Chronic inflammation may be important in prostate carcinogenesis. Several epidemiologic studies have reported inverse associations between non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk, although many studies are limited by assessment of short-term use only.
Participants were male members of the VITamins And Lifestyle cohort, comprised of 34,132 men, age 50-76 years, living in western Washington State. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) of 10-year average use of individual NSAIDs with total prostate cancer (n=1,550) and prostate cancer by grade.
Low-dose aspirin, regular-strength aspirin, ibuprofen, and any non-aspirin NSAID (ibuprofen, naproxen, and COX-2 inhibitors) were not associated with prostate cancer risk. There was a suggestion that regular-strength aspirin was inversely associated with risk of high-grade cancer (HR 0.73, 95% CI: 0.53-1.02).
NSAID use was not associated with prostate cancer risk in the VITAL cohort.
Our findings do not support the use of NSAIDs for chemoprevention of prostate cancer.
The risk of drug interactions with concurrent use of multiple medications is a clinically relevant issue. Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents. Of particular significance is the increased risk of upper abdominal gastrointestinal adverse events in patients who take traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This risk is dose dependent and further increased in patients who take more than one NSAID or use NSAIDs in combination with certain other medications. Some NSAIDs may also mitigate the antiplatelet benefits of aspirin and may increase blood pressure in patients with hypertension. Clinicians should be aware of potential drug interactions with OTC analgesics when prescribing new medications. Additionally, patients should be properly counseled on the appropriate and safe use of OTC analgesics.
The objectives of this study were to assess the prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners and to determine their attitudes to problems caused by this class of drugs. The study consisted of two parts. The first was a questionnaire survey among general practitioners in Fife and Tayside, and the second was an analysis of NSAID prescribing over 12 months among the doctors in the Carnoustie Health Centre, using duplicate prescriptions. In the questionnaire survey 61% of the general practitioners responded. The three most preferred drugs were buprofen (56%), naproxen (20%) and mefenamic acid (7%); choice of drug was determined by efficacy and personal experience. Gastrointestinal side effects were most frequently encountered, although there was little consensus amongst respondents as to their management. The duplicate prescription study showed that 14% of patients (1607 individuals) received at least one NSAID prescription in the year of study. Ibuprofen (31%), naproxen (20%) and piroxicam (15%) were most frequently prescribed and up to 16% of the patients were co-prescribed a gastroprotective agent; ranitidine (75%) was the most commonly prescribed. Despite the introduction of newer NSAIDs, ibuprofen and naproxen are still the most commonly prescribed drugs. Furthermore, although gastrointestinal side effects are commonly encountered, there is some uncertainty about their management.
Non-steroidal anti-inflammatory drug (NSAID) use has been associated with decreased colorectal cancer (CRC) risk. However, NSAID effects on clinical outcomes after CRC diagnosis are not well-defined. We investigated the association of pre-diagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study (CTS) cohort.
Women under 85 years participating in the CTS, without prior CRC diagnosis at baseline (1995-1996), and diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association of pre-diagnosis NSAID use and mortality. NSAID use (including aspirin, and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) for death and 95% confidence intervals (CI).
Among 621 CRC cases identified, 64% reported no pre-diagnosis regular NSAID use, 17% reported use 1-6 days/week, and 20% reported daily use; duration of NSAID use < 5 years was reported by 17% and ≥5 years reported by 18%. Regular pre-diagnosis NSAID use (1-3 days/week, 4-6 days/week, daily) vs. none was associated with improved overall survival (OS) (HR=0.71, 95% CI 0.53-0.95) and CRC-specific survival (CRC-SS) (HR=0.58, 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Pre-diagnosis NSAID use ≥5 years (versus none) was associated with improved OS (HR=0.55, 95% CI 0.37-0.84) and CRC-SS (HR=0.40, 95% CI 0.23-0.71) in adjusted analyses.
When used regularly or over a prolonged duration prior to CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC cases.
