Problems with nonsteroidal anti-inflammatory drug use in elderly persons - Continuing Education, includes test questions - Inside Pharmacy

Sian M. Carr-Lopez

Slan M. Carr-Lopez, Pharm.D. Gerlatric clinical pharmacy coordinator, satellite manager Veterans Administration Medical Center, Martinez, Calif. Assistant clinical professor of pharmacy University of California, San Francisco University of Southern California, Los Angeles University of the Pacific, Stockton, Calif.

Aug. 20, 1990, lesson 679-401-90-08

Goal:

To increase the awareness of problems associated with nonsteroidal anti-inflammatory drug (NSAID) use in the elderly and identify specific areas for community pharmacist intervention.

Objectives:

At the completion of this continuing education program the participant will be able to:

1. State which patients are most likely to experience adverse renal effects from the NSAIDs.

2. Cite the effects of NSAID use on the incidence and type of peptic ulcer disease in the elderly.

3. Describe other common adverse drug effects from NSAIDs in the elderly.

4. Recall the effective therapy for prevention of nonsteroidal-induced peptic ulcer disease.

5. Identify patients who may benefit from analgesic therapy with acetaminophen.

6. Demonstrate an understanding of risks and benefits of NSAIDs in the elderly.

7. Cite clinically sigificant drug-drug interactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used by more than 13 million arthritis sufferers. Since the number of arthritic conditions increases with age, most patients taking chronic NSAIDs are elderly. In fact, elderly persons are the largest user group of nonsteroidal agents.

NSAIDs exhibit analgesie, anti-knflammatory and antipyretic activity. They exert these effects by inhibiting the synthesis of prostaglandins in the body. NSAIDs inactivate cyclooxygenase, the enzyme which forms prostaglandins from archidonic acid.

As the number of available NSAIDs has increased, so have the indicatins for which they are prescribed. These indications include a wide variety of rheumatic conditions, dysmenorrhea and increasingly, analgesia.

The common use of prescribed and over-the-counter nonsteroidal anti-inflammatory agents for chronic diseases in the elderly has predisposed this population to significant iatrogenic illness. Although prostaglandin inhibition exerts beneficial effects on tissue inflammation, prostaglandins also play an important role in the maintenance of gastric mucosa, renal function, and regulation of blood pressure. The adverse drug reaction profile of NSAIDs is no longer considered benign in chronic anti-inflammatory use.

The purpose of this article is to review the risks and benefits of NSAID use in elderly persons.

Special considerations

Elderly persons represent the largest single group of prescription consumers in the United States today. They only represent 13 percent of the population, yet they consume nearly 30 percent of all medication.

As a group, elderly patients are more likely to experience an adverse drug reaction (ADR) from a medication. In 1986, approximately 33 percent of all ADRs and 50 percent of all deaths from iatrogenic causes occurred in patients aged 60 years or older.

The elderly are at significant risk for increased ADRs for several reasons. Altered pharmacokinetics associated with aging may result in increased or prolonged plasma levels of drugs. Altered pharmacodynamics can either exaggerate or diminish the expected response to a drug.

The incresed number of disease states and medications per patient also predispose this population to iatrogenesis. Considering the relationship between chronic diseases and aging, it is not uncommon to find elderly persons prescribed as many as 12 medications simultaneously.

Unfortunately, much of this prescribing is excessive. In a study to determine the impact of a pharmacist on medication discontinuation in a hospital-based geriatric clinic, 33 percent of medications were discontinued without complication. When nonsteroidal agents were addressed specifically, they were successfully discontinued and replaced with acetaminophen in 41 percent of patients on these agents.

In a prospective adverse drug reaction study of 516 consecutive admissions to the Martinez (Calif.) Veterans Administration hospital, 25 percent of the admissions caused by iatrogenic illness were due to the adverse effects of NSAIDs on the gastrointestinal tract.

The expanding role of the

pharmacist

More than two-thirds of elderly persons use over-the-counter (OTC) agents. Because they do not consider them "drugs," they rarely report this use to their physicians or pharmacists. With the advent of OTC NSAIDs, the role of pharmacists as providers of health care becomes even more important. Elderly patients seeking a pharmacist's recommendation for an OTC analgesic or anti-inflammatory agent often present with vague, non-specific complaints. It becomes more difficult to differentiate between several painful conditions solely with patient history and clinical presentation. Proper referral to a physician who can utilize laboratory data including rheumatoid factor, erythrocyte sedimentation rate, synovial fluid analysis, and X-rays to make the diagnosis becomes very important.

