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					                   NSAID-induced Ulcers:
  COX-2 Withdrawals, Low Awareness of Treatment Guidelines
         Maintain High Scientific Interest in Solutions

Recently, concerns over cardiovascular safety resulted in the withdrawal from the
market of two of the three available COX-2-selective pain medications – Vioxx®
and Bextra®. Since then patients with chronic pain and their clinicians have been
struggling to replace what this class of drugs promised: better gastrointestinal
(GI) safety than an older, traditional class of pain relievers known as non-
selective nonsteroidal anti-inflammatory drugs (NSAIDs), with similar levels of
effective pain relief.

At the same time, the medical and scientific communities have shown continued
interest in clinical research on NSAIDs, medications long known for an increased
risk of stomach ulcers, particularly among older patients who take them regularly
or who have a history of gastric ulcers. Recent studies have examined both
prescription and over-the-counter (OTC) doses of this commonly used drug
class, which includes ibuprofen and naproxen, as well as aspirin.

A MEDLINE literature search shows that several hundred studies on NSAID-
associated gastric ulcers were published in peer-review journals during 2005,
while many others await publication. Interest in the subject continues, with a
number of large multi-center clinical trials currently recruiting up to 1,000 patients
each in the United States and abroad.1

Most physicians understand the risk factors for NSAID-associated gastric ulcers
(such as age 60+ or a history of upper GI bleeding), and various professional
societies and managed care organizations have published evidence-based
guidelines for the safe use of NSAIDs. Yet complications from NSAID-associated
gastric ulcers remain a significant clinical problem accounting for nearly 103,000
hospitalizations and 16,500 deaths each year in the United States.2

Some of the research published during the past year suggests several possible
reasons why:

    Low adherence to preventive treatment guidelines recommending the use
     of gastroprotective therapy, such as a proton pump inhibitor (PPI) or
     misoprostol, with a traditional NSAID in high-risk patients
    Misperceptions about the safety of OTC NSAIDs
    Underestimation of the incremental ulcer risks of combining aspirin with
     other NSAIDs

Findings from some of the more recent NSAID-ulcer studies are described in
greater detail in the section that follows.
Low Adherence to Treatment Guidelines
While most physicians are aware of clinical guidelines to prevent NSAID-
associated gastric ulcers, many aren’t following these guidelines in practice.
Consequently some patients, especially those at high risk, are not being
prescribed gastroprotective drugs that can reduce the risk of GI toxicity
associated with NSAIDs, despite clear evidence of their benefits. For example, a
recent study found that there was a 60% reduction in ulcer development among
NSAID users who also took a PPI.3

A study examining prescribing patterns reported that in the United States, less
than one third of NSAID users (29%) are prescribed a PPI, compared to more
than half of NSAID users in Spain.4 Some researchers postulate that high PPI
use may account for a decrease in NSAID-related hospitalizations in Spain over
the last decade.5 These same researchers found that the death rate from
NSAID-induced GI complications in Spain is just a third of that in the United
States.6

Findings from a 707,244-patient study of U.S. veterans, published in
Gastroenterology, reported U.S. physicians’ low adherence to treatment
recommendations. The study found that health care professionals followed
established guidelines for safe NSAID use – i.e., prescribing a gastroprotective
agent such as a PPI with an NSAID – in less than a third of patients (27%) at
high risk for GI bleeding.7 While these physicians were more likely to prescribe a
preventive NSAID-ulcer therapy as the number of risk factors per patient
increased, adherence to guidelines was still low: they prescribed gastroprotective
therapy to 40% of patients with at least two risk factors, and to 42% of those with
three or more risk factors.8

The study authors conclude that there is sufficient evidence to support the GI
benefits of gastroprotective agents as recommended by evidence-based
guidelines, in particular the addition of PPIs to reduce the risk of ulcers from
traditional NSAIDs.9

