Multiple Nonsteroidal Anti-inflammatory Drugs Research Articles

Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study

BackgroundSince 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 FindingsWe 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).ConclusionsExposure 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.

Helicobacter pylori management in non-steroidal anti-inflammatory drug therapy patients in primary care

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastroduodenal ulcers and its complications. Helicobacter pylori infection is recognized as an additional risk factor for ulcer development, its eradication in NSAIDs users being recommended. In this cross-sectional study, during a 1-week period, consecutive patients who were routinely visiting in 58 primary care clinics were enrolled. A questionnaire was used to collect clinical data on the patients who were chronically taking NSAIDs. Patients with age >65 years, a personal history of peptic ulcer, concomitant therapy with steroids, anti-coagulants, multiple NSAIDs, or relevant co-morbidities were considered at high risk for NSAIDs gastroduodenal complications. Data on H. pylori infection management were collected. Overall, H. pylori was searched for in 140 (16.1%) out of 869 patients receiving chronic NSAID therapy, and it was eventually cured in 43 (72.9%) of the infected cases. In detail, H. pylori status was not investigated in 670 (77.1%) of those patients at high risk of NSAID-related gastroduodenal lesions, including 516 patients ≥65 years old, and 154 younger, but with at least 1 adjunctive risk factor. In addition, 234 (35%) of these high-risk patients were not receiving any gastric mucosa protection. Our data find that H. pylori infection is investigated in fewer than one of every five NSAID-user patients in primary care. The low alertness towards such an infection in these patients suggests a need for prompt implementation of current guidelines.

Diclofenac Hypersensitivity: Antibody Responses to the Parent Drug and Relevant Metabolites

BackgroundHypersensitivity reactions against nonsteroidal antiinflammatory drugs (NSAIDs) like diclofenac (DF) can manifest as Type I-like allergic reactions including systemic anaphylaxis. However, except for isolated case studies experimental evidence for an IgE-mediated pathomechanism of DF hypersensitivity is lacking. In this study we aimed to investigate the possible involvement of drug- and/or metabolite-specific antibodies in selective DF hypersensitivity.Methodology/Principal FindingsDF, an organochemically synthesized linkage variant, and five major Phase I metabolites were covalently coupled to carrier proteins. Drug conjugates were analyzed for coupling degree and capacity to crosslink receptor-bound IgE antibodies from drug-sensitized mice. With these conjugates, the presence of hapten-specific IgE antibodies was investigated in patients' samples by ELISA, mediator release assay, and basophil activation test. Production of sulfidoleukotrienes by drug conjugates was determined in PBMCs from DF-hypersensitive patients. All conjugates were shown to carry more than two haptens per carrier molecule. Immunization of mice with drug conjugates induced drug-specific IgE antibodies capable of triggering mediator release. Therefore, the conjugates are suitable tools for detection of drug-specific antibodies and for determination of their anaphylactic activity. Fifty-nine patients were enrolled and categorized as hypersensitive either selectively to DF or to multiple NSAIDs. In none of the patients' samples evidence for drug/metabolite-specific IgE in serum or bound to allergic effector cells was found. In contrast, a small group of patients (8/59, 14%) displayed drug/metabolite-specific IgG.Conclusions/SignificanceWe found no evidence for an IgE-mediated effector mechanism based on haptenation of protein carriers in DF-hypersensitive patients. Furthermore, a potential involvement of the most relevant metabolites in DF hypersensitivity reactions could be excluded.

Nonsteroidal Anti-Inflammatory Drug—Associated Renal Papillary Necrosis in a White-Tailed Deer (Odocoileus Virginianus)

Renal papillary necrosis was diagnosed during postmortem examination of a juvenile white-tailed deer (Odocoileus virginianus) from Oklahoma. The deer was surgically treated for a Salter Harris type II fracture of the proximal tibia of the left hind limb. The animal was administered multiple nonsteroidal anti-inflammatory drugs (NSAIDs), including meloxicam, flunixin meglumine, and ketoprofen for pain management. At postmortem examination, gross lesions included a proximal tibial Salter Harris type II fracture with an associated fibrinonecrotizing myositis and bilateral renal papillary necrosis. Histologically, the kidneys exhibited coagulation necrosis of the renal medulla and renal papilla, thrombosis of renal blood vessels, and interstitial medullary edema. The gross and microscopic lesion coupled with the clinical history of multiple NSAID administration suggests NSAID-induced renal papillary necrosis.

