Maligned non-steroidal anti-inflammatory drugs: Misunderstanding of their safety profile in patients with renal insufficiency

Non-steroidal anti-inflammatory drugs have a fundamental and pivotal position in management of many of the disorders managed by rheumatologists. Promulgation of a false perspective of their toxicity has compromised our ability to advise our patients and participate in the management of their disorders. The literature sources, from which the false perspective derives, do not accurately reflect safety and fail to address the value of appropriate drug use monitoring. We, as rheumatologists, must stand up and proactively address engrained misconceptions-if we are to be able to continue to provide safe, effective care for our patients.     

Preference for nonsteroidal antiinflammatory drugs versus acetaminophen and concomitant use of both types of drugs in patients with osteoarthritis

OBJECTIVE: To analyze results of treatment of osteoarthritis (OA) with acetaminophen and the nonsteroidal antiinflammatory drugs (NSAID) through a patient survey. METHODS: A 15 minute telephone survey was conducted with 300 patients, including 172 with confirmed OA. RESULTS: Twenty-four percent of patients who took acetaminophen rated it as "very helpful," compared to 31% for ibuprofen, 30% for naproxen, and 56% for diclofenac. Drug continuation beyond 24 months was reported by 33% of patients for acetaminophen, 21% for ibuprofen, 17% for naproxen, and 19% for diclofenac. Acetaminophen was significantly less likely to be discontinued because of toxicity than NSAID. Patients who indicated that they would not take a drug again, and therefore be unlikely to participate in a clinical trial involving this drug, were 26% for acetaminophen, 40% for ibuprofen, 38% for naproxen, and 28% for diclofenac. About 30% of patients who took acetaminophen reported concurrent use of ibuprofen, naproxen, or diclofenac. Among the 67% of patients who identified a drug as "most helpful," 80% named an NSAID, compared to 20% who named acetaminophen or another analgesic as the "most helpful" drug. CONCLUSION: Patients take many different drugs for OA, most of which are not continued beyond 2 years. Many patients take both acetaminophen and an NSAID. Most patients who identified a drug as "most helpful" named an NSAID rather than acetaminophen or an analgesic drug. These findings may be of value in further development of management strategies and guidelines for OA.     

Gastrointestinal bleeding: dyspeptic symptoms and clinical course in relation to use of non-steroidal antiinflammatory drugs

To study the symptoms of NSAID-associated gastroduodenal bleeding, 94 patients (median age 71 years, range 19-90), were included in a prospective, clinical trial where hematemesis or melena from gastroduodenal ulceration or haemorrhagic/erosive gastritis were the inclusion criteria. NSAID use within one month was studied in relation to subjective symptoms prior to admission and to clinical course of the episode. Significantly fewer of the NSAID users (n = 54) than the non-users (n = 40) had experienced prior peptic ulceration or dyspeptic symptoms. Otherwise, no differences were seen between users and non-users, as regards pre-admission epigastric pain, heartburn or nausea. Also, the clinical course was similar in the two groups. We also found sporadic and regular NSAID use to be similar in this respect. These data do not support the alleged masking of ulcer symptoms by NSAIDs in bleeding ulcers.     

The effect of non-steroidal anti-inflammatory drugs on the endothelial function of patients with osteoarthritis in short term

Objective: Our primary aim was to test whether non‐steroid anti‐inflammatory drug (NSAID) use may account for endothelial dysfunction (ED) in the acute period. Additionally, we also aimed to compare the effect of diclofenac and naproxen on endothelial function. Methods: Forty patients with osteoarthritis (OA) were included in the study. Subjects currently receiving NSAIDs were asked to discontinue their anti‐inflammatory medications (for at least 5 days) before the study. After the wash‐out period, all subjects underwent vascular ultrasound measurements. Following baseline vascular imaging, patients were randomly assigned in a 1 : 1 ratio to receive either diclofenac (75 mg twice daily, n = 20), or naproxen (500 mg twice daily, n = 20) for 7 days. Endothelial function was evaluated by using the flow‐mediated dilatation (FMD) method, at baseline, and after 1 week of NSAID treatment. Results: There were 40 OA patients (4 male, 36 female). The median age of the patients was 60 ± 14 years. There were equal numbers of subjects in each treatment group. Age, sex distribution, body mass index, serum lipids, erythrocyte sedimentation rate, C‐reactive protein and fasting glucose levels were similar between the diclofenac and naproxen groups (P > 0.05). The brachial artery diameter (BAD), endothelium‐dependent vasodilatation (FMD%) and nitroglycerin‐induced endothelium‐independent vasodilatation (NTG%) values were not different between pretreatment and on the seventh day in the NSAID treatment groups (P > 0.05). Subgroup analysis also showed similar values of BAD, FMD%, and NTG% between naproxen and diclofenac groups (P > 0.05). Conclusion: Our results suggest that nonselective cyclo‐oxygenase antagonists naproxen and diclofenac have no effect on endothelial function during short‐term use.     

Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis

OBJECTIVE: The primary endpoint of this study was to compare the renal tolerability of amtolmetin guacyl (AMG), diclofenac and rofecoxib in elderly patients with symptomatic osteoarthritis (OA). The assessment of efficacy was the secondary endpoint. METHODS: 90 patients who satisfied the American College of Rheumatology classification criteria for hand, hip or knee OA were randomly assigned to 3 treatment groups receiving either: AMG 1,200 mg over thefirst 3 days and and 600 mg/day thereafter; diclofenac 150 mg/day; or rofecoxib 25 mg/day for 2 weeks. At baseline and after therapy patients were clinically assessed by the same examiner who was unaware of the treatment arm assignement. Serum and urinary parameters of renal function and the outcome measures of efficacy were evaluated before (t(0)) and after therapy (t(1)). RESULTS: Diclofenac produced a significant reduction in creatinine clearance (t(0) = 88.93 +/- 11.59; t(1) = 75.90 +/- 16.32; p: < 0.001) and in the daily urine volume (t(0) = 1,337.93 +/- 202.07; t(1) = 1,027.59 +/- 249.14; p: < 0.001). In the same treatment group a significant increase in serum creatinine, blood urea nitrogen, uric acid and potassium were observed. Rofecoxib treated patients showed a significant increase in body weight (t(0) = 75.31 +/- 4.26; t(1) = 76.54 +/- 4.84; p: < 0.001), systolic blood pressure (t(0) = 144 +/- 10.86; t(1) = 154 +/- 11.8; p < 0.001), diastolic blood pressure (t(0) = 80 +/- 6.05; t(1) = 89 +/- 7.66; p < 0.001) and serum sodium (t(0) = 138.73 +/- 1.28; t(1) = 140.12 +/- 1.80; p < 0.005) associated with a significant decrease in the daily urine volume (t(0) = 1294.64 +/- 205.21; t, = 1,115.48 +/- 238.47; p < 0.001) and creatinine clearance (t(0)= 86.73 +/- 8.14; t(1) = 83.15 +/- 7.96; p < 0.01). No significant changes in the clinical and humoral parameters were recorded in AMG treated patients. Diclofenac was more efficacious than the other 2 drugs (p < 0.001). No differences were observed between AMG and rofecoxib. Side effects related to altered kidney function were significantly higher in the rofecoxib group (p < 0.005). CONCLUSION: Diclofenac mainly impaired blood renal flow and the glomerularfiltration rate, while rofecoxib negatively influenced the renal sodium-water exchange. AMG demonstrated a renal sparing effect, although the eract mechanism is unclear     

Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors

OBJECTIVES: Upper gastrointestinal (GI) symptoms are common in patients using non-steroidal antiinflammatory drugs (NSAIDs) including selective cyclooxygenase (COX)-2 inhibitors and may be acid related. We therefore assessed esomeprazole treatment for upper GI symptoms in these patients. METHODS: A total of 794 and 848 continuous NSAID users, free of gastroduodenal ulcers, erosive esophagitis, and Helicobacter pylori, were enrolled into two identical, multinational, multicenter double-blind studies (NASA1, SPACE1). Moreover, 608 and 556 patients were randomized to receive 4 wk esomeprazole 20 mg, or 40 mg, or placebo once daily. The primary variable was the patient-reported change in the upper GI symptom (pain, discomfort, or burning in the upper abdomen) score on a 7-graded severity scale (0-6) from the 7 days prior to treatment to the last 7 days in the study. RESULTS: Esomeprazole was associated with highly significant symptom improvement compared to placebo. Symptom improvements were 2.30 mean [SD 1.63] on esomeprazole 20 mg and 2.03 [1.56] on esomeprazole 40 mg versus 1.64 [1.57] on placebo in NASA1 and 2.17 [1.34] and 2.12 [1.48]versus 1.56 [1.26], respectively, in SPACE1 (all placebo comparisons at least p < 0.001). Esomeprazole-improved symptoms in patients taking selective COX-2 inhibitors, with changes of 2.21 [1.46] and 1.92 [1.38]versus 1.64 [1.46] in NASA1 and 2.20 [1.26] and 2.24 [1.62]versus 1.58 [1.37] in SPACE1 (all placebo comparisons at least p < 0.05), as well as those on non-selective NSAIDs. Esomeprazole was well tolerated and associated with significant improvements in HRQL. CONCLUSION: Esomeprazole 20 mg and 40 mg improve upper GI symptoms associated with continuous, daily NSAID therapy, including selective COX-2 inhibitors.     

