Prescription opioid utilization patterns, and associated outcomes, among privately insured patients prescribed opioids to manage pain associated with osteoarthritis.

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.

Risk Factors Associated with Falls and Fractures Following Prescription of Opioids Among Privately Insured Patients with Osteoarthritis.

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.

All-Cause Health Care and Work Loss Burden Associated With Nonsteroidal Anti-Inflammatory Drug and Opioid Treatment in Employed Patients With Osteoarthritis.

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.

A Retrospective Claims-Based Study Evaluating Clinical and Economic Burden Among Patients With Moderate to Severe Osteoarthritis Pain in the United States.

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.

Drug utilization, clinical and economic outcomes of patients with osteoarthritis of the hip and/or knee treated with long-term use of traditional NSAIDs, topical NSAIDs, and COX-2 inhibitors.

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.

Clinical and economic burden of prescribing tramadol and other opioids for patients with osteoarthritis in a commercially insured population in the United States.

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.

A harm reduction model to assess the impact of new treatments for pain over standard of care among patients with osteoarthritis.

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.

Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signaling in murine embryonic stem cells.

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.