Multimethod quantitative benefit-risk assessment of treatments for moderate-to-severe osteoarthritis.

OBJECTIVE: Demonstrate how benefit-risk profiles of systemic treatments for moderate-to-severe osteoarthritis (OA) can be compared using a quantitative approach accounting for patient preference. STUDY DESIGN AND SETTING: This study used a multimethod benefit-risk modelling approach to quantifiably compare treatments of moderate-to-severe OA. In total four treatments and placebo were compared. Comparisons were based on four attributes identified as most important to patients. Patient Global Assessment of Osteoarthritis was included as a favourable effect. Unfavourable effects, or risks, included opioid dependence, nonfatal myocardial infarction and rapidly progressive OA leading to total joint replacement. Clinical data from randomized clinical trials, a meta-analysis of opioid dependence and a long-term study of celecoxib were mapped into value functions and weighted with patient preferences from a discrete choice experiment. RESULTS: Lower-dose NGFi had the highest weighted net benefit-risk score (0.901), followed by higher-dose NGFi (0.889) and NSAIDs (0.852), and the lowest score was for opioids (0.762). Lower-dose NGFi was the highest-ranked treatment option even when assuming a low incidence (0.34% instead of 4.7%) of opioid dependence (ie, opioid benefit-risk score 808) and accounting for both the uncertainty in clinical effect estimates (first rank probability 46% vs 20% for NSAIDs) and imprecision in patient preference estimates (predicted choice probability 0.26, 95% confidence interval [CI] 0.25-0.28 vs 0.21, 95% CI 0.19-0.23 for NSAIDs). CONCLUSION: The multimethod approach to quantitative benefit-risk modelling allowed the interpretation of clinical data from the patient perspective while accounting for uncertainties in the clinical effect estimates and imprecision in patient preferences.

Predicting Treatment Response with Sensory Phenotyping in Post-Traumatic Neuropathic Pain.

OBJECTIVE: Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and work for only some patients in the clinic. Induced-pain or gain-of-function phenotypes have been shown to predict response to analgesics (vs placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. METHODS: Mixed-effects models for repeated measures were used to evaluate the efficacy of pregabalin vs placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) in data from a recent, multinational randomized clinical trial (N = 539) that identified phenotypic subgroups through the use of a structured clinical exam. RESULTS: The difference in mean pain score between the active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (P = 0.001), compared with 0.19 (P = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (P = 0.0067). The delta for the subgroup with allodynia was -0.31 (P = 0.22), compared with -0.30 (P = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction P = 0.98). CONCLUSIONS: These data suggest that hyperalgesia, but not allodynia, predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics in post-traumatic neuropathic pain. Sensory phenotyping in large, multisite trials through the use of a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.

Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS).

OBJECTIVE: To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP). DESIGN: Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181). SETTING: Multicenter, long-term clinical research study. METHODS: NKTR-181 administered at doses of 100-600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF). RESULTS: The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events. CONCLUSIONS: The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP.

Anatomical Study of Percutaneous Trigeminal Compressive Balloon Positioning on Merged 3-D Rotational X-Ray and Preprocedural Magnetic Resonance Imaging.

BACKGROUND: Percutaneous trigeminal rhizotomy or balloon compression for trigeminal neuralgia carries a potential risk for the brainstem, the carotid artery, and the basilar artery. OBJECTIVE: To detail the relation of critical neural and vascular structures to expanded balloons used for percutaneous compression of the trigeminal ganglion. METHOD: A retrospective analysis of preprocedural magnetic resonance imaging (MRI) and procedural X-ray-based imaging for 9 patients detailed balloon proximity to the brainstem, carotid artery, and basilar artery. RESULTS: Balloons extended 10.96 ± 5.54 mm (mean ± SD) posterior to the clival line. The average distance from the balloon to the brainstem was 6.89 mm, and that to the basilar artery was 12.12 mm (range: 0-18.2). The medial edge of the balloon was an average distance of 1.39 mm from the baseline position of the carotid lumen. CONCLUSION: Preprocedural MRI, merged with 3-D rotational angiography suite imaging, detailed the proximity of the balloon to critical neural and vascular structures. Our study found that the standard technique for percutaneous trigeminal compression, with balloon placement at an average depth of 10.96 mm posterior to the clival line, on average, provided an additional 6.89 mm of space before the brainstem would have been encountered, demonstrating safe positioning.

