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Drugs & Adverse Effects / Complications Due to NSAIDS
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submitted by Dr. Gary Farr - Contact the author here.
Last Updated February, 12, 2002
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Wolfe MM, et al.
N Engl J Med. 1999 Jun 17;340(24):1888-99. Review.
This review presents current knowledge on nonsteroidal antiinflammatory drugs (NSAID)-related gastrointestinal toxicity. NSAIDs were developed in the 1970s as an alternative to aspirin and its side effects, most notably gastric ulcers, and became in the following decades one of the most frequently used class of drugs. Every year, in the U.S., over 70 million prescriptions are written for NSAIDs, and over 30 billion tablets are sold over-the-counter. Toxicity from these drugs is substantial. Particularly affected is the gastrointestinal system. Dyspepsia occurs in 5-50% of patients, and causes discontinuation of treatment within 6 months of initiation in 5-15% of individuals. It has been estimated that for every 1000 rheumatoid arthritis patients using NSAIDs for a year, there are 13 hospitalizations for serious gastrointestinal complications. There are approximately 13 million individuals who use NSAIDs by prescription. Extrapolation of these data reveals that every year in the U.S., at least 103,000 individuals are hospitalized for serious gastrointestinal toxicity from NSAID use, and an estimated 16,500 will not survive the complication. Based on these estimates, death from gastrointestinal complications of NSAIDs represents the 15th cause of death in the U.S. This means that every year NSAIDs kill approximately the same number of people as does AIDS, and considerably more people than does asthma, cervical cancer and Hodgkin's disease combined. These figures are conservative since they do not take in account users of over-the-counter NSAIDs. What is even more worrisome is that patients are by large, unaware of the risks associated with the use of these drugs. A recent survey revealed that 75% of patients taking NSAIDs regularly, were not aware or were not preoccupied with the possibility of gastrointestinal complications, and almost two thirds of them incorrectly believed that there would be warning signs preceding the insurgence of gastrointestinal complications. The cost of NSAID gastrointestinal toxicity is high. Each hospitalization costs approximately $15,000 to $20,000, leading to total annual health care expenses exceeding $2 billion.
Singh G.
Am J Med, 105(1B):31S-38S 1998 Jul 27.
The results of this study show that each year, approximately 107,000 individuals are hospitalized for gastrointestinal (GI) complications derived from nonsteroidal anti-inflammatory drug (NSAID) use and that, among arthritis patients alone, at least 16,500 die as a consequence of NSAID use. Eighty percent of serious GI events occur without warning symptoms and the risk of this complication increases in patients taking gastro-protective medications.
Griffin MR; Piper JM; Daugherty JR; Snowden M; Ray WA.
Ann Intern Med, 114(4):257-63 1991 Feb 15.
The results of this study, conducted on a cohort of 1,415 patients of 65 or more years of age hospitalized for peptic ulcer, show that use of nonsteroidal antiinflammatory drugs is associated with a fourfold increased risk of peptic ulcer compared to nonuse. This could mean that, in this sample population, approximately a third of all peptic ulcers resulted from use of these drugs.
Smalley WE; Ray WA; Daugherty JR; Griffin MR.
Am J Epidemiol, 141(6):539-45 1995 Mar 15.
This study, performed on a sample population of 103,954 elderly individuals, documented a fourfold increased rate of hospitalization for serious ulcer disease among nonsteroidal anti-inflammatory drug (NSAID) users compared to nonusers. Among new users, the risk of hospitalization was found to be increased by a factor of 6.
Bellary SV; Isaacs PE; Lee FI.
Am J Gastroenterol, 86(8):961-4 1991 Aug.
The results of this study, performed on a sample population of 511 consecutive patients admitted for endoscopic evaluation due to upper gastrointestinal disease, show that nonsteroidal antiinflammatory drug (NSAID) users have an over threefold higher incidence of gastric erosions and gastric ulcers and a twofold higher incidence of hemorrhage, compared to nonusers.
Gutthann SP; Garc´ia Rodr´iguez LA; Raiford DS.
Epidemiology, 8(1):18-24 1997 Jan.
The results of this study, performed on a cohort of over 11,000 individuals, show that nonsteroidal antiinflammatory drug (NSAID) users have a 4.3-fold increased risk of upper gastrointestinal bleeding and death, and a 17-fold increased risk of upper gastrointestinal perforations, compared to NSAID abstainers. Current use of NSAIDs in women of 80 or more years of age was associated with a 9-fold increased risk of experiencing severe complications.
Svanes C; Ovrebø K; Søreide O.
Scand J Gastroenterol Suppl, 220():128-31 1996.
This article shows that use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a 5- to 8-fold increased risk of ulcer perforation. Overall, exposure to NSAIDs accounts for about 20% to 40% of all gastric perforations and ulcer bleedings.
MacDonald TM; et al.
BMJ, 315(7119):1333-7 1997 Nov 22.
This study, performed on a sample population of 52,293 individuals of 50 or more years of age and 73,792 controls, found that, over a three-year period, 2% of non-steroidal anti-inflammatory drug (NSAID) users and 1.4% of nonusers were hospitalized for upper gastrointestinal (GI) events. The risk of GI perforation and bleeding remained constant during continuous NSAIDs exposure.
Talley NJ; Evans JM; Fleming KC; Harmsen WS; Zinsmeister AR; Melton LJ 3rd.
Dig Dis Sci, 40(6):1345-50 1995 Jun.
This study shows that nonsteroidal antiinflammatory drug use in the elderly is associated with a 60% and 80% increased risk of dyspepsia and/or heartburn, respectively.
