Non-salicylate Non-steroidal Anti-inflammatory Drugs Research Articles

Upper Gastrointestinal Complications associated with NSAIDs in Children

ObjectiveTo analyse serious upper gastrointestinal (UGI) complications associated with non-salicylate nonsteroidal anti-inflammatory drugs (NSAIDs) in children. MethodsAll serious UGI complications associated with non-salicylate NSAIDs approved in France to treat moderate pain or fever in children, spontaneously reported to the French Pharmacovigilance system or to the companies, between the launching of each study drug in France to December 31, 2000. ResultsSerious UGI complications were reported in 61 children aged from 11 months to 15 years during treatment with niflumic acid (27), ibuprofen (23) and tiaprofenic acid (11). No case was reported with ketoprofen. UGI manifestations were UGI bleeding (15) and 46 gastrointestinal symptoms with endoscopic lesions i.e. gastritis (18), gastric ulcer (13), duodenal ulcer (7), duodenitis (4) and oesophageal ulcer (4). NSAID was combined with a salicylate in 36% of cases, given by the parents in self medication in 6.6% of cases and used outside its product licence in 33.8% of cases. ConclusionNSAIDs used in children for fever or moderate pain are associated with a risk of serious UGI complications which increases with length, dose and association with a salicylate.

Drugs used to treat muscle and joint disease

Paracetamol is the first-line treatment for pain relief in patients with osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) can be used but tend to cause gastrointestinal side effects. The roles of COX-2 inhibition and drugs aimed at preventing cartilage destruction require evidence from long-term trials. Rheumatoid arthritis may be treated with NSAIDs and glucocorticosteroids. In the early stages of the condition, disease modifying antirheumatic drugs (DMARDs) are recommended. The pain of gout can be treated with non-salicylate NSAIDs; alternatives are colchicines and allopurinol. Muscle spasm and spasticity can be treated with GABAB receptor agonists, such as baclofen, or GABAA potentiating drugs, such as the benzodiazepines. Peripherally acting drugs such as dantrolene lack central nervous system side effects. Drugs inhibiting the enzyme acetylcholinesterase are used to treat the autoimmune disease myasthenia gravis, in which the body produces antibodies to nicotinic receptors for acetylcholine.

Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving concepts of their chemopreventive actions

N'onsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used pharmaceutical compounds worldwide. Since it was recognized that certain plant constituents, such as the bark of the white willow (Salix alba vulgaris), were helpful in the treatment of fever, inflammatory diseases, and other maladies, they have been systematically exploited by humankind. Modern medicine has witnessed the isolation of salicin, the active ingredient of the willow bark; the synthesis of sodium salicylate; the formulation of aspirin (acetylsalicylic acid) in 1897; and finally the introduction of indomethacin, the first of many nonsalicylate NSAIDs, in 1963. In the last few years, new uses for these compounds have been recognized such as in the prevention and management of atherosclerotic vascular diseases. NSAIDs have recently been discovered to have antineoplastic properties, particularly in the gastrointestinal tract.l'2 Strong evidence suggests that they prevent colorectal cancer in the general population, and some of them cause regression of adenomatous polyps in patients with familial adenomatous polyposis (FAP)3; very recently, preliminary data indicate that the NSAID sulindac can also cause regression of sporadic adenomas. 4 This Viewpoints article reviews the evidence for the chemopreventive and antineoplastic activity of NSAIDs and discusses the mechanisms by which their remarkable effects occur. NSAIDs Are Antineoplastic: The Evidence That NSAIDs are antineoplastic, prominently in the colon, is derived from three lines of evidence: animal studies, clinical studies and case reports, and epidemiological data.

A Study of Manufacturer-Supported Trials of Nonsteroidal Anti-inflammatory Drugs in the Treatment of Arthritis