Iron status and the use of non-steroidal anti-inflammatory drugs in hemodialysis patients

We examined whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) can affect the anemia and iron status of hemodialysis patients. We recruited patients from six dialysis centers who had undergone maintenance hemodialysis for at least four months. We examined the use of NSAIDs during the past three months based on their medical records and assigned the patients to three groups (group A, non-NSAID group; group B, aspirin group; and group C, non-aspirin NSAID group). Of the 446 patients, 95 (21.3%) were treated with aspirin and 103 (23.1%) were treated with non-aspirin NSAIDs. The serum iron level and transferrin saturation (TSAT) were significantly lower in group C patients than those in group A. However, the ratio of the patients who were administrated iron preparations during the past three months was significantly higher than that in the other two groups. The incidences of positive fecal occult blood tests did not differ substantially between the three groups. The ratios of the patients who were administrated recombinant human erythropoietin were the same between three groups. Using a multiple regression analysis, the administration of non-aspirin NSAIDs was identified as an independent factor for the decreased serum iron and the decreased TSAT levels. A multiple logistic regression analysis revealed that the patients using non-aspirin NSAIDs had an increased the requirement for iron preparation therapy (OR 2.03, 95% CI, 1.28-3.22). The use of non-aspirin NSAIDs may therefore increase the risk of the iron deficiency in patients undergoing hemodialysis.     

Impact of discontinuing non-steroidal antiinflammatory drugs on long-term recurrence in colonic diverticular bleeding

AIM: To determine the effect of discontinuing nonsteroidal antiinflammatory drugs(NSAIDs) on recurrence in long-term follow-up patients with colonic diverticular bleeding(CDB).METHODS: A cohort of 132 patients hospitalized for CDB examined by colonoscopy was prospectively enrolled. Comorbidities, lifestyle, and medications(NSAIDs, low-dose aspirin, antiplatelet agents, anticoagulants, acetaminophen, and corticosteroids) were assessed. After discharge, patients were requested to visit the hospital on scheduled days during the followup period. The Kaplan-Meier method was used to estimate recurrence.RESULTS: Median follow-up was 15 mo. The probability of recurrence at 1, 6, 12, and 24 mo was 3.1%, 19%, 27%, and 38%, respectively. Of the 41 NSAID users on admission, 26(63%) discontinued NSAID use at discharge. Many of the patients who could discontinue NSAIDs were intermittent users, and could be switched to alternative therapies, such as acetaminophen or an antiinflammatory analgesic plaster. The probability of recurrence at 12 mo was 9.4% in discontinuing NSAID users compared with 77% in continuing users(P < 0.01, log-rank test). The hazard ratio for recurrence in the discontinuing NSAIDs users was 0.06 after adjusting for age > 70 years, right-sided diverticula, history of hypertension, and hemodialysis. No patients developed cerebrocardiovascular events during follow-up.CONCLUSION: There is a substantial recurrence rate after discharge among patients hospitalized for diverticular bleeding. Discontinuation of NSAIDs is an effective preventive measure against recurrence. This study provides new information on risk reduction strategies for diverticular bleeding.     

Effects of chronic therapy with non-steroideal antinflammatory drugs on gastric permeability of sucrose： A study on 71 patients with rheumatoid arthritis

AIM: To evaluate the gastric permeability after both acute and chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and to assess the clinical usefulness of sucrose test in detecting and following NSAIDs- induced gastric damage mainly in asymptomatic patients and the efficacy of a single pantoprazole dose in chronic users. METHODS: Seventy-one consecutive patients on chronic therapy with NSAIDs were enrolled in the study and divided into groups A and B (group A receiving 40 mg pantoprazole daily, group B only receiving NSAIDs). Sucrose test was performed at baseline and after 2, 4 and 12 wk, respectively. The symptoms in the upper gastrointestinal tract were recorded. RESULTS: The patients treated with pantoprazole had sucrose excretion under the limit during the entire follow-up period. The patients without gastroprotection had sucrose excretion above the limit after 2 wk, with an increasing trend in the following weeks (P = 0.000). A number of patients in this group revealed a significantly altered gastric permeability although they were asymptomatic during the follow-up period. CONCLUSION: Sucrose test can be proposed as a valid tool for the clinical evaluation of NSAIDs- induced gastric damage in both acute and chronic therapy. This technique helps to identify patients with clinically silent gastric damages. Pantoprazole (40 mg daily) is effective and well tolerated in chronic NSAID users.     

