Bottom line

• The problem of musculoskeletal pain is enormous and growing rapidly. Nonpharmacologic approaches are valuable but the pharmacologic armamentarium is extremely limited. After acetaminophen has been tried, the remaining medications are either narcotics or nonsteroidal anti-inflammatory drugs, each of which has its own potential problems.

• Topical capsaicin is effective for some patients and might be worth trying. Newer cyclooxygenase-2 inhibitor nonsteroidal agents have recently become available, but their effectiveness and long-term adverse effect profile remain unclear. Their cost is substantially higher than the cost of many older agents.

• Many patients continue to suffer with musculoskeletal pain despite use of currently available treatments. For them, we might be justified in trying topical NSAIDs after a thorough discussion of the potential advantages and adverse effects.

• Topical nonsteroidal anti-inflammatory drugs could play a much larger role in treatment of acute and chronic musculoskeletal disorders if long-term safety data were available and if they received Canadian approval for these indications.

What are the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs)?

What is the mechanism of the anti-inflammatory action of NSAIDs?

Answers to case: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Summary: A 16-year-old female with dysmenorrhea is prescribed diclofenac [Voltaren-XR].

Effects of NSAIDs: Anti-inflammatory, analgesic, and antipyretic.

Mechanism of action: Anti-inflammatory effect primarily resulting from inhibition of cyclooxygenase 1 and/or cyclooxygenase 2; may also involve interference with other mediators of inflammation, modulation of T-cell function, stabilization of lysosomal membranes, and inhibition of chemotaxis.

Clinical correlation

NSAIDs are widely used for acute and chronic conditions that cause pain, injury, inflammation, or fever. They are available over-the-counter and by prescription. The anti-inflammatory effect is a result of the inhibition of cyclooxygenase (COX), which converts arachidonic acid to prostaglandins. There are two major subtypes of the COX enzyme, with the COX-2 subtype primarily mediating the pain and inflammation responses in tissues throughout the body. COX-1 has significant activity in producing prostaglandins that appear to protect the GI mucosal lining. Aspirin irreversibly inactivates both COX-1 and COX-2, whereas all other NSAIDs are reversible inhibitors of one or both of these enzymes. The analgesic effect of these medications is thought to be related to the peripheral inhibition of prostaglandin production, but there may be a central inhibition of pain stimuli as well. The antipyretic effect is thought to involve inhibition of IL-1- and IL-6-induced production of prostaglandins in the hypothalamus affecting the thermoregulatory system, resulting in vasodilation and increased heat loss. Nonsteroidal antiinflammatory drugs are metabolized in the liver and excreted by the kidney. They exhibit cross-sensitivity with each other and with aspirin. All NSAIDs can cause non-dose-related episodes of acute renal failure and nephrotic syndrome. They should be used with caution in those with renal insufficiency or in patients taking other potentially nephro-toxic agents. Aspirin and NSAIDs that nonselectively inhibit both COX-1 and COX-2 commonly produce GI disturbances and ulceration. They are con-traindicated in persons with known peptic ulcer disease. Newer agents with higher selectivity for COX-2 inhibition have fewer GI side effects and may reduce the rate of NSAID-related gastric ulcers, but have been linked to increased risk of cardiovascular disease.

Approach to pharmacology of NSAIDs

Objectives

1. Know the mechanism of action of aspirin and other NSAIDs.

2. Know the therapeutic uses of Nonsteroidal anti-inflammatory drugs.

3. Know the adverse effects, toxicities, and contraindications to NSAID use.

Definitions

Inflammation: A local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, and swelling.

Familial adenomatous polyposis (FAP): A genetic disorder leading to abnormal growths in the colon.

Class

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs and are available in various formulations both over-the-counter and by prescription. They are widely used for the relief of pain and fever and to reduce inflammation. There are more than 23 NSAIDs available, and they represent a number of structural classes. Table Classes of NSAIDs summarizes this class of drugs. They are all small acidic compounds. All are orally active with some pharmacologic differences but they all share the following:

Table: Classes of NSAIDs

Analgesic activity. Effective against pain of low-to-moderate intensity. Lower maximal effects compared to opioids, but no CNS liability.

Anti-inflammatory activity. It is their chief clinical application. They provide symptomatic relief only.

Antipyretic activity. Gastric and intestinal ulceration. Two mechanisms include local irritation caused by acidic drug, and inhibition of prostaglandins, which exert a cyto-protective effect.

Carboxylic Acids

The salicylates, acetylsalicylic acid (ASA, aspirin), and sodium salicy-late have been used for hundreds of years for their analgesic properties. ASA acts to covalently and irreversibly inhibit both COX-1 and COX-2. COX-1 becomes acetylated at a serine in the cyclooxygenase-active site, rendering the enzyme inactive. COX-2 is also covalently modified but at a different serine residue. This also eliminates cyclooxygenase activity and alters COX-2 to produce 15-HETE. 15-HETE can be further metabolized to a potent anti-inflammatory compound, 15-epilipoxin A₄. Some of the anti-inflammatory activity of aspirin might be mediated by this metabolite. Inhibition of cyclooxygenase activity of both COX isoforms decreases prostaglandin and thromboxane production, but does not effect the production of eicosanoids through the lipoxygenase pathway. Sodium and magnesium salicylate lack the acetyl group that modifies the COXs and are much weaker anti-inflammatory agents. Their mechanism of action may be to reduce free radical production that is necessary to activate the cyclooxygenases.

