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Objective: To describe utilization patterns, negative clinical outcomes and economic burden of patients diagnosed with osteoarthritis (OA) of the hip and/or knee who received a prescription for tramadol or non-tramadol opioids vs. non-opioid drugs., Methods: Optum Healthcare Solutions, Inc. commercial claims data were used (1/2012--3/2017). Adults with ≥2 diagnoses of OA of the hip and/or knee, and ≥30 days supply of pain medications were identified during the three-year period from the date of first prescription (index date) after the first OA diagnosis. Drug utilization statistics in the follow-up period were summarized by initial treatment (i.e. tramadol, non-tramadol opioids, non-opioid drugs). Opioid initiators were matched to those initiated on non-opioid treatments using a propensity score model accounting for baseline characteristics. Matched pairs analysis compared outcomes for these cohorts., Results: Of 62,715 total patients, 15,270 (24.3%) initiated treatment with opioids, including 3,513 (5.6%) on tramadol and 11,757 (18.7%) on non-tramadol opioids. Opioid initiators had more comorbidities, higher baseline healthcare costs, and were more likely to have OA of the hip. Among non-opioid initiators, 27.5% switched to tramadol and 63% switched to non-tramadol opioids. Among tramadol initiators, 71% switched to non-tramadol opioids. Patients initiated on opioids had 20.4% ( p  < .01) higher all-cause healthcare costs and higher percentages experiencing multiple negative clinical outcomes (all p  < .01) compared to matched controls., Conclusions: Most patients with OA of the hip and/or knee either initiate on or switch to opioids for long-term management of OA-related pain despite known risks. This highlights the need for new treatments that delay or prevent use of opioids.

Objectives: As understanding of the pathogenesis and treatment strategies for osteoarthritis (OA) evolves, it is important to understand how patient factors are also changing. Our goal was to examine demographics and known risk factors of patients with OA over time., Design: Open-cohort retrospective study using electronic health records., Setting: Large US integrated health system with 7 hospitals, 2.6 million outpatient clinic visits and 97 300 hospital admissions annually in a mostly rural geographic region., Participants: Adult patients with at least two encounters and a diagnosis of OA or OA-relevant surgery between 2001 and 2018. Because of geographic region, over 96% of participants were white/Caucasian., Interventions: None., Primary and Secondary Outcome Measures: Descriptive statistics were used to examine age, sex, body mass index (BMI), Charlson Comorbidity Index, major comorbidities and OA-relevant prescribing over time., Results: We identified 290 897 patients with OA. Prevalence of OA increased significantly from 6.7% to 33.5% and incidence increased 37% (from 3772 to 5142 new cases per 100 000 patients per year) (p<0.0001). Percentage of females declined from 65.3% to 60.8%, and percentage of patients with OA in the youngest age bracket (18-45 years) increased significantly (6.2% to 22.7%, p<0.0001). The percentage of patients with OA with BMI ≥30 remained above 50% over the time period. Patients had low comorbidity overall, but anxiety, depression and gastro-oesophageal reflux disease showed the largest increases in prevalence. Opioid use (tramadol and non-tramadol) showed peaks followed by declines, while most other medications increased slightly in use or remained steady., Conclusions: We observe increasing OA prevalence and a greater proportion of younger patients over time. With better understanding of how characteristics of patients with OA are changing over time, we can develop better approaches for managing disease burden in the future., Competing Interests: Competing interests: CB and EC are employees of Pfizer and have stock options. RLR and JH are employees and stockholders of Eli Lilly and Company. JG, BJP, MSK, VAH and EW are employees of Geisinger. During the study period, TN, HS and JAB were also employees of Geisinger. Geisinger received institutional funding from Pfizer and Eli Lilly and Company for the study and in connection with the development of this manuscript. PD was an employee of Pfizer with stock options., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Opioids are commonly used to manage pain, despite an increased risk of adverse events and complications when used against recommendations. This register study uses data of osteoarthritis (OA) patients with joint replacement surgery to identify and characterize problematic opioid use (POU) prescription patterns., Methods: The study population included adult patients diagnosed with OA in specialty care undergoing joint replacement surgery in Denmark, Finland, Norway, and Sweden during 1 January 2011 to 31 December 2014. Those with cancer or OA within three years before the first eligible OA diagnosis were excluded. Patients were allocated into six POU cohorts based on dose escalation, frequency, and dosing of prescription opioids post-surgery (definitions were based on guidelines, previous literature, and clinical experience), and matched on age and sex to patients with opioid use, but not in any of the six cohorts. Data on demographics, non-OA pain diagnoses, cardiovascular diseases, psychiatric disorders, and clinical characteristics were used to study patient characteristics and predictors of POU., Results: 13.7% of patients with OA and a hip/knee