Complications Due to NSAIDS
by Dr. Gary Farr on 12 February 2002
Selected Abstracts
Complications Due to NSAIDS
(Non-steroidal anti-inflammatory drugs)Touted as being "more safe" than aspirin, a class of drugs called non-steroidal anti-infalmmatory drugs are the biggest sellers on the market. But are they really "safe"? Read on and draw your own conclusions.
Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem.
Page J, Henry D.
Arch Intern Med 2000 Mar 27;160(6):777-84.The results of this study indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are an important cause of hospitalization for congestive heart failure (CHF) in individuals with or without a history of heart disease. The study was conducted on 365 patients hospitalized for heart failure and 658 controls. Individuals who used NSAIDs in the previous week had a 2-fold increased risk of hospitalization for CHF, compared to non-users. In patients with a history of heart disease, use of NSAIDs was associated with a 10-fold increased risk of hospitalization for CHF. The risk increased with increasing doses of NSAIDs taken in the previous week, and was greater with NSAIDs of long versus short half-life. The authors concluded that NSAIDs could account for approximately 20% of hospitalizations for congestive heart failure. Heart failure affects approximately 4.6 million Americans and this condition represent the most common hospital discharge diagnosis among patients older than 65 years. If this association is casual, as the dose-response relation suggests, cardiovascular morbidity due to NSAIDs would surpass gastro-intestinal NSAID-related morbidity, which alone is responsible for a minimum of 105,000 hospitalizations and 16,500 deaths occurring each year in the U.S. The economic and health consequences of these findings are staggering.
NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.
Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BH, Bakker A.
Arch Intern Med 1998 May 25;158(10):1108-12.The results of this study, conducted on a sample population of 10,519 individuals older than 55 years taking diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs), show that users of both drugs have a twofold increased risk of being hospitalized for congestive heart failure, compared to users of diuretics only.
Congestive heart failure due to nonsteroidal anti-inflammatory drugs in the elderly.
Van den Ouweland FA, Gribnau FW, Meyboom RH.
Age Ageing 1988 Jan;17(1):8-16.This study indicates that the occurrence of congestive heart failure in elderly individuals with or without a history of cardiovascular disease who are taking nonsteroidal anti-inflammatory drugs (NSAIDs) is a probable treatment-related complication. Multiple factors can be involved in the etiology of this complication, including toxicity from relative overdose, alteration of cardiovascular homeostasis, and interference with anti-hypertensive treatment.
Nonsteroidal anti-inflammatory drugs and blood pressure in an elderly population.
Chrischilles EA, Wallace RB.
J Gerontol 1993 May;48(3):M91-6.This study shows that nonsteroidal anti-inflammatory drugs (NSAIDs) raise systolic blood pressure in elderly individuals by approximately 5 mm Hg and may antagonize the effects of antihypertensive medications. Users of NSAIDs are also twice as likely to have systolic blood pressure higher than 140 mm Hg, compared to nonusers. The authors conclude that NSAIDs may be an important reason for therapeutic failure in the treatment of hypertension.
Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.
Johnson AG, Nguyen TV, Day RO.
Ann Intern Med 1994 Aug 15;121(4):289-300.This study evaluated data from 38 randomized, placebo-controlled trials, to determine the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure. The results of the analysis revealed that use of NSAIDs is associated with an increase in blood pressure levels by an average of 5.0 mm Hg, and with the neutralization of the effects of antihypertensive treatment, particularly in individuals treated with beta-blockers.
Antagonism of antihypertensive drug therapy by nonsteroidal anti-inflammatory drugs.
Oates JA.
Hypertension 1988 Mar;11(3 Pt 2):II4-6.This article discloses the property that certain nonsteroidal anti-inflammatory drugs (NSAIDs) have to antagonize the blood pressure lowering effects of antihypertensive treatment. Indomethacin abolishes the effects of several antihypertensive drugs, while piroxicam raises blood pressure in treated patients. The magnitude of this effect varies from patient to patient, from undetectable to dangerous increases in blood pressure.
Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy.
Gurwitz JH, Avorn J, Bohn RL, Glynn RJ, Monane M, Mogun H.