PS1-28: Optimizing Health Informatics Interventions From the Patient's Perspective: Focus Group on Improving Safe NSAID Use

Background: Patient-provider messaging in an electronic medical record (EMR) system provides an opportunity to create and sustain productive patient-provider interactions. We elicited patient perspectives on design, benefits, and concerns to improve usability and efficacy of a proposed health informatics intervention to support surveillance of, and provider feedback on, over the counter (OTC) non-steroidal anti-inflammatory drug (NSAID) use. Methods: We conducted four focus groups involving Kaiser Permanente Georgia (KPG) adults 25–70 years old who had a medical condition for which NSAIDs should be used cautiously or had a recent prescription for NSAIDs. The focus group elicited information regarding: OTC NSAID use (including recognition of risks and side effects), design of an OTC NSAID survey to be delivered via KP.Org (the secure KP Internet portal for patient- physician messaging), benefits and concerns about transmission of this information via electronic messaging to their primary care physicians, and willingness to participate in a health informatics intervention to improve safe NSAID use. We then developed a concept map and classification scheme for analyzing transcripts from the focus groups. Two trained coders labeled the transcripts using ATLASti. Results: Forty-eight KPG adults participated in the focus groups: 83% female; 50% African American; median age 54 years. Fortyseven participants indicated current or recent use of OTC NSAIDs. Easy access to OTC NSAIDs (low cost, no prescription required) promoted their use; however, self-medication strategies often combined multiple OTC NSAIDs or increased OTC NSAID dosing to obtain pain relief. Participants acknowledged that the proposed intervention would benefit their health care through more complete reporting and documentation of OTC NSAID use in their EMR. Concerns were expressed about: keeping this information up-to-date, if the information would be used or (if used) evaluated by a qualified provider on their health care team, and mode (e-mail or telephone) and timeliness about how they would be informed about potential risks from their OTC NSAID use. Conclusions: Consistent with the Chronic Care Model, participants acknowledged that the proposed intervention would create productive interactions with their providers and likely improve their health outcomes. Their perspectives also yielded some unexpected insights (e.g. importance of timely updating of OTC NSAID use) and have resulted in modifications to the overall intervention design.

Abstract C96: The effect of non-steroidal anti-inflammatory drugs (NSAIDs) in ovarian cancer cells

Abstract Epidemiological and laboratory studies have suggested a protective role for non-steroidal anti-inflammatory drugs (NSAIDs) against various neoplasms, including ovarian cancer. In an attempt to clarify the mechanisms and molecular targets of tumor prevention by NSAIDs, we have studied the effects of multiple NSAIDs in several ovarian cancer cell lines. NSAID treatment decreased the viability of all the ovarian cancer cell lines examined. To determine the effect of NSAIDs on the cell cycle, flow cytometry analysis was performed. Cells treated with indomethacin, ibuprofen or celecoxib were arrested in G1 phase, while cells treated with diclofenac underwent an S/G2 arrest. In addition, induction of apoptosis was cell line specific. The levels of several cell cycle regulatory and apoptosis proteins were examined. The levels of phosphorylated Rb protein decreased and phospho-p53 increased upon treatment with NSAIDs, suggesting an involvement of these proteins in the response of ovarian cancer cells to NSAID treatment. In order to further clarify the mechanisms of action of NSAIDs in ovarian cancer cells, gene expression profiling experiments were performed. Ovarian cancer cell lines Hey, OVCAR5, and UCI101 were treated with diclofenac, indomethacin, celecoxib, and ibuprofen, and microarray analysis was performed. A large number of gene expression changes were observed in the different cell lines treated with various NSAIDs. Among the most consistent and reproducible changes observed, S-phase kinase associated protein 2 (Skp2) was found to be downregulated at the mRNA and protein levels in all cell lines with all NSAIDs tested. In addition, Damage inducible transcript-4 (DDIT4) was found to be upregulated in all cell lines upon treatment with diclofenac, indomethacin and celecoxib. Skp2 forms part of the SCF ubiquitin ligase and is involved in the targeting for degradation of several proteins, including the cyclin dependent kinase inhibitors p21 and p27, therefore facilitating S-phase entry. DDIT-4, is transcriptionally activated upon p53 activation and it is known to inhibit mTOR signaling. In conclusion, we have identified a number of target genes that may be important for the NSAID-induced cell cycle arrest and apoptosis and their exact roles are currently being investigated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C96.

