Intraoral topical nonsteroidal antiinflammatory drug application for headache prevention

Recent evidence suggests an association between migraine and tension-type headache and local inflammation occurring in a maxillary nerve segment. This study was designed to evaluate the efficacy of topical ketoprofen for the prevention of migraine, tension-type, and posttraumatic headache. Patients with a headache frequency of at least once a week recorded the frequency, severity, duration, and type of headache for 60 days. After 30 days, patients applied the medication daily for the next 30 days to the periapical area of the maxillary molars on the symptomatic side(s). Headache medications and analgesics were permitted, as needed. Headache burden was defined as the average intensity of each headache (0-10 scale) multiplied by its duration, in hours. The average monthly headache burden score for the 20 patients enrolled in this study decreased from 454.8 (30-day baseline) to 86.5 P < 0.001 during the 30-day treatment phase. Analgesic and headache medication intake were significantly reduced from baseline during the treatment phase, and side effects were minimal.     

The multiple faces of nonsteroidal antiinflammatory drug hypersensitivity.

Based on the clinical picture and triggering drugs, allergic and pseudoallergic adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) can be classified in four patterns : respiratory, cutaneous, mixed and systemic. This categorization is useful for the purpose of describing patient populations included in studies about NSAID adverse reactions as well as for the routine management of the patient in the clinical setting.     

Rheumatologists' adherence to guidelines for misoprostol use in patients at high risk for nonsteroidal antiinflammatory drug gastropathy

OBJECTIVE: To determine the extent of evidence based practice among rheumatologists in the prevention of nonsteroidal antiinflammatory drug (NSAID) associated peptic ulcer disease and to seek ways to improve the management of high risk NSAID users. METHODS: In March 1996 all 7 rheumatologists from Saskatoon participated in a consensus conference to develop local guidelines for the prophylaxis of NSAID associated peptic ulcer disease. We performed a retrospective chart review for September/October 1995 (baseline) and for June/July 1996 (post-consensus guideline) of all patients from Saskatoon rheumatologists who were being treated with NSAID for either rheumatoid arthritis (RA) or undifferentiated inflammatory polyarthritis (IP). A prospective crossover intervention study was performed from January to April 1997 in which 2 subgroups of rheumatologists (university or private practice) had a reminder sheet of gastrointestinal (GI) bleeding risk assessment placed into the front of each patient's chart prior to each office visit. The GI bleeding risk for each patient at time of visit was later determined by chart review. The primary outcome was the proportion of adherence to guidelines for high risk NSAID users in the combined intervention group (reminder sheet) compared to the combined control group (no reminder sheet) in the prospective controlled crossover study. RESULTS: A total of 484 patients with RA or IP received NSAID during the 4 study periods. Of these, 82 patients (16.9%) were at high risk of GI bleed. In 1995, the proportion of high risk patients taking misoprostol was 29% for university and 33% for private practice rheumatologists. The establishment of local consensus guidelines in 1996 temporarily increased adherence to guidelines to 43%, but only for private practice rheumatologists. During the prospective study, adherence to guidelines was significantly greater in the intervention (reminder sheets) group compared to the control (no reminder sheets) group (53% vs 15%; p = 0.014). CONCLUSION: The simple intervention of reminder sheets for GI bleeding risk assessment resulted in a significant increase in rheumatologists' adherence to guidelines, although a substantial number of patients remained untreated with misoprostol. This study illustrates the difficulty of incorporating new knowledge and recommendations into clinical practice. Additional strategies should be investigated to more effectively incorporate new knowledge in the practice of rheumatology.     

Variation in the risk of peptic ulcer complications with nonsteroidal antiinflammatory drug therapy

Objective. To assess the risk of perforation or hemorrhage of peptic ulcer on treatment with nonsteroidal antiinflammatory drugs (NSAIDs), both as a class and as individual agents. Methods. A case–control study of medication histories in 494 patients and 972 matched control subjects. Results. The increase in risk (odds ratio) with NSAID therapy was 5.1 times the risk in controls. The odds ratio for piroxicam was 6.3 (95% confidence interval [CI] 3.3–12.0), as compared with 2.9 for diclofenac, ketoprofen, and sulindac combined (95% CI 2.0–4.2). The effect of other risk factors was also considered, and the adjusted odds ratios were 4.1 for all NSAIDs, 6.4 (95% CI 2.8–15.0) for piroxicam, and 3.3 (95% CI 2.0–5.5) for diclofenac, ketoprofen, and sulindac combined. Conclusion. The estimate of overall risk of peptic ulcer complications with NSAIDs is similar to that found in other studies. There appear to be differences in risk between agents.     

