NSAIDs adverse events

NSAIDs are one of the most widely used classes of medications in the United States, particularly in the elderly.4 More than 20,000 deaths occur in the United States per year as a direct result of adverse events related to NSAID use. Chronic NSAID ingestion leads to symptoms of nausea and dyspepsia in nearly half of patients. Peptic ulceration occurs in up to 30% of patients who use NSAIDs chronically, with gastrointestinal bleeding or perforation occurring in 1.5% of patients who develop an ulcer. NSAID-related peptic ulcers usually occur in the stomach duodenal ulcers are much less common. 

Refer to Chapter 14 on gastroesophageal reflux disease for more information on the PPIs. The PPI omeprazole is superior to both ranitidine and misoprostol for preventing recurrence of NSAID-associated PUD. In one study, omeprazole 20 mg daily was compared to misoprostol 200 meg twice daily for NSAID-associated PUD prevention. At 6 months, the omeprazole-treated group had significantly fewer ulcers than those taking misoprostol. Furthermore, more patients discontinued ulcer prophylaxis in the misoprostol group due to adverse events.26... 

Theoretically, the risk of serious GI adverse events should be less than with oral NSAIDs, but long-term studies evaluating these events are lacking.38 Studies comparing topical NSAIDs with other topical products, including counterirritants, are also needed.35 Local cutaneous adverse reactions (e.g., erythema, pruritus, and irritation) occur in 1% to 2% of patients and may be due in part to the vehicle used.38... 

Geriatric Considerations - Summary Use with caution due to the higher risk of GI and CNS adverse events. Not a preferred NSAID in older adulfs. Use of NSAIDs in older adulfs increases the risk of GI complicafions including gasfric ulcerafion, bleeding, and perforation. These complications are not necessarily preceded by less severe GI... 

As with allopurinol, prophylactic treatment with colchicine or NSAIDs should start at the beginning of treatment to avoid gout flares. The most frequent treatment-related adverse events are liver function abnormalities, diarrhea, headache, and nausea. Febuxostat appears to be well tolerated in patients with a history of allopurinol intolerance. 

Because its clearance depends on renal function as well as hepatic metabolism, diflunisal s dosage should be limited in patients with significant renal impairment. Its adverse event profile is similar to those of other NSAIDs pseudoporphyria has also been reported. 

Tiaprofen is a racemic propionic acid derivative but does not undergo stereoconversion. It has a short serum half-life (1-2 hours) with an increase to 2-4 hours in the elderly. This drug inhibits renal uric acid reabsorption and thus decreases serum uric acid slightly. It is available for oral and intramuscular administration. Its efficacy and adverse event profiles mirror those of other NSAIDs, but tiaprofen is not available in the USA. 

The most frequent adverse event reported with ketorolac use is transient stinging and burning after instillation of the ophthalmic solution. Rarely, allergic reactions and superficial keratitis have occurred. Although inconsistent cases of corneal toxicity have been reported with NSAIDs, prolonged use of NSAIDs in a select group of patients showed the potential for corneal melt. Because other treatment options exist for allergic eye disease, NSAIDs do not need to be used in patients with compromised corneas or those at risk for potentially serious adverse corneal reactions. 

Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression a new model apphed to chronic NSAID use. Pain 2000 85(l-2) 169-82. 

COX-2 selectivity may be a double-edged sword. Because the cardiovascular risk outweighs the gastrointestinal risk in adults with rheumatoid arthritis or osteoarthritis, the harm would outweigh the benefits in most clinical settings. This means that the total number of serious adverse events would be increased by COX-2-selective NSAIDs compared with non-selective NSAIDs. COX-2 selectivity, which is an appealing theoretical concept, might be a clinical failure (30). 

However, an analysis of FDA data suggested an increase in serious cardiac events with celecoxib (30). The incidence of serious cardiac adverse events (myocardial infarction, combined anginal events, and atrial dysrhythmias) was 0.6% higher with celecoxib than with other NSAIDs (RR = 1.55 Cl = 1.04, 2.30). The reasons for these inconsistencies are not clear. 

In a randomized comparison of celecoxib and diclofenac plus omeprazole, renal adverse events, including hypertension, peripheral edema, and renal insufficiency, were common and similar in the two groups (105). They occurred in the 24% of the patients who took celecoxib and in 31% of those who took diclofenac plus omeprazole. Among patients with renal impairment at baseline, 51% of those who took celecoxib and 41% of those who took diclofenac plus omeprazole had renal adverse events. Careful monitoring of renal function in patients taking COX-2 inhibitors or traditional NSAIDs is mandatory, especially in high-risk subjects (for example those with pre-existing renal disease, diabetes, or heart failure). 