Aspirin can be used to reduce pain, temperature, and inflammation. The anti-inflammatory properties make it useful in rheumatoid arthritis (RA), rheumatic fever, and other diseases that produce joint pain.

The adverse effects of aspirin are dose related. At low doses, most adverse effects are confined to the GI tract, commonly gastritis. At higher doses patients suffer “salicylism,” tinnitus, vomiting, and vertigo. Serious aspirin overdose affects the medulla directly and depresses respiration.

Acetic and Propionic Acids

Indomethacin, ibuprofen, diclofenac, and naproxen are other important NSAIDs. Although they reduce prostaglandin production by inhibiting COX-1 and COX-2, the mechanism of this inhibition is different from aspirin. These drugs are reversible inhibitors of the enzyme and appear to act by interfering with the binding of arachidonate. All have been approved for rheumatic disorders, osteoarthritis, localized musculoskeletal pain, dysmenorrhea, and headache. All are readily absorbed from the GI tract. Indomethacin and diclofenac are the most potent of these drugs in inhibiting cyclooxygenase. Indomethacin also has the highest incidence (35-50%) of adverse effects, most commonly GI. Indomethacin has been found to produce ulceration of the upper GI tract. Naproxen and ibuprofen are also associated with frequent GI adverse effects but are less severe and better tolerated. All of the NSAIDs can produce renal toxici-ties including acute renal failure.

Specific COX-2 Inhibitors

Considerable effort has gone into the development of agents that specifically inhibit COX-2 compared to COX-1. In theory, such agents would be efficacious for treating inflammatory states but have fewer adverse effects, especially in the GI tract because COX-1 would still be able to provide cytoprotection. Two clinical trials support this notion but these drugs still produce adverse effects in the GI tract. Additional studies on total mortality and morbidity will be necessary. Celecoxib [Celebrex] is the only specific COX-2 inhibitor in the US market. Rofecoxib [Vioxx] and valdecoxib [Bextra] were removed from the market due to an increase in risk of cardiovascular disease and stroke. It is unclear whether all members of this class are associated with this increase in cardiovascular risk which appears mostly due to myocardial infarction. Celecoxib is useful in treating osteoarthritis, RA, anky-losing spondylitis, dysmenorrhea, acute pain, and pain caused by migraine. Celecoxib is approved for the treatment of FAR Adverse effects are diminished with COX-2-specific inhibitors, but there are still significant side effects. Rare instances of serious stomach and intestinal bleeding have been reported. Hepatotoxicity and acute renal failure have also occurred. Less serious side effects include dyspepsia, diarrhea, peripheral edema, and dizziness.

Other Agents

Acetaminophen is a non-anti-inflammatory analgesic agent. It is about as effective at reducing fever and as an analgesic as aspirin, but it lacks anti-inflammatory activity and does not inhibit platelet aggregation. The most important toxicity of acetaminophen is hepatotoxicity. This is caused by the metabolism of the drug to N-acetyl-p-benzoquinoneimine (NAPB), which is usually eliminated by hepatic conjugation with glutathione. Toxic levels of acetaminophen deplete glutathione and NAPB accumulates to toxic levels. Other adverse effects include skin rash and mild dyspepsia.

Questions

[1] Which of the following is the most effective in reducing risk of myocardial infarction?

A. Acetaminophen

B. Aspirin

C. Celecoxib

D. Ibuprofen

[2] Which of the following is the advantage of specific cyclooxygenase-2 (COX-2) inhibitors?

A. Decreased GI side effects

B. Decreased vasoconstrictor activity

C. Increased anti-inflammatory activity

D. Increased inhibition of platelet aggregation

[3] A 26-year-old woman takes a “handful” of acetaminophen in a suicide attempt. At the emergency department, it is determined that she has taken enough to be potentially harmful. Which of the following is the best treatment for this patient?

A. Calcium gluconate

B. IgG against acetaminophen

C. JV-acetylcysteine

D. Penicillamine

Answers

[1] B. Aspirin. Because aspirin irreversibly inhibits cyclooxygenase, it effectively eliminates thromboxane production by platelets. It can do this at low doses that do not impair the production of beneficial PGI₂ by endothelial cells.

[2] A. In theory, inhibition of COX-2 would reduce inflammation and pain while leaving the cytoprotective actions of COX-1 intact. However, the two enzymes appear to overlap in their functions to a considerable degree.

[3] C. Excess acetaminophen is metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, NAPB, which has an extremely short half-life and is rapidly conjugated with glu-tathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPB formation or reduced glutathione stores, NAPB is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis. The antidote for acetaminophen poisoning is N-acetyl-L-cysteine (NAC), which prevents the formation and accumulation of NAPB, increases glutathione stores, combines directly with NAPB as a glutathione substitute, and enhances sulfate conjugation.

Pharmacology pearls

Aspirin is an irreversible inhibitor of both COX-1 and COX-2.

Acetaminophen does not have anti-inflammatory activity.