Similarly, patients with a high usage of OTC NSAIDs should be referred to a physicians, not only to monitor for ADRs such as an increased blood urea nitrogen and serum creatinine (signs of declining renal function), and decreased hemoglobin and hematocrit levels (indication of blood loss), but also to rule out or appropriately treat serious conditions such as polymyalgia rheumatica, a condition commonly seen in elderly women.

It is very important to know the specific diagnosis for an arthritic condition because the most appropriate treatment for each of these diseases may differ. The most common rheumatologic disorder afflicting elderly persons is osteoarthritis. Clinical investigators have found radiologic changes indicative of osteoarthritis in 87 percent of females and 83 percent of males aged 55-64 years. Based solely on the large number of osteoarthritis patients in the geriatric population, great opportunities exist for pharmacists to improve patient care through appropriate recommendations.

The clinical presentation for osteoarthritis differs from rheumatoid arthritis (RA) in several ways: (1) the duration of stiffness described for osteoarthritis is shorter than rheumatoid arthritis, usually minutes as opposed to hours respectively; (2) the pain with osteoarthritis is associated with activity--conversely, the pain that occurs with RA often exists at rest; (3) although both conditions commonly have swelling at the joints, those with erythema and warmth are typically associated with RA; and (4) osteoarthritis does not typically present with symmetrical involvement. Many times, questions to elicit the type of arthritis present can be asked within the pharmacy.

Differentiation between these conditions is important because the treatment options differ. Currently, NSAIDs are recommended for both RA and osteoarthritis. However, osteoarthritis, also known as degenerative joint disease, is not typically an inflammatory condition. Therefore, NSAIDS are used primarily for their analgesic effects in this instance. Since acetaminophen has similar analgesic effects as aspirin and other NSAIDs for non-inflammatory conditions, a recommendation by the pharmacist for an initial trial with acetaminophen seems prudent considering the differences in side effect profiles.

Nonsteroidal-induced

peptic ulcer disease

Epidemics of duodenal ulcer occurred at the beginning of the 20th century> Interestingly, aspirin was released to the general public in 1899 by the Bayer Co. The incidence of peptic ulcer disease (PUD) in the elderly is approximately 10 percent and similar to the occurrence rate in the younger population. However, in the elderly, gastric and duodenal ulcers occur with equal frequency.

This differs from PUD in the young where duodenal ulcers occur four times more frequently than gastric ulcers. In the general population, the characteristic symptoms of PUD are burning, gnawing epigastric pain or left upper quadrant pain occurring one to four hours after meals. Patients often state that their symptoms are relieved with antacids or food.

In the elderly, symptoms of PUD are atypical, nonspecific or in many instances, absent. Peptic ulcer disease may present without pain in one-third of elderly patients. IT usually presents with symptoms of gastrointestinal (GI) bleeding, anemia, nausea, vomiting, or weight loss. Even a perforated peptic ulcer may be painless in elderly persons.

Unfortunately, the first indication of nonsteroidal-induced gastric ulcer development may be a catastrophic complication such as a major GI hemorrhage or perforation. These complications are associated with higher morbidity and mortality in the elderly. The lack of ulcer symptoms in patients taking NSAIDs may be due partly to the analgesic and anti-inflammatory properties of the drugs.

The complications of gastropathy resulting from NSAIDs account for hundreds of millions of dollars of costs each year, including hospitalizations, the continued treatment of the actual complication, and lost work time.

The ulcerogenic properties of nonsteroidal agents appear to be multi-factorial, primarily involving prostaglandin inhibition and destruction of the gastric mucosal barrier. Important factors such as gastric acid inhibition and cytoprotection of the gastric mucosa are inhibited by these agents. In addition, they have been shown to decrease blood flow to the gastric mucosa which may allow for delayed removal of the nonsteroidal agent and back diffusion of hydrogen ions. This results in a direct toxic effect to the gastrointestinal mucosa.

At doses of 2,400 mg daily, ibuprofen without gastroprotection evolved to gastric ulceration in more than 20 percent of patients. This correlates with other literature which documented a 10 percent to 20 percent incidence of peptic ulcer disease for osteoarthritic and rheumatoid arthritic patients on chronic nonsteroidal agents.

Association of NSAIDs with upper

gastrointestinal bleeding

Spontaneous reporting for the adverse GI effects of NSAIDs far exceeds all other drugs on the medical marketplace. The Food and Drug Administration has indicated that twice as many GI bleeds as ulcers are reported.