Colon cancer; colorectal cancer; non-steroidal anti-inflammatory drugs; NSAIDs; rectal cancer; survival
Studies suggest that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) may lower estrogen levels in women. However, no large, population-based studies have assessed NSAID/hormone associations in men. Our objective was to examine the association between use of prescription and over-the-counter NSAIDs and levels of estrogens and androgens in men.
The Boston Area Community Health Survey, an observational survey with initial data collection in 2002–2005.
1,766 men who provided a blood sample and data on recent analgesic use.
Adjusted geometric mean levels of androgens, estrogens, SHBG, LH, and FSH for each category of NSAID use and the percent difference in hormone levels for users vs. non-users.
There was no significant association between prescription or over-the-counter NSAID use and any hormone examined after adjustment for potential confounders. For example, geometric mean testosterone levels were 13.8, 13.6, and 14.2 nmol/L in non-users, prescription, and over-the-counter NSAID users, respectively; the corresponding levels for estradiol were 80.3, 70.4, and 79.9 pmol/L. In stratified analyses, however, prescription NSAID use was associated with lower testosterone, estradiol, and estrone levels in obese men and lower testosterone and dehydroepiandrosterone sulfate levels in inactive men.
While overall these data do not provide strong support for an association between NSAID use and hormone levels in men, prescription NSAIDs may decrease levels of certain estrogens and androgens in obese and inactive men.
Androgens; Anti-Inflammatory Agents; Non-Steroidal; Cyclooxygenase 2 Inhibitors; Estrogens; Hormones
To examine the association between non-steroidal anti-inflammatory drug (NSAID) use and cutaneous squamous cell carcinoma (SCC).
Kaiser Permanente Northern California (KPNC), a large population based-health maintenance organization.
Random sample of 415 KPNC members diagnosed with a pathology-verified SCC in 2004 and 415 age-, sex, and race-matched controls with no history of skin cancer.
MAIN EXPOSURE MEASURE
Self-reported NSAID use in the 10 years prior to baseline. NSAID use was categorized based on type (any NSAIDs, aspirin, ibuprofen, non-aspirin NSAIDs). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, dose and duration of exposure to the different NSAID types. Information on pharmacy-dispensed NSAIDs was also examined to assess its association with SCC risk. Models were adjusted for all ascertained SCC risk factors (fully adjusted model) and only those variables associated with both SCC risk and NSAID use (parsimonious model).
Fully adjusted analyses showed no statistically significant reduction in SCC risk with self-reported regular use of any NSAID (OR=1.32, 95% CI: 0.92–1.89), aspirin (OR=1.38, 95% CI: 0.96–1.97), ibuprofen (OR=0.74, 95% CI: 0.46–1.19), or non-aspirin NSAIDs (OR=0.84, 95% CI: 0.56–1.26). Analyses examining duration, dose, and variables combining duration and dose of NSAID exposure did not appreciably change results. Analysis using the parsimonious model showed similar results. The data on pharmacy dispensed NSAIDs also showed no association with SCC risk.
Neither self-reported, nor pharmacy-dispensed NSAID exposure was associated with cutaneous SCC risk.
Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.
Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD).
We investigated associations between use of aspirin, nonaspirin NSAIDs, and acetaminophen and PD in a large population-based case-control study using Danish health and pharmacy registries. We identified 1,931 PD cases reported in hospital or outpatient clinic records who had received a primary diagnosis of PD between 2001 and 2006, and 9,651 age- and sex-matched controls from the Danish population register. Prescription medication use was documented in a pharmacy database covering all residents of Denmark since 1995.
Adjusting for age, sex, use of cardiovascular disease drugs, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity scores, and excluding prescriptions filled within 5 years before diagnosis, we found no evidence for an association between PD and either aspirin use (OR = 0.97; 95% CI 0.82, 1.14) or nonaspirin NSAID use (OR = 0.97; 95% CI 0.86, 1.09), regardless of intensity of use; further, there was no association between use of ibuprofen or acetaminophen and PD.
Our findings provide no evidence for a protective effect of nonaspirin and aspirin NSAID prescription drug use shortly before PD onset.
