Rational Use of NSAIDs

By: Somayyeh nasiripourClinical pharmacist

Assistant professor in IUMS

• (NSAIDs) are in use throughout the world .NSAIDs are popular because of their versatile effectiveness as analgesics, antipyretics, and as antiinflammatory agents. Aspirin is also used as an anti-thrombotic agent

• More than 17 million Americans use various nonsteroidal antiinflammatory drugs (NSAIDs) on a daily basis, making this class of drugs one of the most commonly used in the world

• The Center for Disease Control in the United States predicts that, with the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions. This will probably lead to a parallel increase in the use of NSAIDs.

• Each year, approximately 60 million NSAID prescriptions are written, with the number of prescriptions for older patients approximately 3.6-fold higher than that for younger patients

• Increased use of NSAIDs in an aging population will increase the number of adverse events related to NSAID use. It has been estimated that 5 to 7 percent of hospital admissions are related to adverse effects of drugs, and, of these hospitalizations, those that result from gastrointestinal, nervous system, renal, or allergic effects of non- aspirin NSAIDs are responsible for approximately 11 to 12 percent

COX-1 is expressed in most tissues, but variably.regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function). COX-1 activity is stimulated by hormones or growth factors.

COX-2 is constitutively expressed in the brain, kidney, bone, and probably in the female reproductive system. Its expression at other sites, including the cardiovascular system, is increased during states of inflammation or, experimentally, in response to mitogenic stimuli.

Both COX isoforms are regulated by physiologic stimuli. Increased expression of COX-2 mRNA and protein has been noted in patients with hypertension, heart failure, and diabetic nephropathy

• A presumed advantage of the coxibs was a reduction in gastrointestinal toxicity compared to nsNSAIDs. However, an increased risk of ischemic cardiovascular disease has been described with rofecoxib, celecoxib , and valdecoxib.

Therapeutic use and variability of response in adults

• All NSAIDs appear to be absorbed completely, have negligible first pass hepatic metabolism, are tightly bound to albumin, and have small volumes of distribution.

• Patients with hypoalbuminemia may, therefore, have higher free serum concentrations of drug.

• At equipotent doses, the clinical efficacy of the various NSAIDs in patient populations is similar

• in contrast, individual responses are highly variable

• Some of the observed individual differences with specific NSAIDs are particularly evident with respect to toxicity

• As an example, it is not unusual for indomethacin to induce headaches after a single dose in some patients.

• More commonly, individual patients have more symptoms or signs of gastrointestinal toxicity with one NSAID than with another

• Some differences in toxicity may be explained by variations in absorption, distribution, and metabolism. Differences in the mode of action may be important as well.

HYPOTHESES CONCERNING VARIABILITY OF RESPONSE

• Mechanism of action. Some NSAIDs are more potent inhibitors of prostaglandin synthesis, while others are more effective in altering other nonprostaglandin mediated biologic events.

Observed variations in patient response may result in part from the pharmacodynamics of a particular drug. Thus, it is believed that, if a patient fails an NSAID of one class, the substitution of an NSAID of a different class is a reasonable therapeutic option.

Each attempt to achieve a response should probably last for about two weeks.

Overview of adverse effects

Risk factor

• The risk of acute renal failure is increased in patients with existing glomerular disease, renal insufficiency, hypercalcemia, in states of effective volume depletion (such as heart failure and cirrhosis), and in the presence of true volume depletion due to gastrointestinal or renal salt and water losses.

The risk of gastrointestinal toxicity is increased by the presence of one or more of the following: a prior history of a gastrointestinal event (ulcer, hemorrhage), age >60, a high dose of a NSAID, the concurrent use of glucocorticoids, and the concurrent use of anticoagulants (eg, aspirin , warfarin , or clopidogrel ). Chronic as opposed to short-term use, untreated Helicobacter pylori infection, and use of (SSRI) may also increase the risk of bleeding or perforation

GASTROINTESTINAL EFFECTS

• Mucosal damage by aspirin and NSAIDs is primarily a consequence of inhibition of COX-1 in the upper GI tract.

• COX-1 inhibition reduces mucosal generation of protective prostaglandins such as PGE2

SYSTEMIC VERSUS TOPICAL EFFECTS

• Aspirin and many other NSAIDs are carboxylic acid derivatives

As a result, they are not ionized at the acidic pH found in the gastric lumen and thus can be absorbed across the gastric mucosa.

