Quantifying sustained pain worsening in knee osteoarthritis.

OBJECTIVE: Recent work suggests that many persons with knee osteoarthritis (OA) experience stable symptoms over time. Whether patients experience periods of symptom exacerbation or flare which interrupt this stable course, and how long such periods last, has received little study. Our objective is to describe the frequency and duration of episodes of pain worsening in persons with knee OA. METHODS: We selected participants from the Osteoarthritis Initiative with radiographic, symptomatic knee OA. We defined a clinically relevant increase in knee pain as an increase in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain of ≥9 points. We defined sustained worsening as maintaining at least 80% of the initial increase. We used Poisson regression to estimate the incidence rate (IR) of episodes of pain worsening. RESULTS: 1093 participants were included in the analysis. Eighty-eight percent had ≥1 increase in WOMAC pain ≥9 points (IR: 26.3 per 100 person years (95% CI: 25.2, 27.4)). Forty-eight percent had ≥1 episode of sustained worsening (IR: 9.7 per 100 person-years (95% CI: 8.9, 10.5)). Elevated pain was maintained an average of 2.4 years after the initial increase. CONCLUSION: Most participants with knee OA reported at least one clinically relevant increase in WOMAC pain, but fewer than half experienced an episode of sustained pain worsening. These individual-level data portray a more nuanced and fluctuating course of OA pain than suggested by trajectory studies. These data could be useful in shared decision-making regarding prognosis and treatment choices in persons affected by symptomatic knee OA.

Does gabapentin provide benefit for patients with knee OA? A benefit-harm and cost-effectiveness analysis.

OBJECTIVE: Gabapentin can treat neuropathic pain syndromes and has increasingly been prescribed to treat nociplastic pain. Some patients with knee osteoarthritis (OA) suffer from both nociceptive and nociplastic pain. We examined the cost-effectiveness of adding gabapentin to knee OA care. METHOD: We used the Osteoarthritis Policy Model, a validated Monte Carlo simulation of knee OA, to examine the value of gabapentin in treating knee OA by comparing three strategies: 1) usual care, gabapentin sparing (UC-GS); 2) targeted gabapentin (TG), which provides gabapentin plus usual care for those who screen positive for nociplastic pain on the modified PainDETECT questionnaire (mPD-Q) and usual care only for those who screen negative; and 3) universal gabapentin plus usual care (UG). Outcomes included cumulative quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. We derived model inputs from published literature and national databases and varied key input parameters in sensitivity analyses. RESULTS: UC-GS dominated both gabapentin-containing strategies, as it led to lower costs and more QALYs. TG resulted in a cost increase of $689 and a cumulative QALY reduction of 0.012 QALYs. UG resulted in a further $1,868 cost increase and 0.036 QALY decrease. The results were robust to plausible changes in input parameters. The lowest TG strategy ICER of $53,000/QALY was reported when mPD-Q specificity was increased to 100% and AE rate was reduced to 0%. CONCLUSION: Incorporating gabapentin into care for patients with knee OA does not appear to offer good value.

Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative.

OBJECTIVE: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). DESIGN: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by ≥80% of participants were retained, and participants could suggest additional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if ≥80% rated it ≥6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if ≥80% of participants rated it ≥9 and as "optional" if ≥80% rated it ≥7. RESULTS: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. CONCLUSION: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context.

The burden of OA-health services and economics.

Osteoarthritis (OA) is a highly prevalent and disabling condition that affects over 7% of people globally (528 million people). Prevalence levels are even higher in countries with established market economies, which have older demographic profiles and a higher prevalence of obesity, such as the US (14%). As the 15th highest cause of years lived with disability (YLDs) worldwide, the burden OA poses to individuals is substantial, characterized by pain, activity limitations, and reduced quality of life. The economic impact of OA, which includes direct and indirect (time) costs, is also substantial, ranging from 1 to 2.5% of gross national product (GNP) in countries with established market economies. In regions around the world, the average annual cost of OA for an individual is estimated between $700-$15,600 (2019 USD). Though trends in OA prevalence vary by geography, the prevalence of OA is projected to rise in regions with established market economies such as North America and Europe, where populations are aging and the prevalence of obesity is rising.

