Long-term Nonsteroidal Anti-inflammatory Drugs Research Articles

DA-9601 has protective effects comparable to those of proton pump inhibitor and rebamipide against nonsteroidal anti-inflammatory drugs-induced upper and lower gastrointestinal bleeding in patients with rheumatoid arthritis: A nationwide study using Korean Health Insurance Review and Assessment Service database.

DA-9601 extracted from Artemisia asiatica contains a bioactive compound - eupatilin - that can protect against gastric mucosal damage through anti-inflammatory and anti-oxidative properties and is approved for treating acute and chronic gastritis in Korea, but their ability to protect gastrointestinal (GI) bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is unclear. We aimed to compare the protective effects of DA-9601 to those of proton pump inhibitors (PPI) and rebamipide against upper and lower GI bleeding in patients with rheumatoid arthritis (RA) undergoing long-term NSAIDs therapy using the Korean Health Insurance Review and Assessment database. In this nationwide retrospective cohort study, we evaluated patients with RA who concurrently received NSAIDs for >3 months with DA-9601, PPI, or rebamipide between January 2015 and December 2017. The index date was the date of NSAIDs initiation, and all patients were followed up until December 2020 to detect upper and lower GI bleeding. In total, 24,258 patients with RA were eligible, and 5468 (22.5%), 4417 (18.2%), and 14,373 (59.3%) received DA-9601, PPI, or rebamipide, respectively, on the index date. During follow-up, upper and lower GI bleeding occurred in 508 (2.1%) and 402 (1.6%) patients with RA, respectively. The incidence rate of upper and lower GI bleeding was 615/100,000 and 485/100,000 person-years, respectively. Among patients with RA receiving DA-9601, PPI, or rebamipide, the frequencies of NSAIDs-induced upper GI bleeding were 0.5%, 0.4%, and 1.2%, respectively. The frequencies of NSAIDs-induced lower GI bleeding were 0.4%, 0.4%, and 0.9%, respectively. The incidence of NSAIDs-induced upper GI bleeding in patients with RA receiving DA-9601, PPI, and rebamipide was 601/100,000, 705/100,000, and 596/100,000 person-years, respectively, while the incidence of NSAIDs-induced lower GI bleeding in the same groups was 449/100,000, 608/100,000, and 465/100,000 person-years, respectively. In the multivariate Cox regression analysis, no significant difference was observed in lower and upper GI bleeding hazards between patients with RA using DA-9601, PPI, and rebamipide. Our results suggest that DA-9601 may exhibit protection against NSAIDs-induced GI bleeding that is comparable to those of PPI and rebamipide in patients with RA.

Association of long-term use of non-steroidal anti-inflammatory drugs with knee osteoarthritis: a prospective multi-cohort study over 4-to-5 years

This study examines the long-term impact of non-steroidal anti-inflammatory drugs (NSAIDs) on the progression of symptoms and structural deterioration of the joint in knee osteoarthritis. The study analyzes data from 4197 participants (8394 knees) across the Osteoarthritis Initiative (OAI), Multicenter Osteoarthritis Study (MOST), and Cohort Hip and Cohort Knee (CHECK) over 4-to-5 years. Adjustments were made for major covariates. We focussed on binary outcomes to assess the presence or absence of significant changes. We found that, relative to non-users, individuals using NSAIDs long-term were significantly more likely to experience aggravated symptoms exceeding the minimally clinically important difference, specifically, pain (OR: 2.04, 95% CI: 1.66–2.49), disability (OR: 2.21, 95% CI: 1.74–2.80), and stiffness (OR: 1.58, 95% CI: 1.29–1.93). Long-term users also faced a higher probability than non-users of having total knee replacement (OR: 3.13, 95% CI: 2.08–4.70), although no significant difference between long-term users and non-users was observed for structural deterioration in the knee joint (OR: 1.25, 95% CI: 0.94–1.65). While acknowledging the limitations of this study due to its observational design and the potential for bidirectional causality, these findings suggest that long-term NSAID use could accelerate the progression to total knee replacement by markedly exacerbating symptoms.

Determinants of pressure injury development in patients with COVID-19.

