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1.  Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries 
PLoS Medicine  2013;10(2):e1001388.
Patricia McGettigan and David Henry find that, although some non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac are known to increase cardiovascular risk, diclofenac is included on 74 countries' essential medicine lists and was the most commonly used NSAID in the 15 countries they evaluated.
Background
Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries.
Methods and Findings
Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7–58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%.
Conclusions
Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Aspirin, the first NSAID, was developed in 1897 but there are now many different NSAIDs. Some can be bought over-the-counter but others are available only with prescription. NSAIDs can help relieve short- and long-term pain, reduce inflammation (redness and swelling), and reduce high fevers. Common conditions that are treated with NSAIDs include headaches, toothache, back ache, and arthritis. NSAIDs work by stopping a class of enzymes called cyclo-oxygenases (COXs) from making prostaglandins, some of which cause pain and inflammation. Like all drugs, NSAIDs have some unwanted side effects. Because certain prostaglandins protect the stomach lining from the stomach acid that helps to digest food, NSAID use can cause indigestion and stomach ulcers (gastrointestinal complications). In addition, NSAIDs increase the risk of heart attacks and stroke to varying degrees and therefore should be avoided by people at high risk of cardiovascular diseases—conditions that affect the heart and/or blood vessels.
Why Was This Study Done?
Different NSAIDs are associated with different levels of cardiovascular risk. Selective COX-2 inhibitors (e.g., rofecoxib, celecoxib, etoricoxib) generally have fewer stomach-related side effects than non-selective COX inhibitors (e.g., naproxen, ibuprofen, diclofenac). However, some NSAIDs (rofecoxib, diclofenac, etoricoxib) are more likely to cause cardiovascular events than others (e.g., naproxen). When doctors prescribe NSAIDs, they need to consider the patient's risk profile. Particularly for patients with higher risk of cardiovascular events, a doctor should either advise against NSAID use or recommend one that has a relatively low cardiovascular risk. Information on the cardiovascular risk associated with different NSAIDs has been available for several years, but have doctors changed their prescribing of NSAIDs based on the information? This question is of particular concern in low- and middle-income countries where cardiovascular disease is increasingly common. In this study, the researchers investigate the extent to which evidence on the cardiovascular risk associated with different NSAIDs has translated into guidance and sales in 15 low-, middle-, and high-income countries.
What Did the Researchers Do and Find?
The researchers derived data on the relative risk of cardiovascular events associated with individual NSAIDs compared to non-use of NSAIDs from published meta-analyses of randomized trials and observational studies. They obtained information on the NSAIDs recommended in 100 countries from national Essential Medicines Lists (EMLs; essential medicines are drugs that satisfy the priority health care needs of a population). Finally, they obtained information on NSAID sales for 13 countries in the South Asian, Southeast Asian, and Asian Pacific regions and NSAID prescription data for Canada and England. Rofecoxib, diclofenac, and etoricoxib consistently increased cardiovascular risk compared with no NSAIDs. All three had a higher relative risk of cardiovascular events than naproxen in pairwise analyses. Naproxen was associated with the lowest cardiovascular risk. No national EMLs recommended rofecoxib, which was withdrawn from world markets 8 years ago because of its cardiovascular risk. Seventy-four national EMLs listed diclofenac, but only 27 EMLs listed naproxen. Diclofenac was the most commonly used NSAID, with an average market share across the 15 countries of nearly 30%. By contrast, naproxen had an average market share of less than 10%. Finally, across both high- and low-/middle-income countries, diclofenac and etoricoxib accounted for one-third of total NSAID usage.
What Do These Findings Mean?
These findings show that NSAIDs with higher risk of cardiovascular events are widely used in low-/middle- as well as high-income countries. Diclofenac is the most popular NSAID, despite its higher relative risk of cardiovascular events, which is similar to that of rofecoxib. Diclofenac is also widely listed on EMLs even though information on its higher cardiovascular risk has been available since 2006. In contrast, naproxen, one of the safest in relative terms of the NSAIDs examined, was among the least popular and was listed on a minority of EMLs. Some aspects of the study's design may affect the accuracy of these findings. For example, the researchers did not look at the risk profiles of the patients actually taking NSAIDs. However, given the volume of use of high-risk NSAIDS, it is likely that these drugs are taken by many individuals at high risk of cardiovascular events. Overall, these findings have important implications for public health and, given the wide availability of safer alternatives, the researchers suggest that diclofenac should be removed from national EMLs and that its marketing authorizations should be revoked globally.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001388.