Inhibitory effect of fluvastatin on ileal ulcer formation in rats induced by nonsteroidal antiinflammatory drug

AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage as one of their side effects in humans and experimental animals. Lipid peroxidation plays an important role in NSAID-induced ulceration. The aim of this study was to investigate the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the ulceration in small intestines of rats. METHODS: The effects of three HMG-CoA reductase inhibitors, fluvastatin, pravastatin and atorvastatin on ileal ulcer formation in 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT)-treated rats were examined. Antioxidative activity of the inhibitors was measured by a redox-linked colorimetric method. RESULTS: Fluvastatin, which was reported to have antioxidative activity, repressed the ileal ulcer formation in rats treated with BFMeT an NSAIDs. However, the other HMG-CoA reductase inhibitors (pravastatin and atorvastatin) did not repress the ileal ulcer formation. Among these HMG-CoA reductase inhibitors, fluvastatin showed a significantly stronger reducing power than the others (pravastatin, atorvastatin), CONCLUSION: Fluvastatin having the antioxidaitive activity suppresses ulcer formation in rats induced by NSAIDs.     

Modulation of cartilage destruction by select nonsteroidal antiinflammatory drugs

Non-enzymatic factors produced by synovial tissue can potentially mediate cartilage destruction by inducing the synthesis and release of matrix-degrading proteinases from chondrocytes. Pharmacologic control of this process is of potential clinical relevance. The in vitro effect of therapeutic concentrations of select nonsteroidal antiinflammatory drugs on the synthesis and activity of catabolism-inducing cytokines produced by 6-day explant cultures of osteoarthritic and rheumatoid synovial tissue was studied. Piroxicam regularly suppressed such factor synthesis by both types of tissue without significantly affecting total protein synthesis. This did not occur using sodium salicylate or indomethacin in osteoarthritis tissue cultures and was observed only occasionally in rheumatoid arthritis cultures. None of the nonsteroidal antiinflammatory drugs studied consistently blocked catabolism-inducing activity in osteoarthritis tissue, whereas piroxicam more consistently inhibited activity produced by rheumatoid arthritis tissue. Results suggest that the catabolism-inducing factors produced by the 2 tissue sources may differ.     

Clinical use of multiple nonsteroidal antiinflammatory drug preparations within individual rheumatology private practices

The clinical use of nonsteroidal antiinflammatory drugs (NSAID) was studied in 15 rheumatology private practices in the USA (in California, the District of Columbia, Florida, Idaho, Minnesota, Pennsylvania and Tennessee). Among 1,423 patients with rheumatoid arthritis (RA) under care in these 15 practices, the most extensively used NSAID preparation within any of the 15 individual practices was taken by a median of 19.5% of patients (mean 20.7%, range 8-36%), and the 3 most extensively used preparations by a median of 45.9% (mean 47.7%, range 34.7-63.5%). The median number of NSAID preparations used (singly) in each of the individual practices was 15 (range 8-20), including a median of 7 (range 4-10) used by more than 5% of the patients with each practice. The NSAID usage of these patients with RA seen in private practice settings was met by 8 preparations for 70%, by 10 preparations for 80%, and by 14 preparations for 90% of the 1,423 patients.     

Diaphragm disease of the small bowel: a case without apparent nonsteroidal antiinflammatory drug use

BACKGROUND: Diaphragm-like strictures of the small bowel are an infrequent complication of the treatment of patients with nonsteroidal antiinflammatory drugs (NSAIDs). STUDY: We report a patient with this condition in whom the use of NSAIDs was ruled out by both clinical history and objective blood testing of current aspirin use. RESULTS: He reported a history of recurrent episodes of colic abdominal pain during the past 25 years; he underwent three surgical operations for this condition. Before these symptoms, he had an undefined abdominal process with diarrhea, weight loss, and diffuse edema, which resolved spontaneously without reaching a diagnosis. CONCLUSIONS: We suggest that diaphragm-like strictures might be developed as a nonspecific response to different damaging insults to the intestine and are not necessarily associated with NSAID use.     

Inhibition of interleukin 1 induced chondrocyte protease activity by a corticosteroid and a nonsteroidal antiinflammatory drug.

We report that administration of the corticosteroid, methylprednisolone (PRED) inhibited interleukin 1 (IL-1) induction of chondrocyte caseinolytic activity (25-55%) and collagenolytic activity (15-24%). The nonsteroidal antiinflammatory drug (NSAID), naproxen (NAP) had no effect on either enzyme activity over a therapeutic range (7-30 micrograms/ml) but at 120 micrograms/ml inhibited IL-1 induced caseinolytic and collagenolytic activity by 17 and 19%, respectively. However, PRED (2 micrograms/ml) in combination with NAP (30 micrograms/ml) significantly increased the inhibition of caseinolytic activity (p less than 0.001) compared to that observed with PRED (2 micrograms/ml) alone. The suppression of IL-1 induced collagenolytic activity noted with PRED in combination with NAP did not exceed that observed with PRED alone.     

Informed consent and the prescription of nonsteroidal antiinflammatory drugs

Objective. To examine disclosure of side effects of nonsteroidal antiinflammatory drugs (NSAIDs) and to identify patient- and physician-specific factors associated with greater disclosure. Methods. Forty-six encounters between rheumatologists and new adult outpatients who were prescribed an NSAID they had not been taking prior to the visit were audiotaped. Reviewers coded the NSAID prescribed, specific side effects mentioned, demographic features of patients and physicians, and patient clinical characteristics. Neither patients nor physicians were aware that side effect disclosure was being studied. Results. A mean of 1.7 side effects was mentioned per encounter. Epigastric discomfort was mentioned in 72% of encounters, while other side effects, including hepatic, renal, hematologic, or central nervous system effects, were mentioned in ≤15% of encounters. Three factors were identified as independent predictors of less disclosure of side effects: senior clinician (versus less experienced), patient not taking another NSAID immediately prior to the visit, and patient age <40. Increased disclosure by less experienced clinicians occurred exclusively with patients who were taking another NSAID prior to the visit. Conclusion. Disclosure of side effects other than epigastric discomfort to patients who are prescribed a new NSAID is limited. Patients not taking NSAIDs previously, who presumably have the most to gain from such discussions, are told the least. These results have implications with regard to doctor—patient decision-making and malpractice litigation in the outpatient setting.     

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by approximately 50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G(1) and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.     

Frequency of gastroduodenal lesions in asymptomatic patients on chronic aspirin or nonsteroidal antiinflammatory drug therapy

Endoscopy in 49 patients without upper gastrointestinal symptoms and who were receiving chronic aspirin or nonsteroidal antiinflammatory drug therapy showed the frequency of gastric and duodenal mucosal lesions to be 76 and 27%, respectively. Fifteen (31%) had gastric ulcers, 31 (63%) had gastric erosions, and 10 (20%) had gastric mucosal hemorrhages. Gastric mucosal lesions were noted in 9 (90%) patients taking plain aspirin, in 25 (74%) receiving nonsteroidal antiinflammatory agents, and in 3 (60%) patients taking enteric-coated aspirin. Duodenal lesions were noted in 30 and 26% of patients taking plain aspirin and nonsteroidal antiinflammatory drugs, respectively. Patients taking enteric-coated aspirin had less severe duodenal injury than patients receiving ibuprofen or indomethacin, but the difference was not statistically significant. Endoscopy in 20 normal subjects not taking aspirin or nonsteroidal antiinflammatory drugs showed no gastroduodenal ulcers, erosions, or hemorrhage. Patients chronically taking antiarthritic drugs, including enteric-coated aspirin, have a high frequency of asymptomatic gastroduodenal lesions.     

Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs—ibuprofen, naproxen, and celecoxib—to cause a drug–drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug–drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk.Chronic pain, most commonly inflammatory musculoskeletal pain, afflicts hundreds of millions worldwide (1). Nonsteroidal antiinflammatory drugs (NSAIDs) consumed chronically or intermittently remain the mainstay of therapy for inflammation-associated pain. These agents inhibit cyclooxygenase (COX)-1 and COX-2, thereby reducing the production of inflammatory prostanoids, lipid mediators that lower the activation threshold of nociceptors and sensory neurons. The prevalence of chronic pain rises in the elderly, coinciding with an increase in concomitant disease (1), which complicates drug treatment. Pain management in patients with preexisting cardiovascular disease is a particular challenge because of the cardiovascular adverse effects of NSAIDs and the risk of drug–drug interactions that might undermine the antiplatelet effects of aspirin prescribed for cardioprotection (2).Although NSAIDs relieve pain effectively, they can cause serious renal and cardiovascular complications by inhibiting COX-dependent prostanoids with homeostatic functions (3, 4). All NSAIDs have the potential to elevate blood pressure and may cause heart failure. COX-2–selective NSAIDs, which were developed to reduce gastrointestinal toxicity, additionally raise the rate of myocardial infraction and stroke (5, 6), affecting ∼1–2% of patients exposed per year (3, 4). This adverse drug reaction may have caused thousands of deaths in the general population. Traditional NSAIDs (tNSAIDs) have also been associated with cardiovascular events, but although pharmacoepidemiological studies and metaanalyses of randomized, controlled trials suggest that not all tNSAIDs carry the same risk, there is considerable heterogeneity across studies in the comparative estimates of risk. It remains uncertain which NSAID to choose for patients at risk for cardiovascular complications. This uncertainty has been the argument in support of two ongoing large randomized, controlled trials comparing the cardiovascular safety of celecoxib with the most commonly prescribed tNSAIDs (7, 8).Aspirin is a unique COX inhibitor: it acetylates serine-529 in the substrate binding channel of COX-1 and inactivates the enzyme irreversibly, whereas tNSAIDs are reversible COX inhibitors. Experiments with radio-labeled aspirin in vitro and X-ray crystallography suggested that some but not all NSAIDs may compete with aspirin for binding COX-1 (9, 10). This concept was borne out further in clinical studies that exploited the distinct recovery kinetics of platelet function between reversible COX inhibitors and the irreversible inhibitor aspirin to predict whether a drug–drug interaction might occur (11–18). Again, heterogeneity was observed between studies, NSAIDs, doses, and time of dosing.We devised a direct MS assay with which to quantitate acetylation of platelet COX-1 by aspirin and used this methodology to address its interaction with NSAIDs. Although ibuprofen, naproxen, and celecoxib all have the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro (9, 10), exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug–drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. This observation has relevance to the interpretability of ongoing randomized trials.