Managing the Adverse Effects of Nonsteroidal Anti-inflammatory Drugs

Paola Patrignani; Stefania Tacconelli; Annalisa Bruno; Carlos Sostres; Angel Lanas

Expert Rev Clin Pharmacol. 2011;4(5):605-621.

Management of Patients With Peptic Ulcers or Dyspepsia Associated With NSAID Use

Nonsteroidal anti-inflammatory drugs and coxib therapy delay the healing of active peptic ulcers. In patients who develop a peptic ulcer during NSAID or coxib treatment, the drug should be stopped, patients treated with PPI therapy and H. pylori eradicated if the infection is present. If patients are unable to discontinue NSAID therapy, patients need to be treated with PPI twice a day co-therapy until the ulcer is healed, which must be confirmed by endoscopy.^[139]

Nonsteroidal anti-inflammatory drug-associated dyspepsia is common, occurring in up to 25–50% of patients.^[86,96,97] The presence of dyspepsia does not predict the presence of mucosal lesions in patients taking NSAIDs,^[96,97,140] since up to 40% of persons with endoscopic evidence of erosive gastritis are asymptomatic, and conversely, as many as 50% of patients with dyspepsia have normal-appearing mucosa. COX-2-selective NSAIDs have a better GI tolerability and lower incidence of dyspepsia than non-selective NSAIDs.^[141,142] Antisecretory drugs, especially PPIs, reduce the incidence of dyspepsia,^[96,97] although up to 10% of patients with NSAID-induced dyspepsia will not obtain relief with antisecretory therapy.^[78] In this clinical setting, two studies comparing omeprazole with ranitidine^[97] or misoprostol^[96] have shown that omeprazole provided greater relief of dyspeptic symptoms than ranitidine. Patients receiving the PPI reported a greater improvement in QOL than patients receiving misoprostol. The role of esomeprazole was evaluated in patients with upper GI symptoms taking NSAIDs, including COX-2 selective NSAID.^[143] Esomeprazole was associated with highly significant symptom improvement compared with placebo. Esomeprazol improved symptoms in patients taking selective COX-2 NSAIDs, as well as those receiving nonselective NSAIDs. Esomeprazol was well tolerated and associated with significant improvements in QOL. Similar data were observed in a post hoc analysis of other studies that aimed to evaluate the role of esomeprazole versus placebo and versus ranitidine.^[144,145]

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Abstract and Introduction
Mechanism of Action of Nonsteroidal Anti-inflammatory Drugs
GI Toxicity of NSAIDs
CV Effects of NSAIDs
COX-inhibiting NO Donators
Managing GI Toxicity
Management of GI Risk With Asprin
Management of Patients With Peptic Ulcers or Dyspepsia Associated With NSAID Use
NSAIDs & Lower GI Damage
Managing CV Toxicity
Expert Commentary
Five-year View
References
Sidebar

Table 1. Suggested strategies for analgesic/anti-inflammatory treatment and cardiovascular prevention among patients with inflammatory disease and different levels of risk of vascular events.
Risk of vascular event^†	Pharmacological strategies
Low (<1% per year)	tNSAID or coxib depending on GI risk
Intermediate (1–3% per year)	tNSAID (low-dose ibuprofen or naproxen + PPI); if aspirin is indicated, naproxen + PPI and aspirin, given 2 h before^‡
High (>3% per year)	Naproxen + PPI and aspirin, given 2 h before^‡

^†Vascular event is defined as the combined outcome of a nonfatal myocardial infarction, nonfatal stroke or vascular death [168].
^‡Recent findings suggest that the possible interference of naproxen on the antiplatelet effect of aspirin can be minimized by the administration of aspirin 2 h before naproxen [167]. By contrast, ibuprofen should be avoided if aspirin is indicated [165,166].
GI: Gastrointestinal; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