Cost-effectiveness of duloxetine for knee OA subjects: the role of pain severity.

OBJECTIVE: Establish the impact of pain severity on the cost-effectiveness of generic duloxetine for knee osteoarthritis (OA) in the United States. DESIGN: We used a validated computer simulation of knee OA to compare usual care (UC) - intra-articular injections, opioids, and total knee replacement (TKR) - to UC preceded by duloxetine in those no longer achieving pain relief from non-steroidal anti-inflammatory drugs (NSAIDs). Outcomes included quality-adjusted life years (QALYs), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs). We considered cohorts with mean ages 57-75 years and Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 25-55 (0-100, 100-worst). We derived inputs from published data. We discounted costs and benefits 3% annually. We conducted sensitivity analyses of duloxetine efficacy, duration of pain relief, toxicity, and costs. RESULTS: Among younger subjects with severe pain (WOMAC pain = 55), duloxetine led to an additional 9.6 QALYs per 1,000 subjects (ICER = $88,500/QALY). The likelihood of duloxetine being cost-effective at willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY was 40% and 54%. Offering duloxetine to older patients with severe pain led to ICERs >$150,000/QALY. Offering duloxetine to subjects with moderate pain (pain = 25) led to ICERs <$50,000/QALY, regardless of age. Among knee OA subjects with severe pain (pain = 55) who are unwilling or unable to undergo TKR, ICERs were <$50,600/QALY, regardless of age. CONCLUSIONS: Duloxetine is a cost-effective addition to knee OA UC for subjects with moderate pain or those with severe pain unable or unwilling to undergo TKR. Among younger subjects with severe pain, duloxetine is cost-effective at WTP thresholds >$88,500/QALY.

Estimating contextual effect in nonpharmacological therapies for pain in knee osteoarthritis: a systematic analytic review.

OBJECTIVE: Conduct a systematic review and use meta-analytic techniques to estimate the proportion of total treatment effect that can be attributable to contextual effects (PCE) in adults receiving nonpharmacological, nonsurgical (NPNS) treatments for knee osteoarthritis (OA). DESIGN: We reviewed the published literature to identify five frequently studied NPNS treatments for knee OA: exercise, acupuncture, ultrasound, laser, and transcutaneous electrical nerve stimulation (TENS). We searched for randomized controlled trials (RCTs) of these treatments and abstracted pre- and post-intervention pain scores for groups receiving placebo and active treatments. For each study we calculated the PCE by dividing the change in pain in the placebo group by the change in pain in the active treatment group. We log transformed the PCE measure and pooled across studies using a random effects model. RESULTS: We identified 25 studies for analysis and clustered the RCTs into two groups: acupuncture and topical energy modalities (TEM). 13 acupuncture studies included 1,653 subjects and 12 TEM studies included 572 subjects. The combined PCE was 0.61 (95% CI 0.46-0.80) for acupuncture and 0.69 (95% CI 0.54-0.88) for TEM. CONCLUSION: Our findings suggest that about 61% and 69% of the total treatment effect experienced by subjects receiving acupuncture and TEM treatments, respectively, for knee OA pain may be explained by contextual effects. Contextual effects may include the placebo effect, changes attributable to natural history, and effects of co-therapies. These data highlight the important role of contextual effects in the response to NPNS OA treatments.

Long-term clinical and economic outcomes of a short-term physical activity program in knee osteoarthritis patients.

