Medication use and comorbidities in an increasingly younger osteoarthritis population: an 18-year retrospective open-cohort study.

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.

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.

Annual indirect costs savings in patients with episodic or chronic migraine: a post-hoc analysis of phase 3 galcanezumab clinical trials in the United States.

BACKGROUND: Galcanezumab (GMB) improved quality-of-life and reduced disability of patients with episodic (EM) and chronic migraine (CM) in Phase 3 trials. AIM: To estimate indirect cost savings associated with GMB treatment in patients with migraine in the United States (US). METHODS: We analyzed data of patients from the US from three randomized, Phase 3, double-blind, placebo (PBO)-controlled GMB studies: EVOLVE-1 and EVOLVE-2 (EM patients), REGAIN (CM patients). Annual indirect costs were calculated using items of the Migraine Disability Assessment (MIDAS) questionnaire: lost time/productivity at work/school, household work, and leisure time. All costs were annualized and expressed in 2019 US dollars. While the main analysis considered lost time/productivity at work/school and household work as a full day, a sensitivity analysis was performed by discounting them by half. For EM, annual indirect costs savings were estimated using mixed model repeated measures analysis. For CM, ANCOVA models were used to estimate annual indirect costs savings as change from baseline. RESULTS: The analysis included 805 patients with EM (mean age = 41.4 years; PBO = 534; GMB = 271) and 423 patients with CM (mean age = 38.9 years; PBO = 279; GMB = 144). Compared to PBO, GMB significantly reduced annual indirect costs among patients with EM at 3 months (least square mean [95% confidence interval] work/school = $1,883.6 [603.64-3,163.65], p = .0040, household work = $628.9 [352.95-904.88], p <.0001, and leisure activity = $499.17 [42.36-955.98], p = .0323) and 6 months (work/school = $2,382.29 [1,065.48-3,699.10], p = .0004, household work = $559.45 [268.99-849.90], p = .0002, and leisure activity = $753.81 [334.35-1,173.27], p = .0004), whereas a significant difference was not observed among patients with CM. Sensitivity analysis results were similar to primary analysis results. CONCLUSIONS: GMB treatment versus PBO resulted in significantly greater indirect cost savings in patients with EM through improved productivity at work/school, household work, and leisure days. Patients with CM receiving GMB versus PBO attained greater cost savings, although not statistically significant, through reduced lost productivity at work/school.

Migraine causes missed time or reduced productivity at home and work, which further imposes an economic burden on patients, referred to as indirect costs. In this study, we evaluated the indirect cost savings in patients with episodic or chronic migraine taking either galcanezumab or placebo for treatment. We collected data using a questionnaire called the Migraine Disability Assessment (MIDAS) that was completed by patients enrolled in three clinical studies in the United States (US), namely EVOLVE-1, EVOVLE-2 (episodic migraine patients), and REGAIN (chronic migraine patients). The MIDAS questionnaire evaluated time lost/reduced productivity at work/school, household work, and leisure activity in patients with episodic or chronic migraine. Using scores of the MIDAS questionnaire and standard annual wages for the US population, we calculated indirect costs in patients. A total of 805 patients with episodic migraine and 423 patients with chronic migraine were included in this study. In galcanezumab-treated patients with episodic migraine, a significant indirect cost saving was observed through decrease in time lost/reduced productivity at work/school, household work, and leisure activity compared with patients who received placebo. In galcanezumab-treated patients with chronic migraine, indirect cost saving observed through decrease in time lost/reduced productivity at work/school were not statistically different from placebo-treated patients. The relatively lower cost savings observed in patients with chronic migraine may be due to greater disease burden compared to patients with episodic migraine. Results of this study suggest that patients with migraine receiving galcanezumab may obtain indirect cost savings.

Associations of Healthcare Utilization and Costs with Increasing Pain and Treatment Intensity Levels in Osteoarthritis Patients: An 18-Year Retrospective Study.

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.

Concern about addiction is associated with lower quality of life in patients with osteoarthritis: an exploratory, real-world data analysis.

