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.

Meaningful within-patient change for clinical outcome assessments: model-based approach versus cumulative distribution functions.

OBJECTIVES: The FDA recommends the use of anchor-based methods and empirical cumulative distribution function (eCDF) curves to establish a meaningful within-patient change (MWPC) for a clinical outcome assessment (COA). In practice, the estimates obtained from model-based methods and eCDF curves may not closely align, although an anchor is used with both. To help interpret their results, we investigated and compared these approaches. METHODS: Both repeated measures model (RMM) and eCDF approaches were used to estimate an MWPC on a target COA. We used both real-life (ClinicalTrials.gov: NCT02697773) and simulated data sets that included 688 patients with up to six visits per patient, target COA (range 0 to 10), and an anchor measure on patient global assessment of osteoarthritis from 1 (very good) to 5 (very poor). Ninety-five percent confidence intervals for the MWPC were calculated by the bootstrap method. RESULTS: The distribution of the COA score changes affected the degree of concordance between RMM and eCDF estimates. The COA score changes from simulated normally distributed data led to greater concordance between the two approaches than did COA score changes from the actual clinical data. The confidence intervals of MWPC estimate based on eCDF methods were much wider than that by RMM methods, and the point estimate of eCDF methods varied noticeably across visits. CONCLUSIONS: Our data explored the differences of model-based methods over eCDF approaches, finding that the former integrates more information across a diverse range of COA and anchor scores and provides more precise estimates for the MWPC.

Impact of Electronic Chronic Pain Questions on patient-reported outcomes and healthcare utilization, and attitudes toward eCPQ use among patients and physicians: prospective pragmatic study in a US general practice setting.

Objective: The Electronic Chronic Pain Questions (eCPQ) has been developed to help healthcare providers systematically capture chronic pain data. This study evaluated the impact of using the eCPQ on patient-reported outcomes (PROs) and healthcare resource utilization (HCRU) in a primary care setting, and patient and physician perceptions regarding use of, and satisfaction with, the eCPQ. Methods: This was a prospective pragmatic study conducted at the Internal Medicine clinic within the Henry Ford Health (HFH) Detroit campus between June 2017 and April 2020. Patients (aged ≥18 years) attending the clinic for chronic pain were allocated to an Intervention Group to complete the eCPQ in addition to regular care, or a control group to receive regular care only. The Patient Health Questionnaire-2 and a Patient Global Assessment were assessed at baseline, 6-months, and 12-months study visits. HCRU data were extracted from the HFH database. Telephone qualitative interviews were conducted with randomly selected patients and physicians who used the eCPQ. Results: Two hundred patients were enrolled, 79 in each treatment group completed all 3 study visits. No significant differences (p > 0.05) were found in PROs and HCRU between the 2 groups. In qualitative interviews, physicians and patients reported the eCPQ as useful, and using the eCPQ improved patient-clinician interactions. Conclusion: Adding the eCPQ to regular care for patients with chronic pain did not significantly impact the PROs assessed in this study. However, qualitative interviews suggested that the eCPQ was a well-accepted and potentially useful tool from a patient and physician perspective. By using the eCPQ, patients were better prepared when they attended a primary care visit for their chronic pain and the quality of patient-physician communication was increased.

Quantifying The Burden of Persistent Musculoskeletal Pain in Employees at Rolls-Royce in The United Kingdom: A Real-World Cross-Sectional Survey.

OBJECTIVE: We aimed to investigate the burden of persistent musculoskeletal (MSK) pain in Rolls-Royce UK employees. METHODS: Employees with ( n = 298) and without ( n = 329) persistent MSK pain completed a cross-sectional survey. Weighted regression analyses were conducted to compare sickness absence, work ability, workplace accommodations/adaptations, and emotional well-being between these cohorts, controlling for confounders. RESULTS: Persistent MSK pain (particularly back pain) had a significant impact on physical work ability and was associated with increased sickness absence due to pain. Many employees (56%) had not disclosed their condition to their managers. Of these, 30% felt uncomfortable doing so, and 19% of employees reported insufficient support at work for their pain. CONCLUSIONS: These findings highlight the importance of creating a workplace culture that encourages the disclosure of work-relevant pain, enabling organizations to consider improved, tailored support for employees.