Fries JF, Williams CA, Bloch DA, Michel BA.
Am J Med 1991 Sep;91(3):213-22.
The results of this study, performed on a cohort of 2,747 rheumatoid arthritis patients, show that users of nonsteroidal anti-inflammatory drugs have a 5.2-fold increased risk of hospitalization for gastrointestinal events, compared to nonusers.
McCarthy D.
Am J Med, 105(5A):3S-9S 1998 Nov 2.
In this article, gastrointestinal (GI) bleeding and perforations are described as the two most frequent cause of death from nonsteroidal anti-inflammatory drug (NSAID)-related GI toxicity, the risk of these complications being highest during the first month of use. Other adverse effects such as heartburn, dyspepsia and pain occur frequently in users of this class of drugs, but their presence is unrelated with the insurgence of more severe GI complications, which, in the majority of cases, occur without warning signs.
Davies NM.
Dis Colon Rectum, 38(12):1311-21 1995 Dec.
This review article explains that nonsteroidal anti-inflammatory drug (NSAID)-related toxicity involves not only the upper gastrointestinal tract, but also the large intestine, where it can manifest as diarrhea, colonic blood loss and anemia, strictures, ulcerations, perforations, worsening of inflammatory bowel disease and ulcerative colitis, and death.
Damage to the intestinal lining seems to be mediated by the inhibition of prostaglandin synthesis. It is important that clinicians and patients be fully aware of the risk of these complications among users of NSAIDs.
Bjorkman D.
Am J Med, 105(5A):17S-21S 1998 Nov 2.
This article describes some of the possible adverse reactions associated with use of nonsteroidal anti-inflammatory drugs, including colitis, ulcerations, strictures, worsening of inflammatory bowel disease and hepatotoxicity, the latter being especially associated with use of aspirin, diclofenac and sulindac.
A prospective observational cohort study.
Singh G; Ramey DR; Morfeld D; Shi H; Hatoum HT; Fries JF.
Arch Intern Med, 156(14):1530-6 1996 Jul 22.
The results of this study, conducted on a cohort of 1,921 individuals treated for rheumatoid arthritis with nonsteroidal anti-inflammatory drugs (NSAIDs) and followed-up for at least 2.5 years, show that approximately 15% of them developed adverse reactions involving the gastrointestinal (GI) tract such as abdominal pain and vomiting. In addition, during the study period, 42 individuals were hospitalized for severe GI complications such as ulcers and bleeding, the majority of them without previous warning signs. Of note, prophylactic use of antacids and H2 receptor antagonists instead of exerting a protective effect, was found to be associated with an over twofold increased risk of GI complications.
Lanas A; Serrano P; Bajador E; Esteva F; Benito R; S´ainz R.
Gastroenterology, 112(3):683-9 1997 Mar.
In this study, 76 consecutive patients with gastrointestinal (GI) perforation and 152 matched controls were evaluated for nonsteroidal anti-inflammatory drug (NSAID) use. Seventy-one percent of patients and 27% of controls were using NSAIDs, especially over-the-counter aspirin, suggesting a strong association between NSAID intake and GI perforation.
Henry D., Lim LL., et al.
BMJ, 312(7046):1563-6 1996 Jun 22.
This study evaluated the risk of severe gastrointestinal (GI) complications associated with use of different non-steroidal anti-inflammatory drugs (NSAIDs). Ibuprofen was associated with the lowest risk of GI toxicity, mainly because it is commonly used at low doses in clinical practice, with the risk of GI complications rising to that of other NSAIDs when used at higher doses. With ibuprofen used as reference, all the other NSAIDs had relative risks of inducing GI toxicity greater than one, ranking from 1.6 to 9.2. Azapropazone, tolmetin, ketoprofen, and piroxicam were associated with the highest risk of GI complications. First line treatment with low doses of NSAIDs would result in a reduction of the incidence of severe complications and death.
Garc´ia Rodr´iguez LA; Walker AM; P´erez Gutthann S.
Epidemiology, 3(4):337-42 1992 Jul.
This study shows that nonsteroidal antiinflammatory drug (NSAID) users have a fourfold increased risk of hospitalization for gastrointestinal complications compared to nonusers. The risk persists after discontinuation of NSAID use, with an over 2-fold increased risk found in recent past users and a 30% increased risk shown in less recent past users.
Kaufmann HJ, Taubin HL.
Ann Intern Med 1987 Oct;107(4):513-6.
This article reports on the case of 4 patients who experienced activation of quiescent inflammatory bowel disease (IBD) after ingestion of nonsteroidal anti-inflammatory drugs. Since both exacerbation of this condition and de-novo occurrence of colitis and ileitis have been previously reported, extreme caution is warranted before administering this class of drugs to patients with IBD.
Meloxicam Large-scale International Study Safety Assessment.
Hawkey C, Kahan A, Steinbr¨uck K, Alegre C, Baumelou E, B´egaud B, et al.
Br J Rheumatol, 37(9):937-45 1998 Sep.
This study investigated the gastrointestinal tolerability of the non-steroidal anti-inflammatory drugs meloxicam and diclofenac on a cohort of 9323 osteoarthritis patients. During a trial period of 28 days, 4635 patients received meloxicam and 4688 received diclofenac. Thirteen percent of patients on meloxicam and 19% of those on diclofenac experienced gastrointestinal (GI) adverse events. Overall, 12 patients experienced serious GI complications such as: perforations, ulcers and bleeding events. Five percent of patients on meloxicam and 8% of those on diclofenac withdrew from the study because of adverse reactions, and 80 patients on meloxicam and 49 on diclofenac discontinued treatment for lack of efficacy.
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