Once the drug moves from the acidic environment of the gastric lumen into the pH–neutral mucosa, the drug ionizes and is trapped temporarily in epithelial cells where it may damage these cells.

THE CENTRAL ROLE OF (PROSTAGLANDINS)

• PGs such as PGE2 protect the mucosal lining from injury by luminal acid-pepsin.

• COX-1 is a constitutive enzyme with a fairly steady rate of expression in most cells of the body.

• In contrast, COX-2 is expressed in many cells only when bacterial polysaccharides, pro-inflammatory cytokines such as TNFa or IL-1b, or growth factors (mitogens) induce its expression.

• COX-3 in the brain may be one target of acetaminophen

• The healthy gastric and duodenal mucosa constitutively use COX-1 to produce its mucosal-protective PGs

• Many NSAIDs block COX-1 and COX-2 more or less equally (ie, are non-selective) and thus may impair gastric PG production at low (<1µM) concentrations

• Examples include ibuprofen , indomethacin , and naproxen .

• Drugs that more selectively inhibit COX-2 than COX-1 have less suppressive effects on gastric PG synthesis

• Examples include celecoxib and etodolac

• inhibitors of COX-2, and also COX–3 inhibitors such as acetaminophen , preserve PG-mediated GI mucosal protection

• However, COX-2 selective inhibitors may still block COX-1 at clinically recommended doses and thus have the potential to also block COX-1 in the stomach and duodenum and cause damage

Gastric damage

• Aspirin doses as low as 10 mg/day inhibit gastric PG generation considerably and can damage the stomach

• GI damage increases as the aspirin dose is raised• After low-dose aspirin therapy is stopped, the human stomach requires 5-8 days to

recover its COX-1 activity and its ability to synthesize protective PGs, suggesting a very slow turnover of gastric COX-1

• gastric mucosa somewhat resembles the platelet, which requires 10 to 14 days to recover from aspirin

• In contrast to aspirin , which acetylates COX irreversibly, most NSAIDs inhibit COX-1 and COX–2 reversibly

• Nevertheless, even transient COX-1 inhibition in the gastric mucosa by an NSAID is sufficient to predispose the stomach to injury.

• That this injury is due to loss of PG-mediated cytoprotection is supported by the observation that NSAID-related gastric damage is prevented by PGE analogs such as misoprostol

• (H2RAs), have little or no protective effect against NSAID-induced gastric damage. On the other hand, the relative failure of H2RAs to protect the stomach from damage by NSAIDs can be overcome by using higher H2RA doses or by using more potent acid-inhibitory compounds such as the proton pump inhibitors.

Duodenal damage• Aspirin doses as low as 325 mg every other day

increase the risk of duodenal ulcers • In contrast to the stomach, damage to the duodenal

mucosa by aspirin and NSAIDs seems to depend highly upon gastric acid.

• Thus, not only misoprostol but also by histamine-2 blockers with their modest acid inhibition can largely prevent endoscopic evidence of duodenal injury by NSAIDs.

• PPIs are also highly effective.

ROLE OF HELICOBACTER PYLORI INFECTION

• At least two meta-analyses concluded that NSAID use and H. pylori infection represent independent and synergistic risk factors for uncomplicated and bleeding peptic ulcer disease

Patients with a history of uncomplicated or complicated peptic ulcers (gastric, duodenal) should be tested for H. pylori prior to

beginning a course of NSAID or low dose aspirin therapy.

If present, H. pylori should be treated with appropriate therapy, even if it is believed that the prior ulcer was due to NSAIDs.

RISK OF GASTROINTESTINAL COMPLICATIONS duration of therapy:> 1 w

Age ≥60 years

history of ulcer disease or complication,

Dyspepsia or gastroesophageal reflux disease (GERD) symptoms

higher NSAID dose(s),

a past history of peptic ulcer disease

dual antiplatelet therapy

concurrent use of glucocorticoids, anticoagulants, and clopidogrel (and probably

of, bisphosphonates and [SSRIs])

RELATIONSHIP BETWEEN DYSPEPTIC SYMPTOMS AND GASTRODUODENAL MUCOSAL INJURY

aspirin and many NSAIDs, and even acetaminophen , may produce dyspeptic symptoms (epigastric discomfort, upper abdominal pain, nausea, epigastric fullness or bloating), especially as the dose of the drug is increased.