OBJECTIVE: Physical activity (PA) in the US knee osteoarthritis (OA) population is low, despite well-established health benefits. PA program implementation is often stymied by sustainability concerns. We sought to establish parameters that would make a short-term (3-year efficacy) PA program a cost-effective component of long-term OA care. METHOD: Using a validated computer microsimulation (Osteoarthritis Policy Model), we examined the long-term clinical (e.g., comorbidities averted), quality of life (QoL), and economic impacts of a 3-year PA program, based upon the SPARKS (Studying Physical Activity Rewards after Knee Surgery) Trial, for inactive knee OA patients. We determined the cost, efficacy, and impact of PA on QoL and medical costs that would make a PA program a cost-effective addition to OA care. RESULTS: Among the 14 million with knee OA in the US, >4 million are inactive. Participation of 10% in the modeled PA program could save 200 cases of cardiovascular disease, 400 cases of diabetes, and 6,800 quality-adjusted life-years (QALYs). The program had an incremental cost-effectiveness ratio (ICER) of $16,100/QALY. Tripling PA program cost ($860/year) raised the ICER to $108,300/QALY; varying QoL benefits from PA yielded ICERs of $8,800/QALY-$99,900/QALY; varying background cost savings from PA did not qualitatively impact ICERs. Offering the PA program to any adults with knee OA (not only inactive) yielded $31,000/QALY. CONCLUSION: A PA program with 3-year efficacy in the knee OA population carried favorable long-term clinical and economic benefits. These results offer justification for policymakers and payers considering a PA intervention incorporated into knee OA care.

The impact of painful knee osteoarthritis on mortality: a community-based cohort study with over 24 years of follow-up.

OBJECTIVE: To investigate the impact of knee osteoarthritis (OA) and/or knee pain on excess mortality. METHOD: We analyzed data from 4,182 participants in a community-based prospective cohort study of African American and Caucasian men and women aged ≥45 years. Participants completed knee radiographs and questionnaires at baseline and at up to three follow-ups to determine knee OA (rOA), knee pain and covariate status. Mortality was determined through 2015. We used Cox proportional hazards regression with time-varying covariates (TVC) to estimate hazard ratios (HR) and 95% confidence intervals (CI). Additional analyses stratified by sex, race and age were carried out. RESULTS: Median follow-up time was 14.6 years during which 1822 deaths occurred. Baseline knee radiographic osteoarthritis (rOA) was 27.7%, 38.8% at first follow-up, 52.6% at second follow-up and 61.9% at the third follow-up. Knee rOA with pain and knee pain alone were both associated with a >15% increase in premature all-cause mortality. In analyses stratified by sex, race and age, associations between knee pain, with or without knee rOA, and all-cause death were found among women, Caucasians, those ≤65 years of age, and those with a body mass index (BMI)≥30, with observed increased risks of death between 21% and 65%. We observed similar, somewhat attenuated, results for cardiovascular disease (CVD) deaths. CONCLUSION: In models taking into account variables that change over time, individuals who had knee pain, alone or with knee rOA, had increased mortality. These effects were particularly strong among those obese. Effective interventions to reduce knee pain, particularly those including weight management and prevention of comorbidities, could reduce mortality.

Trends in procedure type, patient characteristics, and outcomes among persons with knee osteoarthritis undergoing bariatric surgery, 2005-2014.

OBJECTIVE: To evaluate trends in the utilization, clinical characteristics, and inpatient outcomes among persons with knee osteoarthritis undergoing bariatric surgery. METHOD: We used the National Inpatient Sample (NIS) to examine trends of bariatric surgeries performed on adults with clinically documented knee osteoarthritis between 2005 and 2014. We abstracted hospital setting, procedure, demographic and clinical characteristics, and inpatient surgical outcomes from each discharge. We examined temporal trends using linear regression and Cochran-Armitage test for trend. RESULTS: The utilization of bariatric surgery among persons with knee osteoarthritis from 2005 to 2014 remained consistent, with an annual total of about 3,300 procedures performed nationally. The most common procedure type changed from laparoscopic Roux-en-Y (65%) in 2005-2006 to laparoscopic sleeve gastrectomy (58%) in 2013-2014. The median age, proportion on Medicare, and age- and sex-adjusted prevalence of diabetes increased from 46 to 51 years, 7-23%, and 28-32%, respectively. From 2005 to 2014, the median adjusted costs, in 2017 USD, for laparoscopic and open Roux-en-Y surgeries decreased from $15,100 to $13,300 (p < 0.01) and $14,100 to $10,100 (p = 0.0001), respectively, whereas the costs of laparoscopic sleeve gastrectomy and laparoscopic banding did not change significantly. In-hospital mortality remained at 0.0-0.1% from 2005 to 2014. CONCLUSION: Although growing evidence suggests that bariatric surgery is associated with improvements in osteoarthritis pain and functional status, the utilization of bariatric surgery among morbidly obese persons with knee osteoarthritis remained consistent from 2005 to 2014. Bariatric surgery in persons with knee osteoarthritis is generally safe, as inpatient complication and mortality rates remained low despite an increase in age and number of comorbidities.