Using Random Forest Models to Identify Correlates of a Diabetic Peripheral Neuropathy Diagnosis from Electronic Health Record Data.

Objective: To identify variables correlated with a diagnosis of diabetic peripheral neuropathy (DPN) using random forest modeling applied to electronic health records. Design: Retrospective analysis. Setting: Humedica de-identified electronic health records database. Subjects: Subjects ≥ 18 years old with type 2 diabetes from January 1, 2008-September 30, 2013 having continuous data for 1 year pre- and postindex with DPN (n = 35,050) and without DPN (n = 288,328) were identified. Methods: Demographic, clinical, and health care resource utilization variables (e.g., inpatient and outpatient encounters, medications, and procedures) were input into a random forest model to identify the most important correlates of a DPN diagnosis. Random forest modeling is a computationally extensive, robust data mining technique that accommodates large sets of variables to identify associated factors using an ensemble of classifications trees. Accuracy of the model was evaluated using receiver operating characteristic curves (ROC). Results: The final random forest model consisted of the following variables (importance) associated with a DPN diagnosis: Charlson Comorbidity Index score (100%), age (37.1%), number of pre-index procedures and services (29.7%), number of pre-index outpatient prescriptions (24.2%), number of pre-index outpatient visits (18.3%), number of pre-index laboratory visits (16.9%), number of pre-index outpatient office visits (12.1%), number of inpatient prescriptions (5.9%), and number of pain-related medication prescriptions (4.4%). ROC analysis confirmed model performance, with an area under the curve of 0.824 and accuracy of 89.6% (95% confidence interval 89.4%, 89.8%). Conclusions: Random forest modeling can determine likelihood of a DPN diagnosis. Further validation of the random forest model may help facilitate earlier diagnosis and enhance management strategies.

Effects of Pregabalin in Patients with Neuropathic Pain Previously Treated with Gabapentin: A Pooled Analysis of Parallel-Group, Randomized, Placebo-controlled Clinical Trials.

OBJECTIVES: This analysis compared the therapeutic response of pregabalin in patients with neuropathic pain (NeP) who had been previously treated with gabapentin to the therapeutic response in patients who had not received gabapentin previously. METHODS: Data were pooled from 18 randomized, double-blind, placebo-controlled trials of pregabalin in patients with NeP. Pregabalin-mediated changes in pain and pain-related sleep interference scores, patient global impression of change scores at endpoint, and the occurrence of adverse events were compared between patients who had received gabapentin previously (+GBN) and patients who had not received gabapentin previously (-GBN). RESULTS: There were no significant differences between the -GBN and +GBN cohorts with regard to the extent of pain relief and relief of pain-related sleep interference for any dose of pregabalin (150, 300, 600, or 150 to 600 mg/day) at any time point (6, 8, or 12 weeks). Additionally, there was no significant difference in the distribution of patient global impression of change scores at study endpoint, or the occurrence of adverse events, between the -GBN and +GBN cohorts. DISCUSSION: The findings presented here support the idea that pregabalin may be used successfully to treat patients with NeP who may be refractory, respond inadequately, or are intolerant to gabapentin. These findings highlight the importance of tailoring treatment of NeP based on individual patient response to different treatments, including the trial of multiple agents within the same mechanistic class.

Screening for neuropathic characteristics in failed back surgery syndromes: challenges for guiding treatment.