The COX-2-specific anti-inflammatory agents may have fewer GI side effects but increase the risk of cardiovascular events.

The increase in over-the-counter (OTC) sales comes as no surprise. Buying an analgesic off the shelf is considerably easier and more convenient – and far less expensive – than seeing a doctor and going through the process of getting a prescribed drug. OTC medications are widely promoted and readily available. Unfortunately, the average American does not realize that a drug purchased OTC may be associated with the same adverse effects as the same drug purchased by prescription. In the case of OTC NSAIDs, adverse reactions may include kidney damage, hypertension, and gastrointestinal (GI) symptoms ranging from mild dyspepsia to serious or even fatal GI bleeding.

NSAID-induced GI Disease

GI disease associated with NSAIDs has been reported as the most common serious adverse drug effect in the United States. Nonsteroidal antiinflammatory drugs (NSAIDs) can exacerbate underlying disease or cause new lesions. From 38% to 50% of patients taking NSAIDs report dyspepsia, and gastric ulcers may develop in up to 28% of patients taking NSAIDs regularly. Studies have shown that a person exposed to NSAIDs has three to four times the risk of non-users for upper GI bleeding, perforation, or both. Increased risk of a serious adverse reaction has been associated with age, female sex, and rheumatoid arthritis, while independent risk factors associated with upper GI bleeding include male sex, history of peptic ulcer (with or without complications), and the use of alcohol, cigarettes, anticoagulants, and corticosteroids.

Lands et al. found that 80% of patients with either upper or lower GI bleeding, and 78% of patients with upper GI bleeding only, had recently consumed NSAIDs (verified by measuring platelet cyclooxygenase activity and serum salicylate levels, as well as taking patient history). Klein et al. also found a higher frequency of GI bleeding in NSAID users. They examined discharge data from hospitalized patients who had suffered GI hemorrhage (both NSAID users and nonusers). Patients using nonsteroidal antiinflammatory drugs (NSAIDs) spent more time in intensive care than nonusers (median 1 day versus 0 days), and daily users had a higher transfusion requirement than nonusers (4 units versus 1 unit), both of which suggest that NSAID use has a substantial impact on health-care resource allocation.

OTC NSAIDs and GI Hemorrhage

A two-year study of hospitalized patients admitted with upper GI bleeding has demonstrated that the self-administration of OTC NSAIDs can substantially increase the risk of bleeding. Wilcox et al. evaluated consecutive patients admitted with upper GI hemorrhage to a large inner-city hospital in Atlanta, Georgia. The use of any OTC or prescription nonsteroidal antiinflammatory drug (NSAID) during the week before admission was assessed prospectively (from patient and family interview and pharmacy records). Inclusion criteria included age more than 18 years; presence of hematemesis and a subnormal hematocrit (or a decrease in hematocrit of more than 5 points from baseline); and documented lesion (disclosed by endoscopy, barium upper GI series, or at autopsy). Patients were excluded if the GI bleeding first occurred during hospitalization.

During the 2-year period, 421 patients were evaluated. Mean age was 50 (range 18-89); 352 patients were black, 63 white, 4 Hispanic, and 2 Asian; 276 patients were male, and 145 were female. Peptic ulcer was the most common cause of bleeding, identified in more than half the patients. Acute gastric mucosal lesions – including nonspecific gastritis, portal hypertension, and gastropathy (alcohol- or aspirin- induced) – were relatively infrequent. More women than men and more subjects over age 60 than under 60 were taking prescription NSAIDs; those younger than 60 were more likely to use OTCs, and those over 60 were more likely to use prescription NSAIDs. Drug use was not related to race.

Aspirin was taken during the week before admission by 41% of patients (and OTC aspirin by a total of 35%). OTC nonaspirin-NSAIDs were taken by 9% of patients and prescription NSAIDs by 14%. The investigators described the use of OTC aspirin and nonaspirin NSAIDs as “striking” in patients with upper GI bleeding (all causes). These products were used most frequently by patients with ulcer-related bleeding (66%), esophagitis (62%), and Mallory-Weiss tears (laceration of the gastric cardia) (56%) but were also used commonly by patients with bleeding unrelated to ulcers. The investigators concluded, “We believe, as do others, that short-term NSAID use (less than 1 week) may be one of the most important precipitating factors for ulcer related hemorrhage.”

Epidemiology of NSAID-GI Bleeding

A large retrospective study of NSAID use and upper GI (gastrointestinal) bleeding has illuminated the use and misuse of nonsteroidal antiinflammatory drugs (NSAIDs). Rodriguez et al. used a database of 4 million patients (the UK General Practitioners’ Computerized Records) to identify 1467 patients with upper GI bleeding over a 3-year period, and 10,000 matched controls. The site of bleeding was gastric in 483 patients and duodenal in 787; 40 patients had multiple sites of bleeding, 147 had peptic ulcer only, and 261 had perforation; 64 patients died. One major indication for NSAID therapy was ill-defined back pain (13% for cases and 10% for controls). Although patients used any of 17 different NSAIDs, sufficient data for individual analyses were obtained for ibu- profen, naproxen, diclofenac, ketoprofen, indomethacin, piroxicam and azapropanone (the latter not available in the United States). Aspirin use was not specifically addressed, because use was seen as too widespread and underreported.