Cost-effectiveness of health coaching and financial incentives to promote physical activity after total knee replacement.

OBJECTIVE: We evaluated the cost-effectiveness of Telephonic Health Coaching and Financial Incentives (THC + FI) to promote physical activity in total knee replacement recipients. DESIGN: We used the Osteoarthritis Policy Model, a computer simulation of knee osteoarthritis, to evaluate the cost-effectiveness of THC + FI compared to usual care. We derived transition probabilities, utilities, and costs from trial data. We conducted lifetime analyses from the healthcare perspective and discounted all cost-effectiveness outcomes by 3% annually. The primary outcome was the Incremental Cost-Effectiveness Ratio (ICER), defined as the ratio of the differences in costs and Quality-Adjusted Life Years (QALYs) between strategies. We considered ICERs <$100,000/QALY to be cost-effective. We conducted one-way sensitivity analyses that varied parameters across their 95% confidence intervals (CI) and limited the efficacy of THC + FI to 1 year or to 9 months. We also conducted a probabilistic sensitivity analysis (PSA), simultaneously varying cost, utilities, and transition probabilities. RESULTS: THC + FI had an ICER of $57,200/QALY in the base case and an ICER below $100,000/QALY in most deterministic sensitivity analyses. THC + FI cost-effectiveness depended on assumptions about long-term efficacy; when efficacy was limited to 1 year or to 9 months, the ICER was $93,300/QALY or $121,800/QALY, respectively. In the PSA, THC + FI had an ICER below $100,000/QALY in 70% of iterations. CONCLUSIONS: Based on currently available information, THC + FI might be a cost-effective alternative to usual care. However, the uncertainty surrounding this choice is considerable, and further research to reduce this uncertainty may be economically justified.

Cost-effectiveness of generic celecoxib in knee osteoarthritis for average-risk patients: a model-based evaluation.

OBJECTIVE: The cost-effectiveness of the recently-introduced generic celecoxib in knee OA has not been examined. METHOD: We used the Osteoarthritis Policy (OAPol) Model, a validated computer simulation of knee OA, to evaluate long-term clinical outcomes, costs, and cost-effectiveness of generic celecoxib in persons with knee OA. We examined eight treatment strategies consisting of generic celecoxib, over-the-counter (OTC) naproxen, or prescription naproxen, with or without prescription or OTC proton-pump-inhibitors (PPIs) to reduce gastrointestinal (GI) toxicity. In the base case, we assumed that annual cost was $130 for OTC naproxen, $360 for prescription naproxen, and $880 for generic celecoxib. We considered a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) and discounted costs and benefits at 3% annually. In sensitivity analyses we varied celecoxib toxicity, discontinuation, cost, and pain level. RESULTS: In the base case analysis of the high pain cohort (WOMAC 50), celecoxib had an incremental cost-effectiveness ratio (ICER) of $284,630/QALY compared with OTC naproxen. Only under highly favorable cost, toxicity, and discontinuation assumptions (e.g., annual cost below $360, combined with a reduction in the cardiovascular (CV) event rates below baseline values) was celecoxib likely to be cost-effective. Celecoxib might also be cost-effective at an annual cost of $600 if CV toxicity were eliminated completely. In subjects with moderate pain (WOMAC 30), at the base case CV event rate of 0.2%, generic celecoxib was only cost-effective at the lowest plausible cost ($190). CONCLUSION: In knee OA patients with no comorbidities, generic celecoxib is not cost-effective at its current price.

The association of pre-operative body pain diagram scores with pain outcomes following total knee arthroplasty.

