Sun, 12 Jan 1997 06:52:30 -0800 (PST) From: "Michael D. Beattie" Subject: NSAIDs "There is an epidemic of adverse drug reactions to NSAIDs. The Food and Drug Administration believes anywhere from 10,000 to 20,000 deaths each year are the result of severe bleeding caused by NSAIDs. It is a big problem." Dr. James F. Fries. Professor of Medicine at Stanford University School of Medicine. - Marsa L. "America's Other Drug Problem," Los Angeles Times Magazine, September 29, 1996. *************************** Date: 14 Dec 1996 08:37:04 EDT Subject: Non-Surgical Avascular Necrosis Treatment?/Questio Reply-To: lushke@nlenx.com The following is from Luke Bucci's book "Pain Free". These NSAID's have been shown to inhibit proteoglycan synthesis in animal cultures: *diclofenac (Voltaren) *diflunisal (Dolobid) *fenoprofen (Nalfon) *ibuprofen *aspirin *indomethacin (Indocin) *isoxicam *naproxen (Naprosyn, Anaprox, Aleve) *oxyphenbutazone *phenylbutazone ("Butazolidin) *piroxican (Feldene) *tolmetin (Tolectin) A few studies have been done with aspirin, ibuprofen, indomethacin, and naproxen on osteoarthritic animals and have shown increased cartilage deterioration. The one NSAID that stimulates proteoglycans is benoxaprofen, now banned for causing liver and kidney-damage -related deaths. Steve Santolin ST>Listers: ST> I have a new patient who was diagnosed with avascular necrosis in both ST>hips and the recommendation by the surgeons is, of course, surgery. He was ST>given prednisone for two months after laminectomy surgery last year. ST> They said they'd like to try "conservative therapy" for pain relief ST>first....NSAIDs and pain pills. Don't NSAIDS eat up cartilage? He's a ST>building maintenance person who works hard. ST> Do any of you know of any dietary, herbal or other help for him? ST> Lynn Kelly, D.C. STAR CHIRO @ AOL.COM ******************************* Michael D. Beattie writes - > Does anyone know of any studies or opinions about the duration and dosage > of NSAIDS require to cause ulcer formation? My parents and others I know > believe that taking an aspirin every day will decrease their chance of a > heart attack. Is this amount enough to induce ulcer formation ? Michael - I found this article some five years ago and put it in my newsletter. You may be able to trace back to the original study if you want. "A study, from researchers at the Oregon Health Sciences University in Portland, finds that between 5 and 10 percent of all people in the US with kidney disease had sustained that damage through excessive and habitual use of aspirin and other over the counter pain killers. The researchers said that there is no doubt that aspirin, taken over a long period of time in a cumulative dose of more than two kilograms, can cause permanent kidney damage requiring dialysis or trans-plants. One kilogram is roughly 3,000 aspirins, the researchers noted that _three tablets a day for three years would yield such a harmful dosage_. In addition to aspirin, other pain killers are also suspected of causing kidney damage. The researchers found that is not uncommon for people to take over the counter pain killers habitually in the danger-level amounts, despite package label warnings against the practice." Here's another I found recently - Alcohol and Tylenol - DON'T MIX! "A former White House aide who claims that ordinary doses of Tylenol destroyed his liver has been awarded more than $8.8 million in a federal court suit against the manufacturer of the popular pain-reliever. "I had the flu and then I wake up with my liver gone," Antonio Benedi said. "They ruined my life." The drug's manufacturer, McNeil Consumers Products Co., denied that Tylenol had any thing to do with Benedi's liver disorder and said it would appeal Thursday's decision by a federal court jury in suburban Alexandria, Va. Benedi, 39, a former special assistant to President Bush claimed in the suit that his liver had been "sensitized" to react to Tylenol by his habit of drinking wine with dinner every day. When he took the drug for several days to combat the flu, he lapsed into a coma and was hospitalized. Patrick A. Malone, Benedi's attorney, said McNeil Consumer Products knew of the danger of mixing the habitual use of alcohol with the pain reliever but has taken no action to warn the public. Bob