This study is further discussed in a PLOS Medicine Perspective by K. Srinath Reddy and Ambuj Roy
The UK National Health Service Choices website provides detailed information on NSAIDS
MedlinePlus provides information about aspirin, ibuprofen, naproxen, and diclofenac; it also provides links to other information about pain relievers (in English and Spanish)
The American Heart Association has information on cardiovascular disease; Can Patients With Cardiovascular Disease Take Nonsteroidal Antiinflammatory Drugs? is a Cardiology Patient Page in the AHA journal Circulation
The British Heart Foundation also provides information about cardiovascular disease and has a factsheet on NSAIDs and cardiovascular disease
The World Health Organization has a fact sheet on essential medicines; the WHO Model List of Essential Medicines (in English and French), and national EMLs are available
doi:10.1371/journal.pmed.1001388
PMCID: PMC3570554  PMID: 23424288
2.  Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies 
PLoS Medicine  2011;8(9):e1001098.
David Henry and colleagues reevaluate the evidence from observational studies on the cardiovascular risk associated with non-steroidal anti-inflammatory drugs.
Background
Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings.
Methods and Findings
We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment.
Conclusions
This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The analgesic (pain relieving), anti-pyretic (fever reducing), and anti-inflammatory (inflammation reducing) properties of the class of drug called non-steroidal anti-inflammatory drugs (NSAIDs)—so called to distinguish this class of drug from steroids, which have similar but additional effects—make NSAIDs one of the most frequently used drugs for the symptomatic treatment of many common conditions. Some preparations of NSAIDs can be bought over the counter, and all are available on prescription, but this class of drug has well documented side effects and risks: people taking NSAIDs are on average four times more likely to develop gastrointestinal complications than people not taking these drugs (that is, the relative risk of gastrointestinal complications is 4), and the relative risk for associated cardiovascular complications—cardiovascular events during treatment with NSAIDs has been one of the most studied adverse drug reactions in history—ranges from 1.0 to 2.0.
Why Was This Study Done?
Several large systematic reviews, including one conducted by these researchers, have previously highlighted apparent differences in cardiovascular risk between individual drugs, but these reviews have provided limited information on dose effects and relevant patient characteristics and have not directly compared the cardiovascular risks of each drug. Furthermore, most of these analyses extensively investigated only a few drugs, with little information on some widely available compounds, such as etoricoxib, etodolac, meloxicam, indomethacin, and piroxicam. Therefore, the researchers conducted this study to update cardiovascular risk estimates for all currently available NSAIDs and to compare the risks between individual drugs. In order to investigate the likely effects of over-the-counter use of NSAIDS, the researchers also wanted to include in their review an analysis of the cardiovascular risk at low doses of relevant drugs, over short time periods, and in low risk populations.
What Did the Researchers Do and Find?
The researchers included only controlled observational studies in their literature search and review (conducted by searching a wide range of databases for studies published from 1985 until November 2010) because randomized controlled trials have reported only small numbers of cardiovascular events that are insufficient for the purposes of this study. The researchers assessed the methodological quality of selected studies, analyzed adjustment variables (for example, age, sex, other medications), and summarized overall results for individual drugs across studies as pooled relative risk estimates. For the subsets of studies that provided relevant data, they pooled within-study relative risk estimates with high and low doses and in people at high and low risk of cardiovascular events, and performed a series of within-study (pair-wise) comparisons and for each pair of drugs, to estimate their comparative relative risks by using a validated online tool to give a ratio of relative risks.
Using this methodology, the researchers included 30 case-control studies and 21 cohort studies: the highest overall risks were with rofecoxib and diclofenac, and the lowest risks were with ibuprofen and naproxen, The researchers found that risk was elevated with low doses of rofecoxib, celecoxib, and diclofenac, and rose with higher doses. Ibuprofen risk was only evident with higher doses. Naproxen did not cause any additional risks at any dose. Of the less studied NSAIDs, etoricoxib, etodolac, and indomethacin had the highest risks. In the pair-wise comparisons, the researchers found that etoricoxib had a higher relative risk than ibuprofen and naproxen, etodolac was not significantly different from naproxen and ibuprofen, and naproxen had a significantly lower risk than ibuprofen. Finally, the researchers showed that relative risk estimates were constant with different background risks for cardiovascular disease and increased early the course of treatment.
What Do These Findings Mean?
This updated systematic review gives some new information on some familiar NSAIDs, and provides potentially important information on some little studied ones, which will help to inform clinical and regulatory decisions. The specific findings suggest that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk, whereas diclofenac in doses available without prescription elevates risk. Based on sparse data, etoricoxib has a high risk of cardiovascular events and is similar to drugs that have been withdrawn because of safety concerns. Indomethacin is an older, rather toxic drug, and the new evidence on cardiovascular risk casts doubt on its continued clinical use.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001098.
Wikipedia defines and discusses NSAIDs
The UK National Health Service and MedicineNet have useful information on NSAIDs that is suitable for patients
The National Prescribing Service in Australia has a range of information on the use of NSAIDs
doi:10.1371/journal.pmed.1001098
PMCID: PMC3181230  PMID: 21980265
3.  Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999–2012 
Clinical Epidemiology  2014;6:155-168.