To study the relation between reported drug performance in published trials and support of the trials by the manufacturer of the drug under evaluation, we studied a sample of trials of nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of arthritis. All randomized control trials of NSAIDs published between September 1987 and May 1990 identified by MEDLINE were reviewed. If an article met the following criteria (n = 61), it was selected: trials involving adult patients with osteoarthritis or rheumatoid arthritis (n = 180), use of nonsalicylate NSAIDs marketed in the United States (n = 101), randomized control trial (n = 81), duration of the trial 4 or more days (n = 78), and use of an efficacy outcome measure (n = 61). Reviewers, "blinded" to manufacturer status, evaluated the narrative interpretation of results and extracted numeric data on efficacy and toxicity. Manufacturer-associated trials were defined as those that acknowledged an association with a pharmaceutical manufacturer. Because of the scarcity of non-manufacturer-associated trials (n = 9), we report only on the manufacturer-associated articles. Fifty-two publications (85.2%) representing 56 trials were associated with a manufacturer. The manufacturer-associated drug was reported as comparable with (71.4%) or superior to (28.6%) the comparison drug in all 56 trials. These narrative claims of superiority were usually justified with trial data. Of the trials identifying one drug as less toxic (n = 22), the manufacturer-associated drug's safety was reported as superior to the comparison drug in 86.4% of cases. Justification for the narrative interpretation of the trial findings regarding less toxicity was provided in only 12 (54.5%) of 22 trials. The manufacturer-associated NSAID is almost always reported as being equal or superior in efficacy and toxicity to the comparison drug. These claims of superiority, especially in regard to side effect profiles, are often not supported by trial data. These data raise concerns about selective publication or biased interpretation of results in manufacturer-associated trials.

Gastric mucosal damage induced by nonsalicylate nonsteroidal antiinflammatory drugs in rats is mediated systemically

The gastric toxicities of an enteric-coated formulation and conventional indomethacin were compared in rats. Both formulations were equally damaging to the mucosa, suggesting that topical damage was not the major route of injury. The importance of systemically mediated damage was further determined by gastrotoxicity dose-response curves and pyloric ligation experiments in which indomethacin was administered either orally or parenterally, or into stomach or duodenum with the pylorus occluded. Gastric damage was significantly higher in those groups that had received the drug parenterally or intraduodenally. The extent of deeper mucosal damage, assessed histologically, was greater in parenterally dosed rats. In further experiments, oral and parenteral routes of administration of two other nonsalicylate NSAIDs, naproxen and sodium diclofenac, were found to be equally damaging to the mucosa. Our results show that indomethacin-induced gastric damage, unlike aspirin injury, is mediated mainly systemically. Enteric-coating may not be a useful strategy in reducing gastric injury by nonsalicylate, nonsteroidal antiinflammatory drugs.

Cost-Conscious Prescribing of Nonsteroidal Anti-inflammatory Drugs for Adults With Arthritis

Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of painful disorders. This article reviews the efficacy, side effects, and costs of these agents and proposes a practical approach to using them in a cost-effective manner. Although there may be some differences in efficacy among available drugs, these do not appear sufficient to justify using the more expensive agents in most cases. Adverse effects, especially gastrointestinal (GI), add to the cost of using these drugs. Aspirin and all nonsalicylate NSAIDs share a risk of causing gastric ulcer, upper GI bleeding, and GI perforation. Prostaglandin inhibition by these agents may lead to reduced glomerular filtration rate and renal failure. There may be modest differences in GI and renal risks with the different agents, but these are minimal. Prophylaxis against gastric ulceration with anti-ulcer drugs has been recommended, and one agent, misoprostol, is approved for use in the United States for this purpose. Whether use of prophylaxis will increase or decrease the costs associated with NSAID therapy remains to be determined. Nonacetylated salicylates may cause less GI adverse effects and may be somewhat "renal sparing." Strategies that would reduce the cost of care for painful musculoskeletal disorders without compromising quality of care include using acetaminophen instead of an NSAID for noninflammatory disorders, trying nonacetylated salicylates as less expensive and safer alternatives to NSAIDs, using one agent at a time, allowing sufficient time to evaluate the therapeutic effect before changing agents, returning to the least expensive and/or safest drug if a trial of several in succession fails to find one that is clearly better, and reserving prophylactic use of antiulcer agents for patients who are at especially high risk and for whom anti-inflammatory effects are clearly needed.