Kniffin, a spokesman for Johnson & Johnson, the parent company of McNeil, said the verdict would be appealed. He said the company believed a virus destroyed Benedi's liver and that Tylenol played no role. After hearing four days of testimony in U.S. District Court, a six- member jury awarded Benedi $7.8 million in compensatory damages and $1 million in punitive damages. When Bush left the White House in January 1993 Benedi was offered an executive position with a private firm. "The week before I got sick, I was preparing to join a company as vice president," he said. "After I got out of the hospital, they wouldn't even talk to me." Benedi said his medical bills have topped $325,000 and that for the rest of his life he will take anti-rejection drugs and other medications that cost about $2,000 monthly. Malone, Benedi's lawyer, said his client, who had a liver transplant, is losing his kidneys due to the anti-rejection drugs and that he eventually will have to start kidney dialysis. During the trial, Malone presented testimony from experts who claimed that ordinary doses of Tylenol can cause a toxic reaction in the liver of someone who regularly drinks alcohol. Malone said data from McNeil's own files indicates that the company was aware of the danger but continued to adver tise heavily that "doctor recommended" Tylenol was completely safe. Kniffin said Tylenol has a 30 year record of safety. He said the company has no record of any person ever experiencing liver damage from the combination of moderate drinking and the recommended doses of Tylenol. All cases connecting alcohol and Tylenol with liver damage have involved patients who were alcoholics or who took an over dose of Tylenol, or a combination of both, Kniffin said. The spokesman said the company does not believe Benedi abused either alcohol or Tylenol but that his liver was destroyed by a form of the herpes virus. Malone, however, said laboratory tests show no evidence of virus in Benedi's failed liver. There were signs, he said, of poisoning by acetaminophen, the primary ingredient in Tylenol. A Food and Drug Administration advisory panel recommended last year that Tylenol and several other types of over the-counter pain relievers carry alcohol warning labels. Some Tylenol products do carry the warning label now, but not the Extra Strength Tylenol that Benedi used." And I just got a patient whose doctor has her taking 12(!) Tylenol per day for the last three years (another story for another time). ___ I am - Gary A. Knutson, DC | | | | gaknutson@delphi.com | * | Bloomington, Indiana, USA /,-' ************************************************* Dr. Beattie wrote: > In the recent JMPT there is a literature review of the Risk Assessment of > Cervical Manipulation vs NSAIDS for the treatment of Neck Pain. > > Does anyone know of any studies or opinions about the duration and dosage of > NSAIDS require to cause ulcer formation? My parents and others I know believe > that taking an aspirin every day will decrease their chance of a heart attack. > Is this amount enough to induce ulcer formation ? I came across this somewhat related study you might find of interest: _______________________________________________________________ Nonprescription NSAIDs: Efficacy and Safety - Excerpted from the June 1994 issue of Medical Sciences Bulletin, (copyrighted material). Aspirin and nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used medications. In 1993, prescriptions for nonaspirin NSAIDs alone totaled 6 million. Prescription use of NSAIDs in the United States appears to be stabilizing, but nonprescription (over-the-counter, OTC) use is growing. Sales of ibuprofen -- Advil, Motrin IB, Nuprin -- have more than tripled since the analgesic was approved for OTC sales nearly a decade ago. The increase in OTC sales comes as no surprise. Buying an analgesic off the shelf is considerably easier and more convenient -- and far less expensive -- than seeing a doctor and going through the process of getting a prescribed drug. OTC medications are widely promoted and readily available. Unfortunately, the average American does not realize that a drug purchased OTC may be associated with the same adverse effects as the same drug purchased by prescription. In the case of OTC NSAIDs, adverse reactions may include