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.

An Observational Retrospective Matched Cohort Study of Healthcare Resource Utilisation and Costs in UK Patients with Moderate to Severe Osteoarthritis Pain.

INTRODUCTION: Using data from patients residing in Salford, UK, we aimed to compare healthcare resource utilisation (HCRU) and direct healthcare costs between patients with moderate to severe (M-S) or severe osteoarthritis (OA) pain and those without OA. METHODS: Patients with a M-S OA pain event within a period of chronic pain were indexed from the Salford Integrated Record (SIR) between 2010 and 2017. Patients with a severe pain event formed an OA subcohort. Patients in each OA pain cohort were independently matched to patients without OA, forming two control cohorts. HCRU, prescribed analgesic drugs, and total direct costs per UK standardised tariffs were calculated for the year post-index. Multivariable models were used to identify drivers of healthcare cost. RESULTS: The M-S OA pain and control cohorts each comprised 3123 patients; the severe OA pain and control cohorts each comprised 1922 patients. Patients in both OA pain cohorts had a significantly higher mean number of general practitioner encounters, inpatient, outpatient, and accident and emergency visits, and were prescribed a broader range of analgesic drugs in the year post-index than respective controls. Mean healthcare costs of all types were significantly higher in the M-S and severe OA pain cohorts vs controls (total: M-S £2519 vs £1379; severe £3389 vs £1397). Paracetamol (M-S: 40% of patients had at least one prescription; severe: 50%) and strong opioids (34% and 59%) were the analgesics most prescribed to patients with OA pain. In all cohorts, multivariable models showed that a higher age at index, the presence of gout, osteoporosis, type 2 diabetes, or coronary artery disease, significantly contributed towards higher healthcare costs. CONCLUSION: In the population of Salford, UK, patients with M-S OA pain had significantly higher annual HCRU and costs compared with matched controls without OA; generally, these were even higher in patients with severe OA pain.

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].

Impact of tanezumab on health status, non-work activities and work productivity in adults with moderate-to-severe osteoarthritis.

BACKGROUND: To evaluate the impact of tanezumab on health status, non-work activities, and work productivity in a pooled analysis of two large phase 3 osteoarthritis (OA) studies. METHODS: Subcutaneous tanezumab (2.5 mg and 5 mg) was tested in double-blind, placebo-controlled, 16-week (NCT02697773) and 24-week (NCT02709486) clinical trials in patients with moderate-to-severe OA of the hip or knee. At baseline and week 16, all patients completed EQ-5D-5L and the Work Productivity and Activity Impairment-OA (WPAI-OA) activity impairment item. Those currently employed also completed WPAI-OA work time missed, impairment while working, and overall work impairment items. Between-group differences in least squares (LS) mean changes from baseline at week 16 were tested using analysis of covariance. RESULTS: Of 1545 pooled patients, 576 were employed at baseline. Improvements in EQ-5D-5L index value at week 16 were significantly greater for the tanezumab 2.5-mg group (difference in LS means [95% confidence interval (CI), 0.03 [0.01, 0.05]; p = 0.0083) versus placebo. Percent improvements (95% CI) in activity impairment (- 5.92 [- 8.87, - 2.98]; p < 0.0001), impairment while working (- 7.34 [- 13.01, - 1.68]; p = 0.0112), and overall work impairment (- 7.44 [- 13.22, - 1.67]; p = 0.0116) at week 16 were significantly greater for the tanezumab 2.5-mg group versus placebo. Results for the tanezumab 5-mg group were generally comparable to the tanezumab 2.5-mg group, although, compared with placebo, percent improvement (95% CI) in work time missed was significantly greater for the tanezumab 5-mg group (- 3.40 [- 6.47, - 0.34]; p = 0.0294), but not the tanezumab 2.5-mg group (- 0.66 [- 3.63, 2.32]; p = 0.6637). CONCLUSIONS: These pooled analyses showed that health status, non-work activities, and work productivity were significantly improved following tanezumab administration, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02697773, NCT02709486.