JAMA 1994 Sep 14;272(10):781-6.This case-control study, conducted on over 9,400 patients aged 65 or older with newly diagnosed hypertension, shows that users of NSAIDs have a 66% increased risk of starting antihypertensive treatment, compared to nonusers. The risk increases with increasing doses of NSAIDs. The adverse effects on blood pressure levels can have a major impact on public health, particularly since approximately 20 millions Americans are currently taking both class of drugs.
The impact of nonsteroidal anti-inflammatory drugs on hypertension: alternative analgesics for patients at risk.
Ruoff GE.
Clin Ther 1998 May-Jun;20(3):376-87; discussion 375.This article highlights that in the U.S., approximately 20 million individuals and 12% of those aged 60 years and older, use concurrently both nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive drugs. Since NSAIDs limit the efficacy of antihypertensive therapy, their use, unless deemed really necessary, should be avoided, and substituted with other class of analgesics.
Gastrointestinal Toxicity
Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.
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.
Recent considerations in nonsteroidal anti-inflammatory drug gastropathy.
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.
Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.
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.
Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons.
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.
Upper gastrointestinal lesions in elderly patients presenting for endoscopy: relevance of NSAID usage.
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.
Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation.
Gutthann SP; GarcŽia RodrŽiguez 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.
Ulcer bleeding and perforation: non-steroidal anti-inflammatory drugs or Helicobacter pylori.
Svanes C; Ovrebű K; Sűreide 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.
Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.
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.
Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly.
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.
Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models.
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.
Nonsteroidal anti-inflammatory drug-related gastrointestinal toxicity: definitions and epidemiology.
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.
Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine.
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.
Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus.
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.
Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis.
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.
Evidence of aspirin use in both upper and lower gastrointestinal perforation.
Lanas A; Serrano P; Bajador E; Esteva F; Benito R; SŽainz 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.
Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.
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.
Nonsteroidal antiinflammatory drugs and gastrointestinal hospitalizations in Saskatchewan: a cohort study.
GarcŽia RodrŽiguez LA; Walker AM; PŽerez 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.
Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease.
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.
Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA Study Group.
Meloxicam Large-scale International Study Safety Assessment.
Hawkey C, Kahan A, Steinbršuck K, Alegre C, Baumelou E, BŽegaud 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.
Neurotoxicity
Complications Due to NSAIDS
(Non-steroidal anti-inflammatory drugs)Touted as being "more safe" than aspirin, a class of drugs called non-steroidal anti-infalmmatory drugs are the biggest sellers on the market. But are they really "safe"? Read on and draw your own conclusions.
Nonsteroidal antiinflammatory drugs and cognitive decline in the elderly.
Saag KG; Rubenstein LM; Chrischilles EA; Wallace RB.
J Rheumatol, 22(11):2142-7 1995 Nov.The results of this study indicate that use of high doses of nonsteroidal anti-inflammatory drugs is associated with a two-fold increased risk of immediate memory decline in the elderly.
Relation of prescription nonsteroidal antiinflammatory drug use to cognitive function among community-dwelling elderly.
Hanlon JT, Schmader KE, Landerman LR, et al.
Ann Epidemiol 1997 Feb;7(2):87-94.The results of this study, performed on a cohort of 2765 elderly individuals with intact cognitive performance at baseline, show that during a 3-year period, current users of moderate or high doses of nonsteroidal anti-inflammatory drugs scored worse at memory function tests, compared to users of low doses of NSAIDs. These results indicate that moderate and high doses of these drugs may impair memory function in the elderly.
Nonsteroidal antiinflammatory drug use and cognitive function in the elderly: inconclusive results from a population-based cohort study.
Fourrier A, Letenneur L, Begaud B, Dartigues JF.
J Clin Epidemiol 1996 Oct;49(10):1201.The results of this study, conducted on a sample population of 53 elderly patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) and 1,199 controls not on NSAID treatment, show that during a two-year period of follow-up, deterioration of performance at the Mini-Mental Status Examination was 3 times more likely to occur in users of NSAIDs, compared to nonusers.
Assessment of cognitive function in elderly patients treated with naproxen. A prospective study.
Wysenbeek AJ, Klein Z, Nakar S, Mane R.
Clin Exp Rheumatol 1988 Oct-Dec;6(4):399-400.In this study, 4 of 12 patients who took the NSAID Naproxen for three weeks at doses of 750 mg/day showed signs of deterioration in one of four cognitive tests, compared to baseline.
Nonsteroidal anti-inflammatory drug toxicity: increased risk in the elderly.