kidney damage, hypertension, and gastrointestinal (GI) symptoms ranging from mild dyspepsia to serious or even fatal GI bleeding. NSAID-induced GI Disease: GI disease associated with NSAIDs has been reported as the most common serious adverse drug effect in the United States. NSAIDs can exacerbate underlying disease or cause new lesions. From 38% to 50% of patients taking NSAIDs report dyspepsia, and gastric ulcers may develop in up to 28% of patients taking NSAIDs regularly. Studies have shown that a person exposed to NSAIDs has three to four times the risk of non-users for upper GI bleeding, perforation, or both. Increased risk of a serious adverse reaction has been associated with age, female sex, and rheumatoid arthritis, while independent risk factors associated with upper GI bleeding include male sex, history of peptic ulcer (with or without complications), and the use of alcohol, cigarettes, anticoagulants, and corticosteroids. Lands et al. found that 80% of patients with either upper or lower GI bleeding, and 78% of patients with upper GI bleeding only, had recently consumed NSAIDs (verified by measuring platelet cyclooxygenase activity and serum salicylate levels, as well as taking patient history). Klein et al. also found a higher frequency of GI bleeding in NSAID users. They examined discharge data from hospitalized patients who had suffered GI hemorrhage (both NSAID users and nonusers). Patients using NSAIDs spent more time in intensive care than nonusers (median 1 day versus 0 days), and daily users had a higher transfusion requirement than nonusers (4 units versus 1 unit), both of which suggest that NSAID use has a substantial impact on health-care resource allocation. (Klein WA et al. Dig Dis Sci. 1993; 38: 2049-2055.) OTC NSAIDs and GI Hemorrhage A two-year study of hospitalized patients admitted with upper GI bleeding has demonstrated that the self-administration of OTC NSAIDs can substantially increase the risk of bleeding. Wilcox et al. evaluated consecutive patients admitted with upper GI hemorrhage to a large inner-city hospital in Atlanta, Georgia. The use of any OTC or prescription NSAID during the week before admission was assessed prospectively (from patient and family interview and pharmacy records). Inclusion criteria included age more than 18 years; presence of hematemesis and a subnormal hematocrit (or a decrease in hematocrit of more than 5 points from baseline); and documented lesion (disclosed by endoscopy, barium upper GI series, or at autopsy). Patients were excluded if the GI bleeding first occurred during hospitalization. During the 2-year period, 421 patients were evaluated. Mean age was 50 (range 18-89); 352 patients were black, 63 white, 4 Hispanic, and 2 Asian; 276 patients were male, and 145 were female. Peptic ulcer was the most common cause of bleeding, identified in more than half the patients. Acute gastric mucosal lesions -- including nonspecific gastritis, portal hypertension, and gastropathy (alcohol- or aspirin- induced) -- were relatively infrequent. More women than men and more subjects over age 60 than under 60 were taking prescription NSAIDs; those younger than 60 were more likely to use OTCs, and those over 60 were more likely to use prescription NSAIDs. Drug use was not related to race. Aspirin was taken during the week before admission by 41% of patients (and OTC aspirin by a total of 35%). OTC nonaspirin-NSAIDs were taken by 9% of patients and prescription NSAIDs by 14%. The investigators described the use of OTC aspirin and nonaspirin NSAIDs as "striking" in patients with upper GI bleeding (all causes). These products were used most frequently by patients with ulcer-related bleeding (66%), esophagitis (62%), and Mallory-Weiss tears (laceration of the gastric cardia) (56%) but were also used commonly by patients with bleeding unrelated to ulcers. The investigators concluded, "We believe, as do others, that short-term NSAID use (less than 1 week) may be one of the most important precipitating factors for ulcer related hemorrhage." (Wilcox CM et al. Arch Intern Med. 1994; 154: 42-46.) Epidemiology of NSAID-GI Bleeding A large retrospective study of NSAID use and upper GI bleeding has illuminated the use and misuse of NSAIDs. Rodriguez et al. used a database of 4 million patients (the