Pressure injuries (PIs) often develop in critically ill patients due to immobility, and underlying comorbidities that decrease tissue perfusion and wound healing capacity. This study sought to provide epidemiological data on determinants and current managements practices of PI in patients with COVID-19. A US national insurance-based database consisting of patients with coronavirus or COVID-19 diagnoses was used for data collection. Patients were filtered by International Classification of Diseases (ICD) codes corresponding to coronavirus or COVID-19 diagnosis between 2019-2020. Diagnosis of PI following COVID-19 diagnosis was queried. Demographic data and comorbidity information was compared. Logistic regression analysis was used to determine predictors for both PI development and likelihood of operative debridement. A total of 1,477,851 patients with COVID-19 were identified. Of these, 15,613 (1.06%) subsequently developed a PI, and 8074 (51.7%) of these patients had an intensive care unit (ICU) admission. The average and median time between diagnosis of COVID-19 and PI was 39.4 and 26 days, respectively. PI was more likely to occur in patients with COVID-19 with: diabetes (odds ratio (OR): 1.39, 95% confidence interval (CI): 1.29-1.49; p<0.001); coronary artery disease (OR: 1.11, 95% CI: 1.04-1.18, p=0.002), hypertension (OR: 1.43, 95% CI: 1.26-1.64; p<0.001); chronic kidney disease (OR: 1.18, 95% CI: 1.10-1.26; p<0.001); depression (OR: 1.45, 95% CI 1.36-1.54; p<0.001); and long-term non-steroidal anti-inflammatory drug use (OR: 1.21, 95% CI: 1.05-1.40; p=0.007). They were also more likely in critically ill patients admitted to the ICU (OR: 1.40, 95% CI: 1.31-1.48; p<0.001); and patients requiring vasopressors (OR:1.25, 95% CI: 1.13-1.38; p<0.001), intubation (OR: 1.21, 95% CI 1.07-1.39; p=0.004), or with a diagnosis of sepsis (OR: 2.38, 95% CI 2.22-2.55; p<0.001). ICU admission, sepsis, buttock and lower back PI along with increasing Charlson Comorbidity Index (CCI) (OR: 1.04, 95% CI 1.00-1.08; p=0.043) was associated with surgical debridement. The vast majority of patients with COVID-19 did not undergo operative debridement or wound coverage. PIs are widely prevalent in patients with COVID-19, especially in those who are critically ill, yet the vast majority do not undergo operative procedures. The authors have no conflicts of interest to declare.

Gastrointestinal perforations induced by long-term non-steroidal anti-inflammatory drugs use: a case series analysis and discussion

Non-steroidal anti-inflammatory drugs (NSAIDS) are used in a wide range but may cause harm to the gastrointestinal mucosa, which leads to various complications. This study shows the impact of long term NSAID use on small and large intestine and presents 2 cases of patients with NSAID induced perforations. The first case involves a 62-year-old male patient with RA on long term Ibuprofen use, presented with abdominal pain, vomiting, and lower limbs pain. Laparotomy revealed a 5 mm perforation in the proximal jejunum. The second case, a male patient of 65 years of age using diclofenac without a prescription, which lead to a 4×4 cm sigmoid colon perforation. The comparison of both the cases presents a difference in examination and laboratory findings. Long-term NSAID use has been associated with various GI complications, including perforations. The case presents the importance of considering NSAID related complications, mainly in older patients and the persons with ulcers. Combining NSAIDS with other drugs, like misoprostol may minimize the risk of the GI complications. NSAIDs are also linked with cardiovascular events, and heart related issues. This study shows the need of careful NSAID prescription, with their association with preventable adverse effects. 30% of hospitalizations for adverse drug reactions are only by the NSAIDs. PPIs and H2 receptor antagonist are commonly used to protect the gastrointestinal mucosa which minimizes the occurrence of ulcers. Healthcare professionals should be careful particularly in case of high risk patients to minimize the NSAID related complications.