Nabumetone is a naproxen derivative, whose efficacy is related to its active metabolite, 6-methoxy-2-naphthyla-cetic acid. Not unexpectedly, a study in 2000 patients, mostly treated for more than 6 months, ehcited an adverse events pattern similar to the other derivatives of this class of NSAIDs (SEDA-13, 81). Adverse effects were reported in 18% of patients and 10% stopped taking the drug because of adverse reactions. Diarrhea was the most common problem (13%) followed by abdominal pain (9.9%), dyspepsia (9.3%), nausea (7.8%), and flatulence (4.7%). Ten ulcers were detected. Nervous system reactions, skin rashes, edema, unspecified eye disorders, and liver function test abnormahties aU occur (1). 

A series of 11 spontaneously reported cases in which renal impairment was associated with the use of nimesulide has been described (17). The adverse events were represented by acute renal insufficiency n — 2), acute deterioration of chronic renal insufficiency n — 3), fluid retention n = 4), and oliguria and macro hematuria n = 1 each). The patients had a median age of 57 (range 17-81) years and six had some predisposing condition (chronic renal insufficiency, heart failure, diabetes, use of diuretics) to NSAID-induced functional renal impairment. Apart from one patient, nimesulide was taken for a very short time (less than 8 days). A favorable outcome ensued after withdrawal of therapy in aU patients. The acute deterioration of renal function described in these patients pointed to hemodynamically mediated renal impairment in all cases, with the exception of one man in whom interstitial nephritis was suspected. 

Despite these complexities, COX-2-specific inhibitors relieve pain in many OA patients with a lower risk of GI adverse events than nonspecific NSAIDs. COX-2 inhibitors, members of the coxib class newly created by the World Health Organization, have become extremely widely used over a short period of time. These agents continue to be studied intensely not only for their efficacy and toxicity profile in rheumatic disease, but also for exciting potential applications such as the prevention of Alzheimer s disease and colorectal cancer. 

One of the largest costs associated with OA is hospitalization for joint replacement or treatment of NSAID-related complications, particularly serious GI adverse events. To provide perspective on patient care costs for GI complications of NSAIDs, a 1997 report on more than 10,000 OA patients followed in a managed-care setting showed that the mean annual cost of care per patient was 543, with hospital costs accounting for 46%, medications 32%, and ambulatory care 22% 100 Consequently, intense focus has emerged on the cost benefit ratio of medications to prevent ulcer complications, and the use of coxibs, which cause fewer ulcer complications. 

There are two forms of COX, COX-1 and COX-2. COX-1 is a primarily constitutive isoform found in most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production. However, COX-2 also is constitutively expressed in certain areas of kidney and brain, and is induced in endothelial cells by laminar shear forces. Importantly COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. Inhibition of COX-1 at this site is thought to account largely for the gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2. 

ADVERSE EFFECTS OF NSAID THERAPY Common adverse events that complicate therapy with aspirin and NSAlDs are outlined in Table 26-2. Age generally is correlated with an increased probability of developing serious adverse reactions to NSAIDs, and caution is warranted in choosing a lower starting dose for elderly patients. 

CONCOMITANT NSAIDS AND LOW-DOSE ASPIRIN Many patients combine either tNSAIDs or COX-2 inhibitors with cardioprotective low-dose aspirin. Epidemiological studies suggest that this combination therapy increases significantly the fiketihood of G1 adverse events over either class of NSAID alone. 

Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. The NSAIDs, Including celecoxib, cause an increased risk of serious Gl adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious Gl events. 

A 6-month study in 20 patients with severe rheumatoid arthritis given diclofenac 100 to 200 mg with ciclosporin 3 mg/kg daily found that the AUC of diclofenac was doubled and serum creatinine levels raised from 71 to 88.4 micromol/L. The overall pattern of adverse events and laboratory abnormalities were similar to those in patients with rheumatoid arthritis treated with ciclosporin and other NSAIDs. It was suggested that it would be prudent to start with low doses of diclofenac and to monitor well. A study in 24 healthy subjects found that diclofenac 50 mg every 8 hours for 8 days caused no changes in the pharmacokinetics of ciclosporin, but there was some inconclusive evidence that diclofenac serum levels were increased. ... 

The manufacturer notes that in phase IH osteoporosis studies of risedronate, no clinically relevant interaetions were noted, even though aspirin and NSAIDs being used by 33% and 45% of patients, respectively. Similarly, in a retrospective analysis of a 2-year placebo-controlled study, in those using regular NSAIDs (about two-thirds of patients) there was no difference in incidence of upper gastrointestinal adverse events between those given risedronate and those given placebo. ... 

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