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Volume 38, No. 2


Nonsteroidal anti-inflammatory drugs, often referred to as NSAIDS, are assumed to be well tolerated and are widely used as an initial therapy for common inflammation.  Everyone is familiar with these types of drugs with millions using them for pain relief.  They range from over the counter aspirin and ibuprofen to a whole host of prescription brands.  These pharmaceutical agents constitute one of the most widely used class of drugs, with more than 70 million prescriptions and more than 30 billion over-the counter tablets sold annually in the United States alone.  NSAIDs are often called nonsteroidal because they are not steroids.  Steroids affect inflammation by suppressing part of the immune system, which is the body’s natural healing response to trauma.  Instead NSAID drugs mainly inhibit the body's ability to synthesize prostaglandins.  Prostaglandins are a family of hormone-like chemicals, some of which are made in response to cell injury.

Common over the counter names include: ibuprofen (Advil®), naproxen (Aleve®), and aspirin (Bayer®).  Prescription brands include: celecoxib (Celebrex®), diclofenac (Voltaren®), etodolac (Lodine®), fenoprefen (Nalfon®), indomethacin (Indocin®), ketoprofen (Orudis®, Oruvail®), ketoralac (Toradol®), oxaprozin (Daypro®), nabumetone (Relafen®), sulindac (Clinoril®), tolmetin (Tolectin®), and rofecoxib (Vioxx®).

It is generally stated that the side effects of NSAIDs are fairly mild causing a possible upset stomach and/or nausea and vomiting.  It is often recommended that the stomach upset, nausea and vomiting can be avoided by taking the medication with a little food or milk.  It is also well stated that long-term or extensive ingestion of NSAIDs can result in the drugs having toxicity to the kidneys and also to the lining of the stomach, possibly causing ulcers.  Except for these mild warning these medications are considered safe and effective.  But in reality just how safe are these types of drugs?

A statement from a July 1998 issue of The American Journal of Medicine states the following:

“Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone.  The figures of all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated.”  

And again a year later (June 1999) in the prestigious New England Journal of Medicine there is a similar statement:
“It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the United States.  This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin’s disease.  If deaths from gastrointestinal toxic effects from NSAIDs were tabulated separately in the National Vital Statistics reports, these effects would constitute the 15th most common cause of death in the United States.  Yet these toxic effects remain mainly a “silent epidemic,” with many physicians and most patients unaware of the magnitude of the problem.  Furthermore the mortality statistics do not include deaths ascribed to the use of over-the-counter NSAIDS.”  

What these journal articles are stating is shocking.  Over 100,000 people are hospitalized for GI bleeding and of those 16,500 die every year.  And these values are considered “conservative”.  Also the figures only include prescription NSAIDs used to treat only arthritis and only in the United States.  If prescription and over the counter NSAID-related hospitalizations and death rates were counted for not only arthritis, but for all conditions, and throughout the world, the figures would no doubt be enormous.  Taking those figures and applying them over the many years that this class of drug that has been available since the early 1970s and the numbers would be horrific.  And yet, no study to date has attempted to quantify these figures.  A graph from the same article shows this alarming statistic relative to other causes of deaths.
U.S. Mortality Data for Seven Selected Disorders in 1997.  A total of 16,500 patients with rheumatoid arthritis or osteoarthritis died from the gastrointestinal toxic effects of NSAIDs.  Data are from the National Center for Health Statistics and the Arthritis, Rheumatism, and Aging Medical Information System. 

Looking at this information from another perspective we can compare yearly estimated NSAID deaths since 1991 with the number of murders committed with firearms each year in the United States and with the number of U.S. Forces killed in Vietnam if that war was being fought in the 1990s instead of 1961-1972.  Although no data shows the exact number of NSAID deaths each year 7,600 deaths were estimated in 1991 and 16,500 deaths were estimated in 1998. 

Another important observation is that most people have no warning signs that these drugs are causing them internal damage before they ending up in the hospital with a serious medical condition.  And as we have seen from the statistics, approximately 10% of these hospitalizations end in death.

“… 81% of the patients who were hospitalized with a serious GI complication did not have any prior GI adverse event.  This finding has important clinical and health policy implications.  Since most patients who have a hospitalization do not have a prior GI side effect and most patients who have a side effect are not subsequently hospitalized, a clinician cannot depend on early GI symptoms to identify patients at risk or provide a warning for subsequent serious complications.” 

Since there is knowledge that these medications can cause stomach upset, other drugs, such as antacids, are prescribed to alleviate those symptoms.  And while these additional medications may provide symptom relief they do not prevent the underlying damage that is occurring.  And by hiding these symptoms antacids actually increase the chances of having a serious problem.  Despite this evidence, many patients are prescribed these additional drugs.