PURPOSE: To evaluate the relationship between self-reported concerns about becoming addicted to a medication and health-related quality of life (HRQoL) in patients with osteoarthritis (OA). METHODS: This real-world study used patient-level cross-sectional survey data collected from the US Adelphi Disease Specific Programme (DSP). The DSP for OA selected 153 physicians who collected de-identified data on their next nine adult patients with OA. Each patient completed a disease-relevant survey, which included the Likert-scale question, "I am concerned about becoming addicted to my medicine," (CAA) with responses ranging from "completely disagree" [1] to "completely agree" [5]. HRQoL was measured by the EQ-5D-5L index value and the EQ Visual Analogue Scale (VAS). A set of ordinary least squares regressions using HRQoL measures as outcomes and CAA as a continuous predictor were estimated. Standardized effect size (ES) was used to gauge the magnitude of effects. RESULTS: A total of 866 patients with OA completed the survey (female, 61.2%; White, 77.7%; mean age, 64.2 years). Of the 775 patients who completed the CAA question, almost one-third responded that they "agree" (18%) or "completely agree" (11%), while 27% responded "completely disagree" and 20% "disagree." Regression analyses found that patients who have concerns about medication addiction have significantly different EQ-5D-5L index values and EQ VAS scores compared with patients who do not have this concern (p < 0.0001). CONCLUSION: Our findings suggest that concern about medication addiction in patients with OA may have an impact on patient HRQoL, with more concerned patients reporting poorer HRQoL outcomes.

Treating osteoarthritis pain: mechanisms of action of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, and nerve growth factor antibodies.

Osteoarthritis (OA) is a common difficult-to-treat condition where the goal, in the absence of disease-modifying treatments, is to alleviate symptoms such as pain and loss of function. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are common pharmacologic treatments for OA. Antibodies directed against nerve growth factor (NGF-Abs) are a new class of agents under clinical investigation for the treatment of OA. This narrative review describes (and uses schematics to visualize) nociceptive signaling, chronification of pain, and the mechanisms of action (MOAs) of these different analgesics in the context of OA-related pain pathophysiology. Further, the varying levels of efficacy and safety of these agents observed in patients with OA is examined, based on an overview of published clinical data and/or treatment guidelines (when available), in the context of differences in their MOAs.

Less common etiologies of exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include unresectable pancreatic cancer, metabolic diseases (diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin (CCK); celiac or inflammatory bowel disease (IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery (asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy (PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI (66%-92%). EPI occurs in patients with type 1 (26%-57%) or type 2 diabetes (20%-36%) and is typically mild to moderate; by definition, all patients with type 3c (pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease (4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD (14%-74%) and up to 100% of gastrointestinal surgery patients (47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

Electronic health databases for epidemiological research on joint replacements: considerations when making cross-national comparisons.

PURPOSE: The purpose of this study was to examine the rate of primary knee, hip, or shoulder replacement among persons with osteoarthritis (OA) of the knee by gender and age comparing two nations in similar periods using electronic health records, but with different health-care systems. METHODS: Two electronic health care databases of anonymized information were used to construct cohorts of adults with OA of the knee from the United Kingdom (UK) and the United States. Patients were required to have activity in the database at least 6 months before the first diagnosis of knee OA ("index diagnosis") in the study period to ensure that the patient samples were eligible for medical evaluation. The outcomes (numerator) measured were primary knee, hip, or shoulder replacement or the composite of primary knee, hip, or shoulder replacement. The denominator was the person-time at risk computed from time from the date of the index diagnosis to the date of each outcome separately or to the end of the database period if no outcome was documented. RESULTS: There were 93,146 subjects in the UK and 1,468,217 in the United States who were aged 18+ years and met the study eligibility criteria. The composite joint replacement rate (hip, knee, or shoulder) ranged from 11.89 per 100 person-years (PY) in the Unites States to 4.13 per 100 PY in the UK Primary knee replacements rates ranged from 10.38 per 100 PY in the Unites States to 3.40 per 100 PY in the UK and occurred at a somewhat higher rate in males than females in both countries. Both primary hip and shoulder replacement rates were higher in the Unites States than in the UK (hip: 1.19 per 100 PY and 0.76 per 100 PY; shoulder: 0.19 per 100 PY and 0.03 per 100 PY, respectively). The median time to a primary hip or knee replacement in the UK was approximately twice as long as in the Unites States. CONCLUSIONS: Knee replacements are not an uncommon event in persons with knee OA occurring throughout the adult life span, with the rate steeply rising in both sexes until aged 75 years. Although the pattern of the age-specific joint replacement rates was similar between sexes, the magnitude of the rates was markedly lower in the UK.