Weinblatt ME.
Scand J Rheumatol Suppl, 91():9-17 1991.This article describes some of the adverse effects caused by the use of nonsteroidal anti-inflammatory drugs. These include gastrointestinal, renal and hepatic toxicity, and effects on the central nervous system such as dizziness, headaches, mood alteration and confusion, to which the elderly are particularly exposed.
The problems and pitfalls of NSAID therapy in the elderly (Part I).
Johnson AG; Day RO.
Drugs Aging, 1(2):130-43 1991 Mar.This article highlights that adverse reactions to nonsteroidal anti-inflammatory drugs, the most frequently prescribed class of drugs in the world, account for approximately one fourth of all reported adverse drug reactions, their incidence being particularly high in the elderly. Toxicity is directed not only toward the gastrointestinal tract, but also toward the renal, hepatic, cardiovascular, hematopoietic and central nervous system.
Drug-induced cognitive impairment in the elderly.
Moore AR, O'Keeffe ST.
Drugs Aging 1999 Jul;15(1):15-28.This article highlights that nonsteroidal anti-inflammatory drugs are a known cause of acute and, more rarely, chronic confusion in elderly patients.
Recurrent meningitis due to nonsteroidal anti-inflammatory drugs.
Peterson DI, Ben Chong Y.
Bull Clin Neurosci 1987;52:40-2.This article reports on the case of two patients who experienced recurrent meningitis (inflammation of the membranes surroundings the brain and spinal cord) related to nonsteroidal anti-inflammatory drug treatment.
Ibuprofen-induced aseptic meningitis in rheumatoid arthritis.
Horn AC, Jarrett SW.
Ann Pharmacother 1997 Sep;31(9):1009-11.This article reports on the case of 56-year old man with rheumatoid arthritis who developed aseptic meningitis after ingestion of ibuprofen.
The challenge of drug-induced aseptic meningitis.
Moris G, Garcia-Monco JC.
Arch Intern Med 1999 Jun 14;159(11):1185-94.This review shows that nonsteroidal anti-inflammatory drugs, antibiotics, intravenous immunoglobulins, and monoclonal antibodies against the T3 receptor are the most frequent cause of drug-induced aseptic meningitis.
Renal Toxicity
Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
Griffin MR, Yared A, Ray WA.
Am J Epidemiol 2000 Mar 1;151(5):488-96.The results of this study show that nonsteroidal antiinflammatory drugs (NSAIDs) significantly increase the risk of acute renal failure in elderly patients. The study was conducted on 1,800 patients aged 65 or older, who had been hospitalized for acute renal failure. The authors evaluated use of NSAIDs in these patients, and compared it to that of a control group of almost 10,000, randomly selected, individuals. Use of NSAIDs was associated with a 60% increased risk of acute renal failure, compared to non-use. Since acute renal failure is associated with important mortality in this age group, particular caution is warranted when prescribing this class of drugs to frail, elderly individuals with or without concomitant renal disease.
Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure.
PŽerez Gutthann S; GarcŽia RodrŽiguez LA; Raiford DS; Duque Oliart A; Ris Romeu J.
Arch Intern Med, 156(21):2433-9 1996 Nov 25.This study shows that current users of nonsteroidal antiinflammatory drugs (NSAIDs) have a fourfold increased risk of idiopathic acute renal failure (ARF) compared to the general population. New users of NSAIDs have an 8.5-times higher risk of ARF during the first month of use. The risk of developing ARF increases by a factor of 10 in individuals using prescriptions of high daily doses of NSAIDs.
Acute renal failure of medical type in an elderly population.
Baraldi A, Ballestri M, Rapana R, Lucchi L, Borella P, Leonelli M, Furci L, Lusvarghi E.
Nephrol Dial Transplant 1998;13 Suppl 7:25-9.The results of this study, conducted on a cohort of 109 unselected patients with acute renal failure, show that in 39 of them (35%) the condition was caused by drugs. In particular, non-steroidal anti-inflammatory drugs and ACE-inhibitors were responsible for the occurrence of this serious and potentially lethal complication in 24 and 8 patients, respectively. These data indicate that non-steroidal anti-inflammatory drugs are an important cause of acute renal failure in the elderly.
Consumption of non-steroidal anti-inflammatory drugs and the development of functional renal impairment in elderly subjects.
