Low-dose Non-steroidal Anti-inflammatory Drugs Research Articles

NSAIDs do not influence exercise effects on muscle size in rats or muscle protein synthesis signaling in humans

BACKGROUND: The aim of this project was to determine the impact of non-steroidal anti-inflammatory drugs (NSAIDs) on skeletal muscle adaptations to exercise. NSAIDs possess analgesic and anti‐inflammatory properties that occur by blocking cyclooxygenase (COX) enzymes, thereby inhibiting the production of prostaglandins. In the first study, we determined if low-dose chronic NSAID use affects muscle size in rodents exercising for six weeks. In the second study, we determined if a single high dose of NSAIDs effects the muscle protein synthetic signaling response to a bout of plyometric exercise. Our hypotheses were that NSAIDs would reduce both muscle size and muscle protein synthesis (MPS) signaling. METHODS: Study 1: 9-wk-old male Wistar rats (n=80) were randomized to placebo (PLA), naproxen (NAP), ibuprofen (IBU), or flurbiprofen (FLU) with or without exercise (EX) for six weeks. Exercise consisted of treadmill running at 25 m/min, for 30 minutes per day, five days per week. Soleus muscle was stained for myosin heavy chain (MHC) I or MHC IIA then analyzed for cross sectional area (CSA) and fiber type percentage. Rodent data were analyzed using a one-way ANOVA. Study 2: In a randomized, counter-balanced order, 12 participants (2 females, 10 males), performed four independent plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% of their 1RM, separated by a minimum of one week. Prior to each session, participants consumed a single dose of celecoxib (CEL 200 mg), IBU (800 mg), FLU (100 mg) or PLA. Muscle biopsies were collected before (PRE) and 3-hours post (POST) exercise. Muscle was analyzed via immunoblot for the following: phospho(p)-AKT(S473), total AKT, p-mTOR (S448), total mTOR, p-S6 (S235/236), total S6, p-4EBP1, and total 4EBP1. Fold changes were calculated from PRE to POST. Data were analyzed using a repeated measures ANOVA. All data are presented as mean ± SD. RESULTS: Study 1: There was no significant difference (p<0.05) in muscle CSA (PLA: 4060±517; PLA+EX: 3965±605; IBU: 3720±804; IBU+EX:4129±477; FLU: 3743±671; FLU+EX: 3649±541; NAP: 4157±1011; NAP+EX: 4123±586) or MHC IIA percentage (PLA: 10±7; PLA+EX: 10±5; IBU: 7±5; IBU+EX:9±3; FLU: 11±4; FLU+EX: 11±6; NAP: 11±4; NAP+EX: 12±3) between groups. Study 2: There was no significant difference (p<0.05) in fold-change between groups for p-AKT/total AKT (PLA: 1.23±0.4; IBU: 1.13±0.3; CEL: 1.26±0.4; FLU: 1.31±0.4), p-mTOR/total mTOR (PLA: 1.21±0.2; IBU: 1.21±0.3; CEL:1.34±0.2; FLU: 1.49±0.3), p-S6/total S6 (PLA: 11.48±10.6; IBU: 10.9±6.8; CEL: 6.01±2.98; FLU: 25.25±19.38), or p-4EBP1/total 4EBP1 (PLA: 1.71± 1.35; IBU: 1.23±0.98; CEL: 1.07 ±0.64; FLU: 2.03±1.49). CONCLUSION: Chronic low-dose NSAID consumption does not influence muscle size or MHC in exercising rodents. Similarly, an acute high dose of an NSAID does not affect the MPS signaling response in exercising humans. Funding was provided by the Military Operational Medicine Research Program. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as offcial or as reflecting the views of the Army or the Department of Defense. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Low-dose non-steroidal anti-inflammatory drugs: a promising approach for the treatment of symptomatic bone marrow failure in Ghosal hematodiaphyseal dysplasia.

Not available.

Potential Role of Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention for Inflammatory Bowel Disease: An Umbrella Review.

Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn's Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs' induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD.

Rectal administration of low-dose diclofenac does not reduce post-endoscopic retrograde cholangiopancreatography pancreatitis: a propensity score matching analysis.

