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.

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.

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.