OBJECTIVE: Approximately 20% of total knee arthroplasty (TKA) recipients have suboptimal pain relief. We evaluated the association between pre-surgical widespread body pain and incomplete pain relief following TKA. METHOD: This prospective analysis included 241 patients with knee osteoarthritis (OA) undergoing unilateral TKA who completed questionnaires preoperatively and up to 12 months post-operatively. Questionnaires included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and a body pain diagram. We derived the number of non-index painful body regions from the diagram. We used Poisson regression to determine the association between painful body regions identified preoperatively and both WOMAC pain at follow-up and improvement in pain as defined by the minimal clinically important difference (MCID). RESULTS: Mean subject age was 66 years (SD 9), and 61% were females. Adjusting for age, sex, co-morbid conditions, baseline pain, pain catastrophizing, and mental health, we found that more widespread body pain was associated with a higher likelihood of reporting 12-month WOMAC pain score >15 (relative risk [RR] per painful body region 1.39, 95% CI 1.18-1.63) and a greater likelihood of failing to achieve the MCID (RR 1.47, 95% CI 1.16-1.86).). Pain catastrophizing was an independent predictor of persistent pain and failure to improve by the MCID (RR 3.57, 95% CI 1.73-7.31). CONCLUSIONS: Pre-operative widespread pain was associated with greater pain at 12-months and failure to reach the MCID. Widespread pain as captured by the pain diagram, along with the pain catastrophizing score, may help identify persons with suboptimal TKA outcome.

Associations among meniscal damage, meniscal symptoms and knee pain severity.

OBJECTIVE: Meniscal tears occur frequently in patients with knee osteoarthritis (OA). The aim of our study was to determine whether meniscal damage identified on magnetic resonance imaging (MRI) is associated with the severity of knee pain or the frequency of meniscal symptoms in patients with knee OA. METHODS: We performed a cross-sectional study using data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial. We characterized meniscal damage hierarchically as: root tear; maceration; long and short complex or horizontal tears; and simple tears. Subjects completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Scale and a survey of frequency of meniscal symptoms. We used multivariable general linear models to assess the relationships between meniscal damage and 1) pain severity; and 2) meniscal symptoms, after adjusting for demographic and radiographic features. In further analysis root tear was considered as a binary variable. RESULTS: Analysis included 227 knees. Root tears were present in 19%, maceration in 14%, long complex or horizontal tears in 22%, short complex or horizontal tears in 30%, and simple tears in 14%. Root tears were associated with higher WOMAC pain scores. The adjusted mean WOMAC pain score was 45.2 (standard error (SE) 2.7) for those with root tear and 38.7 (SE 1.2) for subjects without root tear (P = 0.03). We did not find statistically significant associations between meniscal morphology and frequency of meniscal symptoms. CONCLUSION: Root tears were associated with greater pain than meniscal tears or maceration. We did not find a relationship between meniscal damage and meniscal symptoms.

Factors associated with fractures in HIV-infected persons: which factors matter?

This study aims to determine what factors are associated with increased risk of fracture among patients with HIV, in particular whether an important medication used to treat HIV, tenofovir, is associated with fracture. Our study found that while co-infection with hepatitis C and markers of HIV severity were associated with fracture, tenofovir was not. INTRODUCTION: Growing evidence suggests that tenofovir disoproxil fumarate decreases bone density among patients with HIV, but there are conflicting reports as to whether this decrease in bone density translates to higher fracture risk. We aimed to determine what factors were associated with an increased risk of fracture for patients with HIV, in particular whether tenofovir is associated with elevated fracture risk. METHODS: We conducted a retrospective cohort study at two tertiary care hospitals in Boston, MA, between 2001 and 2012 to determine whether tenofovir use is associated with elevated all-site fracture risk, as compared to other antiretroviral medications. We also examined other potential factors associated with fracture among patients with HIV. RESULTS: We identified 1981 HIV-infected patients who had at some point used tenofovir and 682 patients who had not. The mean age was 43 years, and 72 % were male. The hepatitis C co-infection rate was 28 %, about 40 % had nadir CD4 count <200, and about 40 % had a history of an AIDS-defining illness. We did not find an association between risk of fracture and tenofovir disoproxil fumarate (TDF) (adjusted RR (aRR) 0.8, 95 % CI 0.6-1.1). However, co-infection with hepatitis C did increase risk of fracture (aRR 1.6, 95 % CI 1.1-2.3), as did nadir CD4 count <200 (aRR 3.1, 95 % CI 1.9-5.0) and history of AIDS-defining illness (aRR 1.6, 95 % CI 1.1-2.2). CONCLUSION: There was no association found between fracture and tenofovir use, but there were associations between co-infection with hepatitis C and markers of advanced HIV disease and fracture.

