Use of patient-reported global assessment measures in clinical trials of chronic pain treatments: ACTTION systematic review and considerations.

ABSTRACT: Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fifty-two (54.2%) studies included a global assessment measure. The PGIC was most common (n = 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n = 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n = 9; 17.3%), satisfaction (n = 8; 15.4%), or overall health status/recovery (n = 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n = 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n = 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis.

BACKGROUND: To illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting. METHODS: Data from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI). RESULTS: ES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were - 0.416 (- 0.796, - 0.060), - 0.195 (- 0.371, - 0.028), and - 0.196 (- 0.373, - 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab. CONCLUSION: Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

Neuropsychology of chronic back pain managed with long-term opioid use.

Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits' dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.

Does sex affect the efficacy of systemic pharmacological treatments of pain in knee osteoarthritis? A systematic review.

Objective: To determine whether sex influences the analgesic efficacy of systemic pharmacological treatment in patients with knee osteoarthritis. Design: A systematic review, guided by Cochrane methods, sourced studies from Medline, Cochrane Library, Embase, and CINAHL Plus with Full Text as of October 10, 2022. Eligible studies were double-blind RCTs evaluating systemic pharmacological treatments for knee osteoarthritis in adults, with minimum 30-day treatment duration, reporting sex-specific results or mentioning sex subgroup analysis for analgesic efficacy. The risk of bias was assessed using the Cochrane Risk of Bias tool version 2 (RoB 2). Results: 9 studies (5201 participants) met inclusion criteria, analyzing drugs including duloxetine, etoricoxib, tapentadol, naproxcinod, lutikizumab, and rofecoxib. Only one study reported sex-specific results. Review findings suggested no significant sex-based differences in treatment efficacy, however, data were limited due to a lack of sex-specific reporting or inclusion of sex in subgroup analyses. Conclusions: Current evidence does not support the existence of sex differences in the analgesic efficacy of systemic knee osteoarthritis treatments. However, this conclusion is substantially limited by the paucity of sex-specific reporting of results or subgroup analyses in most primary studies, emphasizing the need for future research to report on sex-stratified data to allow for comprehensive, personalized treatment strategies.

Subcortical brain anatomy as a potential biomarker of persistent pain after total knee replacement in osteoarthritis.

ABSTRACT: The neural mechanisms for the persistence of pain after a technically successful arthroplasty in osteoarthritis (OA) remain minimally studied, and direct evidence of the brain as a predisposing factor for pain chronicity in this setting has not been investigated. We undertook this study as a first effort to identify presurgical brain and clinical markers of postarthroplasty pain in knee OA. Patients with knee OA (n = 81) awaiting total arthroplasty underwent clinical and psychological assessment and brain magnetic resonance imagining. Postoperative pain scores were measured at 6 months after surgery. Brain subcortical anatomic properties (volume and shape) and clinical indices were studied as determinants of postoperative pain. We show that presurgical subcortical volumes (bilateral amygdala, thalamus, and left hippocampus), together with shape deformations of the right anterior hippocampus and right amygdala, associate with pain persistence 6 months after surgery in OA. Longer pain duration, higher levels of presurgical anxiety, and the neuropathic character of pain were also prognostic of postsurgical pain outcome. Brain and clinical indices accounted for unique influences on postoperative pain. Our study demonstrates the presence of presurgical subcortical brain factors that relate to postsurgical persistence of OA pain. These preliminary results challenge the current dominant view that mechanisms of OA pain predominantly underlie local joint mechanisms, implying novel clinical management and treatment strategies.

Zoledronic acid after spinal cord injury mitigates losses in proximal femoral strength independent of ambulation ability.

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI. INTRODUCTION: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes. METHODS: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment. RESULTS: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength. CONCLUSION: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.

Bone Mineral Loss at the Distal Femur and Proximal Tibia Following Spinal Cord Injury in Men and Women.

PURPOSE: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI. METHODS: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI. RESULTS: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences. CONCLUSIONS: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men.

Opioids for Osteoarthritis: Cross-Sectional Survey of Patient Perspectives and Satisfaction.