The investigators found that the mean relative risk for upper GI bleeding associated with current NSAID use was 4.7 (7.0 with high doses and 2.6 with low doses). Current users were patients who most likely used nonsteroidal antiinflammatory drugs (NSAIDs) within the previous month (last NSAID prescription ordered during the month before the index date, or duration of therapy including the index date). NSAIDs associated with highest risk of GI bleeding were azapropanone (relative risk 23.4) and piroxicam (relative risk 18). Ibuprofen at low doses had the smallest risk (2.1), although risk was substantially increased with higher doses (6.5 for 1500 mg/day or more). Both short- and long-duration exposure increased the risk of upper GI bleeding, long duration only slightly more than short duration. Patients who recently switched from one NSAID to another or used more than one NSAID simultaneously had more than twice the risk of patients exposed to only one NSAID. In cases where current aspirin use was recorded on the computer, adjustment did not greatly alter risks, which differs from the other studies.

The biggest risk factor for GI bleeding in NSAID users was a history of peptic ulceration (relative risk 17.2). Age also played a role: people under 60 exposed to NSAIDs had a relative risk of 2.8; people over 60 had a relative risk of 13.2. NSAID use was slightly greater in women than in men, yet male sex was associated with a greater risk. The investigators described the patient at greatest risk of presenting with an episode of upper GI (gastrointestinal) bleeding as “a male smoker of advanced age who has a history of peptic ulcer, and is a user of oral corticosteroids, anticoagulants, and NSAIDs.”

Managing NSAID-induced Dyspepsia

How should patients with NSAID-induced dyspepsia be managed? A prospective study by questionnaire (sent to 300 general practitioners, 261 of whom responded) found that management strategies include NSAID discontinuation (87%), switching to another NSAID (12%), and referral for endosco-py (14%) or barium meal (2%). The drugs preferred for management of dyspepsia included histamine2-receptor blockers (41%), antacids (about 25%), and misoprostol (25%).

The authors of the report offered the following guidelines for patients with persistent NSAID- related dyspepsia when simple analgesics are inadequate: Endoscopy is advisable when symptoms persist for more than 3 weeks in patients who need long-term NSAID therapy; when dyspeptic symptoms or signs suggest organic disease; and when the patient is receiving both steroids and NSAIDs. Misoprostol prophylaxis for NSAID-related dyspepsia is recommended at the onset of NSAID therapy for patients with a history of peptic ulcer disease and may also be justified if NSAID therapy is short term, or if endoscopy is intolerable, impractical, or unavailable.

NSAIDs and hypertension in the elderly.

Do NSAIDs alter blood pressure? In elderly patients, the answer to this question is a qualified “maybe.” Johnson et al. found NSAID use an independent risk factor for hypertension in nearly 3000 Australian subjects aged 60 years or more who answered a questionnaire and underwent blood pressure mea- surements. Frequency of NSAID usage was determined for all study participants – 1237 men and 1568 women stratified by age, sex, blood pressure group, and history of arthritis.

Nonsteroidal antiinflammatory drug (NSAID) usage was 26% overall (females 28% and males 23%). Usage increased with age and was higher in females than males in every group studied. Among patients with a history of “arthritis,” 45% were using NSAIDS; 12% were taking both NSAIDS and antihypertensive agents. NSAID usage significantly predicted the presence of hypertension, with an attributable risk of 29%. It is difficult to tell whether NSAIDs raise blood pressure or antagonize the effects of antihypertensive agents, said the investigators, however, “In this elderly population… 29% of the hypertension occurring amongst those taking NSAIDs could be attributed to the NSAID, underscoring the potential contribution of NSAID usage to the prevalence of hypertension in the elderly.”

It is available in two strengths. One formulation (Arthrotec 50) contains 50 mg of diclofenac and 200 mcg of misoprostol while the other (Arthrotec 75) contains 75 mg of diclofenac and 200 mcg of misoprostol. The usual dose of Arthrotec in the management of osteoarthritis is 50 TID and for rheumatoid arthritis is 50 TID or QID; BID dosing can be used.

How it works:

Diclofenac sodium:

Diclofenac sodium is an NSAID that exhibits classical anti-inflammatory, antipyretic, as well as analgesic properties. As with other NSAIDs, its exact mechanism is not completely understood but it is believed that diclofenac, like other NSAIDs, works in part by inhibiting prostaglandin synthetase.

Misoprostol:

Misoprostol is a synthetic prostaglandin E1 analog. In animals, misoprostol inhibits gastric acid secretion and promotes mucosal protective properties. Misoprostol can increase bicarbonate and mucus production and decrease the secretion of gastric acid. The exact reason for protection against ulcers has not be determined.

Clinical Tips

Diclofenac:

Diclofenac is completely absorbed through the gastrointestinal tract following oral administration. The diclofenac portion of Arthrotec is stable in the acidic environment of the stomach. However, it is rapidly released from the formulation once it enters the more basic environment of the duodenum. Peak plasma levels of this portion are reached in about 2 hours. Because of the extensive first pass effect, only 50% of the dose is available for absorption. The diclofenac portion of Arthrotec is metabolized by the liver and cleared by the urine (65%) and the biliary route (35%).