Misperceptions about the Safety of OTC NSAIDs
Some recent consumer-perception surveys suggest that many of the 23 million
Americans who use OTC NSAIDs daily10 are either unaware or unconcerned
about the drugs’ risks. Consequently, they may take higher than normal doses of
these medications or use them in other inappropriate or dangerous ways.
Two recent surveys, the results of which were published in the Journal of
Rheumatology, showed that one-fourth of people who take an OTC pain
medication exceed the manufacturer’s recommended dose,11 and half are either
unaware or unconcerned about the drug’s potential for GI toxicity. 12 Many
regular OTC NSAID users also believe that any side effects or complications
from the drugs will always be preceded by warning symptoms.13


    Based on the percentage of all patients hospitalized with NSAID-related GI complications.


                                                                                                2
Similarly, a survey on behalf of the American Chronic Pain Association found that
nearly two-thirds of people age 55 and over with chronic pain said they know that
stomach ulcers are a common side effect of NSAIDs, but only 31% think they are
at moderate or high risk for developing an NSAID-induced ulcer in the next 10
years.14 Yet 45% of the respondents took an OTC or prescription NSAID four or
more times a week, which put them at increased risk for an ulcer.15

Underestimation of the Risks of Using Aspirin with Other NSAIDs
Studies have shown that low-dose aspirin taken alone as cardiovascular
prophylaxis may increase the risk of upper GI bleeding,16 and that the risk may
be even greater when aspirin is combined with either a traditional NSAID or a
COX-2.17 While most clinicians recognize that using multiple NSAIDs increases
the risk for GI complications, they may overlook the incrementally harmful effects
of combining aspirin with other NSAIDs.18

While no recent studies have examined the use of gastroprotective agents when
aspirin is taken with traditional NSAIDs, several studies have shown the value of
adding a PPI to low-dose aspirin alone. A study of healthy volunteers taking low-
dose aspirin over the short term demonstrated that the addition of a PPI offered
protection against significant stomach damage.19

A Serious Problem with a Clear Solution
Hospitalizations and deaths attributed to complications from chronic NSAID use
remain a significant public health concern in the United States, despite strategies
that already exist to reduce these risks. This is a problem that can be addressed
with increased patient education and stricter adherence to treatment guidelines.
With significantly less in their pain-relief armamentarium, patients and clinicians
must carefully weigh the benefits and risks of available NSAIDs, as well as
individual GI risk factors, before deciding on treatment and whether additional
protective measures are needed.



                                        ###




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                                             References