These bleeds are silent in more than half of the cases. The number of yearly fatalities associated with chronic NSAIDs use in the United States is between 10,000 and 20,000. Because 10-25 percent of these bleeds can be fatal, attempts to increase awareness and to prevent this occurrence are ongoing. Before its release in the United States, the British Medical Journal reported that naproxen caused gastrointestinal bleeding and deaths, all in elderly patients.

Nevetheless, naproxen went on to the most used NSAID in the United States, at doses increasing from 250 mg to 750 mg twice daily.

The role of acid in

the development of ulcers

Endoscopic studies in healthy volunteers showed that a single dose of two aspirin tablets produced petechial hemorrhages in the stomachs of all patients within an hour of ingestion. Continued intake of two aspirin tablets every six hours for four doses resulted in gastric erosions in all subjects and duodenal erosions in about 50 percent of subjects. Seventy-nine percent of patients given aspirin in doses to treat rheumatoid arthritis demonstrated significant lesional disease with erosions and microbleeding. Twenty percent had actual ulcer cracters seen after the first month of aspirin exposure. Gross bleeding has also been observed during irrigation with aspirin.

However, aspirin was not the immediate cause of the bleeding because it occurred only when the mucosa was simultaneously exposed to the salicylate and strong acid. The role played by acid in the mucosal damage caused by aspirin is reflected in the infrequent and insignificant blood loss in achlorhydric patients and by the absence of lesions seen after buffering aspirin to maintain gastric contents at a pH of six to seven. Prevention of GI mucosal damage has been demonstrated with Alka Seltzer. Other combination salicylate-antacid preparations such as Bufferin and Ascription do not contain enough antacid to prevent marked damage. Non-acetylated salicylates do not seem to have the same degree of GI toxicity as aspirin.

At least two mechanisms for gastrointestinal damage have been described. NSAIDs appear to increase the permeability of gastric mucosa to hydrogen ions. This increased entry of acid causes cellular damage. Secondly, NSAIDs inhibit the production of PGE2 and prostacyclin which appear to be cytoprotective.

Erosions associated with NSAIDs most often present in the antrum of the stomach. It has been shown that cell turnover is less in the antrum than the corpus or the duodenum. This may help to explain the predilection of non-steroidal-induced ulcers for the antrum.

Enteric coating

Studies in healthy volunteers comparing regular, buffered and enteric-coated aspirin confirm the lower amount of gastric damage caused by enteric-coated aspirin despite similar serum salicylate concentrations. Topical irritation of aspirin related to its low pH may be the only factor prevented with enteric-coated products; however, more information relating to this hypothesis is needed.

Short-term studies have demonstrated that both enteric-coated aspirin and enteric-coated naproxen are less damaging than their non-enteric-coated counter-parts and demonstrate a lower frequency of gastric ulcers. Nonsteroidal agents have been reported to have detrimental effects on the small bowel. Several cases of acute enterocolitis were attributed to the use of these agents and the symptoms greatly improved when the NSAID was discontinued. Whether enteric coating might increase the frequency of injury to the small or large intestine is not clear. A slow release formulation of indomethacin was recently withdrawn from the United Kingdom market because of associated small bowel and colonic perforation.

Association of systemic prostaglandin

inhibition with upper

gastrointestinal bleeding

A documented association between increasing age and increased incidence of GI bleeding exists. Studies designed to address whether age alone could be responsible for this increased incidence have been performed. A retrospective study in 1980 examined the relative rate of upper gastrointestinal (UGI) tract bleeding in the 30 days following exposure to each nonsteroidal drug.

The rate of UGI bleeding for persons over 60 years was nearly three times higher in NSAID users than non-users. Interestingly, sulindac users had the highest rate of UGI tract bleeding and it was the only drug statstically higher than ibuprofen. This finding was confirmed in the follow-up 1982 data when sulindac was again associated with the highest rate of bleeding.

Some clinicians have hypothesized that sulindac and fenoprofen should cause fewer adverse gastric reactions because they are ingested in biologically inactive forms. However, there is conflicting evidence whether this is physiologically important. The hypothesis that toxic gastrointestinal reactions may be secondary to direct chemical irritation by these drugs has been tested.

