High Doses Of Non-steroidal Anti-inflammatory Drugs Research Articles

Short-pulse of systemic steroids in acute pericarditis: an alternative in refractory cases

Abstract Introduction Acute pericarditis accounts for 5% of emergency room admissions for chest pain. First line treatment consists of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. Systemic corticosteroids (SCS) are usually reserved as a second-line therapy due to a higher rate of recurrences and side effects. Whether a short pulse of low-dose SCS is safe and effective during the acute phase of the disease remains unknown. Purpose To investigate safety and efficacy of a 3 day pulse of 40 mg intravenous methylprednisolone in patients hospitalized for acute pericarditis with a lack of response to NSAIDs and colchicine. Methods A retrospective, observational and unicentric study was performed including patients hospitalized for acute pericarditis between 2019 and 2023. Patients with asymptomatic pericardial effusion or predominance of myocardial injury were excluded. Patients were considered to be refractory to conventional treatment when at least one of the following criteria was present despite five days of high-dose NSAIDs and colchicine: 1- Moderate/severe pericardial effusion persistence. 2- Chest pain persistence. 3- Increase of inflammatory biomarkers. These patients received methylprednisolone 40mg for three days on top of standard treatment. Baseline characteristics, treatment received during hospitalization and events during follow-up were analysed. Data were expressed as mean and standard deviation (quantitative variables) and percentages (categorical variables). Two-sided P value of less than 0.05 was considered statistically significant. Results 70 patients with acute pericarditis requiring hospitalization were included (54±19 years; 71% male) with a mean follow-up of 10±21 months. 26 of them (37%) received methylprednisolone 40mg for three days due to lack of response to standard treatment. Table 1 includes a comparison of patients who received systemic corticosteroids versus those who did not (control group). C-reactive protein (CRP) was significantly higher in the group receiving corticosteroids (188±86 mg/L vs 135±85 mg/L; p=0.014) and it significantly decreased during hospital stay compared to the control group (151±87 mg/L vs 97±74 mg/L; p=0.013). 14 patients (20%) experienced a recurrence of chest pain during follow-up with no significant difference according to the treatment received (27% vs 16%; p=0.266) Conclusion A 3-day pulse of low-dose SCS seems to be useful and safe for hospitalized patients with acute pericarditis who show lack of response to NSAIDs and colchicine, with no increase in recurrence rate. However, more evidence based on randomized control trials is needed to support this therapeutic approach.Table 1

Derivation and validation of a risk prediction score for nonsteroidal anti-inflammatory drug-related serious gastrointestinal complications in the elderly.

Few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score for severe GI complications to identify high-risk elderly patients using NSAID. We used the following two Korean claims datasets: customized data with an enrolment period 2016-2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥65 years) who received NSAIDs for more than 30 days. Serious GI complications were defined as hospitalizations or emergency department visits, with a main diagnosis of GI bleeding or perforation. We applied the logistic least absolute shrinkage and selection operator (LASSO) regression model for variable selection and model fitting. We identified 8176 cases and 81 760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254 551 patients. The risk predictors were high-dose NSAIDs, nonselective NSAID, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease and cirrhosis. Area under the receiver operating characteristic curve was 0.79 (95% confidence interval, 0.77-0.81) in the external validation dataset. The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.

The Role of Nuclear Medicine in the Clinical Management of Benign Thyroid Disorders, Part 2: Nodular Goiter, Hypothyroidism, and Subacute Thyroiditis.