little correlation between the dyspeptic symptoms sometimes seen with these drugs and the presence or absence of erosive/ulcerative lesions in the stomach and duodenum.

evaluating gastric and duodenal toxicity of NSAIDs should not include dyspepsia as a part of a combined GI endpoint

Comparison between NONSELECTIVE NSAIDS

complications was highest with indomethacin (relative risk {RR} 2.25)

followed by naproxen (RR 1.83), diclofenac (RR 1.73), piroxicam (RR 1.66), tenoxicam (RR 1.43), ibuprofen (RR 1.43),

and meloxicam (RR 1.24).

associated with a high risk of GI toxicity, particularly when used in higher doses, in older patients, and for

more than five days.

One study found that ketorolac was 5.5 times more likely to cause GI toxicity than other NSAIDs

Because of the risks associated with ketorolac (both gastrointestinal and renal), its use is generally

restricted to short-term pain treatment

ENTERIC-COATED AND BUFFERED ASPIRINIt has been proposed that a way to prevent gastrointestinal (GI) toxicity from aspirin is the use of enteric-coated or buffered aspirin.

Enteric-coated aspirin is designed to resist disintegration in the stomach, dissolving in the more neutral-to-alkaline environment of the duodenum.

Although enteric-coated aspirin diminishes endoscopic signs of gastroduodenal injury, it does not appear to protect against the clinically relevant end point of gastrointestinal bleeding

These findings are not surprising, since injury severe enough to induce bleeding is thought to reflect the systemic rather than the topical effects of aspirin

The systemic effect of aspirin on the stomach and duodenum probably explains why buffered aspirin is no more effective than plain aspirin in preventing ulcer bleeding

SELECTIVE COX-2 INHIBITORS

Two related isoforms of COX exist: COX-1 and COX-2

COX-1 is involved in gastric and duodenal cytoprotection COX-2 is involved in inflammation and perhaps healing of

gastroduodenal lesions.

It has been proposed that the ideal NSAID would inhibit the inducible COX-2 isoform (thereby decreasing tissue inflammation) without having any effect on the constitutive COX-l isoform (thereby minimizing gastrointestinal [GI]

toxicity)

data suggest that COX-2 inhibitors are associated a reduced risk of gastrointestinal bleeding compared with nonselective NSAIDs but the risk is increased

compared with placebo.

Thus, COX-2 inhibitors may be safer than conventional NSAIDs for reduction in the risk of

gastrointestinal bleeding but are still associated with an increased risk.

patients receiving both aspirin and a selective COX-2 inhibitor

may require prophylactic antiulcer therapy if they are at

increased risk for gastroduodenal toxicity.

Patients taking warfarin concomitantly with a selective COX-2 inhibitor have an

increased risk of hospitalization for upper gastrointestinal bleeding

The magnitude of risk was similar to the risk in anticoagulated patients

taking nonselective NSAIDs, suggesting that the COX-2 inhibitors may not be

protective in this population.

concern with using a selective COX-2 inhibitor compared to a nonselective NSAID is their

cardiovascular risk

PREVENTION STRATEGIES

using misoprostol or a proton pump inhibitor (PPI) together with a nonselective nonsteroidal antiinflammatory drug (NSAID)

using a selective COX-2 inhibitor with or without a PPI

None of these approaches is universally effective and their cost-effectiveness

Clinical studies of PPIs have suggested that they are better tolerated but have slightly lower efficacy compared to full-dose

misoprostol (ie, 200 micrograms four times daily)

H2 receptor antagonists

• Standard doses of H2 receptor antagonists were not effective for the prevention of NSAID-induced gastric ulcers in most reports, although they may prevent duodenal ulcers

CONSENSUS STATEMENTS AND GUIDELINES

Patients who are at high GI/high CV risk should not receive NSAIDs, including COX-2 inhibitors.

Patients at high GI/low CV risk should receive a COX-2 inhibitor in combination with either a PPI or misoprostol .

Patients at moderate GI/low CV risk should receive a COX-2 inhibitor alone or a conventional NSAID + either a PPI or misoprostol .

Patients at moderate GI/high CV risk should receive naproxen (due to its putative cardioprotective properties) and either a PPI or misoprostol . This same strategy is endorsed for patients at low GI/high CV risk.

Patients at low GI/low CV risk can receive a conventional NSAID alone, although the "least ulcerogenic NSAID at the lowest effective dose" is recommended (see 'Nonselective NSAIDs' above).