Are Patients Aware of Upper Gastrointestinal (GI) Side Effects of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? An Inner City Community Hospital Experience

Purpose: NSAID associated GI side effects are a significant cause of morbidity and mortality. Although much is known about NSAIDs and their GI side effects, little is known about patient awareness of NSAID related upper GI side effects in the United States. The aim of our study was to evaluate patient awareness about NSAID induced upper GI side effects. Methods: A retrospective analysis utilizing a standard questionnaire completed during physician encounter at Interfaith Medical Center, Brooklyn NY from March to May 2009. All patients 18 years of age or older currently taking NSAID or having used NSAID in the last 2 years were included in the study. Those who never used NSAID and critical care patients were excluded. The questionnaire included demographics, co-morbidities, indication and duration of NSAID use and awareness of upper GI side effects. Complications of NSAID such as heartburn, abdominal pain, ulcer, bleeding and perforation were evaluated. There were 130 females and 180 males included in the study. The data was analyzed using regression analysis, t-test, correlation and Chi-square test as indicated. Results: The ages ranged from 18-93 years with mean age of 52 years. African-Americans comprised 88.7% of the study population. Only 15.8% patient had achieved education beyond high school. Motrin was the most commonly used NSAID (41.6%) and 37.7% patients had used two or more types of NSAIDs at different times. 68% of patients were not aware of any upper GI side effects while 32% were aware of some side effects. Of those who were aware of some side effects, only 44% patients knew NSAIDs could cause peptic ulcers and upper GI bleeding. About 50% of patients who were prescribed NSAID claimed that they were not counseled of potential GI side effects. Patients who had used 2 or more types of NSAID were more aware of side effects compared to those taking less than 2 types (p: 0.016). Among those patients who had used multiple NSAIDs, only 30% had been made aware of upper GI side effects (p: 0.009). 37% of patients who claimed they read side effects profile of NSAID were aware of some side effects compared to 14% of those who never read side effects profile (p: 0.04). Only 5 out of 26 patients with PUD were aware of side effects (p: 0.02). There was no statistically significant difference in awareness in terms of education, duration, indications and between patients who were prescribed vs. those who took OTC. Conclusion: Despite the associated significant mortality and morbidity and high cost of treatment, most patients remain unaware of upper GI side effects of NSAID. We can hope that increased patient knowledge of side effects may reduce the incidence and prevalence of GI complications due to these medications.Table

Selective and non‐selective non‐steroidal anti‐inflammatory drugs and the risk of acute kidney injury

Use of non-steroidal anti-inflammatory drugs (NSAID) is associated with risk of acute kidney injury (AKI). Risk of AKI may vary with selectivity of the NSAID, but this has not been studied in a large cohort where AKI was assessed directly from laboratory data. The objective was to compare AKI risk between selective and non-selective NSAIDs using a laboratory-based definition of AKI. We conducted a retrospective nested case-control study in the U.S. Department of Veterans Affairs health care system. From a cohort of 1 459 271 new NSAID users, we identified 22 824 cases of AKI (97% male; mean age: 63 years), and 336 734 matched controls between 2000 and 2006. AKI was defined as a creatinine increase of greater than 50%. We found higher risk of AKI in new users of any single NSAID (adjusted odds ratio = 1.82; 95%CI: 1.68, 1.98) compared to non-users without recent use. The risk of AKI varied among different NSAIDs with risk generally increasing with decrease in selectivity: rofecoxib (0.95; 0.64, 1.42), celecoxib (0.96; 0.63, 1.47), meloxicam (1.13; 0.63, 2.05), etodolac (1.31; 1.08, 1.59), diclofenac (1.11; 0.84, 1.48), piroxicam (1.53; 1.05, 2.23), salsalate (1.51; 1.22, 1.87), sulindac (1.61; 1.12, 2.30), ibuprofen (2.25, 2.04, 2.49), naproxen (1.72; 1.52, 1.95), high dose aspirin (3.64; 2.46, 5.37), indomethacin (1.94; 1.56, 2.42), keterolac (2.07; 1.78, 2.41). Those using multiple NSAIDs appeared to have higher risk (2.90; 2.62, 3.22). This study provides evidence that risk of AKI may be lower with more selective agents than with naproxen or other non-selective NSAIDs.