Misoprostol:

Misoprostol is rapidly absorbed following oral administration, but must undergo metabolic activation into misoprostol acid before it can exerts it pharmacologic actions. The misoprostol acid that is present in Arthrotec reaches peak plasma levels in about 20 minutes and is rapidly eliminated with an approximate half-life of 30 minutes.

Arthrotec follows similar pharmacokinetic parameters as the individual components. The amount of absorption of the two components from the preparation of Arthrotec is comparable to the amount of absorption of the two individual components separately. Importantly, food tends to decrease the bioavailability of the two components of Arthrotec. The pharmacokinetic profile of the diclofenac component in Arthrotec is unchanged in elderly patients and in patients who are renally and hepatically challenged. The pharmacokinetics of misoprostol is influenced by age as well as renal and hepatic impairment; the levels of misoprostol in these individual may double. Hence, it is necessary to adjust the dose in elderly patients and in patients who have renal and hepatic problems.

Clinical studies have shown that diclofenac alone, or in combination with misoprostol, is effective in the treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. When given alone, misoprostol has been shown to reduce the occurrence of gastric and duodenal ulcers in patients who were receiving a variety of NSAIDs for the management of arthritic conditions. When Arthrotec was compared to diclofenac alone in patients who had osteoarthritis, the incidence of drug-induced ulcers was lower in patients who were receiving Arthrotec than those who were receiving diclofenac. Even though the incidence of gastric and duodenal ulcers was lower with Arthrotec, only the incidence of gastric ulcers was significantly lower in patients who were receiving Arthrotec than those who were receiving diclofenac.

Abdominal pain, diarrhea, upset stomach, and nausea are among the most common side effects with Arthrotec. Diarrhea may be reduced if this medication is taken with meals. Most adverse effects that occur with misoprostol are mild to moderate and generally resolve following a few days of treatment.

Instructions for the Patient

Arthrotec should not be given to patients who are allergic to aspirin, who have pre-existing asthma, and who have severe renal failure. It should not be given to patients who are pregnant or who are planning to become pregnant because it is believed the misoprostol component can cause fetal death.

Patients should also be advised to swallow Arthrotec whole; they should not chew, crush or dissolve this medication. In addition, patients should be advised to report any signs and symptoms of liver failure (jaundice, itching, nausea) to their physician.

The following are the current monitoring recommendations from the Drug Usage Review Program, which attempt to balance the high frequency of monitoring suggested by the literature with the need for practical guidelines for family physicians.

• Ask patients to weigh themselves twice a week for the first month of therapy and to report any progressive weight gain.

• Monitor blood pressure frequently, especially in hypertensive individuals.

• Measure blood urea nitrogen, serum creatinine, and electrolytes at initiation, at 3 weeks, and then every 6 months.

• Test liver function at initiation, 3 weeks, and then every 6 months.

• Do a complete blood count and platelet estimation at initiation, at 3 weeks, and then every 6 months if indicated.

Clinicians are faced with a dilemma. While potentially severe reactions to non-steroidal anti-inflammatory drugs have been documented, available evidence indicates that such reactions are uncommon and perhaps rare. Thus, in the vast majority of patients, monitoring may be regarded as unwarranted. Yet, the risks of NSAIDs are real, and early detection of toxicity can improve the outcome. We therefore urge physicians to assess patients treated with non-steroidal anti-inflammatory drugs for risk of toxicity and to monitor them appropriately. ■

Hyperkalemia has been reported. In one indomethacin study, an increase in serum potassium levels of 1 mmol/L or more occurred in 26% of patients. The hyperkalemia is also prostaglandin mediated. Renin release is pardy dependent on prostaglandins. Therefore, when non-steroidal anti-inflammatory drugs decrease renin output, lower aldosterone levels and increased serum potassium result.

Sodium and water retention can lead to edema and to the antagonism of the antihypertensive effects of diuretics, (5-blockers, and angiotensin-converting enzyme inhibitors. Prostaglandin effects on the kidney include vasodilation, leading to increased renal blood flow and increased sodium reabsorption in the proximal tubule; inhibition of sodium reabsorption in the ascending loop of Henle; and a reduction of the effect of antidiuretic hormone (ADH). By decreasing this prostaglandin effect, non-steroidal anti-inflammatory drugs increase the effect of ADH in promoting water retention, which can (rarely) lead to hyponatremia. Edema is therefore common and has been observed in 10% of patients taking ibuprofen.

Interstitial nephritis characterized by proteinuria, and a slow rate of recovery is estimated to occur in one in 5000 to 10 000 patients treated with NSAIDs. The cause is postulated to be an immune or a direct toxic effect.

Population at risk. The groups at risk for acute renal failure from non-steroidal anti-inflammatory drug use are 1) those with diseases involving a low circulatory volume and resultant high renin state who are dependent on renal prostaglandins to maintain renal perfusion and 2) those with diseases not related to a high renin state but that may involve low renal synthesis of prostaglandins. Conditions in the first group include decreased cardiac output, volume depletion by high-dose diuretics, hemorrhage or septic shock, cirrhosis with ascites, and sodium depletion. Conditions in the second group include systemic lupus erythematosus, nephrotic syndrome, chronic glomerulonephritis, renal vascular disease, renal artery stenosis, and gout. There is no evidence that the elderly are more susceptible to renal failure, beyond an increased prevalence of some of these risk factors in the elderly population.