Parkinson's disease; Case-control study; Anti-inflammatory drugs
The widely used non-steroidal anti-inflammatory drugs (NSAIDs) function mainly through inhibition of cyclooxygenases 1 and 2 (Cox-1 and Cox-2). Unlike Cox-1, Cox-2 is considered an inducible and pro-inflammatory enzyme. We previously reported that Cox-2 is upregulated in activated human B lymphocytes and using Cox-2 selective inhibitors that Cox-2 is required for optimal antibody synthesis. It is not known whether commonly used non-prescription and non-Cox-2 selective drugs also influence antibody synthesis. Herein, we tested a variety of Cox-1/Cox-2 non-selective NSAIDs, namely ibuprofen, tylenol, aspirin and naproxen and report that they blunt IgM and IgG synthesis in stimulated human peripheral blood mononuclear cells (PBMC). Ibuprofen had its most profound effects in inhibiting human PBMCs and purified B lymphocyte IgM and IgG synthesis when administered in the first few days after activation. As shown by viability assays, ibuprofen did not kill B cells. The implications of this research are that the use of widely available NSAIDs after infection or vaccination may lower host defense. This may be especially true for the elderly who respond poorly to vaccines and heavily use NSAIDs.
human B lymphocytes; Cox-2; NSAIDs; antibody
BACKGROUND: The epidemiology of vulvovaginal candidiasis (VVC) and such recurrent infections (RVVC) has been difficult to study as the majority of episodes of these conditions are self-treated by the women affected. In Sweden, all pharmacies are owned by the state and all prescriptions and over-the-counter (OTC) products, such as antifungals, are registered in a database, which offers unique possibilities to study the epidemiology of VVC/RVVC. OBJECTIVES: To analyze all prescriptions and OTC products purchased for therapy of VVC/RVVC and to establish reasons for any observed variation in the sales figures. METHODS: Sales figures in the Swedish county of Skåne of antifungal drugs for therapy of VVC/RVVC were analyzed by the aid of the 'ACS' database of the National Corporation of Swedish Pharmacies for the years 1990--1999. The size of the female population in the county is approximately half a million. RESULTS: The study showed that 93% of all antifungal drugs for VVC/RVVC were sold as OTC products. An increase in sales of the drugs occurred until mid- 1993/94, followed by a decrease until end of the study period in 1999. Demographic factors (e.g. the number of female inhabitants in the county, pharmacies and health-care units), the pregnancy rate and pharmacy-dependent factors (such as the introduction of shelves for self-selection of antifungal products) did not explain the observed variations in sales. Distinct short-term variations in the number of prescriptions of fluconazole and itraconazole could be explained by drugs company sales campaigns and logistics factors in drug distribution. The sales volumes in the 33 municipalities in the county correlated with the density of the population, which was not the case for the total number of prescriptions made in the county during the 1990s. The variation in antifungal drug sales was similar to that of hormonal intrauterine devices, but this was not the case for oral contraceptives. The total Swedish usage of antibiotics showed a similar variation to that of the antifungal drugs analyzed. CONCLUSION: The study stresses the limited impact on the treatment of VVC/RVVC by the medical community. Behavior-related factors in the female population are the most likely explanation for the marked variations found in the usage of drugs for the two conditions.
National Institute of Health and Clinical Excellence (NICE) guidance stated that a new form of non-steroidal anti-inflammatory drug (NSAID) (selective COX-2 inhibitors) should only be an option for arthritis patients at high risk of a gastro-intestinal (GI) event. Total expenditure on NSAIDs has risen by 57% over five years, to £247 million in 2004. We assess whether this expenditure increase can be accounted for by substitution – an increased prescribing of two (more expensive) selective COX-2 inhibitors (celecoxib and rofecoxib) and a simultaneous equivalent reduction in the prescribing volume of three (cheaper) older NSAIDs (diclofenac, ibuprofen and naproxen).