Comparative study on low back pain misdiagnosed as spondyloarthropathy

This study aims to investigate features of different diseases with low back pain misdiagnosed as spondyloarthropathy so as to improve the accuracy of diagnosis for spondyloarthropathy. The clinical and laboratory data of 24 cases misdiagnosed as spondyloarthropathy in recent 3 years were comparatively and retrospectively analyzed. The diagnostic accuracy of the European Spondyloarthropathy Study Group (ESSG) criteria, Amor criteria, and the combination of them in these misdiagnosed cases was also analyzed. The final diagnoses of these 24 cases were listed below: four malignant tumors (retroperitoneal adipose sarcoma, advanced gastric carcinoma, ovarian papillary epithelioma, acute lymphocytic leukemia), six benign tumors (two parathyroid adenoma with hyperparathyroidism, one intraspinal lipoma, intraspinal ependymomas, sacral tubulocyst, and intraspinal schwannoglioma, respectively). The other 14 cases included fibromyalgia syndrome (3), osteitis condensans (3), diffuse idiopathic skeletal hyperostosis (2), lumbar intervertebral disk protrusion (1), congenital scoliosis (1), Wilson's disease (1), ochronosis (1), Fanconi syndrome (1) and hypophosphatemic rachiopathy (1). Among patients with tumor, all except three patients had persistent low back pain without morning stiffness, which aggravated at night and could not be relieved by rest or exercise. The symptoms could not be relieved by administration of multiple nonsteroidal anti-inflammatory drugs. Eleven patients had inflammatory low back pain defined by Calin. Of the total misdiagnosed cases, 54.17-83.33% could be prevented by application of ESSG criteria or Amor criteria, or a combination of them. From the data, we could see that the clinical features of different diseases with low back pain were different from each other and from those of spondyloarthropathy. The various criteria for spondyloarthropathy may be more effective in combination, along with other clinical information like these clinical features.

Myositis, Vasculitis, Hepatic Dysfunction in Adult-Onset Still's Disease

Although hepatic dysfunction is common in adult-onset Still's disease (AOSD), sometimes it is difficult to differentiate hepatic dysfunction due to AOSD itself from drug-induced hepatic dysfunction. Further, myalgia often occurs in patients with AOSD; however, AOSD patients complicated with myositis are rare. We report a 43-year-old Japanese man with AOSD who developed myositis and hepatic dysfunction which were deteriorated by multiple nonsteroidal antiinflammatory drugs (NSAIDs) and were dramatically ameliorated by a low-dose steroid therapy. A skin biopsy of salmon pink rash which is characteristic for AOSD showed leukocytoclastic vasculitis, and the markers for vasculitis, plasma von Willebrand factor, and vascular endothelial growth factor levels were elevated in this patient, suggesting an association between AOSD and systemic vasculitis.

The Pharmacist's Role in the Nonsteroidal Anti-Inflammatory Drug Selection Process

The pharmacist provides an integral role in pain management and treatment by focusing on the selection and evaluation of analgesic agents in a process that is patient specific and patient centered. Counseling patients (and the families of patients) who are using nonsteroidal anti-inflammatory drugs (NSAIDs) for acute musculoskeletal pain and inflammation regarding the appropriate use of these agents is a key component of the pharmacist's overall pharmacotherapeutic role. This article reviews the importance of explaining the therapeutic and nontherapeutic effects of NSAIDs and cautions, contraindications, dosing parameters, and the avoidance of multiple NSAID use to patients and prescribers. The article also discusses the need to evaluate the cytochrome P450 system and the patient's pharmacotherapy and comorbid disease history to identify potential drug interactions. Evaluation of patients for comorbidities, allergies, and gastrointestinal, renal, hepatic, hematologic, and cardiovascular risks is also addressed, as are essential laboratory tests and the special needs of elderly patients.