Background
Due to over-the-counter availability, no consensus exists on whether adequate information on nonsteroidal anti-inflammatory drug (NSAID) use can be obtained from prescription registries.
Objectives
To examine utilization of aspirin and nonaspirin NSAIDs in Denmark between 1999 and 2012 and to quantify the proportion of total sales that was sold on prescription.
Method
Based on nationwide data from the Danish Serum Institute and the Danish National Prescription Registry, we retrieved sales statistics for the Danish primary health care sector to calculate 1-year prevalences of prescription users of aspirin or nonaspirin NSAIDs, and to estimate the corresponding proportions of total sales dispensed on prescription.
Results
Both low-dose aspirin and nonaspirin NSAIDs were commonly used in the Danish population between 1999 and 2012, particularly among elderly individuals. The 1-year prevalence of prescribed low-dose aspirin increased throughout the study period, notably among men. Nonaspirin NSAID use was frequent in all age groups above 15 years and showed a female preponderance. Overall, the prevalence of prescribed nonaspirin NSAIDs decreased moderately after 2004, but substantial variation according to NSAID subtype was observed; ibuprofen use increased, use of all newer selective cyclooxygenase-2 inhibitors nearly ceased after 2004, diclofenac use decreased by nearly 50% after 2008, and naproxen use remained stable. As of 2012, the prescribed proportion of individual-level NSAID sales was 92% for low-dose aspirin, 66% for ibuprofen, and 100% for all other NSAIDs.
Conclusion
The potential for identifying NSAID use from prescription registries in Denmark is high. Low-dose aspirin and nonaspirin NSAID use varied substantially between 1999 and 2012. Notably, use of cyclooxygenase-2 inhibitors nearly ceased, use of diclofenac decreased markedly, and naproxen use remained unaltered.
doi:10.2147/CLEP.S59156
PMCID: PMC4026552  PMID: 24872722
drug utilization; NSAID; registries; over-the-counter
4.  Usage patterns of ‘over-the-counter’ vs. prescription-strength nonsteroidal anti-inflammatory drugs in France 
Aims
Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or ‘over-the-counter (OTC)’ NSAIDs may influence risks, but are not commonly described.
Methods
The Echantillon Généraliste de Bénéficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009–2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users.
Results
Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years.
Conclusions
Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised.
doi:10.1111/bcp.12239
PMCID: PMC4004409  PMID: 24102791
drug-related risks; over-the-counter nonsteroidal anti-inflammatory drugs; prescription nonsteroidal anti-inflammatory drugs; usage patterns
5.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
Background
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
Objective
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
Methods
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Results
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Conclusion
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
doi:10.1016/j.atherosclerosis.2013.05.002
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
6.  High-risk use of over-the-counter non-steroidal anti-inflammatory drugs: a population-based cross-sectional study 
The British Journal of General Practice  2014;64(621):e191-e198.
Background
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug events (ADEs).
Aim
To determine the prevalence of over-the-counter (OTC) NSAID use in the general population and in patients with a high risk of developing a serious NSAID-related ADE.
Design and setting
Cross-sectional study in four general practices in the Netherlands.
Method
Two patient samples were selected: a random sample of adults (general population sample); and adult patients with a high risk of developing a serious ADE in case of NSAID use (high-risk sample). All included patients were sent a questionnaire regarding their use of OTC NSAIDs in the 4 weeks prior to participation.
Results
In the general population sample, 118 of 456 (26%) invited patients completed the questionnaire. Of these, 35 (30%) had used an OTC NSAID. In the high-risk sample, 264 of 713 (37%) invited patients completed the questionnaire, and of these high-risk patients 33 (13%) had used an OTC NSAID. Over 20% of OTC NSAID users in the general population sample and over 30% in the high-risk sample had used the OTC NSAID for >7 days. OTC NSAIDs were used in a dosage exceeding the recommended daily maximum by 9% and 3% of OTC NSAID users in the general population and the high-risk sample respectively.
Conclusion
OTC NSAIDs are used by almost one-third of the general population. In the high-risk patients selected, one in eight patients used an OTC NSAID. Continued efforts by health authorities and healthcare professionals to inform patients of the risks of these drugs are warranted.
doi:10.3399/bjgp14X677815
PMCID: PMC3964463  PMID: 24686883
anti-inflammatory agents, non-steroidal; general practice; over-the-counter drugs; primary care