Quarterly prescription data was collated from January 1999 to September 2004. Over this period, the level of correlation between the total prescribing volumes for i) celecoxib and rofecoxib, and ii) diclofenac, ibuprofen, and naproxen were compared, the change in total expenditure on the five NSAIDs was also estimated. The latter was apportioned into that which was estimated to have arisen due to i) substitution, and ii) increased NSAID prescription volume.
Total prescription volumes for the two NSAID groups were negatively correlated (r = -0.97, p < 0.001). In the last quarter there were 1.23 million prescriptions for celecoxib and rofecoxib, and 0.46 million fewer prescriptions for naproxen, diclofenac, and ibuprofen (than in the first quarter, when celecoxib and rofecoxib were not prescribed). Total expenditure for the five NSAIDs was £32.7 million higher in the last quarter, than the first, £12.2 million of which was estimated to be due to substitution, and £20.4 million due to increased volume.
The introduction of celecoxib and rofecoxib was associated with a reduction in the prescription volume for naproxen, diclofenac, and ibuprofen. However, overall quarterly prescription volume for these five NSAIDs increased by 0.76 million, and we estimate that quarterly expenditure increased by £20.4 million more than would have been expected if overall NSAID volume had remained constant. This suggests that the prescription of both celecoxib and rofecoxib may have 'leaked' to population groups who would not previously have received an older NSAID.
Background & Aims
Limited evidence suggests that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins may be associated with low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett’s esophagus (BE) is unclear.
We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans Affairs (VA) computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAID/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socio-economic status.
In a cohort of 11,823 patients with first time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs. 94%, p=0.5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio: 0.64; 95% CI, 0.42–0.97). Filled statin prescriptions were also associated with a reduction in EAC risk (0.55; 95% CI, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding.
This observational study indicates that in patients with Barrett’s esophagus using PPI, NSAID/aspirin or statin therapy might reduce the risk of developing esophageal adenocarcinoma.
epidemiology; chemoprevention; GERD; VA; Medicare
Evidence suggests that both selective cyclooxygenase (COX)‐2 inhibitors and non‐selective non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX‐2 inhibitors and non‐selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX‐2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low‐dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non‐fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).
In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.
These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non‐aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study.
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR = 1.7 (95% CI = 1.3–2.1; Pc = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc = 0.008 and Pc = 0.004, respectively).
Conclusions and implications
The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.
We investigated the risk of lung cancer in relation to non-steroidal anti-inflammatory drugs (NSAIDs) among 573 cases and 857 sex- and age-matched controls for whom we had information on use of NSAIDs, from a prescription database covering all pharmacies in Denmark since 1995, and self-reported NSAID use, smoking habits and other potential confounders. Associations were expressed as odds ratios, assessed by logistic regression in unmatched analyses. After controlling for smoking habits, length of education and concomitant use of acetaminophen, we found a slightly decreased relative risk of 0.86 (95% confidence intervals, 0.65–1.14) for lung cancer associated with any use of NSAIDs. The risk decreased significantly (P=0.02) with increasing numbers of dispensed prescriptions per year during the 1–3 years before the index date with a relative risk of 0.49 (0.28–0.84) among those with four or more prescriptions per year during this period. Our findings suggest that regular use of NSAIDs is associated with a slightly or moderately reduced risk for lung cancer.