Results of a case-control study.
Henry D; Page J; Whyte I; Nanra R; Hall C.
Br J Clin Pharmacol, 44(1):85-90 1997 Jul.This study shows that users of non-steroidal anti-inflammatory drugs have, during the first week and month of treatment, a 50% and 80% increased risk of functional renal impairment, respectively, compared to nonusers. In individuals with a history of renal disease and gout/hyperuricemia, the risk increases by a factor of 6.6 and 7.2, respectively.
The renal effects of nonsteroidal anti-inflammatory drugs in older people
Findings from the Established Populations for Epidemiologic Studies of the Elderly.
Field TS, Gurwitz JH, Glynn RJ, Salive ME, Gaziano JM, Taylor JO, Hennekens CH.
J Am Geriatr Soc 1999 May;47(5):507-11.The results of this study, conducted on more than 4,000 individuals aged 70 years and older, show that users of nonsteroidal anti-inflammatory drugs have a two-fold increased risk of having signs of kidney dysfunction (as measured by levels of serum creatinine and blood urea nitrogen), compared to nonusers.
Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs.
Radford MG Jr, Holley KE, Grande JP, Larson TS, Wagoner RD, et al.
JAMA 1996 Aug 14;276(6):466-9.This study, conducted on a sample population of 125 patients with stage I or early stage II membranous nephropathy, shows that 23% of them were on nonsteroidal anti-inflammatory drug (NSAID) therapy at the time the syndrome developed. In over 10% of patients the nephropathy was judged to be related to the use of these drugs.
Chronic nephrotoxicity of anti-inflammatory drugs used in the treatment of arthritis.
Segasothy M; Chin GL; Sia KK; Zulfiqar A; Samad SA.
Br J Rheumatol, 34(2):162-5 1995 Feb.The results of this study indicate that the incidence of renal papillary necrosis and chronic renal impairment in arthritis patients with a history of long-term use of NSAIDs is 12% and 24%, respectively.
Management of acute renal failure in the elderly. Treatment options.
Mandal AK; Baig M; Koutoubi Z.
Drugs Aging, 9(4):226-50 1996 Oct.This study illustrates how drugs are a frequent cause of acute renal failure in the elderly, with nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics being the agents most frequently implicated in renal toxicity.
Acute renal failure: clinical outcome and causes of death.
Barretti P; Soares VA.
Ren Fail, 19(2):253-7 1997 Mar.This study shows that the incidence of acute renal failure (ARF) in hospitalized patients is 4.9/1000 patients. Over 46% of patients who develop ARF die. Nephrotoxic drugs are the main cause of ARF in 21% of cases.
Drug-induced nephrotoxicity. Aetiology, clinical features and management.
Hoitsma AJ; Wetzels JF; Koene RA.
Drug Saf, 6(2):131-47 1991 Mar-Apr.This article describes the spectrum of renal diseases caused by a growing number of drugs, and lists, among the most nephrotoxic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, captopril, amphotericin B and radiographic contrast agents.
Prevention of drug-induced nephrotoxicity in the intensive care unit.
Hock R; Anderson RJ.
J Crit Care, 10(1):33-43 1995 Mar.This article emphasizes that 5% to 25% of patients admitted to the intensive care unit develop acute renal failure (ARF). ARF cause an increase in mortality from 15% to over 60% and prolongs hospital stay and costs. In a considerable percentage of cases, drugs, particularly aminoglycosides, nonsteroidal anti-inflammatory drugs and radiocontrast agents cause this condition.
Nephrotoxicities of nonsteroidal anti-inflammatory drugs.
Wen SF.
J Formos Med Assoc, 96(3):157-71 1997 Mar.This article emphasizes that the risk of renal toxicity in users of nonsteroidal anti-inflammatory drugs is increased in individuals with congestive heart failure, cirrhosis, old age, history of renal disease, and volume depletion from diuretic use or other causes.
More NSAID Complications
Complications Due to NSAIDS
(Non-steroidal anti-inflammatory drugs)Touted as being "more safe" than aspirin, a class of drugs called non-steroidal anti-infalmmatory drugs are the biggest sellers on the market. But are they really "safe"? Read on and draw your own conclusions.
Diclofenac-associated hepatotoxicity.