Non-steroidal anti-inflammatory drug-related sodium retention and edema are more common in patients with incipient heart failure, renal disease, or other high renin states, but can occur in healthy patients. The occurrence of interstitial nephritis with NSAIDs is unpredictable, and all patients are at risk. The prostaglandin-related effects can occur with any non-steroidal anti-inflammatory drug.

It has been suggested that sulindac is “renal-sparing” because it is metabolized into an inactive form in the kidneys; and initial studies reported a lack of inhibition of renal prostaglandin synthesis. Subsequent studies have reported decreased glomerular filtration rate and urinary prostaglandins with sulindac, a case of renal failure in an elderly patient with congestive heart failure and hypertension who was using diuretics, and a case of hyperkalemia above 6 mmol/L. It therefore appears that sulindac is only relatively “renal-sparing”.

Interstitial nephritis is most common with fenoprofen. Interstitial nephritis has been reported after 2 weeks to 18 months of non-steroidal anti-inflammatory drug treatment. Eosino-philia is sometimes present.

Monitoring. Acute renal failure, hyperkalemia, and sodium retention related to NSAIDs are all of rapid onset, within days of starting the drugs.’ Acute renal failure and interstitial nephritis are usually rapidly reversible if the NSAID is withdrawn early. If it is not, acute renal failure can progress to tubular necrosis; tubular necrosis and nephritis can progress to renal failure.

Monitoring strategies (Table 3) include 1) in patients at risk, measuring initial baseline serum creatinine, blood pressure, serum potassium, and body weight, and repeating within the first 3 weeks; 2) monitoring all patients regularly (the same monitoring schedule should be followed for patients receiving sulindac); 3) checking for urine protein and cells to aid in early detection of intestinal nephritis; and 4) asking patients to report symptoms of interstitial nephritis and papillary necrosis (back pain, polyuria, edema, hematuria).

Preventive measures. Preventive measures include 1) avoiding non-steroidal anti-inflammatory drugs in patients with risk factors if suitable alternatives exist; 2) otherwise using the lowest effective dose; and 3) using sulindac, a reasonable choice in these patients. But be aware that NSAID-related renal toxicity is still possible.

The exact incidence of NSAID-related blood dyscrasias is unknown. The most recent investigation was the International Agranulocytosis and Aplastic Anaemia Study (IAAAS), in which the risk of aplastic anemia was estimated to be on the order of six to 10 events per million subjects per year, following an exposure of at least 5 months.

Most of the hematologic effects of NSAIDs (agranulocytosis, red cell aplasia, aplastic anemia, hemolytic anemia, thrombocytopenia) are thought to result from an immune reaction and are, therefore, drug specific. Drugs that bind strongly to proteins, such as non-steroidal anti-inflammatory drugs, can act as haptens and elicit antibody production and other immune responses.

Nonimmune hematologic effects of non-steroidal anti-inflammatory drugs include inhibition of platelet aggregation and hemolysis. Reversible inhibition of platelet cyclooxygenase occurs for all NSAIDs except acetylsalicylic acid (ASA), which irreversibly acetylates the cyclooxygenase for the lifetime of the platelet. Hemolysis can occur owing to the ability of non-steroidal anti-inflammatory drugs to oxidize hemoglobin to methemoglobin or sulfhemoglobin.

Populations at risk. Patients of all ages appear to be at risk for NSAID-related blood dyscrasias. Aplastic anemia associated with phenylbutazone and oxyphenbutazone use has occurred mainly in women older than 60 years. In the IAAAS study, only indomethacin, diclofenac, phenylbutazone, and oxyphenbutazone were significantly associated with aplastic anemia, although there have been reports of an association with acetylsalicylic acid. Agranulocytosis has been associated with the use of indomethacin, phenylbutazone, oxyphenbutazone, sulindac, tolmetin, naproxen and mefenamic acid.

The pharmacologic reactions (platelet aggregation inhibition, hemolysis) could be caused by any member of this class of drugs, in a dose-dependent manner. But nonacetylated salicylates are weak, reversible inhibitors of prostaglandin synthesis and are less likely to inhibit platelet aggregation.

Interestingly, ibuprofen has been used without reported adverse effects in hemophiliacs. Patients with glucose-6-dehydrogenase deficiency who take NSAIDs are at risk of hemolysis. Patients with defective platelet function, gastrointestinal lesions, or a bleeding diathesis are at increased risk of hemorrhage, as are patients receiving anticoagulant therapy. Two deaths from hemorrhage have been reported associated with the combined use of non-steroidal anti-inflammatory drugs and coumarins.

Monitoring. Monitoring strategies (Table 2) include 1) informing the patient of the warning symptoms of agranulocytosis (sore throat, fever, muscle pain, headache) and of thrombocytopenia (ecchymoses, purpura); and 2) monitoring blood cell counts at initiation, at 3 weeks, and regularly over the long term (the risk of allergic reactions is usually highest when a drug is initiated or re-instituted, but can occur after long-term drug therapy).