Investigation of the association of long-term NSAID use with radiographic hip osteoarthritis over four to five years: Data from the OAI and CHECK studies

ObjectiveTo examine the relationship between long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence and progression of radiographic hip osteoarthritis (RHOA), as well as the degeneration of individual radiographic features. MethodsWe analyzed data from the Osteoarthritis Initiative (OAI) and the Cohort Hip and Cohort Knee (CHECK) study. Our exposure was the number of years of NSAID use over a 4-to-5-year follow-up period. Our outcomes were the incidence and progression of RHOA over a 4-to-5-year follow-up as assessed using a modified Croft grade in OAI and the Kellgren-Lawrence (K/L) grade in CHECK. The incidence of RHOA was defined as having RHOA (grade ≥2) at follow-up and investigated in “incidence cohorts” of hips without RHOA at baseline (grade <2). The progression of RHOA was defined as an increase of ≥1 grade at follow-up from baseline and investigated in “progression cohorts” of hips with RHOA at baseline (grade ≥2). Additionally, we assessed the degeneration of nine specific radiographic features, such as joint space narrowing and osteophytes, defined by a grade increase of ≥1 ​at follow-up from baseline, in all cohorts. ResultsIn the incidence cohorts, there were 5153 hips in OAI and 1011 in CHECK; in the progression cohorts, there were 285 and 106 hips, respectively. There was no association between NSAID use and the outcomes investigated. ConclusionOver 4-to-5 years, long-term NSAID use showed no association with the incidence or progression of RHOA, or with the degeneration of individual radiographic features.

Lithium precipitated acute kidney injury: A rare case report

Lithium is known to cause nephrogenic diabetes insipidus, chronic tubule-interstitial nephropathy, and partial distal renal tubular acidosis. We are describing a rare instance of lithium precipitating acute renal injury within a week in a patient receiving long-term nonsteroidal anti-inflammatory drugs (NSAIDs) for medically unexplained symptoms. The patient presented with fluctuating orientation, cerebellar signs, and brisk deep tendon reflexes. Citing associated lithium toxicity discontinuation of lithium and NSAIDs brought back kidney function test to normal. Lithium toxicity was treated with intravascular fluids. We conclude that lithium may precipitate severe but reversible renal failure.

Role of Potassium-competitive Acid Blockers in the Treatment of Gastric Acid-related Disorders

Owing to their superior pharmacokinetic and pharmacodynamic profiles, potassium-competitive acid blockers (P-CABs) score over proton pump inhibitors (PPIs) in the treatment of gastric acid-related disorders and may provide clinical benefit in the management of these conditions. Previous studies have compared P-CABs with PPIs for treatment of gastric acid-related disorders, and current data show that P-CABs are non-inferior to PPIs in the treatment of erosive esophagitis and as maintenance therapy. P-CABs are useful for effective healing and as maintenance medications in patients with severe esophagitis. These drugs also aid with healing of peptic ulcers and artificial ulcers secondary to gastric endoscopic submucosal dissection (ESD). Few studies have discussed prevention of delayed ulcer bleeding after gastric ESD and ulcers associated with long-term nonsteroidal anti-inflammatory drug administration. Well-controlled, large-scale prospective studies are warranted in future to compare P-CABs with PPIs.

Low prevalence of Clostridioides difficile infection in acute severe ulcerative colitis: A retrospective cohort study from northern India.

The incidence of Clostridioides difficile infection (CDI) is high in ulcerative colitis and is associated with disease flares and adverse outcomes. However, the data on the dynamics of CDI in patients with acute severe ulcerative colitis (ASUC) is rather scarce. We evaluated the prevalence of CDI in patients with ASUC. This retrospective analysis of a prospectively maintained cohort admitted to the All India Institute of Medical Sciences, India, from May 2016 to December 2021, included patients with ASUC (as per Truelove and Witts criteria) who were tested for CDI. CDI testing was performed using enzyme-linked immunoassay for toxins A and B. Risk factors for developing CDI were analyzed along with short-term outcomes of ASUC. Steroid failure was defined as the need for medical rescue therapy or colectomy. Total 153 patients with ASUC were included (mean age 34.92 ± 12.24years; males 56.2%; disease duration 36 (IQR: 16-55.5) months, pancolitis 67.3%). Ninety-eight (63.4%), 72 (47%) and 10 (6.5%) patients, respectively, had received steroids, azathioprine and biologics in the past. Forty patients (26.14%) had a prior history of ASUC. Among risk factors for CDI, 14% of the patients had prior admission within 30days, 22.2% had a recent history of antibiotics and 3.9% had long-term non-steroidal anti-inflammatory drug intake. Only one sample was positive for Clostridioides difficile toxin assay. Tissue Cytomegalovirus DNA-PCR positivity was noted in 57 patients (37.3%). Fifty-seven patients (37.3%) had steroid failure, 35 required medical rescue therapy and 30 (19.6%) required colectomy (eight after medical rescue therapy failure). Despite antecedent risk factors for CDI, the overall prevalence of CDI in ASUC was low and theoutcomes were determined by underlying disease severity.

