Potential Anti-Inflammatory and Analgesic Effects of Saffron in Patients with Osteoarthritis: A Randomized Controlled Trial.

Background: The prevalence of arthritis-attributable activity limitation, work limitation and severe pain are significantly higher among Hispanics than among non-Hispanic Whites (NHWs) in the US. While Hispanics are less likely to report regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), reasons for this decreased NSAID use are unknown. It is also unclear whether there are ethnic differences in the use of both over-the-counter (OTC) and prescription NSAIDs. Objectives: To determine: 1) if there are ethnic differences in the use of OTC and prescription oral NSAIDs for knee/hip osteoarthritis (OA); 2) if there are differences in familiarity with and perceptions of efficacy and risk of NSAIDs between Hispanics and NHWs; and 3) if patient attitudes/beliefs about NSAIDs mediate observed ethnic differences in the use of NSAIDS for OA. Methods: Participants ≥50 years of age with chronic frequent pain due to knee/hip OA completed structured interviews. Data on sociodemographic characteristics, clinical information, actual use of oral NSAIDs for OA treatment (last 6 months), and familiarity with NSAIDs (3 items, yes/no response) were collected. Perceptions of efficacy (4 items) and risk (3 items) of NSAIDs were evaluated using five-category ordinal response scale questions. Responses were averaged, with higher values indicating higher perception of efficacy/risk. Fisher’s exact or Wilcoxon-Mann-Whitney tests were conducted to determine if knowledge and perceptions about NSAIDs differed by ethnicity. Multivariable logistic regression models were built to determine if ethnic differences in NSAID use were mediated by knowledge and perceptions about the medication. Results: Among knee/hip OA patients, Hispanics (n=130), in comparison to NHWs (n=204), were younger (mean age 61.8 vs. 65.7) and less likely to have an annual income of ≥$40K (21.6% vs. 56.5%). Hispanics, compared to NHWs, had lower odds of using an OTC NSAID (OR 0.57, 95% CI 0.36-0.90) but greater odds of using a prescription NSAID (OR 1.66, 95% CI 1.04-2.64) for OA. Hispanics, compared to NHWs, were also less likely to ever hear about OTC and prescription oral NSAID to treat OA or have a good understanding of either oral NSAID type as a treatment for OA (Table 1). Mean [SD] perceived efficacy of OTC and prescription oral NSAIDs were slightly lower among Hispanics than NHWs (2.91 [0.98] vs. 3.12 [0.88], p=0.0565; 3.03 [1.02] vs. 3.34 [0.87], p=0.0047; respectively). Mean [SD] perceived risk of prescription NSAIDs was lower among Hispanics than NHWs (2.44 [1.03] vs. 2.82 [1.01], p=0.0012). After adjustment for all familiarity with OTC NSAIDs questions, and perceived efficacy and risk of OTC oral NSAIDs scores, the association between OTC NSAID use and ethnicity was attenuated and no longer significant (OR 1.01, 95%CI 0.54-1.89). After adjustment for familiarity with and perceptions of efficacy and risk of prescription NSAIDs, the association between prescription NSAID use and ethnicity remained significant (OR 2.62, 95%CI 1.51-4.54). Conclusion: Among patients with knee or hip OA, Hispanics were less likely than NHWs to utilize an OTC oral NSAID as treatment for arthritis. They were also less familiar with the use of NSAIDs for OA treatment and less likely to believe in their efficacy. Patient familiarity and perceptions of OTC oral NSAIDs may mediate ethnic differences in the use of NSAIDs for knee/hip OA. Disclosure of Interests: Ernest Vina Grant/research support from: Astrazeneca, Consultant for: Astrazeneca, Michael Hannon Employee of: Pinney Associates, Jazmin Dagnino: None declared, C. Kent Kwoh Grant/research support from: Abbvie, EMD Serono, Consultant for: Astellas, EMD Serono, Thusane, Express Scripts, Novartis