joint replacement were classified as problematic users and they had more comorbidities and higher pre-surgery doses of opioids than matches. Patients dispensing high doses of opioids pre-surgery dispensed increased doses post-surgery, a pattern not seen among patients prescribed lower doses pre-surgery. Being dispensed 1-4,500 oral morphine equivalents in the year pre-surgery or having a non-OA pain diagnosis was associated with post-surgery POU (OR: 1.44-1.50, and 1.11-1.20, respectively)., Conclusions: Based on the discovered POU predictors, the study suggests that prescribers should carefully assess pain management strategies for patients with a history of comorbidities and pre-operative, long-term opioid use. Healthcare units should adopt risk assessment tools and ensure that these patients are followed up closely. The data also demonstrate potential areas for further exploration in improving patient outcomes and trajectories., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background: While prior research has shown that patients with osteoarthritis (OA) who are prescribed opioids have higher rates of falls and fractures following drug initiation, there is a limited body of work establishing a comprehensive model of factors that influence the risk of falls or fractures among these patients. Objective: Opioids are associated with negative clinical outcomes, including increased risk of falls and fractures. This study assessed the frequency, treatment characteristics, and risk factors associated with falls or fractures among patients with OA taking opioids. Methods: Optum Healthcare Solutions, Inc data (January 2012-March 2017) were used to identify patients over 18 with at least 2 diagnoses of hip and/or knee OA, and at least 90 days' supply of opioids. Patients with cancer were excluded. Falls or fractures outcomes were assessed in the 36-month follow-up period after the date of the first opioid prescription after first OA diagnosis. Demographic, treatment, and clinical characteristics associated with falls or fractures were assessed using logistic regression. Results: Of 16 663 patients meeting inclusion criteria, 3886 (23%) had at least 1 fall or fracture during follow-up. Of these 3886 patients, 1349 (35%) had at least 1 fall with an average of 3 fall claims, and 3299 (85%) patients had at least 1 fracture with an average of 8 claims during follow-up. Spine (15.8%) and hip (12.5%) fractures were most common. Median time to fall or fracture was 18.6 and 13.9 months, respectively. Significant ( P <.05) risk factors associated with at least 1 fall or fracture during the follow-up period included alcohol use (odds ratio [OR], 3.41), history of falling (OR, 2.19), non-tramadol opioid use (OR, 1.31), age (OR, 1.03), benzodiazepine use (OR, 1.21), and at least 1 osteoporosis diagnosis (OR, 2.06). Discussion: This study is among only a few that clearly identifies the substantial impact and frequency of falls and fractures associated with prescribing non-tramadol opioids to patients with OA. Findings suggest that fall or fracture risks need to be considered when managing OA pain with opioids. Conclusion: Falls and fractures impose a major clinical burden on patients prescribed opioids for OA-related pain management. Falls or fracture risks should be an important consideration in the ongoing treatment of patients with OA., Competing Interests: S.S. is a paid consultant to Pfizer and Eli Lilly and Company in connection with this study. B.R., A.W., and W.P. are employees of the Analysis Group, who were paid consultants to Pfizer and Eli Lilly and Company for this study and development of this manuscript. R.R. is an employee and stockholder of Eli Lilly and Company. P.S., C.B., B.E., and S.T. are employees of Pfizer with stock and/or stock options.

Introduction: Osteoarthritis (OA) is a complex disease, and prior studies have documented the health and economic burdens of patients with OA compared to those without OA. Our goal was to use two strategies to further stratify OA patients based on both pain and treatment intensity to examine healthcare utilization and costs using electronic records from 2001 to 2018 at a large integrated health system., Methods: Adult patients with ≥1 pain numerical rating scale (NRS) and diagnosis of OA were included. Pain episodes of ≥90 days were defined as mild (0-3), moderate (4-6), or severe (7-10) based on initial NRS. Patients were initially classified as mild and moved to moderate-severe OA if any of eight treatment-based criteria were met. Outpatient visits (OP), emergency department visits (ED), inpatient days, and healthcare costs (both all-cause and OA-specific) were compared among pain levels and OA severity levels as frequencies and per-member-per-year rates, using generalized linear regression models adjusting for age, sex, and body mass index, with contrasts of p < 0.05 considered significant., Results: We identified 127,656 patients, 92,576 with pain scores. Moderate and severe pain were associated with significantly higher rates of OA-related utilization and costs, and all-cause ED visits and pharmacy costs. Moderate-severe OA patients had significantly higher OA-related utilization and costs, and all-cause OP, ED and pharmacy costs., Conclusions: Pain and treatment intensity were both strongly associated with OA-related utilization but not consistently with all-cause utilization. Our results provide promising evidence of better criteria and approaches for predicting disease burden and costs in the future., (© 2022. The Author(s).)