Informed choice and the widespread use of antiinflammatory drugs

OBJECTIVE: To examine whether the current widespread use of antiinflammatory drugs may reflect a lack of informed choice (i.e., unawareness of adverse effects or potential treatment alternatives) among older patients with knee osteoarthritis (OA). METHODS: Consecutive patients with symptomatic knee OA (n = 100) completed a questionnaire to assess their awareness of drug toxicity. Patients also completed an Adaptive Conjoint Analysis task so that the influence of providing an additional treatment alternative on patient preferences for nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors could be assessed. RESULTS: Fifty-four percent of the patients surveyed were unaware of any adverse effects related to NSAIDs and 80% were unaware of any toxicity related to COX-2 inhibitors. When given a choice between NSAIDs and COX-2 inhibitors, 57% of patients preferred COX-2 inhibitors over NSAIDs. When presented with a third less effective, but safer alternative, 100% of patients switched preferences to the safer, albeit less effective, option. CONCLUSIONS: Our findings suggest that the widespread use of NSAIDs may reflect lack of informed choice among older patients with OA.     

Renal impairment associated with non-steroidal anti-inflammatory drugs.

We have compared the renal function on admission and discharge of 22 patients routinely admitted to our rheumatology ward. None had previously diagnosed renal failure. Of 11 patients in whom we stopped long term non-steroidal anti-inflammatory drug (NSAID) therapy, all showed a rise in creatinine clearance (Ccr) after three to 28 days. In contrast, a control group comprising 11 similar patients who continued to receive NSAIDs showed no significant change. Recent work has suggested that it is possible to identify patients at risk of developing nephrotoxic side effects with NSAIDs. Based on these criteria (but excluding age alone as a risk), six patients from the first group and 10 from the second group would have been without risk. We infer from this that asymptomatic, reversible impairment of renal function is common, and that the potential clinical benefit from the use of NSAIDs should be balanced against this predictable toxicity.     

Turkish patients with osteoarthritis: their awareness of the side effects of NSAIDs.

BACKGROUND/AIMS: The study aim was to determine the awareness of Turkish osteoarthritis patients of the side effects of non-steroidal anti-inflammatory drugs. METHODS: The patients were interviewed by 138 doctors regarding the level of their knowledge of the side effects of non-steroidal anti-inflammatory drugs. RESULTS: A total of 3,755 patients (female/male: 3/1, 35% > 65 years) were included in the study. 35.5% of the patients were aware of side effects of non-steroidal anti-inflammatory drugs. 85.4% and 11.5% were aware of the gastrointestinal and other system-related side effects, respectively. 51% had learned of the side effects from doctors, 19.8% received information from the package inserts, 21.3% had experienced side effects, and 10.0% and 0.8% had learned from their friends and pharmacist, respectively. CONCLUSIONS: Turkish osteoarthritis patients have a moderate level of knowledge of side effects of non-steroidal anti-inflammatory drugs. Defining factors for knowledge of side effects of non-steroidal anti-inflammatory drugs were geographical region, socio-economic level and gender. This study reveals the physician's responsibility to educate patients about the side effects of non-steroidal anti-inflammatory drugs.     

Endemic fluorosis in Turkish patients: relationship with knee osteoarthritis

Fluoride excess primarily effects dental and skeletal tissues. leading to a condition known as endemic fluorosis. The radiological and clinical features of endemic fluorosis vary in different parts of the world. The aim of this study was to investigate the clinical and radiological features of endemic fluorosis in Turkish patients. Physical examination and radiological investigations were performed in 56 patients with endemic fluorosis and 40 age- and sex-matched controls. Knee osteoarthritis (OA) was the main abnormality in both groups, both clinically and radiologically. The radiological severity of knee OA was greater in the endemic fluorosis group than in controls (P=0.01). Osteophytes at the tibial condyles and superior margin of the patellar articular surface of the femur, polyp-like osteophytes on the non-weight-bearing medial side of the femoral condyle, and popliteal loose bodies were detected more frequently in the endemic fluorosis group than in controls (P=0.0001). We suggest that the presence of atypically located osteophytes in the knees may be a feature of endemic fluorosis in Turkish patients and that endemic fluorosis may increase the severity of OA in the knees.