All patients regardless of risk who are about to start long-term traditional NSAID therapy should be considered for testing for H. pylori and treated if positive.

Nonselective NSAIDs: Adverse cardiovascular effects

may have several adverse effects on the cardiovascular system:• interference with the beneficial antiplatelet activity of aspirin ,• an increase in cardiovascular events,• exacerbation of heart failure.

INTERFERENCE WITH BENEFICIAL EFFECTS OF ASPIRIN

• effects of aspirin for secondary or primary prevention of cardiovascular disease result from irreversible acetylation of the active site of cyclooxygenase (COX) in platelets; these effects may be attenuated by prior or ongoing administration of some nonselective NSAIDs, including ibuprofen and naproxen

• regular NSAID use should be avoided, if possible

• In patients who require NSAIDs on an occasional short-term basis, we suggest that aspirin be taken at least two hours before the NSAID

presumed mechanism

• nonselective NSAIDs compete with aspirin for a common binding site on COX-1 and prevents aspirin from binding

• As a result, aspirin is unable to acetylate a serine residue on COX-1, an irreversible reaction that inhibits COX-1 for the remaining life of the platelet

pharmacodynamic interaction is not seen with: celecoxib or diclofenac

The inhibitory effect of naproxen on platelet function is greater than that of ibuprofen and its half-life is significantly longer

Acetaminophen may be an effective alternative to NSAIDs in some patients

Nonselective nonaspirin NSAIDs

• The use of most nonselective NSAIDs is associated with an increased risk of adverse cardiovascular events

• absolute risk is low, but risk increases with higher doses or frequency of use

• Naproxen appears to be the safest with respect to such risk, although an increased risk of myocardial infarction or stroke with naproxen use has also been reporte

• The author prefers to use naproxen or ibuprofen at the lowest effective dose in such patients, based upon the available data and clinical experience.

COX-2 selective inhibitors

• Several COX-2 selective inhibitors (eg, rofecoxib) have been withdrawn from the market because of an increased risk of ischemic cardiovascular events

EXACERBATION OF HEART DISEASE• Use of NSAIDs may cause worsening of heart failure and an increased

risk of new events, including myocardial infarction, in patients with established heart disease.

• suggest that nonselective NSAIDs be avoided in patients with an acute myocardial infarction (MI), unstable angina, or heart failure; during the perioperative period in patients undergoing coronary artery bypass graft surgery; and in patients with a history of a prior MI

If NSAIDs are required, they should be used at the lowest effective dose and for the shortest duration necessary for the given indication. We

suggest naproxen for patients with known cardiovascular disease or increased cardiovascular risk who require treatment with a nonselective

NSAID

Heart failure

• first occurrence of HF was not significantly different from that in individuals who did not use NSAIDs

• Data are also available for the effect of nonselective NSAIDs on the risk of exacerbation of preexisting HF

The adjusted risk of rehospitalization for HF was significantly increased in patients on diclofenac or ibuprofen , and to a numerical but non-significant level for users of naproxen

There was a dose-dependent increase in risk of death, which was highest with diclofenac .Higher doses of ibuprofen (>1200 mg/day) and naproxen (>500 mg/day), but not lower doses, were also associated with an increased risk of death

mechanism for HF exacerbation

• increase in afterload resulting from NSAID-induced systemic vasoconstriction, which can lead to a further reduction in cardiac contractility and cardiac output in advanced HF

• Patients at greatest risk for this complication usually are hyponatremic at presentation

In addition, the vasoconstriction associated with NSAID therapy (including aspirin at a dose ≥325 mg/day) may partially or totally reverse the unloading effect of ACE inhibitors or angiotensin II receptor blockers

ELEVATION IN BLOOD PRESSURE

• Nonselective NSAIDs can raise the blood pressure and worsen control of hypertension in patients already being treated.