Introduction: This study estimated all-cause health care resource utilization (HRU) and costs and work loss outcomes associated with pain management of employed patients with osteoarthritis of the hip and/or knee., Methods: Optum Health Care Solutions data were analyzed for employed patients prescribed nonsteroidal anti-inflammatory drugs, tramadol, or nontramadol opioids following diagnoses of osteoarthritis of the hip and/or knee. A pre-post design was used to evaluate changes in all-cause HRU and costs, and work loss days and associated costs., Results: Costs rose for patients in all three cohorts (up to 198.3% for health care costs [tramadol] and up to 178.7% for work loss costs [tramadol]). Greatest increases in all-cause HRU included inpatient visits (237.9% [nonsteroidal anti-inflammatory drugs]; 600% [tramadol])., Conclusions: Study results provide evidence of increases in all-cause HRU and costs and work loss days and associated costs., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Objectives: Osteoarthritis (OA) is one of the leading causes of disability worldwide. Pain is the most important symptom in OA, driving medical care, disability, reduced functionality, and decreased quality of life. The objective of this study was to describe prescription patterns of difficult-to-treat OA and explore possible predictors of unmet pain relief in Nordic patients., Methods: This observational cohort study included patients with a confirmed diagnosis of OA (index date) in specialty care in Sweden, Norway, Finland and Denmark between 1 January 2011 and 31 December 2012 who were followed for up to 5 years. Four subgroups were pre-defined to characterize difficult-to-treat OA: (1) ≥2 chronic comorbidities in the 3-year pre-index period; (2) top 10% of healthcare resource users, 1-year post-index; (3) ≥3 types of prescription pain medications during pre-index period to first year post-index, with ≥30 days between types; (4) having a contraindication to a nonsteroidal anti-inflammatory drug (NSAID). Patient characteristics, prescription patterns and predictors of unmet pain relief (defined as persistent opioid use, using several types of opioids or long-term NSAID use) were analyzed., Results: We identified 288,174 OA patients and the average age was 63.5 years at time of diagnosis and 58% of them were female. After 5 years, 35-50% of the patients defined as 'difficult-to-treat' had ≥1 prescription of opioids, compared to 20-25% of all OA patients (p-value <0.05). Comorbidities and disability pension were strong predictors of unmet pain relief (p-value <0.001)., Conclusions: This study shows a substantial use of pain medications (NSAID and opioids) in difficult-to-treat OA patients. These findings suggest that pain may be inadequately managed in a considerable number of patients with OA, particularly those with contraindications to an NSAID. A high comorbid and socioeconomic burden are relevant risk factors among patients who continue to use opioids for a long period of time., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Osteoarthritis can have a profound effect on patients' quality of life. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study aimed to describe the impact of osteoarthritis on quality of life and determine the association with factors such as pain severity and pharmacological treatment., Methods: An observational study was performed with a cross-sectional design including patients with a confirmed osteoarthritis diagnosis enrolled in the National Quality Register for Better management of patients with Osteoarthritis (BOA) between 2016 and 2017 in Sweden. Patient-reported information from BOA was linked to administrative data from three national health registers. The impact of osteoarthritis on quality of life was estimated using the EQ-5D-5L and the first developed experienced-based time-trade-off value set for Sweden to calculate the EQ-5D-5L index scores. EQ-5D-3L index scores were also estimated based on a UK hypothetical value set via a crosswalk method. Ordinary least squares regression models were used to analyse the association between quality of life and potential influencing factors., Results: For the 34,254 patients evaluated, mean EQ-5D-5L index score was 0.792 (SD 0.126). Stratifications showed that the index score varied across different levels of pain severity. Increased pain severity and use of pain-relieving medications remained significantly associated with a lower quality of life index score when controlled for potential confounders. The mean EQ-5D-3L index score was 0.605 (SD 0.192)., Conclusions: This large population-based study from Sweden highlights the substantial impact of osteoarthritis on quality of life amongst different patient groups and that currently available treatment options