Endoscopic retrograde cholangiopancreatography (ERCP) is a popular technique; however, post-ERCP pancreatitis (PEP) remains a major adverse event. The administration of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) is reportedly effective in preventing PEP. However, the recommended dose varies and the efficacy of low-dose rectal NSAIDs remains unclear. Therefore, we decided to investigate the effectiveness of low-dose rectal diclofenac on PEP prevention, using propensity score matching. This single-center retrospective study included 401 patients who underwent ERCP between July 2015 and March 2020. After December 2016, we administered rectal diclofenac within 30min before the ERCP procedure as widely as possible. Patients were divided into those who did (diclofenac group) and did not (control group) receive rectal diclofenac. Patients weighing ≥ 50kg were administered a 50mg dose, while those weighing < 50kg were administered a 25mg dose. The incidence and severity of PEP in the two groups were assessed by propensity score matching analysis. Among 401 patients undergoing ERCP, 367 fulfilled the inclusion criteria. Overall, 187 patients received rectal diclofenac (diclofenac group) and 180 did not (control group). After propensity score matching, 105 pairs were selected for evaluation. Overall, seven (6.7%) patients in the diclofenac group and 10 (9.5%) in the control group developed PEP (P = 0.45). Moderate or severe PEP occurred in four (3.8%) patients in the diclofenac group and six (5.7%) in the control group (P = 0.52). The administration of low-dose rectal diclofenac could not reduce the incidence and severity of PEP.

Low-Dose NSAIDs Efficacy in Orthopedic Applications.

Non-steroidal anti-inflammatory drugs (NSAIDs) [cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors] and COXIBs (the COX-2 selective inhibitors) may induce several potentially severe and life-threatening issues especially in elderly patients. The use of low-dose NSAIDs is associated with lower risk of side effects compared to the standard dosage. Low-dose NSAIDs could minimize the side effects of these drugs while maintaining their clinical efficacy and effectiveness. The present study evaluates the effectiveness and safety of low-dose NSAIDs in musculoskeletal applications.

Colchicine for acute gout.

Colchicine for acute gout.

The Analgesic Effect of Aspirin on Inflammatory Pain in Rats Is Affected by Pain Intensity and Administration Timing

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely known as painkillers. The analgesic action of NSAIDs is attributable to the inhibition of prostaglandin synthesis that occurs in response to blocking cyclooxygenase activity. The effective dose of NSAIDs can vary depending on pain intensity and administration timing; however, there are few studies on this. This study aimed to elucidate whether the analgesic effect of NSAIDs changes depending on the situation in which they are taken and we focused on the NSAID, aspirin (ASP). In a rat model of brewer's yeast-induced inflammation, pain caused by 20% (w/v) brewer's yeast-treatment was defined as "strong pain" and that caused by 2.5% (w/v) was defined as "weak pain". The analgesic effect of ASP (low-dose; 44 mg/kg or high-dose; 66 mg/kg) against strong pain was dose-dependent, but that against weak pain was the same. Furthermore, we defined drug administration after 3 h of brewer's yeast-treatment as "late administration" and that after 20 min as "early administration". In the case of strong pain, the analgesic effect of "late ASP administration" was dose-dependent, but that of "early ASP administration" was the same. These results suggest that low-dose NSAIDs have an analgesic effect against weak pain or when taken early.

Anti-Inflammatory Effect of Carprofen Is Enhanced by Avocado/Soybean Unsaponifiables, Glucosamine and Chondroitin Sulfate Combination in Chondrocyte Microcarrier Spinner Culture.

Osteoarthritis is a painful, chronic joint disease affecting man and animals with no known curative therapies. Palliative nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used but they cause adverse side effects prompting the search for safer alternatives. To address this need, we evaluated the anti-inflammatory activity of avocado/soybean unsaponifiables (ASU), glucosamine (GLU), and chondroitin sulfate (CS) with or without the NSAID carprofen. Canine chondrocytes were propagated in microcarrier spinner culture and incubated with (1) control medium, (2) ASU (8.3 µg/mL) + GLU (11 µg/mL) + CS (20 µg/mL) combination for 24 hours; and/or carprofen (40 ng/mL). Cultures were next incubated with control medium alone or IL-1β (10 ng/mL) for another 24 hours. Production of PGE2, IL-6, IL-8, and MCP-1 (also known as CCL-2) were measured by ELISA. Chondrocytes proliferated in microcarrier spinner culture and produced type II collagen and aggrecan. Stimulation with IL-1β induced significant increases in PGE2, IL-6, IL-8, and MCP-1 production. The increases in production were suppressed by carprofen as well as [ASU+GLU+CS]. The combination of carprofen and [ASU+GLU+CS] reduced PGE2 production significantly more than either preparation alone. The inhibitory effect of carprofen on IL-6, IL-8, and MCP-1 production was significantly less than that of [ASU+GLU+CS], whereas the combination did not reduce the production of these molecules significantly more than [ASU+GLU+CS] alone. The potentiating effect of [ASU+GLU+CS] on low-dose carprofen was identified in chondrocyte microcarrier spinner cultures. Our results suggest that the combination of low-dose NSAIDs like carprofen with [ASU+GLU+CS] could offer a safe, effective management for joint pain.

Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis.

Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis. The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n=21536) and control episodes of use of methotrexate alone (n=21725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores. During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia. Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.

Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial

The incidence of obscure gastrointestinal bleeding, which originates from the small bowel and is mainly associated with the use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), is rising. We assessed the efficacy and safety of misoprostol for the treatment of small bowel ulcers and erosions in patients taking low-dose aspirin or NSAIDs with obscure gastrointestinal bleeding. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients (aged ≥18 years) with small bowel ulcers who were taking low-dose aspirin, NSAIDs, or both for a minimum of 4 weeks, at University Hospital Crosshouse (Kilmarnock, UK). Eligible patients had evidence of obscure gastrointestinal bleeding (iron deficiency anaemia, a decrease in haemoglobin concentration of ≥20 × 103 mg/L, or positive faecal occult blood test) and normal upper endoscopy and colonoscopy. Patients were randomly assigned (1:1) using an interactive voice response system to receive 200 μg oral misoprostol or placebo four times daily for 8 weeks. Patients, investigators, and assessors were masked to treatment allocation. The primary endpoint was the complete healing of small bowel ulcers and erosions, assessed by video capsule endoscopy after 8 weeks of treatment. Primary analysis was by modified intention to treat, which included all randomised patients who received at least one dose of study treatment. Safety was assessed in the same population. The trial is registered with ClinicalTrials.gov, number NCT02202967. Between Jan 7, 2016, and Oct 11, 2017, we randomly allocated 104 eligible patients: 52 to receive misoprostol and 52 to receive placebo. Two patients allocated to misoprostol were later found to meet one of the exclusion criteria, thus 50 randomly assigned patients in the misoprostol group and 52 patients in the placebo group received at least one dose of study treatment. Complete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and nine (17%) of 52 patients in the placebo group (percentage difference 36·7%, 95% CI 19·5-53·9; p=0·0002). Adverse events occurred in 23 (46%) of 50 patients in the misoprostol group and 22 (42%) of 52 patients in the placebo group. The most common adverse events were abdominal pain (ten [20%] in the misoprostol group vs 13 [25%] in the placebo group), nausea or vomiting (nine [18%] vs seven [13%]), and diarrhoea (11 [22%] vs six [12%]). Four (8%) of 50 patients in the misoprostol group had severe adverse events, compared with none in the placebo group. No serious adverse events were reported. Misoprostol is effective for the treatment of small bowel ulcers and erosions in patients using low-dose aspirin and NSAIDs. Misoprostol might represent a pharmacological treatment option for lesions causing obscure gastrointestinal bleeding that is associated with aspirin and NSAIDs, but its use should be balanced against the risk of side-effects. National Health Service (NHS) Greater Glasgow and Clyde and NHS Ayrshire and Arran.

Tu1958 - Aspirin, NSAIDs, and Dysplastic Colonic Polyps – Lessons from Bowel Cancer Screening