Association of health‐related quality of life with dual use of prescription and over‐the‐counter nonsteroidal antiinflammatory drugs

Inadequate prescription therapy pain management, lack of doctor-patient communication about over-the-counter (OTC) medications, and easy accessibility of OTC medications may contribute to patients using more than 1 medication to manage pain. It is well established that taking multiple nonsteroidal antiinflammatory drugs (NSAIDs) can lead to serious gastrointestinal problems. Little is known about whether use of more than 1 NSAID (i.e., dual use) is related to patient self-reported outcomes, specifically health-related quality of life (HRQOL). We hypothesized that dual use of NSAIDs would be associated with reduced HRQOL. Patients from a managed care organization who filled > or =1 NSAID prescription over a 6-month period were eligible for a telephone interview focusing on NSAID use, which included the Short Form 12 (SF-12) Health Survey. Dual use was defined as taking 2 NSAIDs, either prescription or OTC, at least twice weekly during the past month. A multivariable linear regression model examined the association between dual use and the Physical Component Summary score (PCS-12) from the SF-12. Dual use was associated with lower PCS-12 scores indicating poorer HRQOL, after controlling for clinical and demographic factors. Patients may self-manage their pain to improve their daily activities by taking more than 1 NSAID. However, by attempting to obtain symptom relief, patients may be putting themselves at risk for complications. Providers are likely unaware of patients' risk. Future research should evaluate the causal factors contributing to dual use.

Perioperative antibiotics and anti-inflammatory agents in cataract surgery

Cataract surgery has benefited from great technical advances but no consensus exists as regards optimal perioperative medical management of inflammation and infection prophylaxis. The present article primarily reviews recent evidence about the most advantageous antibiotic regimen to minimize endophthalmitis, and the utility of steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) in management of both postoperative inflammation and cystoid macular edema. Prospective data from Europe supports the efficacy of intracameral cephalosporins in reducing the incidence of endophthalmitis. We compare this with retrospective data from the United States describing a low incidence of endophthalmitis when using fourth-generation fluoroquinolones as chemoprophylaxis. Other studies demonstrate the anti-inflammatory effect of multiple perioperative topical NSAIDs. Further important questions remain, however, including whether NSAIDs exhibit a superior side-effect profile relative to corticosteroids, whether benefit exists to combination NSAID/corticosteroid therapy, as well as whether NSAIDS can reduce the incidence of cystoid macular edema. New evidence clarifies the use of intracameral antibiotics, and other studies support a niche anti-inflammatory role for NSAIDs.

Endoscopic and histopathological evaluation of acute gastric injury in high-dose acetaminophen and nonsteroidal anti-inflammatory drug ingestion with suicidal intent

To evaluate endoscopic and histopathologic aspects of acute gastric injury due to ingestion of high-dose acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) with respect to some risk factors and patient characteristics. The study group consists of 50 patients admitted to emergency department with high dose analgesic ingestion (group I) with suicidal intent. Thirty patients with or without mild complaints of dyspepsia (group II) were selected as the control group. The study group was stratified according to the use of type and number of analgesics. Endoscopic findings were evaluated according to the Lanza score (LS), expressing the severity of the gastroduodenal damage and biopsies according to a scoring system based on histopathologic findings of acute erosive gastritis. Gastroduodenal damage was signifi-cantly more severe in group I compared to group II (P < 0.01). The LS was similar in both groups Ia and Ib. However LS was significantly higher in patients who had ingested multiple NSAIDs (group Ic) compared to other patients (P < 0.01). The LS was correlated to age (P < 0.01) and total amount of drug ingested (P < 0.05) in group I; but it was not correlated with Helicobacter pylori (H pylori) infection or duration of exposure (P > 0.05). The biopsy score (BS) was higher in group I than group II (P < 0.01), and higher in group Ib than group Ia (P < 0.05). The histopathologic damage was more severe among NSAID ingesting patients compared to those ingesting only acetaminophen and there is no significant difference in the endoscopic findings between the groups. There is no significant difference in the LS between the groups. This lack of significance is remarkable in terms of the gastric effects of high-dose acetaminophen.