Long-term safety and effectiveness of vonoprazan for prevention of gastric and duodenal ulcer recurrence in patients on nonsteroidal anti-inflammatory drugs in Japan: a 12-month post-marketing surveillance study

ABSTRACT Background This study assessed the safety and effectiveness of vonoprazan for prevention of duodenal and gastric ulcer recurrence in patients on long-term nonsteroidal anti-inflammatory drugs (NSAIDs) in routine clinical practice. Research design and methods This 12-month, prospective, observational study (145 sites, Japan, September 2016–April 2020) analyzed patients with a history of gastric or duodenal ulcer who started once-daily vonoprazan and were receiving NSAIDs for pain. The primary outcome was the incidence of adverse drug reactions (ADRs). Results Most patients (86.7% [1099/1268]) received vonoprazan for at least 6 months. Most patients (98.6% [1250/1268]) received the 10-mg dose of vonoprazan, 38.3% (486/1268) received cyclooxygenase-2 inhibitors, and 61.7% (782/1268) received other NSAIDs. The overall incidence of ADRs was 0.71% (9/1268). Most commonly reported ADRs were gastrointestinal (0.32%), nervous system (0.16%), and hepatobiliary system (0.16%) disorders. The overall incidence of gastric or duodenal ulcer recurrence was 1.04% (95% CI 0.56–1.78). Conclusions No new safety concerns were reported for vonoprazan for prevention of secondary ulcer or bleeding in patients receiving long-term NSAIDs. Vonoprazan was effective for preventing NSAID-related peptic ulcer recurrence in this real-world study. Trial registration ClinicalTrials.gov: NCT03214198; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-163436.

Syringaresinol attenuates osteoarthritis via regulating the NF-κB pathway.

Osteoarthritis (OA) is a now regarded as a worldwide whole joint disease with synovial inflammation, cartilage degeneration, and subchondral sclerosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for OA treatment which only relieve the symptoms and restrain the progression of OA. However, various severe adverse effects often occur in patients with long-term NSAIDs use, which heavily burdens the healthcare system and impacts the quality of life. Therefore, it is much imperative to identify alternative drugs with increased efficacy. Syringaresinol (Syr), a naturally occurring phytochemical which belonging to the lignan group of polyphenols, shows anti-tumor and anti-oxidant activities, which to benefit human health. Studies has shown Syr can regulate the inflammatory response by modulating the secretion and expression level of cytokines IL-6, IL-8, and tumor necrosis factor (TNF)-α. it also shows the inhibitory effect on NF-κB pathway in mouse cells. In the present study, we aimed to demonstrate the anti-inflammatory effects of Syr in OA. In vitro Syr treatment in IL-1β-activated mouse chondrocytes significantly restrained the expression of NO, PGE2, IL-6, TNF-α, INOS, COX-2 and MMP-13. Moreover, it considerably ameliorated the degradation of aggrecan and collagen II. Furthermore, the phosphorylation of the NF-kB signaling pathway was significantly suppressed by Syr. Moreover, in vivo, the cartilage degeneration was attenuated and the increased Osteoarthritis Research Society International (OARSI) scores were reversed in the DMM+Syr group, comprared to those in the DMM group. In sum, our study demonstrated that Syr can attenuate the inflammation in vitro and further verified its effect on OA in vivo. Thus, Syr might be a potent therapeautic alternative for OA treatment.