Introduction Studies on bowel cancer chemoprevention have been limited by the failure to distinguish between the activities of low-dose aspirin and standard non-steroidal anti-inflammatory drugs (NSAIDs). Also, little is known about the activities of these agents in bowel cancer screening programs. We, therefore, aimed to assess the numbers and sizes of polyps/cancers detected in bowel cancer screening of patients using low-dose aspirin (75-mg/day), NSAIDs, and controls. Methods Guaiac peroxidase faecal occult blood test kits were sent to 71 026 local residents, aged 50–74 years, over the 12 calendar months of 2016: 38 799 subjects filled in and returned the kits. Those with positive kits (n=849) were interviewed and invited for colonoscopy. Their colonoscopic findings were classified according to their use of aspirin, NSAIDs, or neither. Only dysplastic or cancerous lesions were analysed. The Mann-Whitney test and Fisher’s exact test were used as appropriate. Odds ratios were adjusted for age and sex by logistic regression. Results DEMOGRAPHY: 528 subjects were colonoscoped at one single centre. The aspirin group (n=112) had 74 (66%) males and a median age of 68 years. The NSAID group (n=46) had 23 (50%) males and a median age of 58 years. The control group, not using either of these agents (n=370), had 207 (56%) males and a median age of 63 years (p 5 mm were found in 21 (19%) subjects taking aspirin vs 99 (27%) controls [odds ratio, OR, 0.57; 95% confidence intervals, CI, (0.33–0.98); p=0.042]. Polyps >5 mm or cancer were found in 24 (21%) aspirin users vs 118 (32%) controls [OR, 0.50; 95% CI (0.30.0.84); p=0.009]. POLYPS: NSAIDs vs CONTROLS. Polyps >5 mm were found in 5 (11%) subjects taking NSAIDs vs 99 (27%) controls [OR, 0.36; 95% CI (0.14–0.86); p=0.036]. Polyps >5 mm or cancer were found in 6 (13%) NSAID users vs 118 (32%) controls [OR, 0.35; 95% CI (0.14–0.86); p=0.022]. Conclusions (1) In this bowel cancer screening program, subjects taking low-dose aspirin were older while those taking NSAIDs were younger than controls not using either of these agents. (2) After adjusting the odds ratios for age and sex, the use of aspirin or NSAIDs was associated with lower prevalence of dysplastic colonic polyps or cancers. These results provide further evidence for the potential use of aspirin or NSAIDs for bowel cancer chemoprevention.

Low-dose NSAIDs reduce pain via macrophage targeted nanoemulsion delivery to neuroinflammation of the sciatic nerve in rat

Neuroinflammation involving macrophages elevates Prostaglandin E2, associated with neuropathic pain. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) inhibits cyclooxygenase, reducing PGE2. However, NSAIDs cause physiological complications. We developed nanoemulsions incorporating celecoxib and near infrared dye. Intravenous injected nanoemulsion is incorporated into monocytes that accumulate at the injury; revealed in live animals by fluorescence. A single dose (celecoxib 0.24 mg/kg) provides targeted delivery in chronic constriction injury rats, resulting in significant reduction in the visualized inflammation, infiltration of macrophages, COX-2 and PGE2. Animals exhibit relief from hypersensitivity persisting at least four-days. The total body burden of drug is reduced by >2000 fold over oral drug delivery.

The risk of lower gastrointestinal bleeding in low-dose aspirin users.

Aspirin increases the risk of gastrointestinal bleeding. To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users. Low-dose (75-325mg daily) aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers. A total of 53805 aspirin users and 269025 controls were included. Aspirin group had a higher incidence of LGIB within 1year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio [HR]: 2.75, 95% confidence interval [CI]: 2.06-3.65), NSAIDs (HR: 8.61, 95% CI: 3.28-22.58), steroids (HR: 10.50, 95% CI: 1.98-55.57), SSRIs (HR: 11.71, 95% CI: 1.40-97.94), PPIs (HR: 8.47, 95% CI: 2.26-31.71), and H2RAs (HR: 10.83, 95% CI: 2.98-39.33) were significantly associated with LGIB. The risk of LGIB was higher in low-dose aspirin users than in aspirin nonusers in this nationwide cohort. Low-dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.

The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies.

Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in postoperative pain management. However, their use in the setting of spine fusion surgery setting has long been a topic of controversy. In this review we examined relevant research, including in vivo, animal, and clinical human studies, with the aim of understanding the effect of NSAIDs on spinal fusion. Systematic review of study designs of all types from randomized controlled trials and meta-analyses to single-institution retrospective reviews. A search of PubMed and Embase was conducted using the keywords: "spine," "spinal fracture," NSAIDs, anti-inflammatory non-steroidal agents, bone, bone healing, fracture, fracture healing, yielding a total of 110 studies. Other 28 studies were identified by cross-referencing, resulting in total 138 studies. There is no level I evidence from human studies regarding the use of NSAIDs on spinal fusion rates. The overall tone of the spine literature in the early 2000s was that NSAIDs increased the rate of non-union; however, nearly all human studies published after 2005 suggest that short-term (<2weeks) postoperative use have no such effect. The dose dependency that is seen with a 2-week postoperative course is not present when NSAIDs are only used for 48h after surgery. NSAID appear to have dose-dependent and duration-dependent effects on fusion rates. The short-term use of low-dose NSAIDs around the time of spinal fusion surgery is reasonable. Spine surgeons can consider the incorporation of NSAIDs into pain control regimens for spinal fusion patients with the goal of improving pain control and reducing the costs and complications associated with opioids.

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drug Use and Colorectal Cancer Risk: A Population-Based, Case-Control Study.

A recent comprehensive review concluded that additional research is needed to determine the optimal use of aspirin for cancer prevention. To assess associations between the use of low-dose aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer risk. Population-based, case-control study. Northern Denmark. Patients with first-time colorectal cancer in northern Denmark between 1994 and 2011. Population control participants were selected by risk set sampling. Data on drug use, comorbid conditions, and history of colonoscopy were obtained from prescription and patient registries. Use of low-dose aspirin (75 to 150 mg) and nonaspirin NSAIDs was defined according to type, estimated dose, duration, and consistency of use. Among 10280 case patients and 102800 control participants, the adjusted odds ratios (ORs) for colorectal cancer associated with ever use (≥2 prescriptions) of low-dose aspirin and nonaspirin NSAIDs were 1.03 (95% CI, 0.98 to 1.09) and 0.94 (CI, 0.90 to 0.98), respectively. Continuous long-term use (≥5 years) of low-dose aspirin was associated with a 27% reduction in colorectal cancer risk (OR, 0.73 [CI, 0.54 to 0.99]), whereas the overall OR for cumulative long-term use (continuous or noncontinuous) was close to unity. Nonaspirin NSAID use was associated with a substantial reduction in colorectal cancer risk, particularly for long-term, high-intensity use (average defined daily dose ≥0.3) of agents with high cyclooxygenase-2 selectivity (OR, 0.57 [CI, 0.44 to 0.74]). Data were unavailable on over-the-counter purchases of high-dose aspirin and low-dose ibuprofen or NSAID dosing schedules, there were several comparisons, and the authors were unable to adjust for confounding by some risk factors. Long-term, continuous use of low-dose aspirin and long-term use of nonaspirin NSAIDs were associated with reduced colorectal cancer risk. Persons who continuously used low-dose aspirin comprised only a small proportion of the low-dose aspirin users. Danish Cancer Society, Aarhus University Research Foundation.

Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users.

Helicobacter pylori (H. pylori) infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction between H. pylori infection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use. This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission. H. pylori infection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA and H. pylori infection was estimated by logistic regression analysis. The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): 2.0-3.3) tested positive for H. pylori infection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: 3.0-5.4). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: 1.3-2.7). The RR of PUB for concomitant NSAID use and H. pylori infection suggested an additive effect (RR: 8.0; 95% CI: 5.0-12.8), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: 2.0-6.1). NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies.

Use of Thiazolidinediones and the Risk of Colorectal Cancer in Patients With Diabetes

OBJECTIVEPreclinical data suggest that peroxisome proliferator–activated receptor γ (PPARγ) agonists have antineoplastic effects in colorectal cancer. We aimed to assess the association between the use of synthetic PPARγ agonists, represented by thiazolidinediones (TZDs), and the risk of developing colorectal cancer.RESEARCH DESIGN AND METHODSWe conducted a nationwide, population-based, case-control study using the Taiwan National Health Insurance Research Database. Case subjects were defined as patients who were diagnosed with diabetes at least 365 days prior to a new diagnosis of colorectal cancer between 2000 and 2008. We randomly selected diabetic control subjects for each case subject, which were matched by sex, age, and the duration of diabetes. Among the 24,496 eligible case subjects and control subjects, we used conditional logistic regression to assess the risk of colorectal cancer in association with the use of TZDs. An additional analysis was conducted to assess the effects of concomitant use of TZDs and low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of colorectal cancer.RESULTSA decreased risk of colorectal cancer was observed in patients who had used TZDs compared with those who had never used TZDs (adjusted odds ratio 0.86 [95% CI 0.79–0.94]). Furthermore, the benefit of a decreased colorectal cancer risk was also found with concomitant use of TZDs and low-dose aspirin or NSAIDs.CONCLUSIONSThe use of TZDs may be associated with a decreased risk of colorectal cancer in patients with diabetes. Further studies are warranted to confirm our findings.