Management of chronic low back pain and the impact on patients' personal and professional lives: Results from an international patient survey.

OBJECTIVE: The objective of this study was to investigate the impact of chronic low back pain (CLBP) on patients' personal and professional lives, and management strategies applied to treat CLBP. METHODS: A 60-question survey was developed, and respondents from 16 countries with a self-reported physician's diagnosis of CLBP were recruited via an online market research survey panel. Respondents were stratified as having mild, moderate, or severe pain. Target sample sizes per country and for pain severity were set. Data were weighted according to the known population and prevalence of CLBP in each country and the number of respondents from that country. RESULTS: Results from 9642 CLBP patients indicated that almost a quarter of patients with severe CLBP report a psychological comorbidity. Prescription pain medications were more commonly used by patients with severe CLBP (56%) than those with mild (20%) or moderate (34%) CLBP. Among those with severe CLBP who had been prescribed pain medication, 58% were prescribed opioids, with 1 in 4 patients using opioids for more than 5 years. Patients were primarily managed by general practitioners/primary care physicians, physiotherapists, neurologists, or orthopedic surgeons. CLBP negatively impacted patients' daily activities, social lives, and work productivity. CONCLUSION: Chronic low back pain has pronounced effects on patients' personal relationships, ability to work, and daily living. Almost 1 in four patients with severe CLBP reported a psychological comorbidity. Adherence to guidelines appears inconsistent, which is noteworthy as a substantial subgroup of patients with severe CLBP had been prescribed opioid medication for more than 5 years. Improved education is required to support healthcare professionals (HCPs) in identifying and understanding the complex biopsychosocial needs of CLBP patients to optimize pain management and to encourage referral of CLBP patients to physiotherapists and psychologists.

Safety risk associated with use of nonsteroidal anti-inflammatory drugs in Japanese elderly compared with younger patients with osteoarthritis and/or chronic low back pain: A retrospective database study.

PURPOSE: This study aimed to assess the safety risks associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) in elderly patients (≥65 years) compared with younger patients (<65 years) with osteoarthritis (OA) and/or chronic low back pain (CLBP). METHODS: A retrospective analysis was conducted on anonymized claims data of patients prescribed NSAIDs for OA and/or CLBP from 2009 to 2018 using hospital-based administrative database-Medical Data Vision (MDV). The key outcome was the incidence of developing gastrointestinal (GI), renal, and acute myocardial infarction (AMI) that are well-known events associated with NSAID use. RESULTS: Of 288,715 patients included, 23.7%, 60.5%, and 15.8% had OA, CLBP, or both, respectively. Elderly patients used non-oral NSAIDs more frequently than oral NSAIDs (57.8% and 38.7%, respectively), whereas younger patients showed comparable use (50.7% and 52.8%, respectively). The incidence of events per 10,000 person-years (95% CI) was higher in the elderly than in younger patients: GI, 29.68(27.67-31.68) vs. 16.61(14.60-18.63); renal, 124.77(120.56-128.99) vs. 39.88(36.72-43.03); and AMI, 27.41(25.48-29.35) vs. 10.90(9.27-12.53), respectively. After adjusting for covariates, the increase in risk for these events was seen in patients >70 years compared with younger patients (18-30 years) and was remarkable in patients >80 years with 2-fold, 10-fold, and 7-fold higher risk for developing GI, renal, and AMI events, respectively. CONCLUSION: Risk for developing NSAID-associated events was higher in the elderly; particularly, renal and AMI events that remarkably increased in patients >80 years. To reduce them, NSAIDs should be prescribed at the lowest effective dose for the shortest duration possible.