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

IntroductionThe medicinal treatment of osteoarthritis (OA) is mostly symptomatic to relieve pain and incapacity with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), drugs with well-known risks. Complementary medicines might reduce the symptoms of OA and decrease the need for NSAIDs. This study tested the effects of a food supplement, Phytalgic®, on pain and function in patients with osteoarthritis and their use of analgesic and NSAIDs.MethodsA randomized double-blind parallel-groups clinical trial compared Phytalgic® (fish-oil, vitamin E, Urtica dioica) to a placebo for three months, in 81 patients with OA of the knee or hip using NSAIDs and/or analgesics regularly. The main outcome measures were use of NSAIDs (in Defined Daily Doses per day - DDD/day) or analgesics (in 500 mg paracetamol-equivalent tablets per week (PET/week) measured each month, and Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC) function scales.ResultsAfter three months of treatment, the mean use of analgesics in the active arm (6.5 PET/week) vs. the placebo arm (16.5) was significantly different (P < 0.001) with a group mean difference of -10.0 (95% CI: -4.9 to -15.1). That of NSAIDs in the active arm (0.4 DDD/day) vs the placebo arm (1.0 DDD/day) was significantly different (P = 0.02) with a group mean difference of - 0.7 DDD/day (95% CI: -0.2 to -1.2). Mean WOMAC scores for pain, stiffness and function in the active arm (respectively 86.5, 41.4 and 301.6) vs the placebo arm (resp. 235.3, 96.3 and 746.5) were significantly different (P < 0.001) with group mean differences respectively of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9) and -444.8 (95% CI: -269.1 to -620.4).ConclusionsThe food supplement tested appeared to decrease the need for analgesics and NSAIDs and improve the symptoms of osteoarthritis.Trial registrationClinicaltrials.gov NCT00666523.

Response

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

This Month in Gastroenterology

Glycosaminoglycan-peptide complex (GPC) is a popular injectable extended-release symptomatic agent (ERSA) in Russia for the treatment of osteoarthritis (OA). To date, no large-scale studies of GPC used in real clinical practice have been conducted in our country.Objective: to evaluate the efficacy and safety of GPC in the treatment of OA in real clinical practice.Patients and methods. A multicenter observational non-interventional study was performed to evaluate the efficacy of GPC (Rumalon® , a cycle of intramuscular injections thrice weekly; a total of 25 injections). A study group consisted of 2,955 patients (75.4% female) aged 61.4±11.8 years) with knee and hip OA, and generalized OA (GOA) with the previous inefficacy of oral ERSAs, moderate/severe pain, and the need for regular use of nonsteroidal anti-inflammatory drugs (NSAIDs). 414 (14%) patients received a GPC and diacerein combination 100 mg/day. The investigators assessed the dynamics of pain during movement and at rest, functional disorders (on a numeric rating scale (NRS) of 0–10), as well as the need for NSAIDs at 12 weeks after starting the GPC cycle.Results and discussion. 98.5% of the patients completed their GPC treatment cycle. The therapy decreased the intensity of pain at rest from 4 [3; 5] to 1 [0; 2] and during movement from 6 [5; 7] to 2 [1; 3] and reduced the severity of functional disorders from 5 [4; 6] to 1 [0; 3]. The number of patients with a good response to therapy (a≥50% decrease in symptom severity) for pain at rest and during movement was 55.6 and 53.5%, respectively; and for functional disorders was 50.8%. 68.1% of patients stopped taking NSAIDs. The GPC and diacerein combination was more effective than GPC monotherapy: the number of patients with a ≥50% decrease in movement pain was 62.8 and 54.3%, respectively (p &lt;0.001). GPC was well tolerated. During treatment, there were skin allergic reactions (0.3%), moderate injection-site pain (0.37%), and adverse reactions (ARs) related to the gastrointestinal tract (8%) and cardiovascular system (6%) (which were likely to be caused by NSAIDs). There were no serious ARs that were life-threatening and required hospitalization.Conclusion. GPC allows successful control of the main symptoms of knee and hip OA and GOA, by reducing pain, and those of functional disorders, and the need for NSAIDs. The GPC and diacerein combination is more effective than GPC monotherapy. GPC therapy is well tolerated and very rarely causes ARs.