Gastric erosions in volunteers administered indomethacin orally were compared to others administered the drug in rectal suppository form. Fewer gastric erosions were noted in the latter group, however, blood levels were much lower in patients receiving the suppositeries. Moreover, aspirin administered intravenously in rats produced ulcers. In addition, the development of gastric ulcers was not prevented when ketoprofen was prevented from coming into contact with the gastric mucosa. Researchers have concluded that systemically inhibited PG may result in gastric adverse reactions. Although enteric-coated preparations can reduce the topical toxicity of aspirin and other nonsteroidal agents, they do not necessarily mitigate against the systemic PG mechanism. Thus the potential for drug-induced gastropathy still exists.

Aspirin and other NSAIDs cause a dramatic reduction in the ability of gastric mucosa to generate protective PGs. Acetaminophen is also reported to significantly reduce systemic PG production by 50 percent. In contrast to aspirin, short-term administration of acetaminophen is not associated with mucosal damage. A central mechanism of action has been described for acetaminophen. The importance of this in allowing smaller relative systemic anti-prostaglandin doses to be effective has not been elucidated. Some clinicians have questioned if acetaminophen were studied at doses that were capable of producing an anti-in-flammatory response, would it then lose this advantage. There are some reports of a higher incidence of PUD when acetaminophen and NSAIDs are used concommitantly.

Dyspepsia as an indicator of

gastrointestinal damage

Dyspepsia is one of the most common side effects of the nonsteroidal agents. Unfortunately, there is a poor correlation between dyspeptic symptoms and the presence of gastrodudenal damage.

Less than 10 percent of patients with abnormal endoscopic findings gave a history of dyspepsia. It is also important to note that one in five patients with abnormal endoscopy will progress to serious gastropathy.

Currently, we are unable to predict which patients will advance to this stage. Research is ongoing to determine if signs and symptoms other than dyspepsia or abnormal endoscopy can predict which patients will develop the more severe forms of gastro intestinal damage.

Prophylaxis of

nonsteroidal-induced PUD

It is accepted that Histamine-2 antagonists are effective in preventing and treating duodenal ulcers associated with NSAID use. However, until recently, no treatment had been proven to prevent NSAID-associated gastric ulcers or their complictions. For example, patients have experienced NSAID-induced hemorrhages while receiving therapeutic doses of H-2 antagonists. Sucralfate has also failed to consistently reduce NSAID-induced mucosal lesions. However, some studies comparing sucralfate and placebo have demonstrated decreased lesions and microbleeding with sucralfate prophylaxis.

Misoprostol, a prostaglandin analog, significantly reduces the incidence of NSAID-induced gastric ulcers. It is efficacious because it simulates the activity of endogenous PGE2. Prostaglandins protect microvascular integrity, preserve the ability of the mucosa to re-epithelialize damaged tissue, stimulate gastric mucus secretion, stimulate gastric and duodenal bicarbonate production, inhibit gastric acid secretion and regulate mucosal blood flow. It is possible that some of the benefit observed with misoprostol against NSAID-induced gastric ulcers might relate to suppression of acid secretion. However this mechanism seems unlikely to play more than a minor role because more potent antisecretory drugs such as cimetidine and ranitidine failed to prevent nonsteroidal-induced gastric ulcers.

Although misoprostol was able to decrease the incidence of gastric ulcers, it did not have a significant effect on decreasing abdominal pain. This reinforces the finding that there probably is little correlation between dyspepsia and ulcer development.

Omeprazole, a proton pump inhibitor, has a limited role in the prevention of NSAID-induced peptic ulcer disease primarily because it is cannot be recommended for chronic use.

Renal complications of

nonsteroidal agents

After the fourth decade of life, renal blood flow declines 10 percent per decade. Thus, the geriatric patient inherently has a greater potential for renal harm with agents that decrease renal blood flow further.

NSAIDs have a variety of effects on the kidney, the clinically most important of which is the acute renal ischemia that occurs in susceptible patients. Conditions predisposing the kidneys to ischemia include: (1) volume depletion caused by blood loss, excessive diuresis, and vomiting; (2) cirrhosis with ascites and nephrotic syndrome where fluid is drawn out of the vascular space, and (3) congestive heart failure (CHF) resulting in decreased adequate perfusion pressure.

In patients with the above conditions, compensatory mechanisms are called into play to prevent inadequate perfusion of vital organs and tissues. The compensation includes activation of the renin-angiotensin-aldosterone system, antidiuretic hormone, and the sympathetic nervous system (SNS).

These compensatory mechanisms secondarily increase renal PG activity, thereby averting excessive renal artery vasoconstriction. Local renal synthesis of vasodilating PGs blunts the vasoconstricting effect of catecholamines and angiotensin, thereby maintaining renal perfusion. Inhibiting renal PGs with nonsteroidal agents in this setting can cause unopposed renal vasoconstriction with acute and sometimes profound decreases in glomerular filtration rate and renal blood flow.