“The use of antacids and H2 receptor antagonists for prophylaxis against serious NSAID-induced GI complications remains controversial.  Previous research has shown that although these agents suppress symptoms, they do not prevent endoscopically documented NSAID-induced gastric ulcers, the most common pathology seen with NSAIDs.  There is no data on the role of antacids and H2 receptor antagonists in actually preventing clinically significant serious GI complications.  Nevertheless, antacids and H2 receptor antagonists are widely used in combination with NSAID therapy (30% patients in our study).  Our data indicate that patients taking antacids and H2 receptor antagonists are not afforded a lower risk of significant GI events.  Indeed, asymptomatic patients who started to take antacids or H2 receptor antagonists prophylactically had a higher risk for serious GI complication compared with those who did not take these medications.” 
Even aspirin, the first NSAID that was synthesized over 100 years ago by Felix Hoffman at Bayer industries is not free of risk.  And considering that aspirin is being highly recommended to reduce the incidence of heart disease we must consider the gastrointestinal damage being caused as well.

“We found that no particular dose of aspirin between 75 mg and 300 mg daily currently used in cardiovascular prophylaxis is free of risk of causing bleeding from gastric or duodenal ulcers.  Even very low (75 mg) doses of aspirin reportedly caused gastric bleeding in volunteers. … Some 10,000 episodes of ulcer bleeding occur in people aged 60 and over each year in England and Wales.  Other data of ours suggest that some 3,500 of these will be takers of non-aspirin non-steroidal anti-inflammatory drugs, and if our current figures are representative 1,700 or 17% of the total will be taking prophylactic aspirin compared with 8% of community controls.  If may be deduced that 900 of the 10,000 episodes could be associated with and ascribed to prophylactic aspirin use.  A general change to low doses (75 mg) of aspirin would not eliminate the risk, but again if our figures are soundly based, would reduce the risk by about 40% compared with 300 mg doses and by 30% compared with 150 mg doses.” 

Unfortunately the risk of hospitalization and death is not the only possibility from taking these types of drugs.  Other studies also indicate that the risk of Congestive Heart Failure (CHF) while using NSAIDs is also quite substantial.  One author suggested that the number of deaths could be similar to those that are being seen with gastrointestinal bleeding.  If so the numbers of deaths attributed to NSAIDs would increase dramatically from the already large figure of 16,500.
“In this study we found that recent use of NSAIDs by elderly patients doubles the odds of being admitted to hospital with an episode of CHF [Congestive Heart Failure].  The estimated relative risk for first admission with heart failure, and the risk of this outcome was increased substantially by NSAID use in those with a history of heart disease. … Assuming the association between use of NSAIDs and CHF is unconfounded, the disease burden attributable to these drugs may be large – approaching the levels of morbidity and mortality that we have previously documented for serious upper gastrointestinal complications of NSAID use in NSW [New South Wales].” The risk appears to be especially great in patients using diuretics."

“During periods of concomitant use of diuretics and NSAIDs, a 2-fold increased risk of hospitalization for CHF [Congestive Heart Failure] was found compared with periods of diuretic used only.  Patients with a history of heavy diuretic use showed an increased risk.  This may lead to the hypothesis that an existing condition of CHF that is being treated with diuretics is challenged by the introduction of NSAIDs.” 

Since these medications are marketed and used worldwide we should expect there to be NSAID hospitalizations and deaths worldwide.  Although the available information is limited, there is evidence of this occurring in Germany and Great Britain.

“We thus calculated the total number of NSAID-associated hospital admissions for gastrointestinal PUB [Perforations, Ulcers and Bleeding] in the GKV [German statutory health-insurance fund] to be 10,700 per year, necessitating 157,000 hospital days and total costs of DM 125 million.  1,100 to 2,200 fatal cases in the GKV annually were thus expected.  Multiplying these figures by a factor of 1.1 provides estimates for the entire German populations.” 

“… studies from Great Britain which show an estimated 12,000 NSAID-related hospital admissions and 4,000 NSAID-related deaths.” 

Not only are there enormous deaths and suffering associated with NSAIDs there is also a tremendous financial cost.
“… the annual number of hospitalizations in the United States for serious gastrointestinal complications is estimated to be at least 103,000.  At an estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of such complications exceeds $2 billion.” 

Is this information of NSAID recent?  Unfortunately the answer is no.  Various medical journals in 1991 showed there was information on the toxicity of these types of drugs.

“These results led the investigators to suggest that in the United States the syndrome of NSAID-associated gastropathy accounts for at least 2600 deaths and 20,000 hospitalizations each year in patients with rheumatoid arthritis alone.” 

“Overall death estimates are similarly disquieting.  Conservative calculations, counting only excess deaths, indicate that about 7,600 deaths/year in the United States are attributable to NSAID use.  The Food and Drug Administration suggests even higher figures, estimating NSAID use accounts for 10,000 to 20,000 deaths/year.  These figures are comparable to Hodgkin’s disease or acquired immunodeficiency syndrome and represent a serious problem.” 
In spite of this knowledge, the FDA did little.  Over time certain NSAID medications that were especially toxic were withdrawn or banned, research slowly progressed to find less toxic NSAIDs or to find other medications that would counteract the damage being created.  But there was no large-scale public alert to the potential hazards of these drugs.  Instead the FDA opted to simply provide a warning label on NSAIDs.