Efficacy of duloxetine by prior NSAID use in the treatment of chronic osteoarthritis knee pain: A post hoc subgroup analysis of a randomized, placebo-controlled, phase 3 study in Japan

NSAIDs, Risks, and Gastroprotective Strategies: Current Status and Future

Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin

ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 3, March 2015, pp 609–611 DOI 10.1002/art.38931 © 2015, American College of Rheumatology EDITORIAL Observational Studies, Time-Dependent Confounding, and Marginal Structural Models Charles E. McCulloch Observational studies have an undeniable role in medical research and often have significant advan- tages over randomized trials (1), such as broader gener- alizability. But, we regularly want to use observational studies to draw causal conclusions about the ability of interventions to prevent and treat disease, which can be problematic. In companion articles published in this issue of Arthritis & Rheumatology, Yang, Lapane, and coworkers (2,3) consider the causal impact of glucosamine/chondroitin and nonsteroidal antiinflam- matory drugs (NSAIDs) on knee osteoarthritis (OA), based on data from the Osteoarthritis Initiative (OAI), a longitudinal observational study. They use a statistical technique called “marginal structural models” with the goal of strengthening their ability to infer causation. This is becoming a more common approach to address- ing issues of confounding in observational studies. When should this technique be used, and what are its advan- tages and disadvantages? It is well understood that a key threat to drawing causal conclusions from observational studies is con- founding. For example, a history of knee surgery could easily be associated with both NSAID use and OA, and failure to account for differences in rates of knee surgery in comparing users and nonusers of NSAIDs could lead to biased estimates of the causal effect of NSAIDs. Fortunately, multiple regression analysis is in the statis- tical toolkit of virtually any medical researcher and can, in a wide variety of situations, adjust for or control for the effects of history of knee surgery to reduce or eliminate the effects of confounding. But what about a variable such as inflammation? Inflammation could also easily be associated with both NSAID use and OA. The conventional wisdom is that we should not adjust or control for inflammation be- cause it may be one of the paths by which NSAIDs could work to reduce OA. If we adjusted or controlled for it by multiple regression, we might be removing or reducing the true causal effect of NSAIDs on OA that occurs through reduced inflammation. So, variables such as inflammation (called mediator or intermediate vari- ables) should not be adjusted or controlled for (4). So far, so good. We should adjust for confounders but not intermediate variables. Unfortunately, it is possible for a variable to be both a confounder and an intermediate variable in a longitudinal study. For example, inflammation during the first year of a study (between baseline and year 1) could cause higher NSAID use at the year 1 visit. So, it is a confounder during year 1, and we should adjust for it. NSAID use might then lead to reductions in inflam- mation between year 1 and 2 and be associated with lower rates of OA. So, it is an intermediate variable during year 2, and we should not adjust for it. Variables that are simultaneously confounders and intermediate variables are known as “time-dependent confounders.” The technique of marginal structural models sets out to solve this dilemma by accounting for the associ- ation of inflammation and NSAID use not by adjusting for it in a regression model but instead by using weight- ing methods. The basic idea is to weight the data to break the association between the time-dependent con- founder and the outcome. Continuing the hypothetical inflammation example, suppose that there are 50 partic- ipants with no inflammation during year 1, 10% (or n ⫽ 5) of whom reported NSAID use at year 1, and 100 participants with inflammation during year 1, 20% (or n ⫽ 20) of whom report NSAID use at year 1. The weighting used in marginal structural models is called “inverse probability of treatment” weighting. So, in the no inflammation group, those who took NSAIDs are weighted by 10 (from 1/0.1 ⫽ 10) and those who did not take NSAIDs are weighted by 1.11 (from 1/0.9 ⫽ 1.11). Thus, the 5 participants in the no inflammation group who took NSAIDs are essentially inflated (by the Charles E. McCulloch, PhD: University of California, San Francisco. Address correspondence to Charles E. McCulloch, PhD, Department of Epidemiology and Biostatistics, University of Califor- nia, San Francisco, Box 0560, San Francisco, CA 94143-0560. E-mail: Charles.McCulloch@ucsf.edu. Submitted for publication October 15, 2014; accepted Octo- ber 23, 2014.