Safety and tolerability of duloxetine in the acute management of diabetic peripheral neuropathic pain: analysis of pooled data from three placebo-controlled clinical trials.

OBJECTIVE: Summarize safety and tolerability of duloxetine in treating diabetic peripheral neuropathic pain. RESEARCH DESIGN AND METHODS: Pooled data from three double-blind, randomized studies with 12-week, placebo-controlled (acute) and 52-week, routine-care-controlled (extension) phases. MAIN OUTCOME MEASURES: Frequency/discontinuations due to treatment-emergent adverse events (TEAEs). RESULTS: There were 1139 (placebo, n = 339; duloxetine, n = 800) and 867 (routine-care, n = 287; duloxetine, n = 580) patients in the acute and extension phases, respectively. Patient details were as follow: 60 years (mean age); Caucasian, 84%; and male, 57%. In the acute phase, there were significantly more TEAEs, duloxetine versus placebo (p = 0.001), the most common being nausea and somnolence. Discontinuations due to adverse events were significantly greater (12.5 vs 5.6%, p < 0.001), with similar outcomes in the extension phase. Baseline-to-endpoint aspartate transaminase/alanine transaminase were significantly increased and fasting plasma glucose was increased for duloxetine (0.67 mmol/l) versus decreased in routine-care (-0.64 mmol/l, p < 0.001). HbA1c was significantly increased, duloxetine vs routine-care, in the extension phase (52 vs 19%, p < 0.001). Endpoint measures neuropathy, nephropathy and retinopathy indicated no disease progression. CONCLUSIONS: Duloxetine was generally safe and well tolerated, with the three most commonly reported TEAEs being nausea, somnolence and constipation. Modest changes in glycemia were associated with duloxetine. Aspartate transaminase/alanine transaminase increases were transient and not considered predictive of more severe outcomes.

Prevalence of other diabetes-associated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy.

INTRODUCTION: Diabetic neuropathy (DN) is a common complication associated with diabetes. This study assesses the prevalence of other diabetes-related complications or comorbidities among DN patients and its marginal contribution to health care charges. METHODS: Using administrative claims database, we studied commercially insured patients below 65 years old with at least one claim of DN anytime from July 2004 through June 2005 (Year 1). Using propensity scoring, a 10:1 ratio of demographically matched controls with diabetes but no DN was constructed. Both DN patients and controls had 12 months of continuous enrollment in Year 1 and Year 2 (July 2005-June 2006). We compared the Year 1 prevalence of other diabetes-associated complications or comorbidities between DN patients and diabetic controls. Controlling for comorbidities, we used multivariate regressions to examine the incremental impact of DN or any other diabetes-related complication or comorbidity on Year 2 health care charges. RESULTS: A higher percentage of DN patients had at least one other diabetes-related complication or comorbidity than diabetic controls. Individuals with DN had a higher prevalence of each individual other diabetes-related complication or comorbidity. Controlling for comorbidities, the presence of any other diabetes-related complication or comorbidity was statistically associated with higher outpatient pharmacy and total charges for both DN patients and controls. Total and outpatient pharmacy charges were also significantly higher for DN patients than for controls, among those with or without any other diabetes-related complications or comorbidities. CONCLUSIONS: DN can occur in the absence of other diabetes-related complications or comorbidities. The presence of DN and any other diabetes-related complications or comorbidities significantly increases health care charges.

Does pain cause the perception of fatigue in patients with chronic pain? Findings from studies for management of diabetic peripheral neuropathic pain with duloxetine.