Burden of chronic low back pain: Association with pain severity and prescription medication use in five large European countries.

OBJECTIVE: This study assessed associations between severity of, and prescription medication use for, chronic low back pain (CLBP) and health-related quality of life, health status, work productivity, and healthcare resource utilization. METHODS: This cross-sectional study utilized SF-12, EQ-5D-5L, and work productivity and activity impairment (WPAI) questionnaires, and visits to healthcare providers among adults with self-reported CLBP participating in the National Health and Wellness Survey in Germany, France, UK, Italy, and Spain. Respondents were stratified into four groups according to pain severity (mild or moderate/severe) and prescription medication use (Rx-treated or Rx-untreated). Differences between groups were estimated using generalized linear models controlling for sociodemographics and health characteristics. RESULTS: Of 2086 respondents with CLBP, 683 had mild pain (276 Rx-untreated, 407 Rx-treated) and 1403 had moderate/severe pain (781 Rx-untreated, 622 Rx-treated). Respondents with moderate/severe pain had significantly worse health-related quality of life (SF-12v2 physical component summary), health status (EQ-5D-5L), and both absenteeism and presenteeism compared with those with mild pain, including Rx-untreated (moderate/severe pain Rx-untreated vs. mild pain Rx-untreated, p ≤ 0.05) and Rx-treated (moderate/severe pain Rx-treated vs. mild pain Rx-treated, p ≤ 0.05) groups. Significantly more visits to healthcare providers in the last 6 months were reported for moderate/severe pain compared with mild pain for Rx-treated (least squares mean 13.01 vs. 10.93, p = 0.012) but not Rx-untreated (8.72 vs. 7.61, p = 0.072) groups. Health-related quality of life (SF-12v2 physical component summary) and health status (EQ-5D-5L), as well as absenteeism and presenteeism, were significantly worse, and healthcare utilization was significantly higher, in the moderate/severe pain Rx-treated group compared with all other groups (all p ≤ 0.05). CONCLUSION: Greater severity of CLBP was associated with worse health-related quality of life, health status, and absenteeism and presenteeism, irrespective of prescription medication use. Greater severity of CLBP was associated with increased healthcare utilization in prescription medication users.

Quantifying the Employer Burden of Persistent Musculoskeletal Pain at a Large Employer in the United Kingdom: A Non-interventional, Retrospective Study of Rolls-Royce Employee Data.

OBJECTIVE: To quantify the burden of work-relevant persistent musculoskeletal (MSK) pain to a large UK employer. METHODS: A retrospective, longitudinal, analytical cohort study using linked Rolls-Royce data systems. Cases were employees with a MSK-related referral to occupational health; controls were age-, sex-, and job role-matched employees without such a referral. Outcomes were compared during 12 months' follow-up. RESULTS: Overall, 2382 matched case-control pairs were identified (mean age: 46 y; 82% male). Cases took 39,200 MSK-related sickness absence days in total (equating to £50 million in sickness absence costs). Cases took significantly more all-cause sickness absence days than controls (82,341 [£106 million] versus 19,628 [£26 million]; P < 0.0001). CONCLUSIONS: Despite access to extensive occupational health services, the burden of work-relevant persistent MSK pain remains high in Rolls-Royce. There is a clear need to better understand how to effectively reduce this burden.

Exploring patient preference heterogeneity for pharmacological treatments for chronic pain: A latent class analysis.