Risk and risk perception of knee osteoarthritis in the US: a population-based study.

OBJECTIVE: We sought to investigate risk perception among an online cohort of younger US adults compared with calculated risk estimates. DESIGN: We recruited a population-based cohort 25-44 years of age with no history of knee osteoarthritis (OA) using Amazon's Mechanical Turk, an online marketplace used extensively for behavioral research. After collecting demographic and risk factor information, we asked participants to estimate their 10-year and lifetime risk of knee OA. We compared perceived risk with risk derived from the OA risk calculator (OA Risk C), an online tool built on the basis of the validated OA Policy Model. RESULTS: 375 people completed the study. 21% reported having 3+ risk factors for OA, 25% reported two risk factors, and 32% reported one risk factor. Using the OA Risk C, we calculated a mean lifetime OA risk of 25% and 10-year risk of 4% for this sample. Participants overestimated their lifetime and 10-year OA risk at 48% and 26%, respectively. We found that obesity, female sex, family history of OA, history of knee injury, and occupational exposure were all significantly associated with greater perceived lifetime risk of OA. CONCLUSIONS: Risk factors are prevalent in this relatively young cohort. Participants consistently overestimated their lifetime risk and showed even greater overestimation of their 10-year risk, suggesting a lack of knowledge about the timing of OA onset. These data offer insights for awareness and risk interventions among younger persons at risk for knee OA.

Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review.

OBJECTIVE: Summarize the comparative effectiveness of oral non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in reducing knee osteoarthritis (OA) pain. METHODS: Two reviewers independently screened reports of randomized controlled trials (RCTs), published in English between 1982 and 2015, evaluating oral NSAIDs or opioids for knee OA. Included studies were at least 8 weeks duration, conducted in Western Europe, the Americas, New Zealand, or Australia, and reported baseline and follow-up pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale (0-100, 100-worst). Effectiveness was evaluated as reduction in pain, accounting for study dropout and heterogeneity. RESULTS: Twenty-seven treatment arms (nine celecoxib, four non-selective NSAIDs [diclofenac, naproxen, piroxicam], eleven less potent opioids [tramadol], and three potent opioids [hydromorphone, oxycodone]) from 17 studies were included. NSAID and opioid studies reported similar baseline demographics and efficacy withdrawal rates; NSAID studies reported lower baseline pain and toxicity withdrawal rates. Accounting for efficacy-related withdrawals, all drug classes were associated with similar pain reductions (NSAIDs: -18; less potent opioids: -18; potent opioids: -19). Meta-regression did not reveal differential effectiveness by drug class but found that study cohorts with a higher proportion of male subjects and worse mean baseline pain had greater pain reduction. Similarly, results of the network meta-analysis did not find a significant difference in WOMAC Pain reduction for the three analgesic classes. CONCLUSION: NSAIDs and opioids offer similar pain relief in OA patients. These data could help clinicians and patients discuss likely benefits of alternative analgesics.

Model-based evaluation of cost-effectiveness of nerve growth factor inhibitors in knee osteoarthritis: impact of drug cost, toxicity, and means of administration.