Helfgott SM, Sandberg-Cook J, Zakim D, Nestler J
JAMA 1990 Nov 28;264(20):2660-2.This article reports on the case of 7 patients who developed severe hepatitis, which was fatal in one individual, derived from use of diclofenac sodium, a nonsteroidal anti-inflammatory drug approved in the U.S. in 1988. Search of the European literature revealed 3 more cases of diclofenac-related deaths.
Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions.
Banks AT, Zimmerman HJ, Ishak KG, Harter JG.
Hepatology 1995 Sep;22(3):820-7.This study reviewed 180 reports of possible liver toxicity related to diclofenac use and submitted to the Food and Drug Administration from November 1988 through June 1991. Eighty percent of reactions occurred in women, and 70% in individuals older than 60 years. Most cases occurred during the first 8 months of treatment, but some occurred after more than a year of use, which could reflect the difficulty of establishing a link between drug use and occurrence of an adverse event after long-term treatment. Liver toxicity was detected by clinical symptoms in 67% of cases, and by laboratory analysis in the remainder. Seven of the 90 patients who presented with icterus (yellowing of the skin and the sclera of the eyes, a frequent sign of liver damage) died.
Pancreatitis associated with diclofenac.
Khan IH, Edward N.
Postgrad Med J 1993 Jun;69(812):486-7.This article reports on the case of a 34-year old woman who developed acute pancreatitis after initiation of diclofenac therapy for painful arthropathy.
'Diaphragmlike' stricture and ulcer of the colon during diclofenac treatment.
Whitcomb DC, Martin SP, Trellis DR, Evans BA, Becich MJ.
Arch Intern Med 1992 Nov;152(11):2341-3.This article reports on the case of a woman who developed an intestinal ulcer causing blood loss and anemia and a colonic stricture (the narrowing of the colon due to presence of scar tissue), while on diclofenac therapy. Discontinuation of treatment resulted in resolution of anemia and blood loss, indicating a casual role of diclofenac in this complication.
Nonsteroidal anti-inflammatory drug-induced colonic strictures: two cases and literature review.
Gargot D, Chaussade S, d'Alteroche L, Desbazeille F, Grandjouan S, Louvel A, et al.
Am J Gastroenterol 1995 Nov;90(11):2035-8.This article describes two patients who developed colonic strictures while taking the nonsteroidal anti-inflammatory drugs diclofenac and phenylbutazone. One patient had to undergo removal of the right part of the colon.
Severe hepatotoxicity associated with bromfenac sodium.
Moses PL, Schroeder B, Alkhatib O, Ferrentino N, Suppan T, Lidofsky SD.
Am J Gastroenterol 1999 May;94(5):1393-6.This article reports on the case of a case of 40-year-old woman who developed subacute hepatitis and liver failure after one month of treatment with the nonsteroidal anti-inflammatory drug bromfenac. Liver failure was accompanied by encephalopathy, fluid retention and spontaneous bacterial peritonitis.
Fatal submassive necrosis of the liver associated with piroxicam.
Planas R, De Leon R, Quer JC, Barranco C, Bruguera M, Gassull MA.
Am J Gastroenterol 1990 Apr;85(4):468-70.This article reports on the case of a 64 year-old woman who developed acute hepatitis followed by liver failure and death after 3 weeks of piroxicam (Feldene) use.
Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy.
Klein SM, Khan MA.
J Rheumatol 1983 Jun;10(3):512-3.This article reports on the case of two patients who developed severe adverse reactions to Sulindac therapy. One patient developed acute toxic hepatitis and Stevens-Johnson's syndrome followed by death. The other patient developed acute pancreatitis in two instances following ingestion of the drug.
Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration.
Tarazi EM, Harter JG, Zimmerman HJ, Ishak KG, Eaton RA.
Gastroenterology 1993 Feb;104(2):569-74.This study evaluated 338 reports of sulindac-associated liver injury submitted to the Food and Drug Administration, and found that 247 of them were unconvincingly related to the drug. Of the remaining 91 cases, 4 were deaths, 3 from severe hypersensitivity and one from fulminant liver failure.
The problems and pitfalls of NSAID therapy in the elderly (Part II).
Johnson AG; Day RO.