Preventive measures. Non-steroidal anti-inflammatory drugs should be avoided in patients at risk for hematologic adverse effects: avoid NSAIDs, if possible, in those with platelet dysfunction, gastrointestinal lesions likely to bleed, or other bleeding diathesis and in patients on anticoagulants; use non-steroidal anti-inflammatory drugs with caution in patients with glucose-6-phosphate dehydrogenase deficiency; and avoid phenylbutazone and oxyphenbutazone, or use only for a short time and monitor closely.

Elevated liver enzymes are fairly common with non-steroidal anti-inflammatory drug (NSAID) use. In prospective clinical trials, elevated transaminases or alkaline phosphatase were detected in approximately 4% of non-steroidal anti-inflammatory drug users. While the exact incidence of NSAID-induced hepatitis is not known, it appears to be rare. Fatalities from NSAID hepatotoxicity are also rare: in a 17-year Danish study of voluntary reports of drug adverse drug reactions, three of 67 deaths were due to hepatotoxicity related to non-steroidal anti-inflammatory drug use.

Little is known of the mechanism of NSAID-related hepatotoxicity. There is no evidence that prostaglandin synthesis or hypersensitivity is involved.

Because of the low incidence of hepatic reactions, it has been difficult to identify populations at risk. The mild biochemical changes associated with acetylsalicylic acid have commonly been reported in female patients with collagen diseases, such as SLE and rheumatoid arthritis.

In an analysis of Michigan Medicaid data for ibuprofen, indomethacin, and sulindac, incidence was not related to age. Cholestatic liver dysfunction from benoxaprofen, which led to its ultimate withdrawal from the United Kingdom market, was most evident in elderly, especially small women who had renal dysfunction and who received high doses. Acetylsalicylic acid hepatitis and Reye’s syndrome in children also show a relationship with dose.

Hepatotoxicity has been reported occasionally with almost all of the NSAIDs; the relative risk for specific drugs is not known. Increases in serum transaminase and alkaline phosphatase are observed in all forms of hepatotoxicity from all non-steroidal anti-inflammatory drugs and are, therefore, useful parameters to monitor as an early warning sign. In more severe cases, there may be accompanying signs and symptoms of anorexia, nausea, vomiting, abdominal pain, weakness, and jaundice, as well as increases in bilirubin and prothrombin time. The onset of hepatotoxicity is often within the first few weeks of therapy.

Monitoring. Monitoring strategies include 1) taking initial transaminase and alkaline phosphatase levels to provide a baseline, then repeating regularly (some recommend monthly checks for the first year; others monitor at 1, 3, and 13 weeks. Determinations at initiation, at 3 weeks, and then every 6 months thereafter would appear prudent); and 2) discontinuing the drug and measuring liver enzymes if non-specific symptoms of nausea, vomiting, abdominal pain, and weakness appear.

Preventive measures. No definite methods of prevention exist, but strategies that can minimize occurrence include avoiding acetylsalicylic acid (ASA) use in children and avoiding high doses of any non-steroidal anti-inflammatory drug.

Gastric effects of non-steroidal anti-inflammatory drugs are currently thought to involve both prostaglandin inhibition and a direct local irritant effect. Prostaglandins protect the gastrointestinal tract by increasing mucus production, increasing mucosal blood flow, decreasing acid secretion, and enhancing repair mechanisms. Because all non-steroidal anti-inflammatory drugs can inhibit gastric prostaglandin synthesis, the potential for gastrointestinal adverse effects is inseparable from their beneficial anti-inflammatory effects and can occur with any dosage form.

That a direct local irritant effect also contributes to gastric damage, at least with acetylsalicylic acid, is supported by the observation that enteric-coated forms are less damaging. Other possible mechanisms include an increase in back diffusion of hydrogen ions by ASA, increased leukotriene synthesis, and increased free radical formation by non-ASA non-steroidal anti-inflammatory drugs.

Patients at risk. The populations at risk for the development of ulcers, hemorrhage, and perforation have not yet been precisely identified. In epidemiological studies, the association between non-steroidal anti-inflammatory drug use and hemorrhage or perforation appears to be strongest for elderly women, although this could simply reflect the high use of non-steroidal anti-inflammatory drugs in the elderly female population. Others have reported that male patients are more likely to bleed than female patients. Gastric hemorrhage is a particularly serious event in elderly patients, commonly associated with hospitalization and morbidity.

Other populations at risk include those with a bleeding diathesis, a history of previous gastrointestinal ulceration, and perhaps those with varies secondary to alcoholism or portal hypertension. Patients with inflammatory bowel disease are at risk for activation of the disease.

Other than a high incidence of gastrointestinal bleeding associated with high-dose acetylsalicylic acid (ASA) use, there is no evidence that any specific non-steroidal anti-inflammatory drugs produce less gastropathy than others when used in equivalent anti-inflammatory doses. All can cause gastrointestinal damage.