Part 2 of this series of Continuing Education articles on benign thyroid disorders deals with nodular goiter, hypothyroidism, and subacute thyroiditis. Together with Part 1 (which dealt with various forms of hyperthyroidism), this article is intended to provide relevant information for specialists in nuclear medicine dealing with the clinical management of patients with benign thyroid disorders, the primary audience for this series. Goiter, an enlargement of the thyroid gland, is a common endocrine abnormality. Constitutional factors, genetic abnormalities, or dietary and environmental factors may contribute to the development of nodular goiter. Most patients with nontoxic nodular goiter are asymptomatic or have only mild mechanical symptoms (globus pharyngis). Work-up of these patients includes measurement of thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid autoantibodies, ultrasound imaging, thyroid scintigraphy, and fine-needle aspiration biopsy of nodules with certain ultrasound and scintigraphic features. Treatment for multinodular goiter includes dietary iodine supplementation, surgery, radioiodine therapy (to decrease thyroid size), and minimally invasive ablation techniques. Hypothyroidism ranges from rare cases of myxedema to more common mild forms (subclinical hypothyroidism). Primary hypothyroidism often has an autoimmune etiology. Clinical presentations differ in neonates, children, adults, and elderly patients. Work-up includes thyroid function tests and ultrasound imaging. Nuclear medicine is primarily used to locate ectopic thyroid tissue in congenital hypothyroidism or to detect defects in iodine organification with the perchlorate discharge test. Treatment consists of thyroid replacement therapy with l-thyroxine, adjusting the daily dose to the individual patient's metabolic and hormonal requirements. Subacute thyroiditis is a self-limited inflammatory disorder of the thyroid gland, often associated with painless or painful swelling of the gland and somatic signs or symptoms. Inflammation disrupts thyroid follicles resulting in a rapid release of stored thyroxine and triiodothyronine causing an initial thyrotoxic phase, often followed by transient or permanent hypothyroidism. Although subacute thyroiditis is often related to a viral infection, no infective agent has been identified. Subacute thyroiditis may be caused by a viral infection in genetically predisposed individuals. Work-up includes lab tests, ultrasound imaging, and radionuclide imaging. Thyroid scintigraphy demonstrates different findings depending on the phase of the illness, ranging from very low or absent tracer uptake in the thyroid gland in the hyperthyroid phase to a normal appearance in the late recovery phase. Since subacute thyroiditis is self-limited, treatment is directed toward relief of pain. High-dose nonsteroidal antiinflammatory drugs are usually the first-line treatment. If severe pain persists, a course of corticosteroids may be necessary. Permanent hypothyroidism develops in up to 15% of patients with subacute thyroiditis, even more than 1 y after presentation.

Acetaminophen, Nonsteroidal Anti-inflammatory Drugs, or Combination of Both Analgesics in Acute Posttrauma Pain: A Randomized Controlled Trial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (also called paracetamol) are the most frequent analgesics used to relieve posttrauma pain in the emergency department (ED). However, the utility of combining both treatments is still controversial. We sought to explore the benefits of combining an NSAID with acetaminophen compared to acetaminophen alone, or NSAID alone, in the treatment of posttraumatic pain of the extremity after discharge from the ED. This is a prospective, randomized controlled trial, carried out in a single ED from March 2017 to November 2018. The included patients were randomly assigned to receive paracetamol alone, high-dose NSAID (piroxicam) alone, or a combination of paracetamol and high-dose NSAID for 7days after ED discharge. The primary outcome was need for additional oral analgesics. Secondary outcomes included the change of the visual numeric scale (VNS) between ED discharge (VNS D0) and 7days later (VNS D7), ED revisits for residual pain, side effects, and patient satisfaction as assessed by a Likert satisfaction scale. The need for additional oral analgesics was comparable between the paracetamol-NSAID combination group (9.8%) and the paracetamol group (11.4%; p=0.43). ED readmission rate was also comparable between the two groups at 5.6 and 5.8%, respectively (p=0.86). In contrast, need for new analgesics and ED revisit rates were both more frequent in the high-dose NSAID group.Mean VNS decreases on day 7 compared to day 0 were 66, 63, and 67%, respectively, in the paracetamol, NSAID, and paracetamol-NSAID combination groups (p=0.32). Frequency of dissatisfaction was higher in the NSAID group. Side effects were more frequent in the NSAID and paracetamol-NSAID combination groups. This study found that the combination of a high-dose NSAID with paracetamol does not increase the analgesic effect compared to paracetamol alone. We also found that paracetamol alone is superior to high-dose NSAID alone for posttraumatic extremity pain.