Drugs Aging, 1(3):212-27 1991 May.This article discusses the increased risk of nonsteroidal anti-inflammatory drugs (NSAID) toxicity, especially pronounced in the elderly, derived by the interaction between NSAIDS and drugs such as: other NSAIDs, aminoglycosides, lithium and various antihypertensive, anticoagulant, anticonvulsants and hypoglycaemic drugs.
Is Toxicity Preventable?
Non-steroidal anti-inflammatory drug usage and requirement in elderly acute hospital admissions.
Jones AC; Berman P; Doherty M.
Br J Rheumatol, 31(1):45-8 1992 Jan.This study evaluated the use of non-steroidal anti-inflammatory drugs (NSAIDs) and their adverse effects in a sample population of 500 elderly patients acutely admitted to the hospital. Sixty-five patients were receiving NSAIDs; of them, 56 had conditions possibly caused or worsened by the use of these drugs. Fifty-six patients were successfully taken off NSAID therapy and almost 40% of them did not require any substitute treatment, indicating high rates of unnecessary prescribing and preventable adverse reactions in this sample population.
Drug-related problems in elderly patients admitted to Tayside hospitals, methods for prevention and subsequent reassessment.
Cunningham G; Dodd TR; Grant DJ; McMurdo ME; Richards RM.
Age Ageing, 26(5):375-82 1997 Sep.The results of this study, performed on a sample population of 1011 elderly patients admitted to the hospital over a 9-month period, show that the incidence of adverse drug reactions in this age group is 14%. Adverse drug reactions were the probable or definite cause of hospital admission in 5.3% of patients, and were related to nonsteroidal anti-inflammatory drug (NSAID)-use in 28% of cases. More than two-thirds of hospitalizations due to NSAIDs were judged to be definitively preventable.
Are non-steroidal anti-inflammatory drugs always necessary? A general practice survey.
Swift GL, Rhodes J.
Br J Clin Pract 1992 Summer;46(2):92-4.This study, conducted on 38 randomly selected patients with osteoarthritis or musculoskeletal pain treated with non-steroidal anti-inflammatory drugs (NSAIDs), shows that in 63% of them NSAID treatment was successfully discontinued and replaced by alternative analgesics, while in 5% of them dosage was effectively reduced.
Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs).
Wynne HA; Long A.
Br J Clin Pharmacol, 42(2):253-6 1996 Aug.This study evaluated patients' awareness of the risks associated with non-steroidal anti-inflammatory drug (NSAID)-treatment in a sample population of 50 individuals who experienced acute gastrointestinal bleeding while taking NSAIDs, and 100 matched controls also on NSAID therapy but without this complication. Only 16% of cases and 41% of controls recalled having being instructed on the possibility of adverse effects; in addition, only 4% of cases and 21% of controls were informed on what to do if adverse events occurred. Reduced NSAID intake at the occurrence of epigastric pain was reported by 11% of patients who developed GI bleeding and by 67% of controls. These data indicate that the majority of patients are not informed on the possibility of experiencing severe adverse reactions from treatment with NSAIDs. It is however pivotal that patients be fully informed on the risks associated with treatment, as this information could affect their choice as to whether undergoing treatment, and, as the data collected in this study show, could potentially spare some of the morbidity and mortality from treatment-related complications by supporting more cautious use of these drugs and lower dose intake, should any warning sign occur.
Cost-conscious prescribing of nonsteroidal anti-inflammatory drugs for adults with arthritis.
A review and suggestions.
Greene JM, Winickoff RN.
Arch Intern Med 1992 Oct;152(10):1995-2002.This study discusses the lack of justification for first line use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of painful musculoskeletal conditions, and proposes the use of acetaminophen instead of NSAIDs for the treatment of noninflammatory disorders, and of nonacetylated salicylates as safer and cheaper alternative to NSAID treatment.
Economic Considerations, Cox-2 Inhibitors, & More Studies
Nonnarcotic analgesics: prevalence and estimated economic impact of toxicities.
McGoldrick MD; Bailie GR.
Ann Pharmacother, 31(2):221-7 1997 Feb.This study shows that nonsteroidal anti-inflammatory drugs (NSAIDs) cause about 72.6% of the total toxicities related to the use of NSAIDs, acetaminophen and aspirin. The cost associated with NSAID adverse effects has been estimated at $1.86 billion.
Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury.
Griffin MR.