BACKGROUND: Several pharmaceutical treatments for chronic pain caused by osteoarthritis (OA) and chronic low back pain (CLBP) are available or currently under development, each associated with different adverse events (AEs) and efficacy profiles. It is therefore important to understand what trade-offs patients are willing to make when choosing between treatments. METHODS: A discrete-choice experiment (DCE) was conducted with 437 adults with chronic pain caused by OA and/or CLBP. Respondents were presented with a series of scenarios and asked to choose between pairs of hypothetical treatments, each defined by six attributes: level of symptom control; risks of heart attack, rapidly progressive osteoarthritis and dependency; frequency and mode of administration and cost. Attributes were based on known profiles of oral nonsteroidal anti-inflammatory drugs, opioids and injected nerve growth factor inhibitors, the last of which were under clinical development at the time of the study. Data were analysed using a latent class (LC) model to explore preference heterogeneity. RESULTS: Overall, respondents considered improving symptom control and reducing risk of physical dependency to be the most important attributes. The LC analysis identified four participant classes: an 'efficacy-focused' class (33.7%), a 'cost-averse' class (29.4%), a 'physical-dependence-averse' class (19.6%) and a 'needle-averse' class (17.3%). Subgroup membership was incompletely predicted by participant age and their responses to comprehension questions. CONCLUSIONS: Preference heterogeneity across respondents indicates a need for a personalized approach to offering treatment options. Symptom improvement, cost, physical dependence and route of administration might be important to different patients. SIGNIFICANCE: Multiple treatment options that differ substantially in terms of efficacy and adverse events are available for the management of chronic pain. With a growing emphasis on a patient-centred care model that incorporates patients' priorities and values into treatment decisions, there is a need to understand how individuals with chronic musculoskeletal pain balance the benefits and risks of treatment and how treatment priorities vary among individuals. This study was designed to identify patient preferences for different characteristics of treatments for the management of chronic pain and to investigate how preferences differ among respondents.

Comparing the Fiscal Consequences of Controlled and Uncontrolled Osteoarthritis Pain Applying a UK Public Economic Perspective.

Background: Individuals experiencing osteoarthritis (OA) pain can pose significant costs for governments due to reduced work activity in these individuals and increasing reliance on public support benefits. In this analysis we capture the broader economic impact of OA pain by applying a government perspective, public economic framework to assess controlled and uncontrolled pain. Methods: We used a Markov model to compare labour market participation in people with uncontrolled OA hip or knee pain compared to a cohort with controlled OA pain. The likelihood of employment, long-term sickness, disability, and early retirement in those with controlled pain used publicly available UK data. The relative effect of uncontrolled OA pain on fiscal outcomes is drawn from peer reviewed publications reporting reduced work activity and reliance on public benefits for people with uncontrolled OA pain. Lost tax revenue was derived using UK tax rates and national insurance contributions applied to annual earnings. Social benefit rules were applied to calculate government financial support to individuals. Health-care costs were calculated based on estimates from an UK observational study. The base case analysis compared the projected lost tax revenue and transfer payments for a 50-year-old cohort with severe OA pain, retiring at age 65. Results: For a 50-year-old individual with moderate uncontrolled OA pain with 15-years remaining work expectancy, the model estimated a £62 383 reduction in employment earnings, a £24 307 reduction in tax contributions and a need for £16 034 in government benefits, compared to a person with controlled OA pain. In people with severe uncontrolled OA pain incremental foregone earnings were estimated to be £126 384, £44 925 were not paid through taxation and £25 829 were received in public benefits, compared to the controlled pain cohort. Health-care costs represented 13% and 12% of all OA-related fiscal cost in the moderate uncontrolled OA pain and severe uncontrolled OA pain comparison, respectively. Conclusions: For governments, maintaining an active workforce is paramount to maintaining economic growth and reducing spending on government programs. The approach described here can be used to augment cost-effectiveness models to inform a range of stakeholders of benefits attributed to controlled OA pain.

Database Analysis on the Relationships Between Nonsteroidal Anti-inflammatory Drug Treatment Variables and Incidence of Acute Myocardial Infarction in Japanese Patients with Osteoarthritis and Chronic Low Back Pain.