lung cancer; pharmacoepidemiology; non-steroidal anti-inflammatory drugs; chemoprevention
Pharmacies that sell over-the-counter (OTC) syringes are a major source of sterile syringes for injection drug users in cities and states where such sales are legal. In these cities and states, however, black injectors are markedly less likely to acquire syringes from pharmacies than white injectors. The present analysis documents spatial and temporal trends in OTC pharmacy access in New York City health districts over time (2001–2006) and investigates whether these trends are related to district racial/ethnic composition and to local need for OTC pharmacies. For each year of the study period, we used kernel density estimation methods to characterize spatial access to OTC pharmacies within each health district. Higher values on this measure indicate better access to these pharmacies. “Need” was operationalized using two different measures: the number of newly diagnosed injection-related AIDS cases per 10,000 residents (averaged across 1999–2001), and the number of drug-related hospital discharges per 10,000 residents (averaged across 1999–2001). District sociodemographic characteristics were assessed using 2000 US decennial census data. We used hierarchical linear models (HLM) for descriptive and inferential analyses and investigated whether the relationship between need and temporal trajectories in the Expanded Syringe Access Demonstration Program access varied by district racial/ethnic composition, controlling for district poverty rates. HLM analyses indicate that the mean spatial access to OTC pharmacies across New York City health districts was 12.71 in 2001 and increased linearly by 1.32 units annually thereafter. Temporal trajectories in spatial access to OTC pharmacies depended on both need and racial/ethnic composition. Within high-need districts, OTC pharmacy access was twice as high in 2001 and increased three times faster annually, in districts with higher proportions of non-Hispanic white residents than in districts with low proportions of these residents. In low-need districts, “whiter” districts had substantially greater baseline access to OTC pharmacies than districts with low proportions of non-Hispanic white residents. Access remained stable thereafter in low-need districts, regardless of racial/ethnic composition. Conclusions were consistent across both measures of “need” and persisted after controlling for local poverty rates. In both high- and low-need districts, spatial access to OTC pharmacies was greater in “Whiter” districts in 2001; in high-need districts, access also increased more rapidly over time in “whiter” districts. Ensuring equitable spatial access to OTC pharmacies may reduce injection-related HIV transmission overall and reduce racial/ethnic disparities in HIV incidence among injectors.
Electronic supplementary material
The online version of this article (doi:10.1007/s11524-009-9399-7) contains supplementary material, which is available to authorized users.
HIV/AIDS; Injection drug use; Harm reduction; Geography; Health service access; Health disparities
The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.
anti-inflammatory; cyclooxygenase; codrug; mutual prodrug; NO-NSAIDs; NSAIDs; Phospho-NSAIDs; prodrug
Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs.
Methods and Findings
We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0–12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4–1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9–15.7).
Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.
Cyclo‐oxygenase‐2 selective inhibitors have been associated with cardiovascular side effects, but previous studies have generally excluded people with previous myocardial infarction, thereby limiting our knowledge of their cardiotoxicity in this population.
To determine whether a history of myocardial infarction modified the risk of acute myocardial infarction associated with the use of various non‐steroidal anti‐inflammatory drugs (NSAIDs).
A population‐based cohort of 122 079 elderly people with and without previous myocardial infarction newly treated with an NSAID between 1 January 1999 and 30 June 2002 were identified using the computerised health databases of Québec, Canada. A nested‐case–control approach was used for the analysis, with controls matched by cohort entry and age. Current users of NSAIDs, those whose last prescription overlapped with the index date, were compared with those who were not exposed to NSAIDs in the year preceding the event. Rate ratios of acute myocardial infarction were estimated using conditional logistic regression and adjusted for potential confounders.
Users of rofecoxib, both with and without previous myocardial infarction, were at increased risk of myocardial infarction, with a trend for greater risk among those with a previous event (rate ratio (RR) 1.59, 95% confidence interval (CI) 1.15 to 2.18 v RR 1.23, 95% CI 1.05 to 1.45; p = 0.14 for interaction). By contrast, celecoxib was only associated with an increased risk in people with previous myocardial infarction (RR 1.40, 95% CI 1.06 to 1.84 v RR 1.03, 95% CI 0.88 to 1.20; p = 0.04 for interaction). The available power was insufficient to reliably assess risks among patients with previous myocardial infarction treated with other NSAIDs, dose–response relationships or interaction with aspirin.
Although only rofecoxib use was associated with an increased risk of myocardial infarction in those without a previous event, both rofecoxib and celecoxib were associated with an excess risk of acute myocardial infarction for current users with a history of myocardial infarction. A large randomised trial is required to more completely and reliably assess the cardiovascular safety of celecoxib and traditional NSAIDs in this population of high‐risk patients.
Background: Although clinical trial results suggest that meloxicam has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), in practice it has been associated with a large number of yellow card reports of gastrointestinal complications.