New concepts in the management of adverse drug reactions

Our understanding of drug reactions and their management has changed markedly in recent years with the development of several new concepts. Epidermal cell death seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may result from Fas-Fas ligand-mediated apoptosis. Intravenous immunoglobulin (IVIG) contains anti-Fas antibodies that can abrogate apoptosis. Most studies on IVIG in SJS and TEN reported improvement in arresting disease progression and reduction in time to healing. Furthermore, several studies have dispelled the myth of sulfonamide cross-reactivity. Immune-mediated reactions against antibacterial sulfonamides are directed against two unique side chains that non-antibacterial sulfonamides do not contain. Certain patients seem to have a genetic predisposition for "multiple drug sensitivities." Hence, they may react to several drugs that are not necessarily cross-reacting. Also, multiple studies have shown that IgE-mediated nonsteroidal anti-inflammatory drugs (NSAIDs) cross-reactivity is uncommon. Rather, it is cyclooxygenase (COX) 1 inhibition that results in pseudoallergic reactions to multiple NSAIDs. Several studies have indicated that selective COX-2 inhibitors can be safely administered in patients with aspirin-exacerbated respiratory disease and NSAID-induced cutaneous reactions, although their use has been curtailed by their cardiovascular side effects. Biological agents, such as infliximab, are being increasingly used for a variety of diseases and have caused adverse reactions in some patients. Studies differ as to whether concomitant immunosuppressive use with infliximab affects the development of drug-specific antibodies and infusion reactions. Successful desensitization protocols have been developed for reactions to some of these agents.

Predictive Value of Autologous Plasma Skin Test for Multiple Nonsteroidal Anti-Inflammatory Drug Intolerance

Background: Recent studies show that patients with multiple nonsteroidal anti-inflammatory drug (NSAID) intolerance are frequently characterized by autoreactivity; this can be detected by autologous serum skin test (ASST). Objective: To assess whether the autologous plasma skin test (APST), a test that was recently shown to be more sensitive than ASST, may be usefully employed as a predictive test for multiple NSAID intolerance in patients with a history of single NSAID intolerance. Methods: Thirty otherwise normal adults with a history of acute urticaria following the ingestion of one single NSAID underwent an APST before being challenged with a COX-1-inhibiting NSAID other than the offending drug. Results: Sixteen patients experienced urticaria following the ingestion of the alternative NSAID and were therefore classified as multiple NSAID reactors; all 16 (100%) scored positive on APST. In contrast only 3/14 patients finally classified as single NSAID reactors were positive on APST (p < 0.001). The positive and negative predictive value of APST for multiple NSAID intolerance were 86 and 100%, respectively. Conclusion: In patients with a history of acute urticaria induced by a single NSAID APST can be usefully employed to detect patients that are prone to react to NSAID other than the original offending one.

Clinical Management of Adult Patients with a History of Nonsteroidal Anti-Inflammatory Drug-Induced Urticaria/Angioedema: Update

In the large majority of previous studies, patients with a history of acute urticaria induced by nonsteroidal anti-inflammatory drugs (NSAIDs) seeking safe alternative drugs have undergone tolerance tests uniquely with compounds exerting little or no inhibitory effect on the cyclooxygenase 1 enzyme. In light of recently published studies, however, this approach seems inadequate and should be changed. The present article critically reviews the clinical management of patients presenting with a history of urticaria induced by a single NSAID or multiple NSAIDs and suggests a simple, updated diagnostic algorithm that may assist clinicians in correctly classifying their patients.