High-risk nonsteroidal anti-inflammatory drugs prescribing in primary care: results from National Medical Care Survey Malaysia.

Background Information on the extent of high-risk prescribing for nonsteroidal anti-inflammatory drugs (NSAIDs) across developing countries is scarce. Objectives This study examines the prescribing pattern for NSAIDs in primary care, assesses the extent of high-risk NSAIDs prescribing and identifies associated factors. Setting 129 public and 416 private primary care clinics in Malaysia. Methods Data were derived from the National Medical Care Survey 2014, a cross-sectional survey on primary care morbidity patterns and clinical activities in Malaysia. Types of NSAIDs, indications for NSAIDs use and proportion of high-risk NSAIDs prescribing were assessed. Factors associated with high-risk NSAIDs prescribing were identified with a multivariable logistic regression. Weighted results, adjusted for sampling design and non-response were presented. Main outcome measures Prescribing pattern of NSAIDs, proportion of high-risk NSAIDs prescribing and its associated factors. Results Among the 55,489 patients who received NSAIDs, diclofenac was the most frequently prescribed NSAID (40.5%, 95% CI 40.1-40.9%), followed by mefenamic acid (29.2%, 95% CI 28.8-29.6%). The commonest indications for NSAIDs use were musculoskeletal condition and respiratory tract infection, both at 17.8% (95% CI 17.4-18.1%). A total of 22.9% (95% CI 22.6-23.3%) patients received high-risk NSAID prescriptions. Of these, 47.8% (95% CI 46.9-48.7%) did not receive adequate gastroprotection despite being at risk, 24.8% (95% CI 24.0-25.5%) were prescribed NSAIDs despite having cardiovascular comorbidities and 22.4% (95% CI 21.7-23.2%) were prescribed high-dose NSAIDs. The odds of receiving high-risk NSAID prescriptions increased with the number of drugs prescribed (OR 1.23, 95% CI 1.06-1.43) and the number of diagnoses in one visit (OR 2.21, 95% CI 1.71-2.86). The odds of being prescribed high-risk NSAID prescriptions were lower in patients with secondary (OR 0.52, 95% CI 0.35-0.77) and tertiary education (OR 0.39, 95% CI 0.22-0.68) compared to patients without formal education. Patients' citizenship, indication for NSAID prescriptions and whether a medical certificate was issued were also significantly associated with the likelihood of receiving high-risk NSAID prescriptions. Conclusions A quarter of NSAIDs prescribed in Malaysian primary care setting is categorised as high-risk prescribing. Targeted strategies are necessary to improve patient safety.

Long-term Assessment of NSAID Prescriptions and Potential Nephrotoxicity Risk in Adult Kidney Transplant Recipients.

Nonsteroidal anti-inflammatory drug (NSAID) use is recommended to be avoided in kidney transplantation, with a paucity of studies assessing their safety within this population. This study aims to use a large cohort of Veterans Affairs (VA) kidney transplantation recipients to assess the risk of acute kidney injury (AKI) with NSAID use. This is a 10-year longitudinal cohort study of adult kidney transplant recipients retrospectively followed in the VA system from 2001 to 2010 that assessed for risk of AKI with NSAID prescriptions. NSAID prescriptions, patient characteristics, and estimated glomerular filtration rates were abstracted from the VA comprehensive electronic health record. NSAID exposure was assessed by duration, dosage, and type. AKI events were defined by ≥50% decrease in estimated glomerular filtration rate. Risk was estimated using longitudinal multivariable generalized logistic regression model. About 5100 patients were included with a total of 29 980 years of follow-up; 671 NSAID prescriptions in 273 (5.4%) patients (2.24 per 100 patient-y) with 472 (70%) high dose were identified. High-dose NSAID prescriptions were associated with 2.83 (95% confidence interval [CI], 1.55-5.19; P < 0.001) higher odds of AKI events within a given year; low dose was not associated with AKI (odds ratio, 1.93; 95 % CI, 0.95-6.02; P = 0.256). One 7-day NSAID course was associated with 5% higher odds of increasing AKI events, whereas chronic use (≥180 d) was associated with 3.25 (95% CI, 1.78-5.97; P < 0.001) higher odds of AKI. Prescriptions for NSAIDs were uncommon in this cohort but were associated with a significant increase in the risk of AKI, which was impacted by higher NSAID dose and longer NSAID durations.