Aims: To estimate whether meloxicam and the coxibs, rofecoxib and celecoxib, have been channelled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling.
Patients: Using the UK General Practice Research Database, this study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to older non-specific NSAIDs.
Methods: Cohort study of patients who received a prescription for an NSAID between June 1987 and January 2001. Exposure to newer NSAIDs (meloxicam, rofecoxib, celecoxib) and to older non-specific NSAIDs was identified. Channelling was assessed on factors including: demographic variables; diagnosis of arthritis; history of NSAID use or gastrointestinal events, including gastrointestinal haemorrhage; and use of ulcer healing drugs.
Results: Most risk factors for gastrointestinal haemorrhage were more prevalent among patients prescribed the newer NSAIDs. Adjusting for these risk factors reduced the relative risks of gastrointestinal haemorrhage on meloxicam and coxibs versus older non-specific NSAIDs to 0.84 (95% confidence interval 0.60, 1.17) and 0.36 (0.14, 0.97), respectively.
Conclusions: Channelling towards high risk gastrointestinal patients occurred in the prescribing of newer NSAIDs. After attempting to correct for channelling bias, coxib exposure, but not meloxicam exposure, was associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.
meloxicam, cyclooxygenase 2; non-steroidal anti-inflammatory drugs; gastrointestinal haemorrhage; General Practice Research Database
Objectives To compare the risk of death and recurrent congestive heart failure in elderly patients prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs (NSAIDs) and to determine whether there are class differences between celecoxib and rofecoxib.
Design Population based retrospective cohort study.
Setting Databases of hospital discharge summaries and prescription drug claims in Quebec.
Participants 2256 patients aged 66 or more prescribed celecoxib, rofecoxib, or an NSAID after an index admission for congestive heart failure between April 2000 and March 2002.
Main outcome measures Time to all cause death and recurrent congestive heart failure, combined and separately.
Results The risk of death and recurrent congestive heart failure combined was higher in patients prescribed NSAIDs or rofexocib than in those prescribed celecoxib (hazard ratio 1.26, 95% confidence interval 1.00 to 1.57 and 1.27, 1.09 to 1.49, respectively). The findings were similar when the outcomes were assessed separately. In pairwise analysis, the risks of death and recurrent congestive heart failure, combined and separate, were similar between patients prescribed NSAIDs and rofecoxib.
Conclusions Celecoxib seems safer than rofecoxib and NSAIDs in elderly patients with congestive heart failure. Differences were found among cyclo-oxygenase-2 inhibitors.
This is a cross-sectional observational study undertaken to explore the current prescription pattern of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevalence of NSAID-induced gastrointestinal (GI) risk factors of orthopaedic patients in real clinical practice in Korea. Study cohort included 3,140 orthopaedic outpatients at 131 hospitals and clinics between January 2008 and August 2008. A self-administered questionnaire was completed by each patient and physician. A simplified risk scoring scale (the Standardized Calculator of Risk for Events; SCORE) was used to measure patients' risk for GI complications. The pattern of NSAIDs prescription was identified from medical recordings. Forty-five percents of the patients belonged to high risk or very high risk groups for GI complications. The cyclooxygenase-2 enzyme (COX-2) selective NSAID showed a propensity to be prescribed more commonly for high/very high GI risk groups, but the rate was still as low as 51%. In conclusion, physician's considerate prescription of NSAIDs with well-understanding of each patient's GI risk factors is strongly encouraged in order to maximize cost effectiveness and to prevent serious GI complications in Korea. Other strategic efforts such as medical association-led education programs and application of Korean electronic SCORE system to hospital order communication system (OCS) should also be accompanied in a way to promote physician's attention.