UK General Practitioners' Computerized Records) to identify 1467 patients with upper GI bleeding over a 3-year period, and 10,000 matched controls. The site of bleeding was gastric in 483 patients and duodenal in 787; 40 patients had multiple sites of bleeding, 147 had peptic ulcer only, and 261 had perforation; 64 patients died. One major indication for NSAID therapy was ill-defined back pain (13% for cases and 10% for controls). Although patients used any of 17 different NSAIDs, sufficient data for individual analyses were obtained for ibu- profen, naproxen, diclofenac, ketoprofen, indomethacin, piroxicam and azapropanone (the latter not available in the United States). Aspirin use was not specifically addressed, because use was seen as too widespread and underreported. The investigators found that the mean relative risk for upper GI bleeding associated with current NSAID use was 4.7 (7.0 with high doses and 2.6 with low doses). Current users were patients who most likely used NSAIDs within the previous month (last NSAID prescription ordered during the month before the index date, or duration of therapy including the index date). NSAIDs associated with highest risk of GI bleeding were azapropanone (relative risk 23.4) and piroxicam (relative risk 18). Ibuprofen at low doses had the smallest risk (2.1), although risk was substantially increased with higher doses (6.5 for 1500 mg/day or more). Both short- and long-duration exposure increased the risk of upper GI bleeding, long duration only slightly more than short duration. Patients who recently switched from one NSAID to another or used more than one NSAID simultaneously had more than twice the risk of patients exposed to only one NSAID. In cases where current aspirin use was recorded on the computer, adjustment did not greatly alter risks, which differs from the other studies. The biggest risk factor for GI bleeding in NSAID users was a history of peptic ulceration (relative risk 17.2). Age also played a role: people under 60 exposed to NSAIDs had a relative risk of 2.8; people over 60 had a relative risk of 13.2. NSAID use was slightly greater in women than in men, yet male sex was associated with a greater risk. The investigators described the patient at greatest risk of presenting with an episode of upper GI bleeding as "a male smoker of advanced age who has a history of peptic ulcer, and is a user of oral corticosteroids, anticoagulants, and NSAIDs." (Rodriguez LAG, Jick H. Lancet. 1994; 343: 769-772.) Managing NSAID-induced Dyspepsia How should patients with NSAID-induced dyspepsia be managed? A prospective study by questionnaire (sent to 300 general practitioners, 261 of whom responded) found that management strategies include NSAID discontinuation (87%), switching to another NSAID (12%), and referral for endosco-py (14%) or barium meal (2%). The drugs preferred for management of dyspepsia included histamine2-receptor blockers (41%), antacids (about 25%), and misoprostol (25%). The authors of the report offered the following guidelines for patients with persistent NSAID- related dyspepsia when simple analgesics are inadequate: Endoscopy is advisable when symptoms persist for more than 3 weeks in patients who need long-term NSAID therapy; when dyspeptic symptoms or signs suggest organic disease; and when the patient is receiving both steroids and NSAIDs. (Hardo PG et al. Br J Clin Pract. 1993; 47: 241-242.)NSAIDs and hypertension in the elderly. Do NSAIDs alter blood pressure? In elderly patients, the answer to this question is a qualified "maybe." Johnson et al. found NSAID use an independent risk factor for hypertension in nearly 3000 Australian subjects aged 60 years or more who answered a questionnaire and underwent blood pressure measurements. Usage increased with age and was higher in females than males in every group studied. Among patients with a history of "arthritis," 45% were using NSAIDS; 12% were taking both NSAIDS and antihypertensive agents. NSAID usage significantly predicted the presence of hypertension, with an attributable risk of 29%. It is difficult to tell whether NSAIDs raise blood pressure or antagonize the effects of antihypertensive agents, said the investigators. (Johnson AG et al. Br J Clin Pharmacol. 1993;35:455- 459.) Lon Morgan, D.C. lmorgan@primenet.com