OBJECTIVE: Neuropathic pain screening tools have shown promise in identifying common neuropathic pain characteristics that derive from diverse etiologies (e.g., diabetic peripheral neuropathy, postherpetic neuralgia). However, no prior studies have specifically assessed whether these tools are capable of discerning the underlying pain mechanisms in the vast, heterogeneous group of patients diagnosed with failed back surgery syndrome (FBSS). DESIGN: In this clinical observational study, two tests for neuropathic pain characteristics, the Douleur Neuropathique en 4 (DN4) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaires, were performed on 43 subjects with FBSS. Subjects underwent physical or neurosensory exam components of the DN4 and LANSS in the region of most severe pain (e.g., axial low back or lower extremities). DN4 and LANSS scores were correlated with clinical history and neurologic exam, pain-related quality of life questionnaires, and compared to an independent assessment of pain distribution. RESULTS: The presence of neuropathic characteristics, determined by the DN4 (62% sensitivity, 44% specificity), LANSS (38% sensitivity, 75% specificity; cut-offs of 4 and 12, respectively), or their combination (20% sensitivity, 58% specificity) was associated with higher pain intensity as measured by the visual analog scale (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.042), modified Brief Pain Inventory-Short Form (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.082), and Neuropathic Pain Symptom Inventory (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.001), and greater pain-related functional impairment as measured by the Roland-Morris Disability Questionnaire (DN4 > 4, P = 0.006; LANSS ≥ 12, P = 0.018). The percentage of subjects characterized as neuropathic by the DN4 and LANSS lacked concordance (67.4 vs. 25.6), and the distribution of most severe symptoms (i.e., axial vs radicular) did not correlate with subjects determined to have neuropathic pain. CONCLUSIONS: Unlike other neuropathic syndromes, the neuropathic component of FBSS is less reliably identified by the LANSS and DN4.

Interpretation of urine drug testing results in patients using transdermal buprenorphine preparations for the treatment of chronic noncancer pain.

OBJECTIVE: To determine whether the prevailing liquid chromatography and tandem mass spectroscopy assay (LC-MS/MS) assay designed to monitor buprenorphine compliance of the sublingual formulation used in the substance abuse treatment setting can be extrapolated to the transdermal formulation used in the chronic pain treatment setting, which is 1000-fold less concentrated. DESIGN: Retrospective chart review. SUBJECTS: Self-reported compliant patients using the transdermal or sublingual formulations of buprenorhphine. Transdermal patch application was also visually confirmed during clinic visits. METHODS: Urine drug test results from a LC-MS/MS were compared between samples from transdermal and sublingual patients. RESULTS: While all sublingual patients tested positive for at least one metabolite of buprenorphine, only 69% of the transdermal patients did so. In addition, the most abundant metabolite in the transdermal patients was buprenorphine-glucuronide, as compared with norbuprenorphine-glucuronide in sublingual patients. CONCLUSIONS: These data suggest that currently available urine drug tests for buprenorphine, including the more expensive LC-MS/MS based assays, may not be sufficiently sensitive to detect the metabolites from transdermal buprenorphine patients. This study highlights the need to evaluate the value and sensitivity of urine drug tests given the wide range of buprenorphine dosing in clinical practice. These results underscore the need for additional cost benefit analyses comparing different confirmatory drug testing techniques including many commercially available drug testing options. © 2014 Wiley Periodicals, Inc.

Trigeminal trophic syndrome with histopathologic correlation.

We present the case of a 49-year-old woman with trigeminal trophic syndrome (TTS), also known as trophic trigeminal neuralgia, trigeminal neurotrophic ulceration, and/or trigeminal neuropathy with nasal ulceration. Our case represents an uncommon report of intractable itching and chronic pain associated with TTS. Emphasis was placed on skin biopsy histology, which revealed no neuronal innervation of the affected scalp despite reports of intractable itching and chronic pain. Trigeminal trophic syndrome of the V1 branch of the trigeminal nerve secondary to herpes zoster (HZ) with correlated histology is described. This article provides a discussion of TTS and correlated histology as well as a brief discussion of intractable itching and postherpetic neuralgia.