INTRODUCTION: We aimed to analyze the relationships between nonsteroidal anti-inflammatory drug (NSAID) treatment variables and the incidence of acute myocardial infarction (AMI) in Japanese patients with osteoarthritis (OA) and chronic low back pain (CLBP) using the data from a large-scale, real-world database. METHODS: We retrospectively analyzed anonymized claims data from the Japanese Medical Data Center of medical insurance beneficiaries who were prescribed NSAIDs for OA and/or CLBP from 2009 to 2018. RESULTS: Of 180,371 patients, 89.3% received NSAIDs as first-line analgesics (oral, 90.3%; patch, 80.4%; other transdermal drugs, 24.0%). Incidence of AMI was 10.27 per 10,000 person-years (95% confidence interval 9.20-11.34) in the entire study population. There was a trend towards increased risk in patients using NSAIDs for more than 5 years (P = 0.0784) than in those using NSAIDs for less than 1 year. Risk of AMI significantly increased with age and comorbidities of diabetes and cardiovascular disease (CVD). The risk for AMI was similar for patients who consistently used NSAIDs compared to those using them intermittently and patients who used patch compared to oral NSAIDs. Elderly patients used NSAIDs more consistently and used NSAID patches more frequently. CONCLUSION: In Japanese patients with OA and CLBP, we saw a trend of increased risk for AMI in patients using NSAIDs for more than 5 years. Elderly patients had a higher prevalence of diabetes, hypertension, and other CVD which increased the risk of AMI. Although NSAID patches were preferred to oral NSAIDs in elderly patients, risk for AMI was similar between the two modalities. Therefore, we suggest using NSAIDs carefully, especially in elderly patients and those at risk of developing CVD.

A Retrospective Database Study of Gastrointestinal Events and Medical Costs Associated with Nonsteroidal Anti-Inflammatory Drugs in Japanese Patients of Working Age with Osteoarthritis and Chronic Low Back Pain.

CONTEXT: The real-world burden of gastrointestinal (GI) events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in Japanese patients with osteoarthritis (OA) and/or chronic low back pain (CLBP) remains unreported. OBJECTIVE: To assess the incidence and economic burden of NSAID-induced GI events by using data from large-scale real-world databases. METHODS: We used the Japanese Medical Data Center database to retrospectively evaluate anonymized claims data of medical insurance beneficiaries employed by middle- to large-size Japanese companies who were prescribed NSAIDs for OA and/or CLBP between 2009 and 2018. RESULTS: Overall, 180,371 patients were included in the analysis, of whom 32.9% had OA, 53.8% had CLBP, and 13.4% had both OA and CLBP. NSAIDs were administered as first-line analgesics to 161,152 (89.3%) of the patients in the sample, in oral form to 90.3% and as topical patches to 80.4%. A total of 65.1% used combined oral/topical patches. Of the 21.0% of patients consistently using NSAIDs (percentage of days supplied ≥70%), 54.5% received patches. A total of 51.5% patients used NSAIDs for >1 to ≤6 months. The incidence of GI events was 9.97 per 10,000 person-years (95% confidence interval: 8.92-11.03). The risk of developing GI events was high in elderly patients and patients with comorbidities and remained similar for patients receiving oral vs. topical NSAIDs. Longer treatment duration and consistent NSAID use increased the risk of GI events. The cost (median [interquartile range]) of medications (n = 327) was US$ 80.70 ($14.10, $201.40), that of hospitalization (n = 33) was US$ 2,035.50 ($1,517.80, $2,431.90), and that of endoscopic surgery (n = 52) was US$ 418.20 ($418.20, $418.20). CONCLUSION: NSAID-associated GI toxicity imposes a significant health and economic burden on patients with OA and/or CLBP, irrespective of whether oral or topical NSAIDs are used.