for osteoarthritis pain do not appropriately address the needs for many osteoarthritis patients., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To describe and compare baseline characteristics, healthcare and drug utilization, and negative clinical outcomes of commercially-insured patients diagnosed with OA of the hip and/or knee who initiated treatment on traditional oral NSAIDs (tNSAIDs), topical NSAIDs, or cyclooxygenase-2 inhibitors (COX-2s)., Methods: A commercial claims database (1/2012-3/2017) was used to identify patients ≥18 years old, with ≥2 diagnoses of hip and/or knee OA, and ≥90 days supply of NSAIDs. Patients were assigned to cohorts based on the type of NSAID initially prescribed and observed in the 6 months before (baseline) and 36 months after (follow-up) the date of their first NSAID prescription after the first OA diagnosis. Analyses estimated baseline demographic and clinical characteristics and follow-up period drug utilization. Logistic regressions assessed the risk of gastrointestinal (GI) and acute renal failure (ARF) events., Results: tNSAIDs were the most frequently prescribed treatment. During the follow-up period, less than 15% of patients prescribed tNSAIDs switched to either COX-2s or topical NSAIDs and 37% of patients prescribed a COX-2 and 56% of patients prescribed a topical NSAID switched to tNSAIDs. GI and ARF events during the follow-up period ranged from 7.3-8.1% and 8.0-11.0%, respectively, across cohorts. The tNSAIDs and COX-2s cohorts had increased risk of both types of events relative to patients prescribed topical NSAIDs, controlling for other characteristics., Conclusions: Analyses characterize the long-term real-world utilization of NSAIDs and associated outcomes for patients with OA of the hip and/or knee. Study results highlight the likelihood of switching and the risk of negative clinical outcomes associated with long-term use.

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., (© 2022 Pfizer Inc. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.)

Background: There has been limited evaluation of medication adherence, healthcare resource utilization (HCRU), and healthcare costs over time in patients with osteoarthritis (OA), and stratification by pain severity level has not been reported. Assessing such longitudinal changes may be useful to patients and healthcare providers for tracking disease progression, informing treatment options, and employing strategies to optimize patient outcomes. Objectives: To characterize treatment patterns, HCRU, and costs over time in patients with moderate to severe (MTS) OA pain in the United States. Methods: We conducted a retrospective claims analysis, using IBM® MarketScan® databases, from 2013-2018. Eligible patients were aged ≥45 years with ≥12 months pre-index (baseline) and ≥24 months (follow-up) of continuous enrollment; index date was defined as a physician diagnosis of hip or knee OA. An algorithm was employed to identify MTS OA pain patients, who were propensity score matched with patients having non-MTS OA pain. Data were summarized using descriptive statistics and univariate analyses. Results: After propensity score matching, the overall OA pain cohorts consisted of 186 374 patients each: 61% were female, mean age was 63 years, and two-thirds (65.6%) were of working age (45-65 years). Sleep-related conditions, anxiety, and depression were significantly higher in the MTS OA pain cohort vs non-MTS ( P <0.001). At baseline and 12- and 24-month follow-ups, receipt of prescription pain medications, HCRU, and direct medical costs were significantly higher in the MTS OA pain cohort (all P <0.01). Medication adherence was significantly higher in the MTS OA pain cohort for all medication classes except analgesics/antipyretics, which were significantly lower vs the non-MTS OA pain cohort (all P <0.0001). Conclusions: The burden of MTS OA pain is substantial, with patterns that show increasing medication use, HCRU, and costs vs non-MTS OA pain patients over time. Understanding the heterogeneity within the OA population may allow us to further appreciate the true burden of illness for patients in pain., Competing Interests: The study was sponsored by Pfizer and Eli Lilly and Company. The findings of this manuscript have been presented at The International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) 2020 Virtual World Congress (WCO-IOF-ESCEO); August 20-22, 2020, and at PAINWeek 2020 Virtual Meeting; September 11-13, 2020. The following authors are employees of Pfizer with stock and/or stock options: PS, ST, CB, DM, and BE. RLR is an employee and stockholder of Eli Lilly and Company. RNH received consulting fees associated with this study from Pfizer and Eli Lilly and Company. The authors report no conflicts of interest in this work.