• nonselective NSAIDs should be used with caution in such patients, and if required, they should be used at the lowest effective dose and for the shortest duration necessary for the given indication

ACC/AHA guidelines on acute MI or unstable angina

• 2007 American College of Cardiology/American Heart Association guidelines on the management of acute myocardial infarction (ST elevation or non-ST elevation) or unstable angina strongly recommended immediate cessation all nonaspirin NSAIDs at presentation and made a weak recommendation for avoiding their use during hospitalization

• At hospital discharge, the guidelines concluded that it is reasonable to use a nonselective NSAID, such as naproxen , for patients with chronic musculoskeletal disorders if initial treatment with acetaminophen or small doses narcotics is insufficient

celecoxib • Celecoxib use conveys a small, dose-dependent risk of

cardiovascular events similar to most nonselective NSAIDs• 2011 network meta-analysis : the risk of myocardial infarction

(MI) with celecoxib compared with placebo (RR, 1.35, 95% CI, 0.71-2.72) was lower than that for rofecoxib (RR 2.12, 95% CI 1.26-3.56) or ibuprofen (RR 1.61, 95% CI 0.50-5.77), but greater than naproxen (RR 0.82, 95% CI 0.37-1.67), which had the most favorable cardiovascular risk profile

• Cardiovascular risk may increase with celecoxib use soon after it is initiated in patients with known coronary artery disease.

NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome

• Although renal prostaglandins are primarily vasodilators, they do not play a major role in the regulation of renal hemodynamics in normal subjects, since the basal rate of prostaglandin synthesis is relatively low.

• By contrast, the release of these hormones (particularly prostacyclin and prostaglandin E2) is increased by underlying glomerular disease, renal insufficiency, hypercalcemia, and the vasoconstrictors angiotensin II and norepinephrine.

• secretion of the latter hormones is increased in heart failure, cirrhosis, and true volume depletion due to gastrointestinal or renal salt and water losses

In these settings, vasodilator prostaglandins act to preserve renal blood flow and glomerular filtration rate by relaxing preglomerular resistance. This is particularly

important with effective volume depletion in which the prostaglandins antagonize the vasoconstrictor effects of angiotensin II and norepinephrine.

• Inhibition of prostaglandin synthesis with an NSAID in such patients can lead to reversible renal ischemia, a decline in glomerular hydraulic pressure and acute kidney injury

• The rise in the plasma creatinine concentration is seen within the first 3-7 days of therapy, the time required for attainment of steady state drug levels and therefore maximum inhibition of prostaglandin synthesis

Compared with unexposed individuals, an increased risk of acute kidney injury within 30 days of NSAID initiation was noted with the nonselective NSAIDs other than naproxen (RR of 2.3), rofecoxib (RR 2.3), and celecoxib (RR of 1.5).

There has been concern that ketorolac might have greater nephrotoxic potential than other NSAIDs

• Low-dose aspirin (studied at approximately 40 mg per day), low-dose over-the-counter ibuprofen , and perhaps sulindac appear to be safer

• With aspirin , the inhibition of glomerular cyclooxygenase may only be partial and transient, in contrast to the irreversible acetylation in platelets

• However, even low-dose aspirin in elderly patients or aspirin used in conjunction with indomethacin (and possibly other NSAIDS), may lead to a decline in kidney function

• Over-the-counter ibuprofen in low doses is safe in most patients .However, even low dose ibuprofen can reduce the glomerular filtration rate in patients with reduced renal perfusion

Drug interactions• A potentially clinically relevant interaction between

ibuprofen and aspirin referred to as “aspirin resistance” has been observed in ex vivo platelet assays when ibuprofen is administered to healthy controls before aspirin. Similar effects, which also depend upon timing of drug administration, have been demonstrated with naproxen and may occur with other NSAIDs.

• anticoagulants, antiplatelet agents, antihypertensives, calcineurin inhibitors ( cyclosporine and tacrolimus ), digoxin , diuretics, glucocorticoids, lithium , selective serotonin reuptake inhibitors (SSRIs), methotrexate (MTX), and other medications

Drug Usual analgesic dose and interval

Maximum dose per day (mg

Ibuprofen* 400 mg every 4 to 6 hours 3200 acute, 2400 chronic

Naproxen 250 mg every 8 hours or 500 mg every 12 hours

1250 acute, 1000 chronic

Diclofenac 50 mg every 8 hours 150 mg

Indomethacin 25 to 50 mg every 8 to 12 hours

Controlled release: 75 mg every 12 hours

150

Ketorolac (intravenous and intramuscular)`

<65 yrs : 60 mg IV or IM once 15 to 30 mg every 6 hours

120

Meloxicam 7.5 to 15 mg every 24 hours

15

Piroxicam 10 to 20 mg every 24 hours 20

Mefenamic acid 250 mg every 6 hours 1000

Celecoxib 200 mg daily or 100 mg every 12 hours

400