1
  CenterWatch.com. Available at: http://centerwatch.com/patient/studies/stu70354.html.
ClinicalTrials.gov. Available at:
http://clinicaltrials.gov/ct/show/NCT00153660;jsessionid=A274F050C1836841DEDBA46C366C7CD6?or
der=2, http://clinicaltrials.gov/ct/show/NCT00190255?order=1,
http://clinicaltrials.gov/ct/show/NCT00153673?order=4,
http://clinicaltrials.gov/ct/show/NCT00175032?order=1,
http://clinicaltrials.gov/ct/show/NCT00108992?order=1. As of February 22, 2006.
2
   Wolfe M, Lichtenstein R, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N
Engl J Med 1999; 340 (24): 1888-1899.
3
  Rostom A et al. Prevention of NSAID-induced gastroduodenal ulcers (Cochrane Review). In: The
Cochrane Library Issue 2. Oxford: Update Software, 2003. From Singh G et al. Appropriate choice of
proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal
damage. Int J Clin Pract 2005, 59;10:1210-1217.
4
   Lanas A, et al. A nationwide study of mortality associated with hospital admission due to severe
gastrointestinal events and those associated with NSAID use. Am J Gastroenterol 2005;100:1685-1693.
From Cryer B. NSAID-associated deaths: The rise and fall of NSAID-associated GI mortality. Am J
Gastroenterol 2005;100:1694-1695 (editorial in response to the Lanas study).
5
  Fries JF, et al. The rise and decline of NSAID-associated gastropathy in rheumatoid arthritis. Arthritis
Rheum 2004;50:2433-40. From Cryer B. NSAID-associated deaths: The rise and fall of NSAID-associated
GI mortality. Am J Gastroenterol 2005;100:1694-1695 (editorial in response to the Lanas study).
6
   Cryer B. NSAID-associated deaths: The rise and fall of NSAID-associated GI mortality. Am J
Gastroenterol 2005;100:1694-1695 (editorial in response to the Lanas study).
7
  Abraham NS et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal
anti-inflammatory drugs. Gastroenterology 2005;129:1171-1178.
8
  Abraham NS et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal
anti-inflammatory drugs. Gastroenterology 2005;129:1171-1178.
9
  Ekstrom P et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving
continuous nonsteroidal anti-inflammatory drug therapy. A Nordic multicentre study. Scand J
Gastroenterol 1996;31:753-758.
   Hawkey CJ et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-
inflammatory drugs. Omeprazole vs. Misoprostol for NSAID-induced Ulcer Management (OMNIUM)
Study Group. N Engl J Med 1998;338:727-734.
   Cullen D et al. Primary gastroduodenal prophylaxis with omeprazole for nonsteroidal anti-inflammatory
drug users. Aliment Pharmacol Ther 1998;12:135-140.
   Yeomans ND et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal
anti-inflammatory drugs. Acid Suppression Trial: Ranitidine vs. Omeprazole for NSAID-associated Ulcer
Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719-726.
   All citations above from Abraham NS et al. National adherence to evidence-based guidelines for the
prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology 2005;129:1171-1178.
10
   Wilcox CM et al. Patterns of use and public perception of over-the-counter pain relievers: focus on
nonsteroidal anti-inflammatory drugs. J Rheumatol 2005; 32:2218-24.
11
   Wilcox CM et al. Patterns of use and public perception of over-the-counter pain relievers: focus on
nonsteroidal anti-inflammatory drugs. J Rheumatol 2005; 32:2218-24.
12
   Wilcox CM et al. Patterns of use and public perception of over-the-counter pain relievers: focus on
nonsteroidal anti-inflammatory drugs. J Rheumatol 2005; 32:2218-24.
13
   Wilcox CM et al. Patterns of use and public perception of over-the-counter pain relievers: focus on
nonsteroidal anti-inflammatory drugs. J Rheumatol 2005; 32:2218-24.
14
   Harris Interactive online survey on behalf of AstraZeneca and ACPA: The NSAID Ulcer Risk Awareness
survey. Conducted June 7-17, 2005.
15
   Harris Interactive online survey on behalf of AstraZeneca and ACPA: The NSAID Ulcer Risk Awareness
survey. Conducted June 7-17, 2005.



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16
   Singh G et al. Appropriate choice of proton pump inhibitor therapy in the prevention and management of
NSAID-related gastrointestinal damage. Int J Clin Pract 2005, 59;10:1210-1217.
17
   Scheiman JM. Nonsteroidal anti-inflammatory drugs, aspirin, and gastrointestinal prophylaxis: an ounce
of prevention. Rev Gastroenterol Disord 2005;5(suppl 2):S39-S49.
18
   Scheiman JM. Nonsteroidal anti-inflammatory drugs, aspirin, and gastrointestinal prophylaxis: an ounce
of prevention. Rev Gastroenterol Disord 2005;5(suppl 2):S39-S49.
19
   Müller P et al. The action of the proton pump inhibitor pantoprozol against acetylsalicylic acid-induced
gastroduodenopathy in comparison to ranitidine. An endoscopic controlled double-blind comparison.
Arzneimittelforschung 1998; 48:482-5 (article in German). From Singh G et al. Appropriate choice of
proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal
damage. Int J Clin Pract 2005, 59;10:1210-1217.




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