OBJECTIVE: Studies suggest nerve growth factor inhibitors (NGFi) relieve pain but may accelerate disease progression in some patients with osteoarthritis (OA). We sought cost and toxicity thresholds that would make NGFi a cost-effective treatment for moderate-to-severe knee OA. DESIGN: We used the Osteoarthritis Policy (OAPol) model to estimate the cost-effectiveness of NGFi compared to standard of care (SOC) in OA, using Tanezumab as an example. Efficacy and rates of accelerated OA progression were based on published studies. We varied the price/dose from $200 to $1000. We considered self-administered subcutaneous (SC) injections (no administration cost) vs provider-administered intravenous (IV) infusion ($69-$433/dose). Strategies were defined as cost-effective if their incremental cost-effectiveness ratio (ICER) was less than $100,000/quality-adjusted life year (QALY). In sensitivity analyses we varied efficacy, toxicity, and costs. RESULTS: SOC in patients with high levels of pain led to an average discounted quality-adjusted life expectancy of 11.15 QALYs, a lifetime risk of total knee replacement surgery (TKR) of 74%, and cumulative discounted direct medical costs of $148,700. Adding Tanezumab increased QALYs to 11.42, reduced primary TKR utilization to 63%, and increased costs to between $155,400 and $199,500. In the base-case analysis, Tanezumab at $600/dose was cost-effective when delivered outside of a hospital. At $1000/dose, Tanezumab was not cost-effective in all but the most optimistic scenario. Only at rates of accelerated OA progression of 10% or more (10-fold higher than reported values) did Tanezumab decrease QALYs and fail to represent a viable option. CONCLUSIONS: At $100,000/QALY, Tanezumab would be cost effective if priced ≤$400/dose in all settings except IV hospital delivery.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Prevalence of cryptococcal antigenuria at initial HIV diagnosis in KwaZulu-Natal.

OBJECTIVES: The World Health Organization (WHO) recommends screening HIV-infected people for cryptococcal antigens to identify cryptococcosis, a major cause of AIDS-related deaths. As the burden of cryptococcosis is unknown in South Africa's KwaZulu-Natal province, we assessed the cryptococcal antigenuria prevalence among newly diagnosed HIV-infected adults there. METHODS: We conducted a cross-sectional study of newly diagnosed HIV-infected adults who received voluntary HIV testing in an out-patient clinic. Participants provided a urine specimen in a sterile container, and we performed testing with a WHO-endorsed rapid cryptococcal antigen lateral flow assay (Immy Inc., Norman, OK, USA) per the manufacturer's specifications. We assessed cryptococcal antigenuria prevalence among participants with CD4 counts < 200 cells/µL, and stratified results by CD4 count categories. RESULTS: Among 432 participants, the mean (± standard deviation) age was 36.1 ± 9.9 years and 172 (40%) were female. The overall estimated prevalence of cryptococcal antigenuria was 9.0% [95% confidence interval (CI) 6.5-12.1%]. CD4 counts were available for 319 participants (74%); the median CD4 count was 75 cells/µL [interquartile range (IQR) 34-129 cells/µL]. Participants with a negative cryptococcal antigenuria screening test had a median CD4 count of 79 cells/µL (IQR 36-129 cells/µL), while participants with a positive cryptococcal test had a median CD4 count of 41 cells/µL (IQR 10-112 cells/µL). The estimated prevalence of cryptococcal antigenuria among participants with CD4 counts < 50 cells/µL was 12.5% (95% CI 7.0-20.1%), which was significantly higher than that among participants with CD4 counts of 50-200 cells/µL (4.8%; 95% CI 2.3-8.7%). CONCLUSIONS: Nearly 1 in 10 newly diagnosed HIV-infected adults with CD4 counts < 200 cells/µL in KwaZulu-Natal had evidence of cryptococcal antigenuria. Point-of-care CD4 count testing and cryptococcal antigen screening may rapidly identify cryptococcosis at the time of HIV diagnosis.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of surgical interventions for osteoarthritis.

To highlight methodological challenges in the design and conduct of randomized trials of surgical interventions and to propose strategies for addressing these challenges. This paper focuses on three broad areas: enrollment; intervention; and assessment including implications for analysis. For each challenge raised in the paper, we propose potential solutions. Enrollment poses challenges in maintaining investigator equipoise, managing conflict of interest and anticipating that patient preferences for specific treatments may reduce enrollment. Intervention design and implementation pose challenges relating to obsolescence, fidelity of intervention delivery, and adherence and crossover. Assessment and analysis raise questions regarding blinding and clustering of observations. This paper describes methodological problems in the design and conduct of surgical randomized trials and proposes strategies for addressing these challenges.