Nonsalicylate nonsteroidal antiinflammatory drugs augment prestimulated acid secretion in rabbit parietal cells: Investigation of the mechanisms of action

The effects of nonsalicylate nonsteroidal antiinflammatory drugs on acid secretion were studied in isolated rabbit parietal cells. Indomethacin, naproxen, and carprofen (10−6−10−4 mol/L) potentiated histamine-, forskolin-, 3-isobutyl-1-methylxanthine-, and dibutyryl cyclic adenosine monophosphate-stimulated acid secretion without affecting basal acid secretion. This augmentation of secretagogue-stimulated acid secretion was dependent on extracellular calcium because potentiation was abolished by calcium depletion of the medium or in the presence of the calcium antagonist lanthanum chloride. Potentiation was independent of the H2 and muscarinic receptors and did not appear to involve guanine nucleotide regulatory proteins. Proton pump activity was unaffected by indomethacin. Furthermore, nonsteroidal antiinflammatory drugs increased calcium efflux through the plasma membrane, as measured by calcium 45, and decreased endogenous prostaglandin E2 content. Exogenous dimethyl prostaglandin E2 inhibited the potentiating effect of these drugs on histamine-stimulated but apparently not on dibutyryl cyclic adenosine monophosphate-stimulated acid secretion. The data indicate that nonsalicylate nonsteroidal antiinflammatory drugs interacted at a postreceptor site between adenylate cyclase and the proton pump. The potentiating effects of these drugs were regulated by calcium and possibly modulated by prostanoids.

Cost-Benefit Assessment of Salicylates and NSAIDs in Treating Arthritic Disease

The increasing costs of treating rheumatic diseases has presented a serious challenge to contain the projected expenditures of $96.8 billion by the year 2000. This includes both direct and indirect costs to the patient and society. These expenditures include physician care, prescribed drugs, patient aids, physical and occupational therapy, nursing care, hospitalization, and nursing home care. Indirect costs include lost wages, insurance indemnification, loss of productivity, disability and pension payments, and rehabilitation expenses rendered by government agencies. Sparcity of data presents problems in addressing this onerous tax on society. In 1985 Baum reported that 66.5 million prescriptions for nonsalicylate nonsteroidal anti-inflammatory drugs (NSAIDs) were prescribed in the United States at a cost of over $1 billion. Salicylates were not included. Cost-effectiveness of salicylates v nonsalicylate NSAIDs is reviewed. Most studies carried out have not appropriately presented these comparative data. ...

Sucralfate treatment of nonsteroidal anti-inflammatory drug-induced gastrointestinal symptoms and mucosal damage

In a randomized, double-blind trial, sucralfate therapy, 1 g four times daily, was compared with placebo in 143 symptomatic patients to assess the treatment of gastrointestinal symptoms and gastric mucosal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). All patients followed a fixed regimen of NSAIDs, were assigned to one of two groups based on the presence or absence of gastric erosions at baseline endoscopy, and were then assigned randomly to receive sucralfate or placebo for four weeks. Patients were then followed for up to six months while receiving open-label sucralfate 1 g twice daily to up to 1 g four times daily. After four weeks of double-blind therapy, patients taking either nonsalicylate NSAIDs or long half-life NSAIDs and who were treated with sucralfate experienced a significant reduction in both peptic symptom frequency and intensity (p <0.03) as compared with patients receiving placebo. Sucralfate-treated patients with baseline endoscopic lesions showed a significant reduction in lesion scores (p <0.005) at four weeks as compared with baseline, whereas no improvement was observed in gastric mucosal lesions of patients given placebo. Long-term sucralfate therapy resulted in continued improvement in gastrointestinal symptoms and gastric lesion scores in patients receiving all types of NSAIDs. The results indicate that sucralfate used in conjunction with NSAIDs may allow patients to continue therapy by relieving gastrointestinal symptoms and mucosal damage associated with NSAID therapy.

Antiinflammatory drugs and gastric mucosal damage

N ONSTEROIDAL antiinflammatory drugs (NSAIDs) are among the most often used medications in the United States and throughout the world. Fifteen to 20 billion aspirin tablets are consumed each year in the United States.’ Prescriptions for nonsalicylate NSAIDs represented over 4% of the total prescription market in 1983, with consumers spending over a billion dollars for these medications.’ Approximately 3% of the United States population requires treatment for a rheumatic disorder, and NSAIDs are prescribed in most types of noninfectious arthritis.3,4 NSAIDs may cause gastrointestinal (GI) symptoms, erosions and/or ulcers, and upper GI tract bleeding. Therefore, gastric mucosal damage resulting from NSAID use is potentially a major health problem. Corticosteroids are used in a wide variety of medical conditions, including rheumatoid arthritis (RA), bronchial asthma, allergic disorders, and dermatologic diseases. The relationship of corticosteroids to gastric mucosal damage is controversial. Corticosteroids may increase the incidence of peptic ulcer disease and GI hemorrhage’ and potentiate gastric mucosal injury when used in combination with NSAIDs such as aspirin.6*7 This review is divided into two sections. The first part surveys data regarding NSAID induced gastric mucosal injury, and the second portion discusses the role of corticosteroids in causing gastric mucosal damage.