7.  Prescription of nonsteroidal anti-inflammatory drugs for elderly people in Alberta. 
OBJECTIVE: To examine the extent prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) are used by elderly people in Alberta as well as the degree of concurrent use of multiple NSAIDs, of peptic ulcer medications and of certain medications known to have clinically significant adverse interactions with NSAIDs. DESIGN: Retrospective analysis of the Alberta Blue Cross database. SETTING: Alberta. PATIENTS: All people 65 years of age and older using the subsidized drug benefit plan for whom prescription claims were submitted for reimbursement between Jan. 1 and June 30, 1991. OUTCOME MEASURES: Number of people who received one or more prescriptions for NSAIDs, rates of prescribing peptic ulcer medications and drugs with the potential for clinically significant interactions with NSAIDs among NSAID users and non-NSAID users, and rate of prescribing more than one NSAID concurrently. RESULTS: Of the Albertan population 65 years of age and over 61,601 (26.7%) received at least one prescription for an NSAID during the study period. In decreasing order, the five most commonly prescribed NSAIDs were acetylsalicylic acid, diclofenac, naproxen, indomethacin and ibuprofen. The total cost of NSAID therapy was $5,415,974. Of the people prescribed an NSAID 25.8% were also prescribed a peptic ulcer medication, as compared with 10.5% of the non-NSAID users. There was a significant relation between the increasing number of NSAID prescriptions and the likelihood of receiving a peptic ulcer medication. Those who received a prescription for an NSAID were more likely than non-NSAID users to have been prescribed coumarin anticoagulants, diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, oral corticosteroids, methotrexate and lithium, all of which are known to have possible adverse interactions with NSAIDs. A total of 2,631 people had two or more prescriptions for NSAIDs filled on the same day. CONCLUSIONS: NSAIDs are prescribed frequently for elderly people and are associated with an increased likelihood of concurrent prescription of peptic ulcer medication and medications that could have adverse drug interactions with NSAIDs. Additional study is required to evaluate the appropriateness of NSAID use in elderly patients, to determine the degree of actual patient consumption of these medications, to document the true prevalence of clinically significant drug interactions and to formulate educational strategies to reach physicians with this information.
PMCID: PMC1336922  PMID: 8039085
8.  Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs 
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available.
doi:10.2147/TCRM.S79135
PMCID: PMC4508078  PMID: 26203254
adverse effects; nonsteroidal anti-inflammatory drugs; gastrointestinal; cardiovascular; renal
9.  Non-steroidal anti-inflammatory drug (NSAID) related inhibition of aldosterone glucuronidation and arterial dysfunction in patients with rheumatoid arthritis: a cross-sectional clinical study 
BMJ Open  2011;1(1):e000076.
Objective
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and are also commonly prescribed non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs). New in vitro evidence suggests that this increased CV risk may be mediated through aldosterone glucuronidation inhibition (AGI), which differs between NSAIDs (diclofenac>naproxen>indomethacin>ibuprofen). Our aim was to explore the association between ns-NSAID-related AGI and arterial dysfunction.
Methods
The extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, ms) of aortic wave reflection (measured using radial applanation pulse wave analysis, PWA, SphygmoCor device) were assessed on a single occasion in 114 consecutive RA patients without overt CV disease aged 40–65 years. A higher AIX% and lower RWT indicate arterial dysfunction. Assessment included a fasting blood sample, patient questionnaire and medical record review. Multivariate analysis was used to adjust for age, sex, mean blood pressure, smoking, cumulative erythrocyte sedimentation rate (ESR-years) and Stanford disability score.
Results
We identified 60 patients taking ns-NSAIDs and 25 non-users. Using a ns-NSAID with the highest AGI was associated with a higher AIX% (and lower RWT) versus treatment with a ns-NSAID with the lowest AGI (diclofenac AIX% 32.3, RWT 132.7 ms vs ibuprofen AIX% 23.8, RWT 150.9 ms): adjusted mean differences AIX% 6.5 (95% CI 1.0 to 11.9; p=0.02); RWT −14.2 ms (95% CI −22.2 to −6.3; p=0.001). Indomethacin demonstrated an intermediate level of arterial dysfunction. In relation to arterial dysfunction, both indomethacin and naproxen were more similar to diclofenac than to ibuprofen.
Conclusions
ns-NSAID-related AGI is associated with arterial dysfunction in patients with RA. These findings provide a potentially novel insight into the CV toxicity of commonly used ns-NSAIDs. However, the findings are limited by the small number of patients involved and require further replication in a much larger study.
Article summary
Article focus
Aldosterone glucuronidation inhibition (AGI) potentiates the adverse cardiovascular effects of aldosterone.
Recently published in vivo research suggests that such inhibition differs between non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), with a ranked order of diclofenac>naproxen>indomethacin>ibuprofen, but no previous studies have assessed the relationship between ns-NSAID-related AGI and arterial dysfunction in chronic users.
This study assessed arterial dysfunction using pulse wave analysis.
Key messages
In patients with rheumatoid arthritis we found that chronic use (>3 months) of diclofenac (high AGI) was associated with greater arterial dysfunction compared to ibuprofen (lower AGI); this association was independent of other cardiovascular and rheumatological factors.
Indomethacin (intermediate AGI) was associated with an intermediate level of arterial dysfunction, although naproxen (intermediate AGI) did not fit the anticipated pattern.
Our findings support the concept that AGI may play a role in the cardiovascular toxicity of some ns-NSAIDs commonly used in routine clinical practice.