Anti-Inflammatory Agents, Non-Steroidal; GI risk factor; Cyclooxygenase 2 Inhibitors; SCORE; Korea
A low meat diet and regular non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased mortality among colorectal cancer (CRC) patients. Here we investigated the association between pre-diagnosis usual meat consumption and CRC-specific mortality, and whether meat consumption modifies the previously noted association between NSAID use and CRC-specific mortality among women in the California Teachers Study (CTS) cohort. Women joining CTS in 1995–1996 without prior CRC diagnosis, diagnosed with incident CRC during follow-up through December 2007, were eligible for inclusion. Meat intake (frequency and serving size) and NSAID use (aspirin or ibuprofen use) were ascertained via self-administered questionnaires before diagnosis. Vital status and cause of death were determined by linkage with mortality files. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) for death and 95% confidence intervals (CI). Pre-diagnosis meat consumption was not associated with CRC-specific mortality among 704 CRC patients (and 201 CRC-specific deaths), comparing patients in the lowest consumption tertile (0–5.4 medium-size servings/week) to those with higher consumption. Regular NSAID use (1–3 times/week, 4–6 times/week, daily) vs. none was associated with decreased CRC-specific mortality among patients in the lowest meat consumption tertile (HR=0.22, 95% CI 0.06–0.82), but not among patients in the higher meat intake tertiles. The previously observed mortality risk reduction among female CRC patients associated with regular NSAID use was restricted to patients who reported low meat intake before diagnosis. These findings have implications for CRC survivorship and tertiary CRC prevention.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that can cause serious gastrointestinal (GI) side effects. For patients at increased risk of NSAID-related GI complications, prophylaxis with either a nonselective NSAID plus gastroprotective agent (GPA) or, alternatively, therapy with a cyclooxygenase-2 selective inhibitor with or without a GPA such as a proton pump inhibitor (PPI), is recommended.
To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs.
The Nova Scotia Seniors’ Pharmacare Program beneficiaries for the years 1998 to 2002 were studied. A cohort of incident NSAID and GPA users was selected from all nonselective NSAID users (no prescribed NSAID dispensed 12 months before the index month and no GPA dispensed two months before the index prescription). Monthly coprescribing rates were calculated by dividing the number of patients in the cohort using GPAs by the number of NSAID users. GI prophylactic coprescribing was defined as the coprescribing rate present at the first month (index month) of prescribing an NSAID.
The cohort consisted of 12,906 patients. Seventy-five per cent of the nonselective NSAID prescriptions dispensed were for up to two months duration, with only 2.3% longer than one year. GI prophylaxis was given to only 3.8% of patients starting NSAIDs who were not on a GPA in the two months before starting NSAIDs. Of this 3.8%, 92.7% of the patients received H2-receptor antagonists (H2RAs), and 7% received PPIs. The rate of H2RA coprescribing increased with the number of consecutive months on an NSAID from 3.5% in the first month to 24.1% at 48 months. For PPIs, the coprescribing rate increased from 0.3% to 1.9% of all NSAID users in the cohort. The rate of gastroprophylaxis coprescribing for patients receiving NSAIDs did not rise with increasing age.
In Nova Scotian seniors using nonselective NSAIDs, the rate of GI prophylaxis was low. Most patients received H2RAs as GPAs despite evidence that they offer insufficient protection.
Cohort study; Cyclooxygenase-2 selective inhibitor; Drug utilization; Gastrointestinal prophylaxis; Histamine-2 receptor antagonist; Misoprostol; Nonsteroidal anti-inflammatory drugs; NSAIDs; Proton pump inhibitor; Prescribing; Seniors
Non-steroidal anti-inflammatory drugs (NSAIDs) are rarely associated with side-effects affecting the central nervous system. A case of NSAID-induced recurrent aseptic meningitis is presented. Seven episodes of aseptic meningitis were documented in the patient's life-time (up to the age of 30). General practitioners' records available for the latest four episodes showed that a NSAID (naproxen, piroxicam or diclofenac) was prescribed in the month prior to admission on each occasion. The patient was symptom free for a 3-year period during which no NSAID was prescribed. Clinicians should always elicit a careful drug history (including over-the-counter medications) in patients with aseptic meningitis and be aware of this unusual side-effect of NSAIDs.
Keywords: non-steroidal anti-inflammatory drugs; meningitis; adverse drug reaction