Abstract: In 2019, the American College of Rheumatology conditionally recommended tramadol and conditionally recommended against nontramadol opioids for patients with hip and knee osteoarthritis. Although tramadol is known to be less prone to opioid use disorders, little is known about the differing magnitude of negative clinical outcomes, health care resource utilization, and costs of tramadol relative to nontramadol opioids. Administrative claims records for commercially insured patients with osteoarthritis who were prescribed opioids were used to compare clinical and cost outcomes during a 3-year follow-up period by conducting a pre-post analysis and a matched case-cohort analysis. Data for 14,491 patients were analyzed: 4048 (28%) were initiated on tramadol, and 10,443 (72%) were initiated on nontramadol opioids. After matching, 4048 patients per cohort were analyzed. In each empirical analysis, tramadol patients did develop opioid use disorders; however, opioid use disorder rates were 3.5-fold higher in the nontramadol cohort (1.2% vs 4.2%). In addition, rates of other opioid-related clinical outcomes (falls, fractures, nausea, fatigue, and constipation) were also directionally lower among the tramadol cohort, although quantitatively similar (<5% difference) to the nontramadol cohort. Finally, in both analyses, the nontramadol cohort incurred higher levels of inpatient and emergency department visits and all-cause costs during the 3-year follow-up period. However, tramadol patients incur a higher incremental change (+$24,013) in costs relative to their pretreatment baseline compared with nontramadol (+$18,191). These real-world findings demonstrated lower risks with tramadol relative to other opioids, albeit risks and increased health care costs were present with tramadol, highlighting the need for further strategies to improve outcomes., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

BACKGROUND: Osteoarthritis (OA) affects millions of adults in the United States and can result in substantial pain, functional impairment, and significant clinical and economic burden. To manage chronic pain associated with OA, treatment guidelines recommend a variety of pharmacologic treatments, including traditional oral nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors (COX-2s), and opioids. While these drug treatments can be effective at pain management, they are also associated with significant clinical and economic burden. New treatments for chronic pain among patients with OA of the hip and/or knee have the potential to reduce the occurrence of such negative clinical outcomes, including cardiovascular events, renal events, and opioid use disorder (OUD), thereby reducing health care resource use (HRU) and medical costs. OBJECTIVE: To develop a harm reduction model (HRM) to assess potential reductions of negative clinical outcomes, HRU, and medical costs associated with the use of new treatments in place of oral NSAIDs, tramadol, and non-tramadol opioids among patients with OA of the hip and/or knee in the United States. METHODS: The HRM model integrated findings from the literature and inputs from a variety of sources, along with assumptions regarding potential ability of new treatments to replace existing treatments and market penetration into a unified framework to estimate outcomes and costs. The model outputs included estimated per-patient and population-level reductions in negative clinical outcomes associated with prescribing new treatments in place of oral NSAIDs or opioids along with number needed to treat (NNT) associated with new treatments. The model assumed that new treatments will primarily be used in place of non-tramadol opioids, but more modest adoption in place of oral NSAIDs and tramadol. RESULTS: Among patients with OA of the hip and/or knee who were prescribed oral NSAIDs, tramadol, or non-tramadol opioids for chronic use (≥ 90 days), the HRM estimated total cost savings of $3.8 billion, $5.1 billion, and $29.9 billion, respectively, from prescribing new treatments for OA pain over a 36-month period. The reduced economic burden was driven by significant reductions in the incidence of negative clinical outcomes. Estimates of the NNT to avoid a negative clinical event related to NSAID and opioid treatment initiation were low for most outcomes. Estimates of NNT associated with NSAID use ranged from 4 to 17 patients, depending on outcome, and estimates of NNT associated with opioid use was 35 non-tramadol and 134 tramadol patients for OUD and ranged from 6 to 21 patients for the other clinical outcomes, depending on treatment and outcome. CONCLUSIONS: Results from the HRM suggest that prescribing new treatments in place of oral NSAIDs and/or opioids for OA pain results in a potentially substantial reduction in patients experiencing negative clinical outcomes and reductions in all-cause HRU and costs. DISCLOSURES : This study was sponsored by Pfizer and Eli Lilly and Company. Silverman was a paid consultant to Pfizer and Eli Lilly and Company in connection with this study. Beck and Schepman are employees of Pfizer with stock and/or stock options. Robinson is an employee and minor stockholder of Eli Lilly and Company. Rice, White, and Fernan are employees of the Analysis Group, who were paid consultants to Pfizer and Eli Lilly and Company for this study and development of the manuscript.