Medical management of chronic low back pain: efficacy and outcomes.

OBJECTIVES: Chronic low back pain (CLBP) is common and contributes to significant disability and healthcare costs. The mechanism and etiology of CLBP are frequently unclear, and treatment choices vary. MATERIALS AND METHODS: The scientific literature, including expert-generated treatment guidelines, was reviewed and evaluated for data regarding CLBP prevalence and predictors and for evidence of outcomes from pharmacologic and nonpharmacologic therapies. RESULTS: Evidence is inconclusive as to superior treatments for CLBP. Even therapies with literature support, including cognitive-behavioral therapy, nonsteroidal anti-inflammatory drugs, and opioids administered short term, do not work for every patient, and combination therapies are frequently beneficial. Early intervention with acute pain may stop the progression to chronicity in predisposed patients; however, much acute back pain resolves spontaneously. Predictors of chronicity include continuing poor function, unwillingness to remain active, psychiatric comorbidities, general poor health, and maladaptive coping strategies. Indefinite diagnoses and genetic vulnerabilities are likely factors in variable patient outcomes. CONCLUSIONS: Personalized treatment plans should be informed by response to therapies previously tried, the severity and persistence of symptoms, and the availability of specialist expertise.

Patient engagement in designing, conducting, and disseminating clinical pain research: IMMPACT recommended considerations.

ABSTRACT: In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.

Real-world data and evidence in pain research: a qualitative systematic review of methods in current practice.

The use of routinely collected health data (real-world data, RWD) to generate real-world evidence (RWE) for research purposes is a growing field. Computerized search methods, large electronic databases, and the development of novel statistical methods allow for valid analysis of data outside its primary clinical purpose. Here, we systematically reviewed the methodology used for RWE studies in pain research. We searched 3 databases (PubMed, EMBASE, and Web of Science) for studies using retrospective data sources comparing multiple groups or treatments. The protocol was registered under the DOI:10.17605/OSF.IO/KGVRM. A total of 65 studies were included. Of those, only 4 compared pharmacological interventions, whereas 49 investigated differences in surgical procedures, with the remaining studying alternative or psychological interventions or epidemiological factors. Most 39 studies reported significant results in their primary comparison, and an additional 12 reported comparable effectiveness. Fifty-eight studies used propensity scores to account for group differences, 38 of them using 1:1 case:control matching. Only 17 of 65 studies provided sensitivity analyses to show robustness of their findings, and only 4 studies provided links to publicly accessible protocols. RWE is a relevant construct that can provide evidence complementary to randomized controlled trials (RCTs), especially in scenarios where RCTs are difficult to conduct. The high proportion of studies reporting significant differences between groups or comparable effectiveness could imply a relevant degree of publication bias. RWD provides a potentially important resource to expand high-quality evidence beyond clinical trials, but rigorous quality standards need to be set to maximize the validity of RWE studies.

Examining the Relationships Among Treatment, Pain, and Physical Function in Patients With Osteoarthritis: A Mediation-Modeling Approach.

OBJECTIVES: To better understand the relationships among treatment, pain, and physical function (PF). METHODS: Data were collected from 2 published randomized clinical trials of osteoarthritis patients who received tanezumab or a placebo. PF was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) PF domain. Pain (WOMAC pain domain) was a mediator of the effect of treatment on PF. A set of mediation models were investigated. Variables were treatment (tanezumab vs placebo), WOMAC pain domain, and WOMAC PF domain. Cross-sectional mediation models were assessed separately at different weeks. Longitudinal mediation models used data from all weeks simultaneously. Results could identify a steady-state period. RESULTS: The cross-sectional and longitudinal mediation models showed a stable indirect effect of treatment through the pain on PF across time, indicating that a pseudo-steady-state model was appropriate. Therefore, the longitudinal steady-state mediation models were used with all available data assuming relationships among variables in the model being the same at all time points; results showed that the indirect effect of the treatment on PF was 77.8% in study 1 (NCT02697773) and 74.1% in study 2 (NCT02709486), both P <0.0001, whereas the direct effect was 22.2% for study 1 ( P = 0.0003) and 25.9% for study 2 ( P = 0.0019). DISCUSSION: At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%) that, was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms.