Prediagnostic Nonsteroidal Anti-Inflammatory Drug Use and Lung Cancer Survival in the VITAL Study

Inflammation is important for lung oncogenesis. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to improve colorectal cancer survival. However, few studies have examined the association in lung cancer patients. The VITamins And Lifestyle (VITAL) cohort includes Washington State residents, aged 50 to 76 years, who completed a baseline questionnaire between 2000 and 2002. Participants responded on the frequency and duration of use of individual NSAIDs in the previous 10 years. Subjects of this study were 785 members of the cohort, who were identified with incident lung cancer from baseline through 2007 through linkage to a population-based cancer registry. Participants were followed for lung cancer death through linkage to state records of death through 2009. Adjusted proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAIDs and lung cancer death. Five hundred and twenty-two participants (66%) died from lung cancer. Relative to nonuse, high (≥ 4 days/week and ≥ 4 years) prediagnostic use of regular-strength or low-dose aspirin (HR 0.99, 95% CI: 0.74-1.33 and HR 0.89, 95% CI: 0.67-1.17, respectively) or total nonaspirin NSAIDs (HR 1.20, 95% CI: 0.79-1.83) did not reduce lung cancer death. However, high use of ibuprofen was associated with a 62% increased risk of lung cancer death (HR 1.62, 95% CI: 1.01-2.58). Long-term, prediagnostic NSAID use does not improve lung cancer survival overall. Use of ibuprofen may reduce survival from lung cancer. Our results underscore the need for further study of the mechanisms of action for individual NSAIDs with regard to cancer survival.

Letter: mucosal injury with exposure to low‐dose nonsteroidals

Sirs, We read with interest the article by Hawkey et al., ‘Endoscopic evaluation of the gastro-duodenal tolerance of short-term analgesic treatment with 25 mg diclofenac-K liquid capsules’.1 The study evaluated the incidence of endoscopic gastroduodenal mucosal injury associated with 5 days of exposure to low/over the counter (OTC) doses of nonsteroidal anti-inflammatory drugs (NSAIDs): diclofenac-K liquid or diclofenac-K tablet (each at a total daily dose (TDD) of 75 mg), ASA (TDD of 3 g) or ibuprofen (TDD of 1.2 g). The authors highlight a significant and relatively understudied medical concern; most studies evaluate standard dose NSAIDs for the chronic treatment of inflammatory disorders and focus on endoscopic ulcer rates, tolerability, or bleeding outcomes.2, 3 For short-term low-dose/OTC medications, few studies have looked at such endpoints.4-6 The assumption has been that short courses of low-dose NSAIDs would be both tolerated and have a favourable safety profile. In conducting this study, the authors have attempted to directly compare the relative safety associated with diclofenac-K formulations as compared to comparable doses of ibuprofen or aspirin. The question that arises from this study is how do we accurately evaluate the clinically relevant safety of various medications used at OTC doses for short periods of time? Furthermore, with short exposure and low-dose, do variations in the incidence of erosions actually predict clinical safety? We believe that this may not be the best way to compare safety. Instead, the more clinically relevant endpoints would be to evaluate tolerability and persistence of use in a population who require short-term low-dose therapy. It would also be important to simultaneously measure the therapeutic efficacy for which the safer medication is being tested; as the authors point out, different formulations of medications may impact safety and tolerability differently. We congratulate the authors on highlighting the need to look at the safety of OTC nonsteroidals and look forward to future studies. Declaration of personal interests: Dr Goldstein has served as a speaker, a consultant and/or an advisory board member for Pfizer, Logical Therapeutics, Pozen, AstraZeneca, Takeda, Novartis, Astellas, Proctor and Gamble, and has received research funding from Pfizer, Sucampo, Pozen, Logical Therapeutics and AstraZeneca. Declaration of funding interests: None.