“Gastrointestinal adverse reactions with long-term use of NSAIDs.  A general paragraph regarding the risk of gastrointestinal ulcers, bleeding, and perforation with long-term NSAID treatment is being developed for inclusion on the labels of all NSAIDs.  By life table analysis of prospectively collected data from multiple NSAID submissions, the FDA estimates that these serious events occur in approximately 1-2% of patients using NSAIDs for 3 months, and in approximately 2-5% using them for 1 year.  The cumulative risk appears to increase with the duration of therapy and to be greater in patients with previous peptic ulcer disease.  Fatal outcomes are more likely in elderly or debilitated patients.  Higher dosages of NSAID probably entail greater risk that lower dosages.” 

NSAIDs are truly a silent epidemic that have caused a tremendous amount of pain and death.  Public knowledge of this tragedy is virtually non-existent with an enormous amount of information written primarily existing within the sanctuary of medical libraries.  Pharmaceutical companies still market and promote worldwide sales of these toxic substances and governmental agencies have done nothing of any substance to alert the public.  Pharmaceutical companies are now creating a new class of NSAIDs called COX-2 inhibitors that “maybe” less toxic than their earlier creations.  But these efforts come at the same time large numbers of needless hospitalizations and deaths are occurring.  And considering that these companies originally created such toxic substances can we trust them to create newer drugs to replace their failures?  Also, like the original drugs large scale long term studies are not performed before vigorous market campaigns and sales have promoted these new “safer” drugs.  Instead, once again, the people will play guinea pig and years later we will learn the results of their latest experiments.

Singh Gurkirpal, MD, “Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy”, The American Journal of Medicine, July 27, 1998, p. 31S
Wolfe M. MD, Lichtenstein D. MD, and Singh Gurkirpal, MD, “Gastrointestinal Toxicity of Nonsteroidal Anti-inflammatory Drugs”, The New England Journal of Medicine, June 17, 1999, Vol. 340, No. 24, pp. 1888-1889.
Wolfe M. MD, et al, The New England Journal of Medicine, June 17, 1999, Vol. 340, No. 24, pp. 1888-1889.
Fries James F., “NSAID Gastropathy: The Second Most Deadly Rheumatic Disease?  Epidemiology and Risk Appraisal”, Journal of Rheumatology, 1991, (Supplement 28), Vol. 18, pp. 6-10; Singh Gurkirpal, MD, The American Journal of Medicine, July 27, 1998, p. 31S
Singh Gurkirpal, MD, Ramey Dena, Morfeld Dianne, Shi Hong, MS, Hatoum Hind, PhD, and Fries James, MD, “Gastrointestinal Tract Complications of Nonsteroidal Anti-inflamatory Drug Treatment in Rheumatoid Arthritis”, Archives of Internal Medicine, July 22, 1996, Vol. 156, pp. 1530-1536
Singh Gurkirpal, MD, et al, Archives of Internal Medicine, July 22, 1996, Vol. 156, pp. 1530-1536
Weil, J., Colin-Jones D., Langman M., Lawson D., Logan R., Murphy M., Rawlins M., Vessey M., and Wainwright P., “Prophylactic aspirin and risk of peptic ulcer bleeding”, British Medical Journal (BMJ), April 1, 1995, Vol. 310, pp. 827-829
Page J. MBBS(Hons) and Henry D. MBchB, “Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients”, Archives of Internal Medicine, March 27, 2000, Vol. 160, pp. 777-784
Heerdink E., PhD, Leufkens H., PhD, Herings R., PhD, Ottervanger J., MD, Stricker B., MD and Bakker A., MD, “NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics.”, Achrives of Internal Medicine, May 25, 1998, Vol. 158, pp.1108-1112
Bolten W., Lang B., Wagner A., and Krobot K., “Consequences and Costs of NSAID-Induced Gastropathy in Germany”, Akt Rheumotol, 1999, Vol. 24, pp. 127-134
Bolten W., et al, Akt Rheumotol, 1999, Vol. 24, pp. 127-134
Wolfe M. MD, et al, The New England Journal of Medicine, June 17, 1999, Vol. 340, No. 24, pp. 1888-1889.
Brooks Peter, MD and Day Richard, MD, “Nonsteroidal Anti-Inflammatory Drugs – Differences and Similarities”, The New England Journal of Medicine, June 13, 1991, Vol. 324, No. 24, pp. 1716-1725
Fries James F., “NSAID Gastropathy: The Second Most Deadly Rheumatic Disease?  Epidemiology and Risk Appraisal”, Journal of Rheumatology, 1991, (Supplement 28), Vol. 18, pp. 6-10
Paulus Harold, “FDA Arthritis Advisory Committee Meeting: Risks of Agranulocytosis/Aplastic Anemia, Flank Pain, and Adverse Gastrointestinal Effects with the Use of Nonsteroidal Anti-Inflammatory Drugs”, Arthritis and Rheumatism, May 1987, Vol. 30, No. 5, pp. 593-595



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