Prognosis of Chronic Unexplained Dyspepsia: A Prospective Study of Potential Predictor Variables in Patients With Endoscopically Diagnosed Nonulcer Dyspepsia

The aim of this study was to determine if there were predictors of the symptomatic course of patients with chronic unexplained (essential) dyspepsia. After endoscopic assessment, 111 patients with essential dyspepsia were followed up by telephone interview every second month. Data were gathered, for a mean of 17 mo per patient, on the number of days of upper abdominal pain (the response variable) each month. In the 6-mo period before entry to the study the following predetermined predictor variables were collected: demographic factors (age, sex, social grade), number of pain days in the 6 mo before diagnosis, environmental factors (analgesics, nonsalicylate nonsteroidal anti inflammatory drugs, alcohol, smoking, coffee, tea), length of dyspepsia history, and past history of peptic ulcer. Prospectively for each month of follow-up, the following additional variables were recorded: environmental factors, treatment, and development of gastroesophageal reftux symptoms. It was found, that (a) patients with more pain before diagnosis were significantly more likely to have pain over the follow-up, and (b) the taking of medications for dyspepsia and development of gastroesophageal re f tux were associated with more days of pain over the follow-up (all p < 0.001). Demographic and environmental factors, length of dyspepsia -history, and a past history of ulcer were of no significant predictive value. There was a decrease in pain over the follow-up period (p = 0.002), but this effect was limited to the first two periods after endoscopic diagnosis.

Environmental factors in aetiology of chronic gastric ulcer: a case control study of exposure variables before the first symptoms.

The aim of the present study was to determine whether there is indication that either smoking, alcohol ingestion, or ingestion of analgesic or non-salicylate non-steroidal anti-inflammatory drugs plays any role in the development of chronic gastric ulcer disease. A group of 104 patients with gastric ulcer was compared with an age, sex and social grade matched community control population as regards exposure to the above factors during three time periods--the lifetime, five year and one year periods before the initial onset of the patients' ulcer symptoms. In all three study periods a statistically significant risk of gastric ulcer was found to be associated with smoking, and the daily use of aspirin, indomethacin and of other non-salicylate non-steroidal anti-inflammatory drugs as a group, but not with alcohol or daily use of paracetamol. As exposure to the environmental factors preceded the initial onset of ulcer symptoms, causal relationships are suggested. Assuming the association are causal, it can be calculated that possibly up to 80% of gastric ulcer disease is attributable to smoking and the daily ingestion of analgesic and anti-inflammatory drugs.

Final report on the cost of treating arthritic disease: Comparison between salicylates and nonsalicylate nonsteroidal anti-inflammatory drugs

The cost of antacids or other drugs and hospital admission for the treatment of gastrointestinal side effects must be factored into any comparison between costs of nonsteroidal anti-inflammatory drugs and salicylate drugs in the treatment of arthritis. Records and interviews of 534 patients treated for arthritis, 310 treated with nonsalicylate nonsteroidal anti-inflammatory drugs and 224 treated with salicylates, were evaluated for this comparison. Costs of the basic drug, medical treatment for gastrointestinal side effects, and hospitalization for such treatment were added, averaged for 30-day per patient treatment periods, and compared. When hospital costs were excluded, costs per patient per month of nonsteroidal anti-inflammatory drug therapy were comparable to costs of nonacetylated salicylate therapy, and both sums were more than twice the cost of therapy with an aspirin compound, When hospital costs were included, average nonacetylated salicylate costs per patient per month were far higher than those for treatment with either aspirin or nonsteroidal anti-inflammatory drugs. These findings suggest the value of randomized multicenter studies to establish the cost-effectiveness of nonsteroidal anti-inflammatory drug therapy v salicylate therapy in the treatment of arthritis.