Patients often take opioids to relieve osteoarthritis (OA) pain despite limited benefits and potential harms. This study aimed to compare cross-sectional perspectives of patients that were taking prescription opioid (N = 471) or nonopioid medications (N = 185) for OA in terms of satisfaction, expectations of effectiveness, and concerns. Patients prescribed opioids (>7 days) reported more prior treatments (2.47 vs. 1.74), greater mean pain intensity (5.47 vs. 4.11), and worse quality of life (EQ-5D-5L index value mean 0.45 vs. 0.71) than patients prescribed nonopioid medications (all p < 0.0001). Based on linear regression models adjusting for demographics and pain intensity, patients prescribed opioids were less satisfied with overall regimen (3.40 vs. 3.67, p = 0.0322), had less belief that medications were meeting effectiveness expectations (2.72 vs. 3.13, p < 0.0001), and had more concerns about treatments being "not very good" (3.66 vs. 3.22, p = 0.0026) and addiction (3.30 vs. 2.65, p < 0.0001) than patients prescribed nonopioid regimens. When the models were replicated for subgroups with ≥30 days' medication regimen duration, the findings were consistent with the main analyses. Patients have concerns about the risk of opioid addiction, but those with greater disease burden and more prior treatments continue taking opioid regimens.

Opioid Prescribing for Osteoarthritis: Cross-Sectional Survey among Primary Care Physicians, Rheumatologists, and Orthopaedic Surgeons.

Opioids are often prescribed for osteoarthritis (OA) pain, despite recommendations to limit use due to minimal benefits and associated harms. This study aimed to assess physicians' practice patterns and perceptions regarding opioids by specialty one year following the Centers for Disease Control and Prevention (CDC) published guidance on opioid prescribing. The 139/153 (90.8%) physicians who reported prescribing opioids in the previous year reported decreased prescribing for mild OA (51.3%, 26.5% and 33.3% of primary care physicians, rheumatologists, and orthopaedic surgeons, respectively), moderate OA (50.0%, 47.1% and 48.1%) and severe OA (43.6%, 41.2% and 44.4%). Prescribing changes were attributed to the CDC guidelines for 58.9% of primary care physicians, 59.1% of rheumatologists, and 73.3% of orthopaedic surgeons. Strong opioids were mostly reserved as third-line treatment. Although treatment effectiveness post-CDC guidelines was not assessed, perceptions of efficacy and quality of life with opioids significantly differed across specialties, whereas perceptions of safety, convenience/acceptability and costs did not. Physicians generally agreed on the barriers to opioid prescribing, with fear of addiction and drug abuse being the most important. Across specialties, physicians reported decreased opioid prescribing for OA, irrespective of OA severity, and in most cases attributed changes in prescribing to the CDC guideline.

A Two-Step, Trajectory-Focused, Analytics Approach to Attempt Prediction of Analgesic Response in Patients with Moderate-to-Severe Osteoarthritis.

INTRODUCTION: We sought to predict analgesic response to daily oral nonsteroidal anti-inflammatory drugs (NSAIDs) or subcutaneous tanezumab 2.5 mg (every 8 weeks) at week 16 in patients with moderate-to-severe osteoarthritis, based on initial treatment response over 8 weeks. METHODS: Data were derived from three randomized controlled trials of osteoarthritis. A two-step, trajectory-focused, analytics approach was used to predict patients as responders or non-responders at week 16. Step 1 identified patients using a data-element combination method (based on pain score at baseline, pain score at week 8, pain score monotonicity at week 8, pain score path length at week 8, and body site [knee or hip]). Patients who could not be identified in step 1 were predicted in step 2 using a k-nearest neighbor method based on pain score and pain response level at week 8. RESULTS: Our approach predicted response with high accuracy in NSAID-treated (83.2-90.2%, n = 931) and tanezumab-treated (84.6-91.0%, n = 1430) patients regardless of the efficacy measure used to assess pain, or the threshold used to define response (20%, 30%, or 50% improvement from baseline). Accuracy remained high using 50% or 20% response thresholds, with 50% and 20% yielding generally slightly better negative and positive predictive value, respectively, relative to 30%. Accuracy was slightly better in patients aged ≥ 65 years relative to younger patients across most efficacy measure/response threshold combinations. CONCLUSIONS: Analyzing initial 8-week analgesic responses using a two-step, trajectory-based approach can predict future response in patients with moderate-to-severe osteoarthritis treated with NSAIDs or 2.5 mg tanezumab. These findings demonstrate that prediction of treatment response based on a single dose of a novel therapeutic is possible and that predicting future outcomes based on initial response offers a way to potentially advance the approach to clinical management of patients with osteoarthritis. GOV IDENTIFIERS: NCT02528188, NCT02709486, NCT02697773.

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.

Characterizing 16-Week Responder Profiles Using Group-Based Trajectory Modeling in Over 4300 Clinical Trial Participants Receiving Pharmaceutical Treatment for Moderate to Severe Osteoarthritis.

INTRODUCTION: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo. METHODS: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression. RESULTS: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments. CONCLUSIONS: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188).

Factors associated with physician-reported treatment status of patients with osteoarthritis pain.