The relationship between long-term use of nonsteroidal anti-inflammatory drugs and kidney function in patients with ankylosing spondylitis.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for ankylosing spondylitis (AS), their effect on kidney function remains unclear. This longitudinal study investigated the correlation between long-term NSAID use and kidney function in patients with AS using electronic medical records. The electronic medical records of 1,280 patients with AS collected from a single center between January 2001 and December 2018 were reviewed. The Assessment of Spondyloarthritis International Society (ASAS) NSAID Intake Score was used to determine the cumulative dose of all NSAIDs prescribed for a different time intervals. Each ASAS NSAID Intake Score was obtained for intervals of 6 months, 1 year, 2 years, 3 years, 5 years, and 10 years. The correlation between the ASAS NSAID Intake Score and final estimated glomerular filtration rate (eGFR) for each interval was investigated. The mean ASAS Intake Scores for 6-month, 1-year, 2-year, 3-year, 5-year, and 10-year intervals were 55.30, 49.28, 44.84, 44.14, 44.61, and 41.17, respectively. At each interval, the pearson correlation coefficients were -0.018 (95% CI -0.031 to -0.006, p=0.004), -0.021 (95% CI -0.039 to -0.004, p=0.018), -0.045 (95% CI -0.071 to -0.019, p=0.001), -0.069 (95% CI -0.102 to -0.037, p<0.001), -0.070 (95% CI -0.114 to -0.026, p=0.002), -0.019 (95% CI -0.099 to 0.062, p=0.645), respectively. There was a very weak negative relationship between ASAS Intake Score and eGFR at each interval. Long-term NSAID use did not correlate with kidney function based on real-world data in patients with AS.

Deprescribing initiative of NSAIDs (DIN): Pharmacist-led interventions for pain management in a federal correctional setting.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for management of pain and inflammation. However, these medications are associated with adverse outcomes such as dyspepsia and acute myocardial infarction, especially with long-term uses. We sought to determine the effect of a pharmacist-led deprescribing intervention on oral NSAID use among patients in federal custody. Clinical pharmacists from Correctional Services Canada (CSC) conducted a prospective case series of adult patients with chronic noncancer pain who were on long-term NSAIDs (defined as >90 days supply in the past 120 days) in 3 CSC institutions in British Columbia, Canada. CSC clinical pharmacists met with patients to perform medication reviews and identify drug-related problems, with a focus on analgesic therapy. Pharmacist-led interventions were implemented in consultation with the primary care team to address these drug-related problems. Patient progress was monitored weekly for 3 months. Function, quality of life and pain severity scores (modified SPAASMS, Patient-Specific Functional Scale [PSFS] and visual analog scale [VAS] scores) were compared at baseline, 6 weeks and 3 months postintervention. Patient satisfaction survey results were also collected at 3 months. A total of 53 patients received clinical pharmacist interventions. Modified SPAASMS, PSFS and VAS scores were collected at baseline, 6 weeks and 3 months from 38 patients (some were lost to follow-up when released back into the community). All 38 patients demonstrated clinically significant improvements to all 3 pain scales at 3 months (mean SPAASMS scores decreased by 7 points, mean PSFS scores increased by 2 points, mean VAS scores decreased by 2 points). Twenty-four of 31 patients who completed the patient satisfaction survey agreed that their overall health and well-being improved because of the visit they received from the pharmacist. Clinical pharmacist-led interventions in CSC have shown to reduce oral NSAID use as well as contribute positively to patient pain scores.

Associations of Antibiotics, Hormonal Therapies, Oral Contraceptives, and Long-Term NSAIDS With Inflammatory Bowel Disease: Results From the Prospective Urban Rural Epidemiology (PURE) Study

Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort. This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs. During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P= .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P= .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P= .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity. Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal anti-inflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates.