Experience with canakinumab in a patient with gout and IgA nephropathy

The paper discusses the results of clinically using the interleukin-1_ inhibitor canakinumab in a patient with chronic tophaceous gout, IgA nephropathy, and chronic kidney disease with resistance to traditional anti-inflammatory drugs (colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and high-dose glucocorticoids) and a history of failed urate-lowering therapy. It demonstrates the possibility of safely using subcutaneous canakinumab 150 mg that is superior to therapy with high-dose prednisone (40-80 mg/day) and NSAIDs. Canakinumab has also reduced the risk of exacerbations of arthritis when choosing urate-lowering therapy.

NSAID associated bilateral renal infarctions: a case report.

Renal infarctions (RIs) are caused by interruptions in the renal arterial blood flow. RIs are generally considered to be rare, however we present the case of a 37 year old woman whose renal infarction was likely due to the vasoconstrictive effects of non-steroidal anti-inflammatory drugs. Although high-dose non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause a decrease in renal perfusion, they have not been accepted as causative agents in renal infarction. Theoretically, patients in prostaglandin dependent states should be more vulnerable to renovascular vasoconstriction and resulting hypoperfusion in the presence of NSAIDs. Given the high prevalence of NSAID use, we suspect that this mechanism of renal injury may be more prevalent than previously thought.

Use of therapeutic plasma exchange to treat nonsteroidal anti-inflammatory drug overdose in dogs.

BackgroundTherapeutic plasma exchange (TPE) may be an effective technique for treatment of accidental nonsteroidal anti‐inflammatory drug (NSAID) overdose, but information regarding the use of this technique in veterinary medicine is currently limited.ObjectivesTo evaluate the overall outcome for dogs with NSAID overdose treated with TPE and to determine if any presenting factors can predict or influence overall outcome. Secondary objectives included investigating TPE complications as well as the utility of other adjunctive treatments.AnimalsEleven client‐owned dogs presented for NSAID overdose that received TPE. All patients also received additional supportive treatment including IV lipid infusion.MethodsRetrospective review of medical records.ResultsEleven cases were included in the study. Of these, the NSAID ingested was ibuprofen in 6 (54.5%), naproxen in 4 (36.4%), and deracoxib in 1 (9.1%). All dogs survived to discharge with 3 (27.3%) developing acute kidney injury during hospitalization. A larger initial dose of NSAID ingested was associated with a higher maximum serum creatinine concentration during hospitalization (P = .04) and larger change in serum creatinine concentration from baseline (P = .02). Six dogs (54.5%) developed complications associated with TPE. The use of other treatments did not affect the overall outcome.Conclusions and Clinical ImportanceWe identified TPE as an effective treatment for NSAID overdose with good outcomes despite high doses of NSAID ingestion in dogs treated with a single TPE treatment. Complications were common but did not affect the final outcome. Therapeutic plasma exchange should be considered in patients presenting for high‐dose NSAID ingestion.

Serum protein expression in Equine Glandular Gastric Disease (EGGD) induced by phenylbutazone.

Equine Glandular Gastric Disease (EGGD) is a common disease in sport horses. This disease might be associated with usage of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating inflammatory diseases. Although gastroscopy has been an effective method for diagnosis, but a less invasive, and inexpensive method is preferred. This study used proteomic technology to identify candidate serum proteins that might be used as markers of NSAIDs induced EGGD. Five Thoroughbred horses were given high doses of NSAID, phenylbutazone to treat lameness. The experiment was divided into three periods: (i) Pre-EGGD period, (ii) during EGGD period, and (iii) Post-EGGD period. Gastroscopy were used to diagnose EGGD, serum was collected to perform gel electrophoresis (1D SDS-PAGE) and mass spectrometry (LC-MS) in order to identify serum proteins in each group. The candidate serum proteins were computationally predicted for the interaction between phenylbutazone and proteins, tissue specific expression, and association to gastric ulceration. After EGGD induction, all horses showed clinical signs of colic with marked congestion and erosion appearing in the mucosa of the glandular stomach whereas no change was observed in the mucosa of non-glandular stomach. Our proteomic results identified 14 proteins that might be used as EGGD markers. These proteins were highly expressed in the glandular stomach and some proteins were associated with phenylbutazone or ulcer development. However, confirmation of these candidate marker proteins is required with specific antibodies in the larger horse population before they can be considered for application in the field.

Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.

High versus Low doses of Anti-inflammatory Drugs Do Not Differentially Affect Muscle Molecular Response to Acute Resistance Exercise

PURPOSE: We recently reported that high doses of non-steroidal anti-inflammatory drugs (NSAIDs) attenuate resistance exercise-induced muscle hypertrophy in young adults. Yet, little is known about the molecular mechanisms behind this effect. The current study aimed to examine acute muscle molecular responses to resistance exercise during co- ingestion of high and low doses of anti-inflammatory drugs. METHODS: Thirty one young (age 18-35 years) healthy men and women were randomly assigned to daily consumption of high doses of ibuprofen (IBU; 1200 mg; n=15) or low doses of acetylsalicylic acid (ASA; 75 mg; n=16) during an 8-week training intervention. During this period, subjects performed 20 supervised resistance training sessions (4 x 7-12 repetitions) involving the knee extensor muscles. Gene expression and protein signaling of key muscle growth regulators were analyzed from skeletal muscle biopsies obtained before training/treatment and 3 hours after an acute resistance exercise session during week 4 of the intervention. Real-time qPCR procedures were employed to determine mRNA expression. Protein signaling was assessed using western blots. RESULTS: Gene expression of myostatin (0.4-fold; p>0.0005), MuRF-1 (0.8-fold; p=0.015) and FoxO3 (0.6-fold; p>0.0005) decreased in response to the resistance exercise bout, with no difference across groups. Gene expression of IL-6 and STAT3 were unaltered. Protein phosphorylation of p70S6K increased (24-fold, P>0.0005) in response to the resistance exercise bout, with no difference across groups. Protein phosphorylation of STAT3 remained unchanged. CONCLUSIONS: These results show that high and low doses of NSAIDs do not differentially affect exercise-induced changes in gene expression and protein signaling for key markers of muscle growth in young adults. We therefore conclude that these acute markers do not seem to explain the negative effects of high doses of NSAIDs on muscle hypertrophy.

Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are a broad class of non glucocorticoid drugs which are extensively used in anti-inflammatory, analgesic, and antipyretic therapies. However, NSAIDs may cause many side effects, most commonly in gastrointestinal(GI) tract. Cardiovascular system, kidney, liver, central nervous system and hematopoietic system are also involved. NSAID-induced GI side effects not only endanger the patients' health, increase mortality, but also greatly increase the cost of medical care. Therefore, how to reduce GI side effects is of particular concern to clinicians. The Chinese Rheumatism Data Center(CRDC) and Chinese Systemic Lupus Erythematosus Treatment and Research Group(CSTAR) compose a "Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications" , as following: (1) GI lesions are the most common side effects of NSAIDs. (2) NSAID-induced GI side effects include gastritis, esophagitis, gastric and duodenal ulcers, bleeding, perforation and obstruction. (3) With the application of capsule endoscopy and small intestinal endoscopy, growing attention is being paid to the NASID-induced small intestine mucosa damage, which is mainly erosion and ulcer. (4) Risk factors related to NSAID-induced GI ulcers include: Helicobacter pylori (Hp) infection, age> 65 years, past history of GI ulcers, high doses of NSAIDs, multiple-drug combination therapy, and comorbidities, such as cardiovascular disease and nephropathy.(5) GI and cardiovascular function should be evaluated before using NSAIDs and gastric mucosal protective agents. (6) The risk of GI ulcers and complications caused by selective cyclooxygenase-2 (COX-2) inhibitors is less than that of non-selective COX-2 inhibitors. (7)Hp eradication therapy helps to cure GI ulcers and prevent recurrence when Hp infection is positive in NSAID-induced ulcers. (8) Proton pump inhibitor (PPI) is the first choice for the prevention and treatment of NSAID-induced GI injury. Gastric mucosal protective agents also suggested.(9) H2 receptor antagonist (H2RA) can reduce the risk of NSAID-induced duodenal injury, however, the therapeutic effect of NSAID-induced gastric ulcer remains to be further confirmed. (10) Endoscopic treatment is the first recommendation for NSAID-induced peptic ulcers combined with upper GI bleeding, high-dose PPI effectively prevent rebleeding, reduce the possibility of surgery and mortality rate.