A combination of chondroitin and glucosamine is widely used in clinical practice as both a symptomatic and structure-modifying agent for the treatment of osteoarthritis (OA). The emergence of new drugs based on this combination substantially expands treatment options for OA therapy.Objective: to evaluate the efficacy and safety of Artroflex® that is a combination of chondroitin sulfate 400 mg and glucosamine sulfate 500 mg (CS + GS) to support joint health in patients with knee and/or hip OA.Patients and methods. When implementing an open observational research program, the results of using the CS + GS complex were assessed in 644 OA patients (74.7% women) (mean age, 58.0±14.6 years) who experienced moderate/severe pain and required to continuously take non-steroidal anti-inflammatory drugs (NSAIDs). The CS + GS complex was prescribed in a dose of 2 capsules per day for 3 months. The investigators estimated changes in pain on movement by a 0 to 10 verbal pain scale, general health (GH) by a 0–10 visual analogue scale), the Lequesne index, the need for NSAIDs, and patient satisfaction with treatment and its tolerance.Results and discussion. After 3-month therapy, there were decreases in pain intensity by 49.2±16.8%, GH scores by 45.6±18.1%, the Lequesne index from 9.0 [6.0; 13.0] to 5.0 [3.0; 9.0]; less than half (45.2%) of the patients still needed for NSAIDs. 82.2% of patients were satisfied or completely satisfied with treatment results; 89.6% reported good treatment tolerance.Adverse events (apparently associated with NSAID use) were recorded in 2.2% of cases. There were no serious complications that required CS + GS treatment discontinuation or hospitalization.Conclusion. The findings have indicated that Artroflex® used to support joint health is an effective agent that controls OA symptoms and has a good safety level.

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pain relief in osteoarthritis (OA), and their anti-inflammatory effects may play a role in shaping the disease course. The aim of this investigation was to examine the relationship between new use of prescription NSAIDs and changes in imaging biomarkers of synovitis in the knee, and to evaluate the association of NSAID use with structural cartilage damage over a period of four years.MethodsApplying a new user design to identify treatment effects in observational data, we selected participants from the Osteoarthritis Initiative (OAI) who were prescribed regular, oral NSAID medication between baseline and 48 months follow-up and who had available 3T MRIs of the right knee with whole-organ magnetic resonance imaging score (WORMS) readings as well as semi-quantitative assessments of synovitis for both timepoints. These individuals were frequency-matched with non-NSAID users matching for age, gender, body mass index (BMI), baseline Kellgren & Lawrence (KL) grade, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores, and for the presence of an inflammatory imaging phenotype at baseline. Ordinal regression analyses and marginal estimated means were used to determine the effect of NSAID use on structural imaging outcomes, controlling for age, gender, BMI, and non-prescription NSAID use.ResultsIn this longitudinal analysis over 48 months, 142 individuals met prespecified criteria for new NSAID exposure, and 707 matched controls were identified. Regression analyses did not show a significant association between new NSAID use and changes in effusion-synovitis, Hoffa’s synovitis, or synovial proliferation scores over 4 years. However, NSAID users showed a significantly slower progression of cartilage lesions as measured by WORMS grading; this effect was marginally more pronounced in participants with an inflammatory imaging phenotype (beta − 0.92; p = 0.043) than in the population overall (beta − 0.48; p = 0.020).ConclusionNew NSAID use was not associated with MRI-detected synovitis over 4 years but had a modest association with reduced structural cartilage damage progression. This effect was more pronounced in individuals with an inflammatory imaging phenotype.

Does Concomitant Use of NSAIDs Reduce the Effectiveness of Antidepressants?

Evidence from some studies suggest that osteoarthritis (OA) patients are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) that are not in accordance with their cardiovascular (CV) or gastrointestinal (GI) risk profiles. However, no such study has been carried out in the United States. Therefore, we sought to examine the prevalence and predictors of potentially inappropriate NSAIDs use in older adults (age > 65) with OA using machine learning with real-world data from Optum De-identified Clinformatics® Data Mart. We identified a retrospective cohort of eligible individuals using data from 2015 (baseline) and 2016 (follow-up). Potentially inappropriate NSAIDs use was identified using the type (COX-2 selective vs. non-selective) and length of NSAIDs use and an individual’s CV and GI risk. Predictors of potentially inappropriate NSAIDs use were identified using eXtreme Gradient Boosting. Our study cohort comprised of 44,990 individuals (mean age 75.9 years). We found that 12.8% individuals had potentially inappropriate NSAIDs use, but the rate was disproportionately higher (44.5%) in individuals at low CV/high GI risk. Longer duration of NSAIDs use during baseline (AOR 1.02; 95% CI:1.02–1.02 for both non-selective and selective NSAIDs) was associated with a higher risk of potentially inappropriate NSAIDs use. Additionally, individuals with low CV/high GI (AOR 1.34; 95% CI:1.20–1.50) and high CV/low GI risk (AOR 1.61; 95% CI:1.34–1.93) were also more likely to have potentially inappropriate NSAIDs use. Heightened surveillance of older adults with OA requiring NSAIDs is warranted.