Am J Med 1998 Mar 30;104(3A):23S-29S; discussion 41S-42S.This study shows that 10% to 20% of individuals aged 65 and older are on a recent or current nonsteroidal anti-inflammatory drug (NSAID) prescription. In Tennessee (USA), 6% of elderly people are prescribed NSAIDs for more than 75% of the year, and 40% of them receive at least one prescription annually. Adverse reactions, particularly to the gastrointestinal system, are frequent, and it has been estimated these drugs are responsible for 28% of all anti-ulcer drug prescriptions in this age group.
Analysis of the costs of NSAID-associated gastropathy. Experience in a US health maintenance organisation.
Johnson RE, Hornbrook MC, Hooker RS, Woodson GT, Shneidman R.
Pharmacoeconomics 1997 Jul;12(1):76-88.This study estimated that for every $1.00 spent on nonsteroidal antiinflammatory drug (NSAID) therapy for the elderly, $0.35 is spent for the treatment of NSAID-induced gastropathy. Overall, the costs of each NSAID-related gastropathy episode was estimated at $2172 (1992 values).
NSAIDs and the elderly. Toxicity and economic implications.
Phillips AC; Polisson RP; Simon LS.
Drugs Aging, 10(2):119-30 1997 Feb.This article warns against routine prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) for noninflammatory conditions to the elderly, due to the potential risks associated with this class of drugs. This practice increases the costs of treatment by a staggering amount when expenses derived from use of gastroprotective agents, laboratory monitoring, and physician consultation and intervention for adverse effects are added to drug costs.
A multicenter study of annual health service utilization and costs in rheumatoid arthritis.
Lubeck DP, Spitz PW, Fries JF, Wolfe F, Mitchell DM, Roth SH.
Arthritis Rheum 1986 Apr;29(4):488-93.This study estimated that the overall health care costs per patient with rheumatoid arthritis is $2,533 per year (1986 values). These costs include: hospital care ($913), physician costs ($277), medications ($436), laboratory tests ($217), radiographs ($116), assistive devices ($24), and nontraditional therapies ($22). Total costs were not associated with level of self-reported pain.
Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing.
Jones MK, et al.
Nat Med 1999 Dec;5(12):1418-23.This study challenges the belief that selective cyclooxygenase 2 (COX-2) inhibitors such as celecoxib and rofecoxib, a new generation of NSAIDs designed to overcome some of side effects associated with traditional NSAIDs, are devoid of gastrointestinal toxicity. NSAIDs reduce pain and inflammation by inhibiting the enzyme cyclooxygenase. This enzyme exists in at least 2 isoforms: COX-1, which participates to the homeostatic regulation of many tissues and produces protective prostaglandines in the stomach, and COX-2, involved in the formation of mediators of pain and inflammation. Unlike NSAIDs, COX-2 inhibitors selectively block the action of the isoenzyme COX-2, while sparing the mucosa-protective enzyme COX-1. The results of this study however, demonstrate that both enzymes are required for the production of new blood vessels and for the maintenance of the integrity of the gastrointestinal lining, making Cox-2 inhibitors potentially capable of causing ulcers and gastrointestinal bleeding as much as traditional NSAIDs.
Cyclooxygenase 2 selective agents and upper gastrointestinal disease. Letter.
Fernandez H and Lesser GT.
JAMA Vol. 283 No. 15, April 19, 2000.This letter comments on the results of a study by Dr. Simon and colleagues suggesting that use of the selective cyclooxygenase 2 (COX-2) inhibitor celecoxib in patients with rheumatoid arthritis is associated with a lower incidence of upper gastrointestinal (GI) ulcers compared to treatment with the conventional nonsteroidal anti-inflammatory drug (NSAID) naproxen. The authors of the letter, however, question several aspects of the study design together with the study's conclusions. First, naproxen was the NSAID chosen for comparison in the study, when other NSAIDs have been associated with lower rates of GI toxicity, and should therefore used as first line agents in patients with arthritis. Second, naproxen was used at the highest recommended dose and its intake was not reduced after the achievement of a treatment response, as common clinical experience recommends. Third, 40% of patients were older than 60 years of age, and had therefore an inherent 3-fold increased risk of developing NSAID-related gastric complications, compared to the general population. Fourth, one third of patients were concomitantly receiving long-term corticosteroid treatment, another factor associated with an increased risk of GI toxicity. In addition, among the patients receiving naproxen, was an 80-year-old woman in whom treatment with high-doses is not indicated. She was the only one to suffer severe complications. The authors conclude that the results of Dr. Simon study cannot indicate that selective COX-2 inhibitors are safer than NSAIDs in patients with arthritis.