Recommendations for terminology and the identification of neuropathic pain in people with spine-related leg pain. Outcomes from the NeuPSIG working group.

ABSTRACT: Pain radiating from the spine into the leg is commonly referred to as "sciatica," "Sciatica" may include various conditions such as radicular pain or painful radiculopathy. It may be associated with significant consequences for the person living with the condition, imposing a reduced quality of life and substantial direct and indirect costs. The main challenges associated with a diagnosis of "sciatica" include those related to the inconsistent use of terminology for the diagnostic labels and the identification of neuropathic pain. These challenges hinder collective clinical and scientific understanding regarding these conditions. In this position paper, we describe the outcome of a working group commissioned by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) which was tasked with the following objectives: (1) to revise the use of terminology for classifying spine-related leg pain and (2) to propose a way forward on the identification of neuropathic pain in the context of spine-related leg pain. The panel recommended discouraging the term "sciatica" for use in clinical practice and research without further specification of what it entails. The term "spine-related leg pain" is proposed as an umbrella term to include the case definitions of somatic referred pain and radicular pain with and without radiculopathy. The panel proposed an adaptation of the neuropathic pain grading system in the context of spine-related leg pain to facilitate the identification of neuropathic pain and initiation of specific management in this patient population.

Evaluating the balance of benefits and harms in chronic pain clinical trials: prioritizing individual participants over individual outcomes.

BACKGROUND: Randomized clinical trials (RCTs) generally assess efficacy and safety separately, with the conclusion of whether a treatment is beneficial based solely on the efficacy endpoint. However, assessing and combining efficacy and safety domains, using a single composite outcome measure, can provide a more comprehensive assessment of the overall effect of a treatment. Furthermore, composite outcomes can incorporate information regarding the relationship between the individual outcomes. In fact, such outcomes have been suggested in the clinical trials literature for at least 15 years. OBJECTIVES: To (1) identify whether recent primary publications of chronic pain RCTs from major pain journals included a composite outcome measure of benefits and harms and (2) discuss the potential benefits of such outcomes in various stages of treatment development, including as outcome measures in RCTs, and to support decisions of Data and Safety Monitoring Boards and ordering of treatments in the context of treatment guidelines. EVIDENCE REVIEW: RCTs published in 6 major pain journals published between 2016 and 2021 that investigated interventions for chronic pain were reviewed. FINDINGS: Of 73 RCTs identified, only 2 included a composite outcome measure of benefits and harms. Both of these articles compared 2 active treatments. CONCLUSIONS: Composite outcomes of benefits and harms are underutilized in chronic pain RCTs. The advantages and challenges of using such outcomes are discussed.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement.

ABSTRACT: Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Tanezumab for chronic low back pain: a long-term, randomized, celecoxib-controlled Japanese Phase III safety study.

Aim & methods: This trial investigated long-term (56-week treatment/24-week follow-up) use of subcutaneous tanezumab (5 or 10 mg every 8 weeks) or oral celecoxib (200 mg/day) in Japanese patients with chronic low back pain. Results & conclusion: Tanezumab safety was consistent with previous studies, except overall adverse events (tanezumab 5 mg = 63.0%, tanezumab 10 mg = 54.8%, celecoxib = 67.4%) and events of abnormal peripheral sensation (tanezumab 5 mg = 9.8%, tanezumab 10 mg = 4.3%, celecoxib = 4.3%) were more frequent with 5 mg than 10 mg tanezumab. Joint safety event rates were 1.1% for tanezumab 5 mg, 2.2% for tanezumab 10 mg and 0% for celecoxib. All treatments improved pain and function throughout the treatment period. Clinical trial registration number: NCT02725411.

In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

ABSTRACT: 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.