Burden of Renal Events Associated with Nonsteroidal Anti-inflammatory Drugs in Patients with Osteoarthritis and Chronic Low Back Pain: A Retrospective Database Study.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have long-term benefits but are limited by side effects. We assessed the health and economic burden of renal events associated with NSAID use in patients with osteoarthritis (OA) and/or chronic low back pain (CLBP). METHODS: This retrospective, large-scale, medical claims database study of Japanese patients receiving NSAIDs for OA and/or CLBP between 2009 and 2018 assessed the incidence of renal events and effect of treatment duration, mode of administration, and usage consistency of NSAIDs. RESULTS: Of 180,371 patients, NSAIDs were prescribed as first-line analgesics in 89.3%. Incidence per 10,000 person-years (95% confidence interval [CI]) for renal events was 23.46 (21.84-25.08) and for progression of chronic kidney disease (CKD) was 267.12 (189.93-344.32). Longer treatment duration (> 1 to ≤ 3 years, risk ratio [RR] 1.32, 95% CI 1.12-1.54; P = 0.0007; > 3 to ≤ 5 years, RR: 1.38, 95% CI 1.04-1.84; P = 0.0254 vs. < 1 year) and consistent use (RR: 1.24, 95% CI 0.99-1.55; P = 0.0595) increased the risk of renal events but the latter did not reach statistical significance. The risk was similar in patients using patch/oral NSAIDs and high in elderly patients and in those with diabetes, hypertension, and other cardiovascular disease. Following a renal event, median 1-year cost of drug treatment was $27.90; hospitalization, $1779.40; and dialysis, $33,018.40. CONCLUSIONS: Risk of renal events significantly increased with prolonged and consistent NSAID use (irrespective of mode of administration), with age, and in patients with certain comorbidities. Careful NSAID use is recommended in patients with CKD and those at high risk for CKD.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in patients with osteoarthritis (OA) and/or chronic low back pain (CLBP) for pain relief but their use is limited by side effects. These side effects may include abdominal, heart, and kidney problems. This article presents the results from a large claims database study in Japan that assessed the incidence of renal events and the associated healthcare cost. Impact of NSAIDs treatment duration, mode of administration, and usage consistency on the risk of developing renal events was evaluated. Results showed high incidence of renal events and progression of chronic kidney disease. Longer treatment duration and consistent use increased the risk of developing renal events. The risk was similar in patients using patch/oral NSAIDs and high in elderly patients and those with diabetes, hypertension, and other heart diseases. The estimated cost of drug treatment, hospitalization, and dialysis was also high. The author of the study would recommend NSAIDs to be used carefully in patients at risk for (or with) chronic kidney disease.

Are pain severity and current pharmacotherapies associated with quality of life, work productivity, and healthcare utilisation for people with osteoarthritis in five large European countries?

OBJECTIVES: Although the osteoarthritis (OA) burden is well-recognised, the benefit of currently available OA pharmacological therapy is not clear. This study aimed to assess whether the impact of OA pain on health-related quality of life (HRQoL), work, and healthcare resource utilisation (HRU) differed by both pain severity and prescription medication status. METHODS: This cross-sectional study used pooled data from the 2016/2017 European National Health and Wellness Survey. Respondents with self-reported physician-diagnosed OA and pain were included. Outcomes examined included HRQoL, health utility, health status, work productivity and activity impairment, and HRU. Groups derived from self-reported pain severity and prescription medication use were compared using chi-square tests, analysis of variance, and generalised linear models controlling for socio-demographics, health behaviours, and health status. RESULTS: Respondents with OA (n=2417) reported mild (40.4%, of which 44.9% prescription-treated) and moderate to severe pain (59.6%, of which 54.0% prescription-treated). HRQoL, health utility, health status, and work and activity impairment were substantially worse among the moderate/severe pain prescription-treated group compared to the rest (e.g. SF-12v2 physical component score [PCS] for moderate/severe pain prescription-treated=34.5 versus mild pain prescription-treated =39.3, moderate/severe pain prescription-untreated=40.6, and mild pain prescription-untreated=45.6; p<0.01). HRU such as the mean number of emergency room visits for >6 months was higher in the prescription-treated groups (0.51-0.52, 95% CI 0.437-0.71) than the prescription-untreated groups (0.30-0.34, 95% CI 0.21-0.46; p<0.05). CONCLUSIONS: Persons with moderate to severe OA pain treated with available prescription medications have poor health status and HRQoL and increased HRU compared to those not receiving prescription medications.