Strengths and limitations of this study
A single research nurse assessed rheumatoid arthritis patients who were recruited from a consecutive series attending a hospital rheumatology clinic. We adjusted for several important cardiovascular and rheumatological factors known to be independently associated with arterial function and our multivariate analysis explained a high proportion of the variability in arterial dysfunction among chronic ns-NSAID users. The observational cross-sectional design of our study means that we cannot assess causation, nor exclude residual confounding as an explanation for our findings. The small number of patients taking each NSAID meant that the confidence intervals are wide.
doi:10.1136/bmjopen-2011-000076
PMCID: PMC3191420  PMID: 22021751
10.  Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction? 
PLoS Medicine  2007;4(5):e157.
Background
Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.
Methods and Findings
To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1.
Conclusions
Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
Editors' Summary
Background.
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
  The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040157.
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)
doi:10.1371/journal.pmed.0040157
PMCID: PMC1872041  PMID: 17518513
11.  Individual NSAIDs and Upper Gastrointestinal Complications 
Drug Safety  2012;35(12):1127-1146.
Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety.
Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors.
Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies.
Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses.
Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.
doi:10.1007/BF03261999
PMCID: PMC3714137  PMID: 23137151
12.  Gastroprotective Agent Underuse in High-Risk Older Daily Non-Steroidal Anti-Inflammatory Drug Users Over Time 
Background/ Objectives
Non-steroidal anti-inflammatory drug (NSAID) use is a major risk factor for peptic ulcer disease (PUD) in older adults; thus, a gastroprotective agent is recommended in high-risk patients. This study of older daily NSAID users examined whether gastroprotective agent underuse decreased over time.
Design
Before-after study.
Setting
Health, Aging and Body Composition study.
Participants
Daily users of an NSAID (prescription and over-the-counter [OTC]) at the 2002–03 (pre-period; n=404) and 2006–07 (post-period; n=172) visits. The sample had a mean (standard deviation [±SD]) age of 78.2 [±2.7] years and 81.9 [±2.7] years at the visits, respectively. The majority were white, women and with ≥12 years of education.
Measurements
Underusers were defined as: (1) persons taking non-selective NSAIDs at risk of PUD (due to current warfarin or glucocorticoid use, or history of PUD) and not using a proton pump inhibitor, or (2) COX-2 selective NSAID users taking aspirin at risk of PUD (i.e., having at least one risk factor) and not using a proton pump inhibitor.
Results
Daily NSAID use decreased from 17.6% to 11.3% (p<0.001), and gastroprotective agent underuse decreased from 23.5% and 15.1% (p=0.008) over time. Controlling for important covariates, having prescription insurance was somewhat protective from underuse in the pre-period (adjusted odds ratio [AOR] 0.78, 95% confidence interval [CI] 0.46–1.34; p=0.37), but more so and significantly in the post-period (AOR 0.41, 95% CI 0.18–0.93; p=0.03). Over time, having prescription insurance was more protective in the post versus pre-period (i.e., less gastroprotective agent underuse; adjusted ratio of OR 0.53, 95% CI 0.22–1.29; p=0.16), but this increased protection was not statistically significant.
Conclusion
Among high-risk older daily NSAID users, having prescription insurance and adequate gastroprotective use was more common in the post than in the pre-period.
doi:10.1111/jgs.13066
PMCID: PMC4206578  PMID: 25284702
NSAID; older adults; gastroprotection
13.  Non-steroidal Anti-inflammatory Drugs (NSAIDs) Use in Primary Health Care Centers in A’Seeb, Muscat: A Clinical Audit 
Oman Medical Journal  2015;30(5):366-371.
Objective
We sought to assess the trend of non-steroidal anti-inflammatory drug (NSAID) use in primary health care institutions located in A’Seeb, a province in the capital city of Oman, Muscat. Additionally, we evaluated the relationship between a physician’s years of experience and the number of prescription issued, as well as the presence of risk factors and side effects in the patients who received these prescriptions.
Method
A clinical audit was conducted in four primary health care centers in the Muscat region over a one-week period in April 2014. The target population included patients aged 18 years or over who attended one of the four health centers and were prescribed NSAIDs. Overall, 272 patients were recruited by systematic random sampling. The data were collected by two methods: direct face-to-face interviews and evaluations of the patient’s electronic medical file. The prescribing doctors were blind to the audit. The collected information included patients demographics, past and current medical history of related comorbidities, NSAID type, dose, duration and indications for use, concomitant warfarin or/and aspirin prescriptions, and co-prescription of gastroprotective agents.
Results
In total, 15% of patients received an NSAID prescription: females were issued more prescriptions than males. The percentage of patients who received an NSAID prescription across the health centers ranged from 9% to 24%. The main reason for prescribing NSAIDs was musculoskeletal problems. The most frequently prescribed NSAID was ibuprofen. Sixteen percent of patients who received an NSAID prescription had a risk factor related to its use. The mean and median duration of the NSAID prescriptions of all types were 5.6 and 5.0 days, respectively. Physicians with a greater number of years experience prescribed more NSAIDs.