Purpose: Osteoarthritis (OA) is one of the most common causes of chronic pain and a leading cause of disability in the US. The objective of this study was to examine the clinical and economic burden of OA by pain severity., Patients and Methods: We used nationally representative survey data. Adults ≥18 years with self-reported physician-diagnosed OA and experiencing OA pain were included in the study. OA pain severity was measured using the Short Form McGill Pain Questionnaire Visual Analog Scale (SF-MPQ-VAS). Data were collected for demographics, clinical characteristics, health-related quality of life (HRQoL), productivity, OA treatment, adherence to pain medication, and healthcare resource utilization. Univariate analysis was performed to examine differences between respondents with moderate-to-severe OA pain vs those with mild OA pain., Results: Higher proportions of respondents with moderate-to-severe OA pain (n=3798) compared with mild OA pain (n=2038) were female (69.4% vs 57.3%), <65 years of age (54.8% vs 43.4%), and not employed (70.6% vs 64.5%). Respondents with moderate-to-severe OA pain experienced OA pain daily (80.8% vs 48.8%), were obese (53.0% vs 40.5%), had more comorbidities (sleep disturbance, insomnia, depression, and anxiety), and reported significantly poorer health status and HRQoL, and greater productivity and activity impairment (all P <0.05). Moderate-to-severe OA pain respondents were prescribed significantly more pain medications than mild OA pain respondents (41.0% vs 17.0%) and had higher adherence (75.9% vs 64.1%) yet were less satisfied with their pain medications (all P <0.001). Outpatient and emergency room visits, and hospitalizations in the 6 months prior to the survey were significantly higher in moderate-to-severe OA pain respondents vs those with mild OA pain (all P <0.05)., Conclusion: Patient and clinical burden was significantly greater in moderate-to-severe OA pain respondents vs mild OA pain respondents and may inform decision-making for appropriate resource allocation and effective management strategies that target specific subgroups., Competing Interests: The findings of this manuscript have been presented at the ISPOR 2020 Virtual Annual Meeting; May 18–20, 2020 and at PAINWeek 2020 Virtual Meeting; September 11–13, 2020. The following authors are employees of Pfizer with stock and/or stock options: PS, ST, CB, DM, and BE. RR is an employee and stockholder of Eli Lilly and Company. AS was financially compensated for providing editorial support in the drafting of this manuscript. The authors report no other conflicts of interest in this work., (© 2021 Schepman et al.)

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., Competing Interests: The study was sponsored by Pfizer and Eli Lilly and Company. Mark Connolly, Nikos Kotsopoulous, Rui Martins and Melodi Kosaner Kließ are employees of Global Market Access Solutions, who were paid consultants to Pfizer and Eli Lilly and Company for this study and development of this manuscript. Craig Beck, Lucy Abraham, Samuel Large and Patricia Schepman are employees of Pfizer with stock and/or stock options.

Embryonic stem (ES) cell pluripotency is regulated by a combination of extrinsic and intrinsic factors. Previously we have demonstrated that phosphoinositide 3-kinase (PI3K)-dependent signaling is required for efficient self-renewal of murine ES cells. In the study presented here, we have investigated the downstream molecular mechanisms that contribute to the ability of PI3Ks to regulate pluripotency. We show that inhibition of PI3K activity with either pharmacological or genetic tools results in decreased expression of RNA for the homeodomain transcription factor Nanog and decreased Nanog protein levels. Inhibition of glycogen synthase kinase 3 (GSK-3) activity by PI3Ks plays a key role in regulation of Nanog expression, because blockade of GSK-3 activity effectively reversed the effects of PI3K inhibition on Nanog RNA, and protein expression and self-renewal under these circumstances were restored. Furthermore, GSK-3 mutants mimicked the effects of PI3K or GSK-3 inhibition on Nanog expression. Importantly, expression of an inducible form of Nanog prevented the loss of self-renewal observed upon inhibition of PI3Ks, supporting a functional relationship between PI3Ks and Nanog expression. In addition, expression of a number of putative Nanog target genes was sensitive to PI3K inhibition. Thus, the new evidence provided in this study shows that PI3K-dependent regulation of ES cell self-renewal is mediated, at least in part, by the ability of PI3K signaling to maintain Nanog expression. Regulation of GSK-3 activity by PI3Ks appears to play a key role in this process.