Gastropathy due to celecoxib, a cyclooxygenase-2 inhibitor.
Mohammed S, and Croom II DW.
N Engl J Med. 1999 Jun 24;340(25):2005-6.This article reports on the case of a 69-year old woman who developed acute pain in the upper abdomen after initiation of treatment for arthritis with the COX-2 inhibitor celecoxib (Celebrex). Endoscopic evaluation revealed the presence of severe gastropathy with multiple erosions and signs typical of NSAID-induced gastropathy. The authors emphasize that animal studies have shown that COX-2 inhibitors lose their selective action on the isoenzyme COX-2 when used at doses required for anti-inflammatory action, and cause gastric ulcers which cannot be repaired possibly due to interference with the activity of the COX-2 enzyme. This article adds clinical evidence in support of the experimental data indicating that COX-2 inhibitors, like NSAIDs, are toxic to the gastric lining and cause ulcers and bleeding.
COX 2 inhibitor and fulminant hepatic failure.
McCormick PA, Kennedy F, Curry M, Traynor O.
Lancet. 1999 Jan 2;353(9146):40-1.This article reports on the case of a patient who developed fulminant hepatic failure from treatment with the selective COX2 inhibitor Nimesulide.
Gastric perforation associated with the use of celecoxib.
Reuben SS, et al.
Anesthesiology. 1999 Nov;91(5):1548-9.Acute pancreatitis associated with celecoxib.
Baciewicz AM, Sokos DR, King TJ.
Ann Intern Med 2000 Apr 18;132(8):680.Celecoxib-induced acute pancreatitis and hepatitis: a case report.
Carrillo-Jimenez R, Nurnberger M.
Arch Intern Med 2000 Feb 28;160(4):553-4.
Are Selective COX-2 Inhibitors Nephrotoxic?
Perazella MA, Eras J.
Am J Kidney Dis 2000 May;35(5):937-940.This article reports on the case of two patients with chronic renal insufficiency who developed acute renal failure within 2 weeks of initiation of treatment with the selective cyclooxygenase-2 enzyme inhibitor celecobix. This finding indicates that even the newer generation of nonsteroidal anti-inflammatory drugs have the potential of inducing acute renal failure in patients at risk for this complication, such as those with heart or liver failure or with chronic renal diseases.
Renal side-effects of cyclo-oxygenase-type-2 inhibitor use.
Lancet. 2000 Feb 26;355(9205):753.
Stubanus M, Riegger GA, Kammerl MC, Fischereder M, Kramer BK.This letter reports on several studies indicating that COX-2 selective inhibitors impair renal function in elderly individuals with or without concurrent medical conditions that may put them at risk of experiencing adverse renal effects. In one study, Swan and colleagues demonstrated a 12% reduction in rate of glomerular filtration in elderly individuals with mild renal dysfunction receiving rofecoxib. Another study by Brooks and colleagues demonstrated an important reduction (60-70%) of urine flow, glomerular filtration rate and sodium excretion in dogs with volume depletion injected with celecoxib. In addition, Whelton and colleagues documented a reduction in sodium excretion after only 2 days of treatment with celecoxib in healthy elderly individuals.
Despite enough evidence suggesting an increased risk of kidney toxicity in at-risk individuals treated with COX-2 inhibitors, all randomized published trials failed to include this patient population in their study, and currently no information is available to guide treatment decisions in this category of patients.
Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence.
Muscara MN, Vergnolle N, Lovren F, Triggle CR, Elliott SN, Asfaha S, Wallace JL.
Br J Pharmacol 2000 Apr;129(7):1423-30.The results of this study indicate that celecoxib produces important increase in blood pressure levels in rats with normal or high baseline blood pressure levels. In the study both normal and hypertensive rats were treated for 3 weeks with celecoxib. Blood pressure levels significantly increased in both groups by an average of more than 33 mmHg. In addition, celecoxib induced weight gain (20% increase in body weight), leukocyte adherence and alteration of renal function. This study indicates that selective suppression of the isoenzyme COX-2 is associated with important changes in the cardiovascular, renal and endocrine systems in animals.
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