Conclusion
Our study showed that the number of prescriptions of NSAIDs among various institutes varied, which could reflect the level of awareness concerning NSAID risks among the prescribing doctors. NSAIDs were prescribed for patients with comorbidities and patients with previously documented side effects without considering protective agents. Therefore, we suggest that the use of these medications is controlled, especially in high-risk populations.
doi:10.5001/omj.2015.73
PMCID: PMC4576381  PMID: 26421118
Anti-Inflammatory Agents, Non-Steroidal; NSAIDs; Prescriptions; side effects; utilization
14.  Prevalence of use of non-prescription analgesics in the Norwegian HUNT3 population: Impact of gender, age, exercise and prescription of opioids 
BMC Public Health  2015;15:461.
Background
There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prevalence of daily OTC analgesic use.
Methods
Questionnaire data from the Nord–Trøndelag health study (HUNT3, 2006–08), which includes data from 40,000 adult respondents. The questionnaire included questions on use of OTC analgesics, socioeconomic conditions, health related behaviour, symptoms and diseases. Data were linked to individual data from the Norwegian Prescription Database. A logistic regression was used to investigate the association between different factors and daily use of paracetamol and/or non-steroid anti-inflammatory drugs (NSAIDs) in patients with and without chronic pain.
Results
The prevalence of using OTC analgesics at least once per week in the last month was 47%. Prevalence of paracetamol use was almost 40%, compared to 19% and 8% for NSAIDs and acetylsalicylic acid (ASA), respectively. While the use of NSAIDs decreased and the use of ASA increased with age, paracetamol consumption was unaffected by age. Overall more women used OTC analgesics. About 3-5% of subjects using OTC analgesics appeared to combine these with the same analgesic on prescription. Among subjects reporting chronic pain the prevalence of OTC analgesic use was almost twice as high as among subjects without chronic pain. Subjects with little physical activity had 1.5-4 times greater risk of daily use of OTC compared to physically active subjects.
Conclusions
Use of OTC analgesics is prevalent, related to chronic pain, female gender and physical inactivity.
doi:10.1186/s12889-015-1774-6
PMCID: PMC4428499  PMID: 25934132
Non-prescription analgesics; Pain; General population; Opioids; Physical activity
15.  Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension 
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
Methods
We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Results
Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Conclusion
Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
doi:10.1186/1471-2261-12-93
PMCID: PMC3502533  PMID: 23092442
NSAIDs; Hypertension; Blood pressure; Propensity score
16.  Accounting for the increase in NSAID expenditure: substitution or leakage? 
Background
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1478-7547-4-9
PMCID: PMC1501056  PMID: 16737538
17.  Prevalence, trends, patterns and associations of analgesic use in Germany 
Background
Despite the public health relevance of analgesic use, large-scale studies on this topic in Germany are lacking. This study describes the prevalence, trends, associations and patterns of use of prescription and over-the-counter (OTC) analgesics, focusing on five of the most common agents: aspirin, diclofenac, ibuprofen, naproxen and paracetamol.
Methods
Data from two representative population-based surveys: The German National Health Interview and Examination Survey 1998 (GNHIES98 n = 7099) and the German Health Interview and Examination Survey for Adults 2008–2011 (DEGS1 n = 7091) was investigated. Information on all medicines consumed in the previous 7 days was collected via computer-assisted personal interviews with adults aged 18–79 years. Associations between analgesic use and socio-demographic and health-behaviour factors were analysed using logistic regression models.
Results
Analgesic use has increased over the last decade from 19 to 21 %. This was exclusively due to the rise in OTC analgesic use from 10.0 to 12.2 %. Prescribed analgesic use remained constant (7.9 %). Findings from DEGS1 indicate that ibuprofen is the most commonly used analgesic followed by aspirin and paracetamol. OTC analgesic use is higher among women and smokers, but lower among older adults (65–79 years). Prescribed analgesics use is higher among women, older adults, smokers and obese adults with medium or high socio- economic status. Adults performing more than 2 h/week of physical exercise use fewer analgesics.
Discussion
Among the adult population of Germany, the prevalence of OTC analgesic use has significantly increased over the last decade. We found differences between adults consuming OTC and prescribed analgesics (or both) concerning their health behaviour and health conditions. International direct comparison between prevalence rates of analgesic use was limited due to varying availability of analgesics between countries and to methodological differences.