FORMULATION OF CREAM CONTAINING IBUPROFEN 5%

Background: Non-steroidal anti-inflammatory drug (NSAID) is a group of drugs commonly used to treat musculoskeletal diseases. However, according to statistics, up to 25% of long-term NSAID users had peptic ulcer disease, and 2-4% had gastrointestinal bleeding or perforation. Therefore, it is necessary to study preparations for external use to minimize these undesirable effects. Objectives: The cream containing ibuprofen 5% has been formulated with good physical characteristics and high bioavailability in the in vitro test based on the support of design and optimization software. Methods: According to the D–Optimal model, the formula models of cream containing ibuprofen 5% were designed with the different concentrations of oil phase, water phase, and emulsifier. The formulas of medicinal cream were prepared by direct emulsification method, then evaluated and compared to the criteria consisting of the phase separation, spreadability, and release of the active ingredient through cellulose nitrate membrane with a 0.45 µm pore size. Results: The formulation of the cream containing ibuprofen 5% with various components consisting of ibuprofen (5 g), cetyl alcohol (3.85 g), stearyl alcohol (1.54 g), beeswax (3.85 g), paraffin oil (10.77 g), span 80 (11.70 g), sodium lauryl sulfate (3.30 g), propylene glycol (59.90 g), and nipagin M (0.10 g). The results also showed that the product had good physical characteristics with no separation between the oil and the water phases, a spread area of 618 mm2, and the release of the active ingredient through the cellulose nitrate membrane at 0.209 mg/mL. Conclusion: The cream containing ibuprofen 5% was researched based on excipients of oil and water, making an emulsion structure stable and helping meet the foundational criteria according to the medicinal cream regulations.

Risk of heart failure following short-term non-steroidal anti-inflammatory drug use in patients with type 2 diabetes mellitus

Abstract Background Fluid retention is a known but underappreciated side-effect of non-steroidal anti-inflammatory drug (NSAID) use. As type 2 diabetes mellitus (T2DM) has been linked to both subclinical cardiomyopathy and a decline in kidney function, short-term NSAID use could lead to subsequently development of heart failure (HF) due to aberrations in fluid balances. Purpose We investigated associations between short-term NSAID use and the risk of HF in a nationwide cohort of patients with T2DM. Methods Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998–2018. Follow-up began 120 days after first-time T2DM diagnosis among patients without prior heart failure or a rheumatological diagnosis indicating long-term NSAID use. To describe use of NSAID among patients with T2DM, we reported proportions of patients claiming at least 1, 2, 3 or 4 prescriptions of NSAID within one year of start of follow-up. We investigated associations between use of NSAIDs (celecoxib, diclofenac, ibuprofen and naproxen) and new-onset HF hospitalizations using a case-crossover design with 28-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI). The case-crossover design uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding. Sensitivity analyses using exposure windows of 14 and 42 days were performed as well. Results A total of 334,950 patients with T2DM was included (47.7% female, median age of 61 [interquartile range 50–70]). Celecoxib and naproxen were rarely used; on the contrary, prescriptions of diclofenac and ibuprofen were claimed at least once within one year from the beginning of follow-up by 4.9% and 15.5% of patients, respectively–0.9% and 2.7% claimed at least four prescriptions (Figure 1). The risk of new-onset HF hospitalization was increased following use of diclofenac or ibuprofen with corresponding ORs of 1.3 (95% CI 1.0 to 1.7) and 1.3 (95% CI 1.1 to 1.5) using 28-day exposure windows. An increased risk following use of celecoxib or naproxen was not found (Figure 2). Conclusion NSAIDs diclofenac and ibuprofen were both widely used and associated with an increased risk of new-onset HF hospitalization in patients with T2DM. This suggests a previously unknown and serious, clinically relevant concern of NSAID use in patients with T2DM. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ib Mogens Kristiansens Almene FondHelsefonden

Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study.