BACKGROUND: Osteoarthritis (OA) is typically associated with pain, but many patients are not treated. METHODS: This point in time study explored factors associated with treatment status, using logistic regression of data from the Adelphi OA Disease Specific Programme conducted in the United States. Patients' treatment status was based on physician-reported, current: 1) prescription medication for OA vs. none; and 2) physician treatment (prescription medication and/or recommendation for specified nonpharmacologic treatment for OA [physical or occupational therapy, acupuncture, transcutaneous electrical nerve stimulation, or cognitive behavior therapy/psychotherapy]) vs. self-management (no prescription medication or specified nonpharmacologic treatment). RESULTS: The 841 patients (including 57.0% knee OA, 31.9% hip OA) reported mild (45.4%) or moderate or severe (54.6%) average pain intensity over the last week. The majority were prescribed medication and/or recommended specified nonpharmacologic treatment; 218 were not prescription-medicated and 122 were self-managed. Bivariate analyses showed less severe patient-reported pain intensity and physician-rated OA severity, fewer joints affected by OA, lower proportion of joints affected by knee OA, better health status, lower body mass index, and lower ratings for cardiovascular and gastrointestinal risks, for those not prescribed medication (vs. prescription-medicated). Multivariate analyses confirmed factors significantly (p < 0.05) associated with prescription medication included (odds ratio): physician-rated current moderate OA severity (vs. mild, 2.03), patient-reported moderate OA severity 6 months ago (vs. mild, 1.71), knee OA (vs. not, 1.81), physician-recommended (0.28) and patient-reported (0.43) over-the-counter medication use (vs. not), prior surgery for OA (vs. not, 0.37); uncertain income was also significant. Factors significantly (p < 0.05) associated with physician treatment included (odds ratio): physician-recommended nonpharmacologic therapy requiring no/minimal medical supervision (vs. not, 2.21), physician-rated current moderate OA severity (vs. mild, 2.04), patient-reported over-the-counter medication use (vs. not, 0.26); uncertain time since diagnosis was also significant. Patient-reported pain intensity and most demographic factors were not significant in either model. CONCLUSIONS: Approximately 1 in 4 patients were not prescribed medication and 1 in 7 were self-managed, although many were using over-the-counter medications or nonpharmacologic therapies requiring no/minimal medical supervision. Multiple factors were significantly associated with treatment status, including OA severity and over-the-counter medication, but not pain intensity or most demographics.

WOMAC Meaningful Within-patient Change: Results From 3 Studies of Tanezumab in Patients With Moderate-to-severe Osteoarthritis of the Hip or Knee.

OBJECTIVE: To define meaningful within-patient change (MWPC) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). METHODS: Data were analyzed separately from 3 phase III clinical trials (ClinicalTrials.gov: NCT02697773, NCT02709486, NCT02528188) of tanezumab, a novel treatment intended for the relief of signs and symptoms of moderate-to-severe osteoarthritis (OA), administered subcutaneously every 8 weeks. Patients with moderate-to-severe OA of the hip or knee completed the WOMAC and patient global assessment of OA (PGA-OA) at regular timepoints. A repeated measures longitudinal model with change in WOMAC Pain, Physical Function, or Stiffness domain score as the outcome and change in PGA-OA as the anchor was used to establish MWPC for WOMAC domains. RESULTS: In the 3 studies, there were 688, 844, and 2948 subjects available for analyses, respectively. Analysis showed that a linear relationship between changes in WOMAC domains and changes in PGA-OA was supported and justified. Moreover, the relationships between these changes were very similar for 2 trials and close for the third. The estimated MWPC for the 3 WOMAC domains were from 0.84-1.16 (0-10 numerical rating scale) and from 12.50-16.23%, depending on study and domain, that corresponded to a 1-category change on PGA-OA. For a 2-category change those values were from 1.68-2.31 and from 25.01-32.46%, respectively. CONCLUSION: These results establish MWPCs for WOMAC domains, at the individual patient level, for patients with moderate-to-severe OA of the hip or knee. [ClinicalTrials.gov: NCT02697773, NCT02709486, and NCT02528188].

Satisfaction with Medications Prescribed for Osteoarthritis: A Cross-Sectional Survey of Patients and Their Physicians in the United States.

