrials.gov Identifier: NCT00983073) evaluated the effectiveness, and tolerability of tapentadol for severe, chronic osteoarthritis knee pain that was inadequately managed with World Health Organization (WHO) Step I or II analgesics or co-analgesics, or that was not treated with regular analgesics. Prior to starting study treatment, patients discontinued any WHO Step II analgesics, while Step I analgesics and/or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration period and a 7-week maintenance period. Doses of tapentadol immediate release 50 mg (≤twice/day; ≥4 hours apart) were permitted throughout the study (total daily dose of tapentadol prolonged and immediate release, ≤250 mg bid). The primary endpoint was the change in pain intensity on an 11-point numerical rating scale-3 (NRS-3; recalled average pain intensity [11-point NRS] during the last 3 days) from baseline to Week 6, using the last observation carried forward (LOCF) to impute missing pain intensity scores. The mean (standard deviation) change from baseline to Week 6 (LOCF) in pain intensity was -3.4 (2.10; P < 0.0001) for all patients evaluated for effectiveness (n = 195). Significant decreases in pain intensity were also observed at Weeks 6, 8, and 12 (all P < 0.0001) using observed-case analysis. Corresponding significant improvements from baseline to Weeks 6 and 12 were observed in the Western Ontario and McMaster Universities osteoarthritis index, the EuroQol-5 Dimension health status questionnaire, the Short Form-36 health survey, and the Hospital Anxiety and Depression Scale (all P ≤ 0.0103). Treatment-emergent adverse events were in line with those observed in previous studies of tapentadol prolonged release. Overall, the results of this study indicate that tapentadol treatment results in significant improvements in pain intensity, health-related quality of life, and function in patients with inadequately managed, severe, chronic osteoarthritis knee pain.