Aspririn and nonsteroidal anti-inflammatory drug hypersensitivity

Acetylsalicylic acid (ASA) or aspirin and nonsteroidal anti-inflammatory drug (NSAID) sensitivities encompass a diverse group of both pharmacological and hypersensitivity reactions. Conventionally, hypersensitivities include aspirin-exacerbated respiratory disease (AERD), ASA-induced urticaria, and anaphylaxis. With an increasing prevalence of coronary artery disease in an aging population, aspirin continues to play a significant role in cardiac prophylaxis in a large patient population. Invariably, the clinician will encounter patients with clear indications for aspirin therapy but a history of aspirin sensitivity. Although protocols have been established for aspirin challenge and desensitization, it is not always an efficacious or safe procedure. This article reviews the different classifications of ASA/NSAIDs hypersensitivities to better guide the clinician in dealing with this patient population. History of crossrelativities between multiple NSAIDs implies a non-IgE-mediated process. Similarly, a history of monosensitivity to one NSAID implies an IgE-mediated process, although specific antibodies are often elusive. Despite the name, AERD can potentially be exacerbated by all cyclooxygenase (COX) inhibitors based on dose-dependent inhibition of COX-1. Aspirin desensitization can be achieved to improve both upper and lower respiratory symptoms for most patient with AERD. Aspirin desensitization can usually be achieved for those in need of the antiplatelet effects of aspirin, with the exception of those with aspirin-induced urticaria and baseline chronic urticaria. However, desensitization should only be attempted in those with stable coronary artery disease because the process of desensitization carries the inherent risk of anaphylaxis/anaphylactoid reaction, which may further increase cardiac demand and bring about ischemic injury. Therefore, desensitization is reserved until coronary artery disease is stabilized.

Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs

A summary of the basic science underlying the current controversies regarding cyclooxygenase-2 (COX-2)-selective nonsteroidal antiinflammatory drugs (NSAIDs), including data on their cardiovascular safety, their gastrointestinal (GI) benefits, cost-effectiveness, physician-prescribing trends, and recommendations for prescribing these agents is presented. A number of randomized controlled trials (RCTs) have reported that COX-2-selective NSAIDs increase cardiovascular events, although there appear to be gradations of risks among the COX-2-selective NSAIDs. In addition, traditional NSAIDs may increase the risk for cardiovascular events, complicating the interpretation of RCTs that use traditional NSAIDs as comparators. Selective inhibitors of COX-2-selective NSAIDs are effective antiinflammatory and analgesic drugs with improved upper-GI safety compared to traditional NSAIDs. Data on the cost-effectiveness of COX-2-selective NSAIDs indicate that they should be limited to patients at high risk for upper-GI adverse effects. However, they had been increasingly used in patients with lower GI risks until recent events reversed that trend. Circumstances under which COX-2-selective NSAIDs may be appropriate are in patients at high GI risk and in patients who did not respond to multiple traditional NSAIDs. The national spotlight in the United States on NSAID-related adverse events and recent lawsuits against health care providers prescribing COX-2-selective NSAIDs further highlights the need for provider-patient communication and risk disclosure. The relative cardiovascular risks of NSAIDs are similar in magnitude to other currently prescribed therapies. Health care providers must consider the efficacy, GI and cardiovascular risks, concomitant medications, and costs when determining the appropriateness of COX-2-selective NSAID therapy.

GI Risk and Risk Factors of NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the United States. Ulcers are found at endoscopy in 15% to 30% of patients using NSAIDs regularly. The annual incidence of upper gastrointestinal (GI) complications such as bleeding with regular NSAID use is approximately 1.0% to 1.5%, whereas the annual rate of upper GI clinical events (complicated plus symptomatic uncomplicated ulcers) is approximately 2.5% to 4.5%. Upper GI symptoms such as dyspepsia also occur in many patients taking NSAIDs--at a relative risk of about 1.5 to 2 compared with that in patients without NSAID use. Important risk factors for upper GI clinical events include older age, prior history of upper GI events, use of corticosteroids or anticoagulants, and high-dose or multiple NSAIDs (including NSAID plus low-dose aspirin). Lower GI clinical events such as bleeding may also occur with NSAIDs, although they are less common and less well studied than upper GI events. The decision to employ a protective strategy to decrease NSAID-associated GI clinical events is based on risk stratification. Strategies employed include the use of non-NSAID analgesics, use of lowest effective dose of NSAID, use of medical cotherapy (eg, proton pump inhibitor, misoprostol), or use of coxibs.