Utilization of gastroprotective strategies for nonsteroidal anti-inflammatory drug-induced gastrointestinal events in a major teaching hospital.

Background and purposeClinical guidelines recommend the prescribing of gastroprotective strategies in nonsteroidal anti-inflammatory drug (NSAID) users with risk factors for gastrointestinal (GI) ulcer or ulcer complications. However, these guidelines are not often translated into clinical practice. Therefore, the aim of this study was to investigate the utilization of gastroprotective strategies for NSAID-induced upper GI events in at-risk users in a major teaching hospital.Patients and methodsA cross-sectional, observational, pharmacy-based study was conducted in a major Asian institution with both primary and secondary health care services. This study involved the screening of prescriptions for regular NSAIDs, and patients who met the inclusion criteria were recruited and interviewed using a questionnaire.ResultsOf the 409 participants recruited, 83.1% had at least one GI risk factor, of whom 70.3% did not receive appropriate gastroprotection. The most common GI risk factor was the use of high-dose NSAIDs (69.2%), followed by participants aged 65 years and older (22%) and concomitant use of low-dose aspirin (11.7%). Appropriate gastroprotective strategies utilized consisted of the use of a cyclooxygenase (COX)-2 inhibitor alone or a nonselective NSAID plus a proton pump inhibitor (PPI) in the moderate-risk group and a COX-2 inhibitor plus a PPI in the high-risk group. Gastroprotective strategies were underutilized in 67.1% of at-risk participants and overutilized in 59.4% of those without risk factors. Co-prescription of a histamine-2 receptor antagonist at lower-than-recommended doses constituted 59% of the inappropriate gastroprotective agents used. Logistic regression analysis revealed patients aged 65 years and older (odds ratio, 1.89; 95% CI =1.15–3.09) as a predictor for the prescribing of gastroprotection by the clinicians.ConclusionApproximately 70% of at-risk NSAID users, mainly on high-dose NSAIDs, were not prescribed appropriate gastroprotective strategies. Further measures are warranted to improve the safe prescribing of regular NSAIDs.

Nonsteroidal Antiinflammatory Drugs for Axial Spondyloarthritis: A Cochrane Review.

To determine the benefits and harms of nonsteroidal antiinflammatory drugs (NSAID) in axial spondyloarthritis (axSpA). Systematic review using Cochrane Collaboration methodology. randomized controlled trials (RCT) and quasi-RCT (to June 2014), investigating NSAID versus any control for axSpA, and observational studies of longterm effects (≥ 6 mos) of NSAID on radiographic progression or adverse events. Main outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, radiographic progression, number of withdrawals because of adverse events, and number of serious adverse events. Risk of bias was assessed. Thirty-five RCT, 2 quasi-RCT, and 2 cohort studies were included. Twenty-nine RCT and 2 quasi-RCT (n = 4356) were included in pooled analyses [traditional NSAID vs placebo (n = 5), cyclooxygenase-2 (COX-2) vs placebo (n = 3), COX-2 vs traditional NSAID (n = 4), NSAID vs NSAID (n = 24), naproxen vs other NSAID (n = 3), and low- vs high-dose NSAID (n = 5)]. Compared with placebo, both traditional and COX-2 NSAID were consistently more efficacious at 6 weeks and equally safe after 12 weeks. No significant differences in benefits or harms between the 2 NSAID classes and no important differences in benefits or withdrawals because of adverse events between different NSAID were found, especially if studies with high risk of bias were excluded. Single studies suggest NSAID may retard radiographic progression, especially by continuous rather than on-demand NSAID use. High-quality evidence indicates that both traditional and COX-2 NSAID are efficacious for treating axSpA, and harms are not different from placebo in the short term. Various NSAID are equally effective.

Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant comorbidities: management and mitigation of risks and adverse effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, and this widespread use is complicated by safety issues. A Literature review was conducted. NSAIDs are a leading cause of drug-related morbidity, especially in the elderly and patients with comorbidities. Most adverse effects are related to generalized inhibition of the major targets of NSAIDs: cyclooxygenases I and II. These enzymes are not only involved in pain and inflammation pathogenesis but are also required in the gastrointestinal (GI) tract for mucosal protection and gut motility, and in the kidneys for functional integrity. Thus, the mechanisms of NSAID toxicity are well understood, but the consequences are largely uncontrolled in clinical practice. GI ulcers, including bleeding ulcers, may occur in several percent of all chronic unprotected, high-dose NSAID users. Renal side effects may precipitate renal failure, resulting in acute dialysis and chronic retention. This includes sodium retention, resulting in arterial hypertension, heart failure, and atherosclerotic events. Cardiovascular risk may be tripled by chronic high-dose NSAID use in long-term clinical trials though "real-life studies" indicate lower risk ratios. Off-target side effects include allergic reactions, drug-induced liver injury, and central nervous system effects. Management of pain and inflammation must consider those risks and find alternative drugs or approaches to limit the negative impact of NSAIDs on mortality and morbidity. Alternative drugs, low-dose/short-term use, but especially non-pharmacologic approaches, such as physiotherapy, exercise, neurophysiologic measures, and local therapies, need to be further utilized. The appalling equation "less pain-more deaths/morbidity" ultimately necessitates treatment optimization in the individual patient.

Impact of postoperative non-steroidal anti-inflammatory drugs on adverse events after gastrointestinal surgery.

Recent evidence has suggested an association between postoperative non-steroidal anti-inflammatory drugs (NSAIDs) and increased operation-specific complications. This study aimed to determine the safety profile following gastrointestinal surgery across a multicentre setting in the UK. This multicentre study was carried out during a 2-week interval in September-October 2013. Consecutive adults undergoing elective or emergency gastrointestinal resection were included. The study was powered to detect a 10 per cent increase in major complications (grade III-V according to the Dindo-Clavien classification). The effect of administration of NSAIDs on the day of surgery or the following 2 days was risk-adjusted using propensity score matching and multivariable logistic regression to produce adjusted odds ratios (ORs). The type of NSAID and the dose were registered. Across 109 centres, early postoperative NSAIDs were administered to 242 (16·1 per cent) of 1503 patients. Complications occurred in 981 patients (65·3 per cent), which were major in 257 (17·1 per cent) and minor (Dindo-Clavien grade I-II) in 724 (48·2 per cent). Propensity score matching created well balanced groups. Treatment with NSAIDs was associated with a reduction in overall complications (OR 0·72, 95 per cent confidence interval 0·52 to 0·99; P = 0·041). This effect predominantly comprised a reduction in minor complications with high-dose NSAIDs (OR 0·57, 0·39 to 0·89; P = 0·009). Early use of NSAIDs is associated with a reduction in postoperative adverse events following major gastrointestinal surgery.

Analgesia dose prescribing and estimated glomerular filtration rate decline: a general practice database linkage cohort study

ObjectiveWe aimed to quantify the short-term effect of non-steroidal anti-inflammatory drugs (NSAIDs), aspirin and paracetamol analgesia dose prescribing on estimated glomerular filtration rate (eGFR) decline in the general practice population.DesignA...

75-Year-Old Man With Abdominal Pain and Reflux

75-Year-Old Man With Abdominal Pain and Reflux