Some studies imply that NSAIDs cause a transient, fully reversible effect on the kidneys and that decrements overall on renal function are probably not clinically significant. This conclusion, however, is derived from single-dose or short-term studies. Some clinicians warn that chronic use with short-term agents or periodic use of longer acting NSAIDs may render the kidneys unable to recover. Some are recommending every-other-day dosing with piroxicam for elderly persons for this reason.

Patients with intrinsic renal disease such as chronic renal failure, glomerulonephritis, or interstitial nephritis are also more susceptible to the adverse renal effects of the nonsteroidals. Most studies on the effects of nonsteroidal agents in patients with chronic renal insufficiency (CRI) assessed subjects with CRI related to chronic hypertension or diabetes. Since most patients with CRI would not be expected to have decreased effective or actual circulating volume, theoretically they should not need vasodilating PGs to maintain renal perfusion.

However, these disease states are associated with increased renal PG synthesis. Whether maximized renal blood to the remaining functional nephrons or another mechanism is responsible for maintaining renal function in this situation is unknown. Nonetheless, PG inhibition with nonsteroidals is detrimental in patients with renal disease.

A retrospective review of patients most susceptible to hemodynamically induced renal failure found that advanced age, (patients over 60 years), use of diuretics, renal vascular disease, diabetes mellitus, and atherosclerotic coronary vascular disease were the factors most frequently associated with NSAID-induced renal insufficiency. Patients at risk for renal dysfunctions should be monitored closely for signs and symptoms of volume overload and have renal function checked three to five days after beginning an NSAID.

If renal function deteriorates, the NSAID should be withdrawn to avoid potentially irreversible renal damage. Attempts to treat fluid overload secondary to NSAIDs with diuretics are frequently unsuccessful, and may be a factor in further compromise of renal status.

Nonsteroidal-induced renal dysfunction can be characterized by the length of time the NSAID is used before the problems present. Hemodynamically induced renal ischemia and acute renal insufficiency typically present within days of nonsteroidal initiation. Symptoms of acute renal insufficiency include increased blood urea nitrogen, serum creatinine, serum potassium and decreased urinary output, and weight gain associated with fluid retention.

Interstitial nephritis secondary to NSAIDs have been reported most frequently in older patients and presents clinically between two weeks and 18 months after initiation with NSAIDs. Regular nonsteroidal use over several years is associated with analgesic-associated nephropathy (AAN). AAN has been associated with the long-term use or abuse of high doses of NSAIDs. It occurs more commonly in females and has a higher prevalence in southeastern states. Common coexisting disease that may lead a practitioner to suspect analgesic-associated nephropathy include peptic ulceration, hypertension, anemia, athrerosclerosis, and psychiatric instability.

Autopsy results from patients receiving primarily salicylates for rheumatoid arthritis reveal changes consistent with AAN in 21 percent to 59 percent of cases. High doses of combination analgesic products consumed over extended periods of time is the most consistent risk factor for AAN.

Renal effects of sulindac

Not all NSAIDs may share the same propensity to produce hemodynamically induced renal dysfunction. Sulindac has been reported to selectively spare the inhibition of renal PG. Sulindac is a prodrug reduced mainly in the liver to the active sulfide metabolite. In the kidney, the sulfide is oxidized to the inactive sulfone metabolite and very little sulfide appears in the urine. The lack of renally excreted active metabolite is believed to be the reason for the renal sparing effect.

Studies have cast a doubt as to whether sulindac actually has less effect on renal PG. When administered in sufficient doses to inhibit systemic prostaglandins to a degree similar to other NSAIDs, sulindac has not always been demonstrated to selectively spare renal PG. In other words, renal PG inhibition is similar when the difference in systemic potency of the agents is taken into account.

Previously, PG metabolites recovered in the urine were believed to reflect renal PG synthesis. Although previous studies demonstrated a suppression of urinary PG by sulindac, most did not demonstrate a decrease in renal blood flow, glomerular filtration rate (GFR), or salt or water excretion. However, a decrease in GFR has been documented with sulindac in patients with severe liver disease where markedly elevated plasma levels of sulindac and its active metabolite were present.