Conclusions
About one in five community dwelling adults aged 18–79 years in Germany use analgesics in a given week. Considering the potential harms of analgesic use, monitoring of prevalence, patterns and determinants of use at the population level are important steps to inform disease prevention and health promotion policies.
doi:10.1186/s40360-015-0028-7
PMCID: PMC4591581  PMID: 26428626
Analgesic use; Prevalence; Trends; Over-the-counter; Population based
18.  A review of the benefits and risks of nonsteroidal anti-inflammatory drugs in the management of mild-to-moderate osteoarthritis 
This review is intended to provide physicians with an overview of the benefits and risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of their patients with mild-to-moderate osteoarthritis (OA). New information on the inflammatory component of OA and the cardiovascular (CV) risk associated with cyclooxygenase (COX)-2-specific inhibitors has prompted efforts to revise the current recommendations for the use of NSAIDs in the treatment of patients with OA. Clinical studies have shown that naproxen and ibuprofen are significantly more effective at reducing OA pain than is acetaminophen, the traditional first-line therapy, which has no apparent anti-inflammatory activity in the joints. The theoretical advantage of COX-2-specific inhibitors in reducing gastrointestinal (GI) toxicity has been demonstrated by clinical studies. GI complications can be reduced by using lower NSAID doses for the shortest duration or with a concomitant proton-pump inhibitor. All prescription NSAIDs carry a black box warning regarding CV risks; these risks vary among the NSAIDs. While ibuprofen and diclofenac are associated with an increased CV risk, naproxen was associated with a neutral CV risk relative to placebo. Ibuprofen, but not naproxen, attenuates the antiplatelet effects of aspirin. An understanding of the risks and benefits is important when choosing an NSAID. An exhaustive search of the medical literature since 1990 was conducted using the words "ibuprofen," "naproxen," "COX-2-specific NSAIDs," "nonspecific NSAIDs," "low-dose aspirin," and "nonprescription dosage." Databases searched included MEDLINE, EMBASE, and SCISEARCH. This article provides primary care physicians with the information needed to assist them in making more informed decisions in managing patients experiencing mild-to-moderate OA pain.
doi:10.1186/1750-4732-3-1
PMCID: PMC2646740  PMID: 19126235
19.  Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib 
Annals of the Rheumatic Diseases  2007;66(6):764-770.
Background
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.
Objective
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1136/ard.2006.066001
PMCID: PMC1954641  PMID: 17412741
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
20.  Use of Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk: A Population-Based Nested Case-Control Study 
PLoS ONE  2011;6(1):e16412.
Background
Despite strong laboratory evidence that non-steroidal anti-inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs.
Methods
We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged ≥40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP.
Results
Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95–1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes.
Conclusions
Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk.
doi:10.1371/journal.pone.0016412
PMCID: PMC3030588  PMID: 21297996
21.  The rate of prescribing gastrointestinal prophylaxis with either a proton pump inhibitor or an H2-receptor antagonist in Nova Scotia seniors starting nonsteroidal anti-inflammatory drug therapy 
BACKGROUND:
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.
AIM:
To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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.
PMCID: PMC2947001  PMID: 20711527
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
22.  Non-Steroidal Anti-Inflammatory Drugs and Antibiotics Prescription Trends at a Central West Bank Hospital 
Objectives:
We aimed to reliably describe the pattern of outpatient prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics (ATBs) at a central hospital in the West Bank, Palestine.
Methods:
This was a retrospective, cross-sectional study investigating a cohort of 2,208 prescriptions ordered by outpatient clinics and the emergency room over one year in Beit Jala Hospital in Bethlehem, West Bank. The orders were analysed for the rate and types of NSAIDs and ATBs utilised, and the appropriateness of these drugs to the diagnosis.
Results:
Of the total prescriptions, 410 contained NSAIDs (18.6%), including diclofenac (40.2%), low dose aspirin (23.9%), ibuprofen (17.8%) and indomethacin (15.1%). A minority of these prescriptions contained a combination of these agents (2.5%). Only one prescription contained cyclooxyeganse-2 inhibitors (0.2%). The appropriateness of NSAID use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). The rate of ATB use was 30.3% (669 prescriptions). The ATBs prescribed were amoxicillin (23.3%), augmentin (14.3%), quinolones (12.7%), first and second generation cephalosporins (9.4% and 12.7%, respectively) and macrolides (7.2%). ATB combinations were identified in 9.4%, with the most common being second-generation cephalopsorins and metronidazole (4.3%). Regarding the appropriateness of prescribing ATBs according to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6% and difficult to tell in 34.6% of the prescriptions.
Conclusion:
These findings revealed a relatively large number and inappropriate utilisation of ATBs and NSAIDs. An interventional programme needs to be adopted to reinforce physicians’ knowledge of the rational prescription of these agents.
PMCID: PMC3836647  PMID: 24273668
NSAIDs; Antibiotics; Prescription; Palestine
23.  Non-Steroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results from the Women’s Health Initiative 
Background
Conclusive data regarding cardiovascular (CV) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for CV events in post-menopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 compared with cox-1 inhibition.