Measuring the impact of chronic low back pain on everyday functioning: content validity of the Roland Morris disability questionnaire.

BACKGROUND: Robust outcome measures are needed to assess and monitor the impact of chronic low back pain (CLBP) on physical functioning. The Roland Morris Disability Questionnaire (RMDQ) is a well-established measure designed to capture the impacts of back pain on everyday functioning, with a particular emphasis on physical functioning. It has documented evaluation of psychometric properties. However, there is no documented qualitative evidence to confirm the content validity of the tool, nor have changes made for electronic administration been debriefed in participants with CLBP. METHODS: In-depth, semi-structured, concept elicitation and cognitive debriefing interviews were conducted with 23 US participants with confirmed CLBP. Interviews allowed participants to describe the impact of CLBP on their day-to-day functioning and discuss comprehension and suitability of the RMDQ. Interviews were transcribed verbatim and analyzed using thematic analysis. RESULTS: Concept elicitation and cognitive debriefing revealed the substantial burden associated with CLBP, highlighting 15 key areas of functional impact. These were grouped into overarching themes of mobility (walking, stairs, sitting/standing, bending/kneeling, lifting, lying down), activities (chores/housework, dressing, washing, driving, work) and other (relationships/socializing, mood, sleep, appetite), which are consistent with those evaluated within the RMDQ. All participants found the RMDQ to be relevant with most reporting that the instructions, recall period, and response options were suitable. A few suggested minor changes, however, none were consistent or necessary to support content validity. Updates to the measure for electronic administration and to clarify the response options were well received. CONCLUSION: The qualitative data from individuals with CLBP confirmed that the RMDQ has content validity and, alongside documented psychometric evidence, supports the use of the RMDQ as a reliable and valid tool to assess the impact of CLBP on physical functioning.

Symptoms of Major Depressive Disorder Scale: Performance of a Novel Patient-Reported Symptom Measure.

BACKGROUND: The Symptoms of Major Depressive Disorder Scale (SMDDS) was expressly developed on the basis of qualitative data to directly incorporate patients' voices into evaluation of treatment benefit in major depressive disorder (MDD) clinical trials. OBJECTIVES: To collect quantitative data necessary to refine/optimize the SMDDS and document its psychometric properties. METHODS: In this multicenter, observational study, participants with clinically diagnosed MDD completed questionnaires in 2 waves. Wave 1 was designed to refine the SMDDS using Rasch measurement evaluations and item reduction analyses. On a subset of wave 1 subjects, 7 to 12 months later, wave 2 further examined item performance and measurement properties. Exploratory factor analyses and assessments of construct validity and reliability (internal consistency and reproducibility) were completed. RESULTS: Using wave 1 data (N = 315; females = 71%, white = 81%, mean age = 44 years), the SMDDS was revised from 36 to 16 items. The Rasch item threshold map indicated that all but 1 item (suicidal ideation) were appropriately ordered. The 207 wave 2 participants were 74% females, 82% white, with a mean age of 45 years. The exploratory factor analyses resulted in a single component (all standardized factor loadings >0.46). Cronbach α was 0.93 and the 7-day test-retest intraclass correlation coefficient (n = 93) was 0.84 (95% confidence interval 0.77-0.89). SMDDS scores discriminated between MDD severity levels. CONCLUSIONS: The 16-item SMDDS generated highly reliable scores with substantial evidence of construct validity. On the basis of the evidence of appropriate content validity and sound psychometric performance, the Food and Drug Administration qualified the SMDDS as an outcome measure to support exploratory efficacy endpoints in MDD clinical trials.