Osteoarthritis (OA) and chronic low back pain (CLBP) are common musculoskeletal disorders with substantial patient and societal burden. Nordic administrative registers offer a unique opportunity to study the impact of these conditions in the real-world setting. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study was designed to study disease prevalence and the societal and economic burden in broad OA and CLBP populations. Patients in Sweden, Norway, Finland and Denmark with diagnoses of OA or CLBP (low back pain record plus≥2 pain relief prescriptions to indicate chronicity) were identified in specialty care, in primary care (Sweden and Finland) and in a quality-of-care register (Sweden). Matched controls were identified for the specialty care cohort. Longitudinal data were extracted on prevalence, treatment patterns, patient-reported outcomes, social and economic burden. Almost 1.4 million patients with OA and 0.4 million with CLBP were identified in specialty care, corresponding to a prevalence in the Nordic countries of 6.3 and 1.9%, respectively. The prevalence increased to 11-14% for OA and almost 6% for CLBP when adding patients identified in primary care. OA patients had a higher Elixhauser comorbidity index (0.66 vs. 0.46) and were using opioids (44.7 vs. 10.2%) or long-term nonsteroidal anti-inflammatory drug (NSAIDs) (20.9 vs. 4.5%) more than four times as often as compared to controls. The differences were even larger for CLBP patients compared to their controls (comorbidity index 0.89 vs. 0.39, opioid use 77.7 vs. 9.4%, and long-term NSAID use 37.2 vs. 4.8%). The BISCUITS study offers an unprecedented, longitudinal healthcare data source to quantify the real-world burden of more than 1.8 million patients with OA or CLBP across four countries. In subsequent papers we aim to explore among others additional outcomes and subgroups of patients, primarily those patients who may benefit most from better healthcare management.

Chemo-photodynamic Activity of Silicon Phthalocyanines Bearing Cyclooxygenase Inhibitors on Colorectal Cancer Cell Lines.

Colorectal cancer ranks as the third most lethal cancer worldwide, resulting in over 1 million cases and 900 000 deaths per year. According to population-based studies, administration of long-term non-steroidal anti-inflammatory drugs (NSAIDs) was proven to reduce the risk of a subject developing colorectal cancer. In the present study, the anti-cancer activity of two different NSAIDs, sulindac- (Pc-1) or diclofenac-substituted (Pc-2) asymmetric silicon phthalocyanine derivatives, was evaluated in four different colorectal cancer cell lines bearing various carcinogenic mutations. In this context, the IC50 values of each compound after 24 and 48 h were determined on HCT116, SW480, LoVo, and HT29 cell lines, and the effects of the compounds on programmed cell death pathways apoptosis and autophagy, their impact on cell cycle progression, and the effect of NSAID moieties they bear on COX-1 and COX-2 proteins were analyzed. In addition, the photophysical and photochemical properties of a synthesized Pc derivative bearing axial diclofenac and triethylene glycol groups (Pc-2) have been investigated, and the compound has been characterized by using different analytical techniques. Our results indicated that both compounds inhibit COX protein expression levels, activate apoptosis in all cell lines, and lead to cell cycle arrest in the G2/M phase, depending on the COX expression profiles of the cell lines, indicating that NSAIDs can be coupled with Pc's to achieve increased anti-cancer activity, especially on cancer cells known to have high COX activity.

Opioid and Analgesic Use Before and After Revision Knee Arthroplasty for the Indications “Pain Without Loosening” Versus “Aseptic Loosening” – A Danish Nationwide Study

BackgroundIt is uncertain if patients undergoing revision knee arthroplasty for “pain without loosening” are relieved of pain. This study aimed to compare pre- and postoperative analgesic consumption by patients undergoing revision for “pain without loosening” versus “aseptic loosening” and to determine predictors for postoperative long-term opioid use. MethodsA retrospective nationwide study of 1,037 revisions for “pain without loosening” and 2,317 revisions for “aseptic loosening” during 1997-2018 from the Danish Knee Arthroplasty Register was carried out. Analgesic use was defined by prescription reimbursement, and long-term opioid use by prescription reimbursement in 4 consecutive quarters. ResultsIn the preoperative year, 37% and 29% of patients revised for “pain without loosening” and “aseptic loosening” were opioid users compared to 32% and 30% in the postoperative year. Non-steroidal anti-inflammatory drug (NSAID) use was significantly lower postoperatively for both indications (35% versus 28% for “pain without loosening” and 33% versus 25% for “aseptic loosening”). Use of other analgesics was unchanged. Long-term opioid use increased postoperatively by 4% for patients with “pain without loosening” (P = .029) and by 3% for “aseptic loosening” (P = .003). New long-term opioid users (without preoperative long-term use) were 9% for “pain without loosening” and 8% for “aseptic loosening“. Predictors of new long-term opioid use were other opioid-requiring diagnoses or procedures within the first postoperative year, Charlson Comorbidity Index (CCI) ≥3, and preoperative long-term NSAID use. ConclusionThe consumption of opioids decreased slightly after knee arthroplasty revision for the indication “pain without loosening”, but not for “aseptic loosening”. The amount of new long-term opioid users increased for both indications.