Methods and Results
Post-menopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or non-users of non-aspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total CV disease defined as CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (e.g., celecoxib), non-selective agents with cox-2>cox-1 inhibition (e.g., naproxen), and non-selective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Overall, 160,801 participants were available for analysis (mean follow-up 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. Regular NSAID use was associated with an increased hazard for CV events versus no NSAID use (HR=1.10[95% CI 1.06–1.15], Pitalic>0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for CV events (HR=1.13[1.04–1.23], P=0.004; celecoxib only HR=1.13[1.01–1.27], P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for CV events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR=1.17[1.10–1.24], Pbold>0.001; naproxen only HR=1.22[1.12–1.34], P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR=1.01[0.95–1.07], P=0.884; ibuprofen only HR=1.00[0.93–1.07], P=0.996).
Conclusions
Regular use of selective cox-2 inhibitors and non-selective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for CV events. Non-selective agents with cox-1>cox-2 inhibition were not associated with increased CV risk.
Clinical Trial Registration
www.clinicaltrials.gov NCT00000611
doi:10.1161/CIRCOUTCOMES.113.000800
PMCID: PMC4151243  PMID: 25006185
non-steroidal anti-inflammatory drugs; coronary artery disease; myocardial infarction; stroke; cox inhibition
24.  Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark 
Aims
It is well-known that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of upper gastrointestinal bleeding (UGIB), but characteristics of the association and quantification of excess risk at the population level require clarification.
Methods
All users of nonaspirin prescription NSAIDs in North Jutland County, Denmark during 1991–95 were identified in the regional Pharmaco-Epidemiologic Database. Using the Hospital Discharge Register, all hospitalizations for UGIBs were identified among the 156 138 users of NSAIDs and compared with the number of expected based on the North Jutland population who did not receive NSAID prescriptions.
Results
During periods of NSAID use without use of other drugs associated with UGIB, we observed 365 UGIBs, a number 3.6 times higher than expected (95% CI = 3.3, 4.0). The excess risk varied by sex, type of NSAID and form and route of administration of the NSAID, but not by age at first NSAID prescription or number of prior prescriptions. Risk declined sharply following cessation of use. For ibuprofen and naproxen, there was a clear trend in rising risk by increasing dose, although the lowest doses were also associated with an excess of UGIB. Concurrent use of corticosteroids, anticoagulants and aspirin further increased the risk of UGIB.
Conclusions
All types and formulations of NSAIDs appear to increase the risk of UGIBs, but the effect appear not to be cumulative and diminish rapidly with discontinue of use. Up to 15% of the UGIBs in the entire population of the North Jutland County may be explained by use of this drug.
doi:10.1046/j.0306-5251.2001.01220.x
PMCID: PMC1874281  PMID: 11851641
NSAIDs; pharmacoepidemiology; population-based cohort study; upper GI bleeding
25.  Contraindicated NSAIDs are frequently prescribed to elderly patients with peptic ulcer disease 
Aims
To establish the frequency with which NSAIDs were prescribed to elderly patients after admission to hospital for serious gastrointestinal complications and to study which factors are determinants of the prescription of these contraindicated drugs.
Methods
A retrospective cohort study of patients from The Rotterdam Elderly Study, a prospective population-based cohort study of people older than 55 years of age was carried out. Elderly patients with a hospital admission for serious gastrointestinal complications were followed until prescription of an NSAID, death, removal to another area or end of the study period, whichever came first. The following baseline determinants for receiving a contraindicated prescription were studied: gender, age, presence of rheumatoid arthritis or osteoarthritis, presence of cardiovascular risk factors, number of GP visits, number of visits to a medical specialist, cognitive function and the prescriber being a GP or a medical specialist.
Results
Prescriptions of an NSAID after discharge from hospital, were identified in 73 patients (73%). Fifty-one percent were prescribed aspirin of whom the large majority used it as an antithrombotic agent, and 49% were prescribed a nonaspirin NSAID after discharge from hospital. Twenty percent of the patients used more than one NSAID on one or more occasions after discharge. For patients who were prescribed NSAIDs before admission as well as after discharge, the proportion of contraindicated prescriptions with concomitant use of antiulcer drugs rose significantly from 0.19 before discharge to 0.60 after discharge for aspirin and from 0.11 to 0.61 for nonaspirin NSAIDs. In the multivariate analysis the only remaining factor with prognostic influence on prescription of NSAIDs was a history of NSAID use before cohort enrolment. A history of rheumatoid arthritis or osteoarthritis was not associated with NSAID prescription after discharge.
Conclusions
Contraindicated NSAIDs are prescribed to a great extent in elderly patients, despite their greater vulnerability for life-threatening gastrointestinal blood loss. It is remarkable that a history of rheumatoid arthritis or osteoarthritis is no significant determinant for receiving a contraindicated prescription, which suggests that these drugs are mainly prescribed for uncomplicated arthralgia.
doi:10.1046/j.0306-5251.2001.01190.x
PMCID: PMC1874290  PMID: 11851642
contraindication; drug prescription; elderly patients; NSAIDs; peptic ulcer disease

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