A major issue in pain literature is whether an etiological association between pain, sleep, and vitality exists. We utilized data from clinical trials of duloxetine for management of diabetic peripheral neuropathic pain (DPNP) to investigate these associations. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials of patients without mood disorder (N = 1,139). After excluding 442 patients who reported maximum vitality at baseline, experienced treatment-emergent somnolence, asthenia or fatigue, or were taking sedating concomitant medications or duloxetine 20 mg/day, 697 were included in the analysis. Efficacy measures included weekly mean scores for average daily and night pain, pain interference with sleep, and vitality. Baseline to end point mean improvements in daily and night pain, Brief Pain Inventory sleep interference, and vitality were significantly superior for duloxetine compared with placebo (P < or = 0.001). Correlations between changes in daily and night pain, and sleep interference with vitality changes were -0.34, -0.32, and -0.28, respectively (P < 0.001). The direct effect of treatment on change in vitality was statistically significant (68%, P = 0.010) when assessed in an indirect manner through change in sleep interference alone but not in daily or night pain solely. Path analyses suggested vitality improvement in patients with chronic pain may be secondary to improvement in pain by duloxetine. Results do not prove pain causes fatigue, but indicate in DPNP patients with fatigue that treatment of pain can improve perception of improvement in fatigue. Thus, improvement of pain may be important in the context of trying to improve fatigue in DPNP patients.

Safety and efficacy of duloxetine in the treatment of diabetic peripheral neuropathic pain in older patients.

OBJECTIVE: We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. METHODS: Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age (<65, >or=65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-to-treat analyses were used for safety and efficacy assessment. RESULTS: In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P<0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P<0.01). In the extension phase, a significant therapy-by-age interaction (P<0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had >or=1 TEAE versus 74.6% of younger patients. CONCLUSIONS: Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients>or=65.

Does pain mediate the pain interference with sleep problem in chronic pain? Findings from studies for management of diabetic peripheral neuropathic pain with duloxetine.

Although sleep problems are common in patients with chronic pain, it is unclear whether pain mediates (causes) impaired sleep. The relationship between pain and sleep has been difficult to investigate because of the potential confounds of depression and somnolence. This report used clinical trials data for duloxetine in the management of diabetic peripheral neuropathic pain (DPNP) to investigate the direction of this association. Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials of patients with DPNP without mood disorder (n=1,139). DPNP patients reporting somnolence and those who were receiving sedating concomitant medications were removed from the analyses (n=93). Efficacy measures included weekly mean scores for average daily pain severity, night pain severity, and pain interference with sleep. Duloxetine at 60 and 120 mg per day separated from placebo for average pain and night pain improvement as early as one week after treatment began, whereas sleep interference improvement separated from placebo at the three visits it was assessed (Weeks 4, 8, and 12). Change in sleep interference was moderately to strongly correlated (P<0.001) with changes in average pain (r=0.46) and nighttime pain severity (r=0.53). These results confirm the association between the improvement in daily pain and nighttime pain, and improvement in sleep interference for a large population without depression or somnolence. Although this association cannot establish causality, these results provide some evidence for the possibility that pain may mediate the sleep problem associated with DPNP and perhaps chronic pain in general.

Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain.

OBJECTIVE: To evaluate the impact of baseline disease variables related to diabetes and diabetic neuropathy severity on efficacy and safety of duloxetine in the management of diabetic peripheral neuropathic pain. RESEARCH DESIGN AND METHODS: The impact of baseline conditions was evaluated using the data from three pooled placebo-controlled studies for combined duloxetine, doses of 60 mg q.d. and 60 mg b.i.d., versus placebo. The primary efficacy measure was the weekly mean of 24-h average pain severity, and night pain was the secondary measure. Safety and tolerability were assessed. RESULTS: There were no significant (P > 0.10) interactions of treatment by age (< 65 or > or = 65 years), type of diabetes (type 1 or type 2), duration of diabetes (median split < 9.18 or > or = 9.18 years), duration of diabetic neuropathy (< 2, 2 to < 6, or > or = 6 years), severity of diabetic neuropathy (baseline Michigan Neuropathy Screening Instrument score < 5 or > or = 5), baseline A1C level (median split < 7.6 or > or = 7.6%), or baseline insulin use (yes/no). Significant interactions for both pain measures were observed in baseline pain subgroups (Brief Pain Inventory average pain, > or = 6 and < 6). Duloxetine was more effective in the subgroup with more pain. No significant association was found between any other subgroups (P > 0.10). Significant interactions (P < 0.1) occurred with treatment-emergent adverse events when stratified by subgroups. CONCLUSIONS: Pain severity but not variables related to diabetes or neuropathy may predict the effects of duloxetine in diabetic peripheral neuropathic pain. The efficacy of duloxetine is related to the initial pain severity and is generalizable across a broad spectrum of diabetic patients, including those with the highest severity of diabetes or neuropathy.