Long-term anti-inflammatory effects of injectable celecoxib nanoparticle hydrogels for Achilles tendon regeneration

The treatment of chronic Achilles tendonitis (AT) often requires prolonged therapy and invasive therapeutic methods such as surgery or therapeutic endoscopy. To prevent the progression of chronic AT, excessive inflammation must be alleviated at an early stage. Corticosteroids or nonsteroidal anti-inflammatory drugs are generally prescribed to control inflammation; however, the high doses and long therapeutic periods required may lead to serious side effects. Herein, a local injectable poly(organophosphazene) (PPZ) – celecoxib (CXB) nanoparticle (PCNP) hydrogel system with long-term anti-inflammatory effects was developed for the treatment of tendonitis. The amphiphilic structure and thermosensitive mechanical properties of PPZ means that the hydrophobic CXB can be easily incorporated into the hydrophobic core to form PCNP at 4 °C. Following the injection of PCNP into the AT, PCNP hydrogel formed at body temperature and induced long-term local anti-inflammatory effects via sustained release of the PCNP. The therapeutic effects of the injectable PCNP system can alleviate excessive inflammation during the early stages of tissue damage and boost tissue regeneration. This study suggests that PCNP has significant potential as a long-term anti-inflammatory agent through sustained nonsteroidal anti-inflammatory drugs (NSAIDs) delivery and tissue regeneration boosting. Statement of significanceIn the treatment of Achilles tendinitis, a long-term anti-inflammatory effect is needed to alleviate excessive inflammation and induce regeneration of the damaged Achilles tendon. Injectable poly(organophosphazene)(PPZ)-celecoxib(CXB) nanoparticles (PCNP) generated a long-term, localized-anti-inflammatory effect in the injected region, which successfully induced the expression of anti-inflammatory cytokines and suppressed pro-inflammatory cytokines, while the PCNPs degraded completely. Accordingly, regeneration of the damaged Achilles tendon was achieved through the long-term anti-inflammatory effect induced by a single PCNP injection. The PCNP system therefore has great potential in long-term NSAIDs delivery for various tissue engineering applications.

Cardiorenal risk of celecoxib compared with naproxen or ibuprofen in arthritis patients: insights from the PRECISION trial.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established cardiovascular (CV) disease or risk factors for disease as illustrated by the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen) trial participants (NCT00346216).We further investigated whether the selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile compared with ibuprofen or naproxen in the PRECISION population. Twenty-four thousand eighty-one patients who required NSAIDs for osteoarthritis or rheumatoid arthritis (RA) and had increased CV risk randomly received celecoxib, ibuprofen, or naproxen. The current pre-specified secondary analysis assessed the incidence, severity, and NSAID-related risk of the pre-specified composite cardiorenal outcome (adjudicated renal event, hospitalization for congestive heart failure, or hospitalization for hypertension) in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. Following a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up of 34.1 ± 13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen, and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen [hazard ratio (HR) 0.67, confidence interval (CI) 0.53-0.85, P = 0.001) and a trend to lower risk compared with naproxen (HR 0.79, CI 0.61-1.00, P = 0.058). In the ITT analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14%, and 0.89% for celecoxib, ibuprofen, and naproxen, respectively (P = 0.052), while in the on-treatment analysis the rates were 0.52%, 0.91%, and 0.78% (P &amp;lt; 0.001). In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favourable cardiovascular safety compared with ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure.Clinical Trial Registration: NCT00346216.