INTRODUCTION: Satisfaction with medications prescribed for osteoarthritis (OA) varies; this study aimed to determine the factors associated with satisfaction in US patients and their physicians. METHODS: This point-in-time study used the Adelphi OA Disease Specific Programme (physicians identified from public lists reported on nine consecutive patients diagnosed with OA [any joint]: physicians and patients completed questionnaires). Patient's demographic, clinical, and treatment characteristics associated with patient-reported and physician-rated overall satisfaction with, and expectations of effectiveness of, medication for OA were assessed using multivariate linear regression. RESULTS: Responses from 572 patients (mean age 64.9 years, 60.5% female) currently prescribed medication for OA and 153 physicians (81 primary care, 35 rheumatologists, 37 orthopedic surgeons) were analyzed. Pain intensity was moderate or severe for 59.4% of patients. Greater patient-reported overall satisfaction with medication was significantly associated with (standardized beta, 95% confidence interval) exercise (0.12, 0.03-0.20), comorbid other musculoskeletal or painful conditions (vs none) (0.15, 0.06-0.24), and physicians' report that the best control had been achieved (0.12, 0.03-0.20); lack of efficacy was among factors associated with worse satisfaction. Greater patient-reported expectation of effectiveness was significantly associated with exercise (0.12, 0.03-0.21) and the most troublesome joint not being a knee, hip, or their back (0.08, 0.01-0.14). Greater physician-rated overall satisfaction with medication was significantly associated with their report that the best control had been achieved (0.18, 0.11-0.26), the most troublesome joint being a knee (0.08, 0.01-0.14), comorbid other musculoskeletal or painful conditions (0.07, 0.01-0.12), obesity (0.06, 0.00-0.11), and female patients (0.06, 0.00-0.11); lack of efficacy and adverse events/tolerability issues were among factors associated with worse satisfaction. For physicians, their report that the best control had been achieved (0.19, 0.11-0.27), the most troublesome joint being a knee (0.08, 0.00-0.15), improving (vs stable) OA (0.15, 0.07-0.24), and uncertain duration of OA (0.11, 0.02-0.21) were associated with greater perception that the medication was meeting patients' efficacy expectations. CONCLUSION: Although efficacy was strongly associated with both patients' and physicians' satisfaction with medication, other factors were also important, including exercise (for patients), tolerability (for physicians), and knee OA (for physicians).

General Safety and Tolerability of Subcutaneous Tanezumab for Osteoarthritis: A Pooled Analysis of Three Randomized, Placebo-Controlled Trials.

OBJECTIVE: This pooled analysis of 3 randomized, placebo-controlled trials (16-24 week treatment and 8-24 week follow-up) assessed safety of subcutaneous tanezumab (2.5-10 mg every 8 weeks) in 1,840 patients with hip or knee osteoarthritis. METHODS: Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation (APS) were prospectively assessed in 3 trials. Joint safety events (primary osteonecrosis, rapidly progressive osteoarthritis [RPOA], subchondral insufficiency fracture, and pathologic fracture; adjudicated by an independent expert committee) and TEAEs potentially associated with sympathetic neuropathy were prospectively assessed in 2 trials. RESULTS: During the treatment period, overall TEAE rates were 51.7% for placebo and 39.5-54.8% for tanezumab 2.5-10 mg; treatment discontinuation rates were 2.0% for placebo and 0-1.3% for tanezumab. Rates of composite joint safety events (predominantly RPOA type 1) over the treatment plus follow-up period were 0% for placebo and 0.5-3.2% for tanezumab 2.5-5 mg (5 mg was statistically greater than placebo); total joint replacement rates with tanezumab (5.9-7.0%) were not significantly different from placebo (4.5%). Rates of TEAEs of APS (predominantly paresthesia and hypoesthesia) were 2.2% for placebo and 3.2-12.8% for tanezumab 2.5-10 mg. Rates of TEAEs potentially associated with sympathetic neuropathy (predominantly bradycardia and orthostatic hypotension) were 0.8% for placebo and 0.5-2.8% for tanezumab 2.5-5 mg (exposure-adjusted rates were not significantly different from placebo). CONCLUSION: Tanezumab was generally well tolerated. TEAEs of APS (mostly mild and transient) and joint safety events were infrequent but more common with tanezumab than placebo. A tanezumab dose of 2.5 mg demonstrated a more favorable safety profile than higher doses.

Validating a biosignature-predicting placebo pill response in chronic pain in the settings of a randomized controlled trial.

ABSTRACT: The objective of this study is to validate a placebo pill response predictive model-a biosignature-that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders (predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts-CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.

Single and Composite Endpoints of Within-Patient Improvement in Symptoms: Pooled Tanezumab Data in Patients with Osteoarthritis.

INTRODUCTION: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. METHODS: Endpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders. RESULTS: Pooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints. CONCLUSION: Responders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BACKGROUND: Preventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent. METHODS: A total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months. RESULTS: Both treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration. CONCLUSIONS: These results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.