Box 1. Prevention strategies in patients with gastrointestinal risk factors who need NSAIDs.
General rules Use the lowest effective dose for the shortest period of time Avoid concomitant therapy with corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents Use 'safer' NSAIDs (coxibs, diclofenac, aceclofenac and ibuprofen) Less use of NSAIDs with the highest gastrointestinal toxicity (ketorolac, piroxicam, and ketoprofen) Eradicate Helicobacter pyloriinfection in patients with prior ulcer history Use of prevention strategies No CV risk factors No gastrointestinal risk factors: use tNSAIDs (no need for prevention strategies) One or more gastrointestinal risk factors: coxib (standard dose) alone or nonselective NSAID + PPI or misoprostol If history of ulcer bleeding: coxib + PPI. Eradicate H. pyloriinfection. Avoid nonselective NSAIDs Previous CV events or risk for CV events >10% in 10 years (treatment with low-dose aspirin) One or more gastrointestinal risk factors: nonselective NSAID (naproxen) + PPI or coxib + PPI In Europe, if previous CV event exists, the European Medicine Agency contraindicates use of coxibs Avoid combining with ibuprofen since it may interfere with low-dose aspirin If history of ulcer bleeding: avoid tNSAIDs or coxib. Eradicate H. pyloriinfection If strictly necessary, celecoxib low dose + PPI. If previous CV event in Europe, coxib contraindicated
CV: Cardiovascular; PPI: Proton pump inhibitor; tNSAID: Traditional NSAID.

Sidebar

Key Issues

Conventional medical treatment for rheumatoid arthritis and osteoarthritis requires the use of NSAIDs because they provide unmistakable and significant health benefits in the treatment of pain and inflammation.
NSAIDs share both beneficial and adverse effects due to the same mechanism of action, i.e. the inhibition of cyclooxygenase (COX) activity. Their beneficial therapeutic use as antiinflammatory and analgesic agents is associated with increased risk of gastrointestinal (GI) and cardiovascular (CV) serious adverse events (i.e., upper GI bleeding and nonfatal myocardial infarction [MI]).
The risk of nonfatal MI was increased by 35% with current use of NSAIDs, but there was no increase in the risk of fatal MI. The excess risk increased with increasing treatment duration and daily dose.
The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin (PGI2) can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity.
Degree of inhibition of COX-2 for NSAIDs functionally selective for COX-2 is relevant to CV hazard and relates to drug potency (exposure). It has been proposed that the assessment of whole blood COX-2 ex vivomay represent a valid surrogate end point to predict CV risk for functionally selective COX-2 inhibitors.
NSAIDs injure the GI tract by causing topical injury to the mucosa and by systemic effects associated with mucosal prostanoid depletion derived from COX inhibition. The main clinically relevant GI side effects include GI bleeding, perforation and obstruction.
Management of patients with GI risk factors who require NSAIDs includes the use of the lowest possible dose for the shorter period of time, the use of the safest NSAIDs, the use of co-therapy with with gastroprotectants and the avoidance of co-therapy of NSAIDs with anticoagulants, antiplatelet agents or corticosteroids. Reduced incidence of GI ulcers complications compared with traditional NSAIDs (tNSAIDs) has been demonstrated for COX-2 inhibitors. COX-2 plays an important role in the healing of pre-existing ulcers. This is supported by clinical data showing that coxibs are still associated with a small risk of upper GI bleeding, though smaller than that caused by tNSAIDs.
Despite upper GI bleeding risk being multifactorial, drugs with a long half-life or slow-release formulation and/or associated with profound and coincident inhibition of both COX isozymes – which translates into deficiency of prostanoid generation in the GI tract – were associated with a greater risk of upper GI complications.
The development of biomarkers predictive of the impact of NSAIDs on COX-1 and COX-2 activities in vitro, ex vivoand in vivohas been essential to read out the clinical consequences of selective and nonselective inhibition of COX isozymes in humans. Reduction of the dose is recommended and presumably will limit, but not delete, CV or GI risk by NSAIDs and coxibs.
The use of pharmacogenomic tools to define the role of genetic factors in individual responses to drugs, in association with pharmacoepidemiological methods, represents a very promising approach to predict CV and GI risks for coxibs and tNSAIDs and to create personalized drugs with better efficacy and safety.

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