Responsiveness of Single versus Composite Measures of Pain in Knee Osteoarthritis

Objective In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. WOMAC pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use, and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. Method We used data from a completed trial of Tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at multiple time points, up to 16 weeks. Pain and rescue medication outcomes were standardised and combined into 3 composite outcomes via principal components analysis to produce one score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of Tanezumab into one ‘treatment’ group, for simplicity, and compared this to the control group (placebo). Results The composite outcomes showed modestly but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20- 40% less than trials using WOMAC pain alone Page 4 of 55 Page 4 of 23 Conclusion Combining information from related, but distinct, outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials and might offer a way to better detect treatment efficacy in OA trials

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

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 p = 0.0322), had less belief that medications were meeting effectiveness expectations (2.72 vs. 3.13, p 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

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

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124\u2008513 participants, 68\u2008342 person-years) and 474 trials of one NSAID versus another NSAID (229\u2008296 participants, 165\u2008456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1\ub737, 95% CI 1\ub714-1\ub766; p=0\ub70009) or diclofenac (1\ub741, 1\ub712-1\ub778; p=0\ub70036), chiefly due to an increase in major coronary events (coxibs 1\ub776, 1\ub731-2\ub737; p=0\ub70001; diclofenac 1\ub770, 1\ub719-2\ub741; p=0\ub70032). Ibuprofen also significantly increased major coronary events (2\ub722, 1\ub710-4\ub748; p=0\ub70253), but not major vascular events (1\ub744, 0\ub789-2\ub733). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0\ub793, 0\ub769-1\ub727). Vascular death was increased significantly by coxibs (1\ub758, 99% CI 1\ub700-2\ub749; p=0\ub70103) and diclofenac (1\ub765, 0\ub795-2\ub785, p=0\ub70187), non-significantly by ibuprofen (1\ub790, 0\ub756-6\ub741; p=0\ub717), but not by naproxen (1\ub708, 0\ub748-2\ub747, p=0\ub780). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1\ub781, 1\ub717-2\ub781, p=0\ub70070; diclofenac 1\ub789, 1\ub716-3\ub709, p=0\ub70106; ibuprofen 3\ub797, 2\ub722-7\ub710, p<0\ub70001; and naproxen 4\ub722, 2\ub771-6\ub756, p<0\ub70001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation