High Doses Of Non-steroidal Anti-inflammatory Drugs Research Articles

The gastrointestinal effects of nonselective NSAIDs and COX-2–selective inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin, are among the most frequently prescribed medications worldwide. The main factor limiting use of NSAIDs is concern about their gastrointestinal (GI) side effects. The purpose of this article is to review the incidence, pathophysiology, and risk factors of GI side effects associated with NSAID therapy. Upper GI symptoms, such as dyspepsia, occur in 15% to 60% of NSAID users, twice as often as in individuals not taking NSAIDs. The prevalence of gastric or duodenal ulcers in patients taking NSAIDs regularly is approximately 15% to 30%. The annual incidence of NSAID-related clinical upper GI events (complicated and symptomatic ulcers) is approximately 2.5% to 4.5%, with the annual incidence of serious complications (severe bleeding, perforation, and obstruction) about 1% to 1.5%. A history of ulcer or GI complications, advanced age, concomitant anticoagulation therapy or corticosteroid use, and high-dose or multiple NSAID therapy are associated with an increased risk of GI events during NSAID therapy. The cyclooxygenase (COX)-2 specific inhibitors (coxibs) have been developed in order to improve the GI safety and tolerability profile of therapy with NSAIDs. In numerous clinical trials, coxibs have been shown to have efficacy similar to that of nonselective NSAIDs, but are associated with significantly fewer endoscopic ulcers. In addition, 2 large outcome trials indicated that coxibs can also reduce the incidence of clinically important GI events. Semin Arthritis Rheum 32(Suppl 1):25-32. Copyright 2002, Elsevier Science (USA). All rights reserved.

Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population

Acetaminophen is recommended as initial therapy for patients with arthritis, particularly those at increased risk of nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal (GI) side effects. However, higher doses of acetaminophen inhibit prostaglandin synthesis and have been associated with GI events. This study was undertaken to compare the observed and adjusted rates of GI events (hospitalizations, ulcers, dyspepsia, GI prophylaxis) occurring with higher versus lower doses of acetaminophen. This was a retrospective cohort study of subjects ages >or=65 years who received a prescription for acetaminophen or NSAID between 1994 and 1996. Pharmaceutical and medical records were reviewed for 1 year of historical data prior to the index prescription of acetaminophen or non-aspirin NSAID. Risk factors for GI events were identified based on the historical data. To further control for bias, patients were categorized by propensity score (the likelihood of receiving acetaminophen, given defined risk factor values). Records were then reviewed for the duration of the index prescription or 30 days, whichever was less, to generate data on the occurrence of GI events. Determinants of acetaminophen utilization were identified using logistic regression, and rates of GI events for each therapy were examined using Poisson regression analyses, controlling for duration of exposure, individual risk factors, and propensity scores. The study included 26,978 patients in the NSAID cohort and 21,207 in the acetaminophen cohort. Determinants of acetaminophen utilization compared with NSAIDs (odds ratio [95% confidence interval]) included recent hospitalization (8.6 [7.7-9.5]), concomitant anticoagulation therapy (3.2 [2.7-3.8]), age >85 years (2.3 [2.1-2.4]), and history of prior GI events, especially those requiring hospitalization (14.6 [11.7-18.7]). Unadjusted rates of GI hospitalization, ulcer, and dyspepsia were higher for patients in the acetaminophen cohort than for those in the NSAID cohort. The occurrence of GI events in acetaminophen-treated patients was dose dependent, with rate ratios (compared with high-dose NSAIDs and adjusted for risk susceptibility) ranging from 0.6 (95% confidence interval 0.5-0.7) for <or=650 mg/day to 1.0 (0.9-1.1) for >3,250 mg/day. In this cohort, acetaminophen utilization is more common in patients at higher risk of GI events. After adjustment for risk susceptibility, patients receiving higher doses of acetaminophen have higher rates of GI events compared with those receiving lower doses.

Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increase in upper gastrointestinal complications. There is no agreement, however, on whether all conventional NSAIDs have a similar relative risk (RR), and epidemiologic data are limited on acetaminophen. We studied the association between these medications and the risk of upper gastrointestinal bleed/perforation in a population-based cohort of 958,397 persons in the United Kingdom between 1993 and 1998. Our nested case-control analysis included 2,105 cases and 11,500 controls. RR estimates were adjusted for several factors known to be associated with upper gastrointestinal bleed/perforation. Compared with non-users, users of acetaminophen at doses less than 2 gm did not have an increased risk of upper gastrointestinal complications. The adjusted RR for acetaminophen at doses greater than 2 gm was 3.6 [95% confidence interval (95% CI) = 2.6-5.1]. The corresponding RRs for low/medium and high doses of NSAIDs were 2.4 (95% CI = 1.9-3.1) and 4.9 (95% CI = 4.1-5.8). The RR was 3.1 (95% CI = 2.5, 3.8) for short plasma half-life, 4.5 (95% CI = 3.5-5.9) for long half-life, and 5.4 (95% CI = 4.0-7.1) for slow-release formulations of NSAIDs. After adjusting for daily dose, the differences in RR between individual NSAIDs tended to diminish except for apazone. Users of H2 receptor antagonists, omeprazole, and misoprostol had RRs of 1.4 (95% CI = 1.2-1.8), 0.6 (95% CI = 0.4-0.9), and 0.6 (95% CI = 0.4-1.0), respectively. Among NSAID users, use of nitrates was associated with an RR of 0.6 (95% CI = 0.4-1.0).

Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty.

Heterotopic bone formation (HBF) in the soft tissues surrounding the hip joint is a frequent complication of hip surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) administered in the immediate perioperative period reduce the risk of HBF. However, the magnitude of the effect on HBF, and the effects on other associated outcomes are uncertain. To determine the effects of perioperative NSAID therapy versus control on the risk of HBF and other outcomes in patients undergoing hip arthroplasty. Medline, Current Contents and Cochrane Controlled Trials Register, and reference lists of all relevant reports were searched. Principal investigators and the manufacturers of the study drugs of eligible trials were approached. The most recent search was conducted in July 1998. All trials which enrolled patients scheduled to undergo hip arthroplasty with random or quasi-random allocation to perioperative NSAID or control and that recorded post-operative radiographically determined HBF. The primary outcome was post-operative radiographic HBF. Secondary outcomes were pain, disability, gastro-intestinal and other bleeding complications, and other causes of major morbidity or mortality. Two reviewers independently assessed methodological quality and extracted data. All analyses were conducted on dichotomised outcomes. Twelve randomised and two quasi-randomised trials involving a total of 4,377 patients were included. Overall, in 13 trials that examined the effects of medium to high doses of NSAIDs, there was a reduced risk of developing HBF after hip surgery (62% reduction, 95% confidence interval 56% to 67% reduction). In contrast, one large trial examining low-dose aspirin, demonstrated no effect on the risk of HBF (2% reduction, 95% confidence interval 15% reduction to 12% increase). There was strong evidence of differences in the size of the treatment effects observed between the trials examining medium to high doses of NSAIDs, but reasons were not clearly identified. There was a non-significant one third increased risk of gastro-intestinal side effects among patients assigned NSAIDs (29% increase, 95% confidence interval 5% reduction to 76% increase). Most of this increase was due to an increased risk of minor gastro-intestinal complications. Data on the late post-operative outcomes of pain, impaired physical function and range of joint movement were few and no formal overviews of the effects of NSAIDs on these outcomes were possible. Perioperative NSAIDs appear to produce between a one half and two thirds reduction in the risk of HBF. With routine use, such agents may be able to prevent 15-20 cases of HBF (3-4 severe) among every 100 total hip replacements performed. However, while medium to high doses of perioperative NSAIDs clearly produce a substantial reduction in the incidence of radiographic HBF, there remains some uncertainty about short-term side effects of treatment and substantial uncertainty about effects on long-term clinical outcomes such as chronic pain and impaired physical function. The net effect of routine HBF prophylaxis with NSAIDs requires formal assessment in a randomised trial designed to determine the balance of benefits and risks for all outcomes.

Preventing NSAID toxicity to the upper gastrointestinal tract

Prevention of gastrointestinal toxicity begins with the selection of an appropriate analgesic or anti-inflammatory agent. For conditions without inflammation, such as some cases of osteoarthritis, an analgesic with no risk for gastrointestinal toxicity is appropriate. Risk factors for nonsteroidal anti-inflammatory drug (NSAID)-related complications include advanced age; history of ulcer disease or gastrointestinal bleeding; concomitant corticosteroid or anticoagulant use; use of high-dose or multiple NSAIDs; and certain chronic diseases, such as cardiovascular disease. If an NSAID must be used in a patient with risk factors, the patient should receive the lowest-risk NSAID and, in most cases, co-therapy to reduce the risk for NSAID-associated ulcers and their complications. The PGE1 prostaglandin analogue misoprostol is highly efficacious for the prevention of both gastric and duodenal ulcers and has also been shown to reduce the incidence of NSAID-induced ulcer complications. Side effects, such as diarrhea, may limit patient acceptance of the drug. Acid suppression with traditional ulcer-healing doses of H2-blockers significantly reduces rates of duodenal ulcer but is ineffective in reducing gastric ulceration. More potent acid inhibition with double-dose H2-blockers reduces rates of both gastric and duodenal ulcers. Proton-pump inhibitors, such as omeprazole, have been shown to prevent gastric and duodenal ulcers with an efficacy equal to that of misoprostol. They also reduce NSAID-related dyspepsia. Specific cyclooxygenase-2 (COX-2) inhibitors are associated with a markedly reduced rate of endoscopic ulcers. Very high-risk patients who receive these agents may still require co-therapy to prevent complications or reduce dyspepsia. This protocol may be changed by the results of long-term gastrointestinal outcome studies now underway.

Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Prostanoids produced via the action of cyclo-oxygenase-2 (COX-2) appear central to many inflammatory conditions. Here we show in LPS-treated rats, however, that COX-2 induction alone does not greatly increase prostanoid production in vivo. For this, a second, arachidonic acid liberating stimulus is also required. Thus, only after intravenous injection of bradykinin or exogenous arachidonic acid was a marked increase in prostanoid formation seen. There is, therefore, synergy between proinflammatory mediators: both induction of COX-2 protein and an increase in the supply of arachidonic acid are required to greatly enhance prostanoid production. Second, we show that supplying arachidonic acid to increase prostanoid production reduces the effectiveness of both currently used nonsteroidal antiinflammatory drugs (NSAIDs) (diclofenac) and novel COX-2-selective inhibitors (NS-398, celecoxib) as inhibitors of COX-2 activity. Our data lead to two important conclusions. First, increased prostanoid production in inflammation is a two-component response: increased COX-2 expression and increased arachidonic acid supply. Second, the supply of arachidonic acid to COX-2 determines the effectiveness of NSAIDs. NSAIDs and selective COX-2 inhibitors, therefore, will generally be less effective at more inflamed sites, providing a rationale for the very high doses of NSAIDs required in human conditions such as rheumatoid arthritis.--Hamilton, L. C., Tomlinson, A. M., Mitchell, J. A., Warner, T. D. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.

Comparative efficacy and safety of intravenous non‐steroidal anti‐inflammatory drugs in two animal models of pain

AbstractIn this study, the antinociceptive activity of five non‐steroidal anti‐inflammatory drugs (NSAIDs) was determined in two animal models of different pain intensity and compared with their capacity to produce motor incoordination and death. Intravenous clonixine, diclofenac, dipyrone (metamizole), ketorolac, and piroxicam produced dose‐dependent antinociception in the acetylcholine‐induced writhing test with ED50 values ranging from 14 (clonixine) to 205 (dipyrone) μmol/kg. The behavioral responses in the 55°C hot plate assay were also inhibited in a dosedependent manner, but significantly higher doses were required to display antinociceptive activity, the ED50 values ranging from 116 (clonixine) to 2, 263 (dipyrone) μmol/kg. In the writhing test, the antinociceptive effects of NSAIDs were present at doses far below those producing toxic effects. In contrast, their ED50 values against a more intense nociceptive stimulus approached those producing lethal effects so that the therapeutic ratios were very small, ranging from 1.3 (diclofenac) to 3.0 (dipyrone). The antinociceptive activity of the reference drug morphine is striking, since both types of nociceptive responses were eliminated at doses substantially lower than those producing death (therapeutic ratios of 502 and 121). Morphine exhibited the highest antinociceptive efficacy, followed by dipyrone, ketorolac, clonixine, and piroxicam. Diclofenac showed a more limited efficacy. These findings imply potential risks for patients treated iv with this class of drugs and suggest caution in the use of high doses of NSAIDs. Future development of injectable NSAID formulations should include a detailed analysis of adverse reactions following iv administration of high doses. © 1995 Wiley‐Liss, Inc.

Rheumatic diseases in pregnancy

Rheumatic diseases often present in women of childbearing age. Fortunately, most forms of inflammatory arthritis improve in pregnancy and maternal or fetal complications are rare. Drug therapy may need to be modified as most drugs cross the placenta but only a few are definitely teratogenic. Ankylosing spondylitis may not remit in pregnancy and can be difficult to manage as the high dose non-steroidal anti-inflammatory drugs usually taken by the patient must be discontinued. Providing that systemic lupus erythematosus is well-controlled at the onset of pregnancy, the prognosis for mother and baby is good. Neonatal lupus syndrome is uncommon. The outcome in the rarer systemic conditions such as scleroderma and vasculitis is less predictable and the risk of serious deterioration in the mother is greater. Close liaison between obstetricians and rheumatologists will ensure optimal management of these potentially complicated pregnancies.

Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis.

To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.

Ankylosing spondylitis. Current drug treatment.

The administration of drugs constitutes an important component of the therapeutic programme in ankylosing spondylitis (AS). The main objective of initiating such therapy is to reduce pain, stiffness and discomfort. There are at present 3 groups of drugs available for the management of AS. The first group is represented by drugs thought to influence the disease process itself. In this group, sulfasalazine is the only drug which is controlled trials has been shown to suppress disease activity in AS. We recommend the use of sulfasalazine in patients with high disease activity, with peripheral arthritis and in those with AS of short duration. The second group of drugs includes nonsteroidal anti-inflammatory drugs (NSAIDs), which suppress inflammation without influencing the disease process. These drugs should be administered selectively during periods of high disease activity. Moreover, 1 drug should be used in appropriate dosage before it is assumed to be inefficient. High doses of NSAIDs may be prescribed before bedtime in patients suffering from severe pain and stiffness during the night. The toxicity profile of NSAIDs includes gastrointestinal and renal side effects. The third group comprises analgesics and muscle relaxants. Such drugs should be used rather frequently in patients with longstanding AS refractory to treatment with NSAIDs. Peripheral arthritis and enthesopathy are generally managed by local injections of corticosteroids, while AS complicated by psoriasis or inflammatory bowel disease is treated as primary AS. AS occurring in juveniles is best treated with aspirin and an NSAID, although careful observation is necessary for the development of Reye's syndrome (with aspirin) and gastric irritation (with NSAIDs). When patients with AS undergo surgery, the possibility of silent gastrointestinal bleeding due to the use of NSAIDs and salicylates should not be ignored. Patients treated with oral corticosteroids should receive a bolus injection of soluble corticosteroid prior to surgical intervention. NSAIDs may be administered pre- and postoperatively to relieve stiffness induced by immobility. Rapid treatment of intervening infections and use of NSAIDs is recommended in AS complicated by renal amyloidosis. During pregnancy and lactation, ibuprofen may be the preferred drug in AS.

Genetic predictors of patient response and side effects in the treatment of rheumatoid arthritis with a high dose nonsteroidal antiinflammatory drug regimen.

Clinical, laboratory, genetic, and radiologic studies were evaluated for 18 patients with rheumatoid arthritis who were treated for a mean of 16.6 months with a regimen involving supplementary aspirin and piroxicam, an investigational, nonsteroidal antiinflammatory agent. Although improvement in disease activity was seen, progression was evident on successive radiographs. Disease activity was not associated with the presence of any of the genetic markers. Peptic ulcers developed in 33% of patients, all of whom had type O blood. ABO blood typing may therefore be useful in patients with rheumatoid arthritis before consideration of therapy with potentially ulcerogenic drugs.