Recent clinical studies using more specific assays of renal PG demonstrate that sulindac is a specific inhibitor of systemic versus renal PGs. This selectivity is relative, in that increased doses or altered elimination of sulindac may result in impaired renal function in susceptible individuals. Therefore, caution is in order when using any NSAID, including sulindac at conventional doses, in patients with severe liver disease, as the plasma levels of sulindac sulfide are increased and prolonged.

Sulindac has been shown to have less interactive effects with antihypertensive drugs such as beta blockers, thoazode and loop diuretics, and angiotensin converting enzyme inhibitors when compared to other NSAIDs. Exacerbation of CHF has also been shown to be less problematic with sulindac therapy when compared to other NSAIDs.

Clinically significant drug-drug

interactions

Alcohol use in combination with NSAIDs is correlated with an increase in the number and severity of upper gastrointestinal bleeds.

Corticosteroids have also been shown to be a risk factor in NSAID-induced gastropathy. They may worsen the severity of erosions, ulcers and bleeding. Corticosteroid discontinuation is associated with aspirin toxicity. Some studies have failed to show an increased incidence of GI bleeding in patients on nonsteroidals and anticoagulants concomitantly. However, nonsteroidals may prolong prothrombin time in some patients to a degree that dosage adjustment of the anticoagulant is necessary.

In addition, NSAIDs, cause GI bleeding and inhibit platelet aggregation. This is a potentially dangerous situation and caution should be employed when this combination is utilized. Nonsteroidals may exaggerate the hypoglycemic effects of oral diabetic agents. This interaction with the sulfonylureas is of special concern in older patients with unreliable dietary intake and those who cannot tolerate or recover adequately from hypoglycemia.

The clinical importance of the interaction between NSAIDs and antihypertensive agents remains somewhat controversial. No consistent effects of orally administered indomethacin on blood pressure have been described in healthy subjects. This probably relates to the fact that other regulatory mechanisms unrelated to PGs are intact in the healthy. In contrast, when indomethacin is admininstered to patients with essential hypertension being treated with various antihypertensive agents, it has been shown to increase both systolic and diastolic blood pressures by 5 to 15 mm Hg.

Drugs whose antihypertensive effects appear to be attenuated by concomitant administration of indomethacin include beta blockers, thiazide and loop diuretics, converting enzyme inhibitors and various combinations of the above. Other nonsteroided agents have been shown to have similar interactions with antihypertensive agenst. Pharmacists should monitor patients for a decreased effectiveness of antihypertensive agents and worsening of blood pressure control.

Potassium-sparing diuretics in conjunction with nonsteroidals may lead to increased serum potassium levels, especially in patients with compromised renal function. The reversible renal impairment seen when nonsteroidals are administered concomitantly with triamterence has progressed to acute renal failure in some patients. It is advised that triamterene and triamterence-congtaining products be used with caution in patients taking nonsteroidals chronically.

Renally excreted drugs with potential toxicities associated with increased serum concerntrations should be monitored closely when used in conjuction with nonsteroidals. NSAIDs decrease renal blood flow, decrease renal function, and may decrease renal clearance of drugs. Nonsteroidals have been observed to increase serum digoxin and lithium levels into the toxic range. Similarly, NSAIDs may decrease the renal elimination of methotrexate, resulting in severe and sometimes fatal methotrexate blood concentrations.

Other ADRs with NSAID use

Many pharmacists are currently cautioning patients about drowsiness associated with nonsteroidal use. Other central nervous system (CNS) side effects include significant confusion, dizziness, depression, fatigue, and disorientation, especially in the elderly.

The serotonin-like ring structure of indomethacin is believed to be responsible for the CNS intolerance in the elderly; however, these adverse effects are seen with other nonsteroidals as well.

CNS toxicity is quite common in the form of tinnitus and reversible auditory acuity reduction especially in the elderly. This adverse effect is seen with increasing plasma levels of NSAIDs.

Conclusion

No patient should suffer unnecessarily from pain associated with chronic illness. However, due to the known problems associated with NSAID use in elderly persons, they should be reserved for patients with an appropriate indication such as an inflammatory condition. Casual NSAID use without considering risk/benefit justification is no longer acceptable. It is good practice to try a variety of agents in a single patient in order to find the best response with the least toxicity. Unfortunately, there is no way to predict which will be the best selection for each individual patient due to the considerable individual variation in response.

Nonsteroidal agents should be utilized in the lowest effective dose. Again, this should be determined on an individual patient basis. Patients should be monitored for adverse effects of therapy, including gastrointestinal, renal, and CNS toxicity, along with clinically significant drug-drug interaction.

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