Monitoring. Monitoring is complicated by the fact that the gastrointestinal side effects of non-steroidal anti-inflammatory drugs are often silent; most patients are asymptomatic before bleeding. Nor do symptoms correlate well with endoscopic results. In a study by Caruso and Biancho Porro, 41% of patients without symptoms had endoscopically confirmed lesions, while 79% of patients with symptoms of discomfort had lesions. These results suggest that, while a lack of symptoms is not predictive, the presence of symptoms calls for further investigation. Epigastric tenderness on physical examination may further indicate the likelihood of lesions, but is uncommon.

Monitoring for occult fecal blood loss is a poor indicator of upper gastrointestinal lesions. Collins and Du Toit found that approximately half of their patients with gastric ulcerations did not have detectable occult blood, while approximately half of those with no endoscopic signs of gastric lesions were positive for occult blood. Iron-deficiency anemia can signal gastrointestinal blood loss.- While some authors have reported that bleeding is most likely to occur within the first 3 to 4 months of treatment, gastrointestinal bleeding has been reported after anywhere from 6 days to 2 years of non-steroidal anti-inflammatory drug use. Long-term monitoring is thus needed. Because symptoms of gastrointestinal complications are infrequent and vague, they cannot be relied upon for the purpose of monitoring. Some strategies can help prevent gastrointestinal problems (Table 1).

Preventive measures. The use of cytoprotective agents is still controversial. Because the patients at risk have not been precisely defined, it is not clear which groups should receive preventive agents. It is difficult to justify administering a drug, with its own inherent toxicities, just to prevent toxicity from another drug, unless the risk is high.

Sucralfate: Sucralfate has been shown to increase gastric prostaglandin E₂ secretion in rats. However, a similar effect on prostaglandins did not appear in humans treated with non-steroidal anti-inflammatory drugs. Evidence of preventive benefit in patients taking NSAIDs is weak. Further studies on sucralfate are warranted, because it is a drug of relatively low toxicity lacking the systemic interactions seen with cimetidine.

Cimetidine: Studies with cimetidine have established that doses of 200 to 400 mg are effective in preventing the acute injury associated with the administration of a single 1300-mg dose of acetylsalicylic acid (ASA) to healthy subjects. However, evidence of preventive benefits in long-term studies is required before routine prophylaxis can be recommended.

Misoprostol: Several recent studies have investigated the value of misoprostol, a synthetic analog of PGE, in the prevention of NSAID-related ulceration. It acts by augmenting prostaglandin-mediated mu-cosal defenses. In healthy subjects taking ASA, ibuprofen, or tolmetin for 7 days, misoprostol (200 µg) taken concomitantly four times a day has been shown to be significantly superior to placebo in preventing the occurrence and reducing severity of en-doscopically demonstrated gastric and duodenal ulceration.

The only study investigating long-term gastrointestinal protection reported that both 100- µg and 200- µg misoprostol doses significantly reduced the frequency of gastric ulcers in patients with osteoarthritis taking their usual doses of ibuprofen, piroxicam, or naproxen. Although these initial studies are promising and the mechanism involved intuitively seems appropriate, more studies (particularly long-term ones) are required before misoprostol can be recommended for the routine prevention of non-steroidal anti-inflammatory drug gastropathy.

Comparative performance: In a study comparing misoprostol (200 µg QID) with cimetidine (300 µg QID) over 7 days in the prevention of tolmetin-related (400 mg QID) gastroduodenal ulceration in healthy subjects, both were significantly better than placebo. Misoprostol was more effective than cimetidine in preventing gastric ulcer, but not duodenal ulcer.

This frequent prescribing reflects the benefit derived from NSAIDs in the symptomatic relief of arthritis and other conditions. Yet, although most patients tolerate this group of drugs well, serious and sometimes fatal reactions have been reported. Patients receiving long-term non-steroidal anti-inflammatory drug treatment should be carefully monitored. We review the gastrointestinal, renal, hepatic, and hematologic adverse effects associated with NSAID therapy and recommend preventive measures and monitoring protocols for patients at risk.

Pharmacology

All non-steroidal anti-inflammatory drugs exhibit dose-related inhibition of the enzyme cyclooxygenase, resulting in decreased prostaglandin synthesis. Non-steroidal anti-inflammatory drugs can thereby decrease inflammation, pain, and fever. The inhibition of cyclooxygenase is reversible for all NSAIDs except acetylsalicylic acid, so prostaglandin-related effects should be rapidly reversible in most cases. But other mechanisms of toxicity also exist.

Pharmacokinetics

Non-steroidal anti-inflammatory drugs share several basic pharmacokinetic properties: high plasma albumin binding (99%), hepatic metabolism, and the excretion of a small amount unchanged by the kidneys. Hypoalbuminemia, liver dysfunction, and reduced renal function can therefore place patients at risk for increased plasma levels and toxicity.

While reduced albumin concentration, liver function, and renal function are all associated with aging, in general, the pharmacokinetics of non-steroidal anti-inflammatory drugs are not changed significantly in the elderly. Age-related decreases in clearance have been reported for piroxicam, naproxen, and ketoprofen, but the clinical relevance is unknown.

Half-lives were not prolonged in the elderly in studies with ibuprofen and diclofenac. Low doses of NSAIDs should be used in any patient with compromised liver function. Patients with poor renal function should be prescribed selected non-steroidal anti-inflammatory drugs, keeping in mind that renal dysfunction increases the risk of renal toxicity (see Renal problems).