Nonsteroidal Antiinflammatory Drug-Related Injury to the Gastrointestinal Tract: Clinical Picture, Pathogenesis, and Prevention

Increasing life expectancy in developed countries has led to a growing prevalence of arthritic disorders, which has been accompanied by increasing prescriptions for nonsteroidal antiinflammatory drugs (NSAIDs). These are the most widely used agents for musculoskeletal and arthritic conditions. Although NSAIDs are effective, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular system, skin, and gut. Gastrointestinal (GI) side effects are the most common. The dilemma for the physician prescribing NSAIDs is, therefore, to maintain the antiinflammatory and analgesic benefits, while reducing or preventing GI side effects. The challenge is to develop safer NSAIDs by shifting from a focus on GI toxicity to the increasingly more appreciated cardiovascular toxicity.

Increasing life expectancy in developed countries has led to a growing prevalence of arthritic disorders, which has been accompanied by increasing prescriptions for nonsteroidal antiinflammatory drugs (NSAIDs). These are the most widely used agents for musculoskeletal and arthritic conditions, representing more than 7.7% of all prescriptions in Europe. However, these figures are probably underestimated, because over-the-counter (OTC) use is not included. In absolute terms, in 2004, there were 111 million NSAID prescriptions in the United States. The reason for such widespread use is the clinical effectiveness of NSAIDs, which have been consistently shown to be more effective than acetaminophen (paracetamol) for the management of osteoarthritis (OA), and the fact that NSAIDs are endorsed in current OA management guidelines.

Although NSAIDs are effective, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin, and gut. Gastrointestinal (GI) side effects are the most common and range from dyspepsia, heartburn, and abdominal discomfort to more serious events such as peptic ulcer with the life-threatening complications of bleeding and perforation. The dilemma for the physician prescribing NSAIDs is, therefore, to maintain the antiinflammatory and analgesic benefits, while reducing or preventing GI side effects.

NSAIDs are usually given orally, although intravenous, intramuscular, rectal, or topical administrations are used if specifically designed formulations are available. With the exception of renal colic, in which NSAIDs act faster when given intravenously, in all other pain conditions there is no evidence that injected NSAIDs are superior to oral.

Despite the oral route being the most widely used, and allowing self-medication, it is the most challenging in terms of absorption and drug- and food-drug interactions. Moreover, oral intake allows direct contact between the drug and the entire GI tract mucosa, thus exposing it to topical damage until absorption. However, injury may continue after drug absorption if the mucosa is further exposed as a result of enterohepatic circulation of the NSAID.

The GI tract, like the skin and the respiratory system, is in continuous and direct interaction with the environment. The functions of the GI tract as a protective barrier are as important as digestion and absorption. The large surface area and prolonged exposure increase the risk of drug-mediated damage, and increased permeability (often found in some inflammatory conditions) may augment this. The remarkable tolerance of the GI mucosa to damaging agents including NSAIDs relies on rapid epithelial repair, which depends on restitution and cell replication. When repair fails, erosions and ulcers develop, disrupting the basement membrane, forming persistent ulcers, which then increase the risk of clinically relevant events.

Epidemiology of NSAID-associated mucosal injury

In the United States, a national prescription audit showed an annual NSAID consumption of 111,400,000 at a cost of $4.8 billion, with further sales of OTC oral analgesics of $3 billion. A survey of NSAID use among people older than 65 years showed that 70% were taking an NSAID at least once a week and half of these were taking an NSAID daily. A study in Europe reported an NSAID consumption of 42.82 to 74.17 defined daily dose/1000 inhabitants in 2007, increasing by 25.1% between 2002 and 2007. Diclofenac and ibuprofen were the most prescribed agents, with a notable increase in nimesulide and meloxicam use. Trends for consumption of selective cyclooxygenase-2 (COX-2) inhibitors differed within countries.

Recent data from US veterans older than 65 years shows an overall mortality of 5.5 per 1000 person years after an upper GI event, rising to 17.7 per 1000 person years following a myocardial infarction and 21.8 per 1000 person years following a cardiovascular accident. Predictors of mortality were advancing age, comorbidities, increased COX-2 inhibitor use, and failure to provide gastroprotection.

In the United Kingdom, a previous study reported an overall mortality in patients with GI bleeding of 12%. A more recent systematic review of studies published since 1997 shows that upper GI bleeding or perforation still carries a finite risk of death. Differences in study design, population characteristics, risk factors, definition of mortality, and reporting of outcomes imposes limitations on interpreting effect size. Data published since 1997 suggest that mortality in patients suffering from an upper GI bleed or perforation has fallen to 1 in 13 overall, but remains higher, at about 1 in 5, in those exposed to NSAIDs or aspirin.

There have also been serious consequences to the post-Vioxx anxieties about the use of COX-2 selective drugs. There has been a move back to the use of nonselective NSAIDs (ns-NSAIDs) by rheumatologists in North America. A recent study has shown that COX-2 inhibitor withdrawals also resulted in a rapid decline in NSAID gastroprotection prescribed by US rheumatologists despite the availability of different gastroprotective options. Channeling toward nonselective NSAID use was widespread, also among patients at increased CV risk. Longer-term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities.

There has also been a changing pattern to the location of GI bleeding in patients taking NSAIDs, with increasing reports of bleeding lesions located in the small intestine. However, it is not yet clear whether this reflects increased awareness and ascertainment bias or a real increase in small bowel lesions. A study of hospitalized patients in Spain shows that, in the past decade, there has been a progressive change in the overall picture of GI events leading to hospitalization, with a decreasing trend in upper GI events and a significant increase in lower GI events, causing the rates of these GI complications to converge. Overall mortality has also decreased, but the in-hospital case fatality rate from upper or lower GI complications has remained constant. It will be a challenge to improve care unless new strategies can be developed to reduce the number of events originating in the lower GI tract, as well as reducing associated mortality.

The high risk in elderly patients taking NSAIDs has been repeatedly confirmed, and a study from Argentina in 324 adults with a mean age of 74 years and a similar number of controls found that NSAID exposure increased the risk of hospitalization for peptic ulcer disease (PUD, odds ratio [OR] 5.20; 95% confidence interval [CI] 3.31–8.15). A history of upper GI complications was independently associated with hospitalization for PUD (OR 14.62; 95% CI 6.70–31.91). Thus, ns-NSAIDs are a significant risk factor for PUD-related hospitalizations among older adults.

The use of all medications increases with age and the elderly are at increased risk of adverse drug reactions. The risk of these complications depends on the presence of risk factors, the most frequent and relevant of which is age. Thus, patients at risk should be on prevention strategies including the lowest effective dose of NSAID, cotherapy with a gastroprotective drug, or the use of a COX-2 selective agent. Although the best strategy to prevent lower GI complications has yet to be defined, treatment of associated Helicobacter pylori infection is also important when starting treatment with ns-NSAIDs or aspirin, especially in the presence of an ulcer history.

A recent study exploring gastroprotective strategies among 1.5 million patients in the AGIS database indicated that both the prevalence of NSAID prescriptions and the risk of gastric complications is increasing steadily. Although the number of patients receiving gastroprotective medication increased from 39.6% in 2001 to 69.9% in 2007, more than 30% of patients at risk for GI complications were left unprotected in 2007. To enhance protection rates in patients using NSAIDs and to decrease NSAID-related hospital admissions in the future, the implementation of gastroprotection guidelines needs to be improved.

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