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OCTOBER 8, 1996—Madrid, Spain —Two studies presented this week to the European League Against Rheumatism (EULAR) indicate that many medications commonly used to prevent gastrointestinal complications are actually associated with an increased risk of hospitalization for serious GI damage in arthritis patients who regularly take non-steroidal anti-inflammatory drugs (NSAIDs).

Although the cause of this association is uncertain, the researchers believe that common GI medications — including H2-receptor antagonists (acid blockers), proton-pump inhibitors and sucralfate — may suppress warning signs of serious disease and delay appropriate therapy. However, one of the two studies presented at EULAR also found that another drug — misoprostol — offers a significantly greater level of protection against serious GI complications among high-risk individuals. Misoprostol is a key ingredient in the NSAID Arthrotec® (diclofenac sodium 50/75mg and misoprostol 200 mcg).

"It is well established that NSAID use leads to potentially life-threatening GI problems in some patients," said Gurkirpal Singh, MD, a clinical instructor in medicine at Stanford University Medical School who presented his research at the EULAR symposium. "Now, data from studies of several thousand arthritis patients suggest that some GI medications used to protect against this danger may ultimately do more harm than good."

Hidden Warning Signs

Dr. Singh presented an analysis of a subset of data from Stanford's Arthritis, Rheumatism and Aging Medical Information System (ARAMIS), a prospective, observational database containing clinical and outcome information on more than 23,000 patients with rheumatic disease. For this research, Dr. Singh and his team analyzed statistics for 1,921 rheumatoid arthritis patients who had taken NSAIDs for at least six months and were followed for a minimum of 2.5 years. More than 15 percent of these individuals reported gastrointestinal side effects ranging from nausea to bleeding ulcers, and 2 percent were hospitalized as a result. Of those hospitalized, 81 percent had not experienced any prior warning signs.

Overall, nearly a third (29.4 percent) of the patients studied were taking acid blockers or antacids for preventive reasons. However, Dr. Singh's analysis showed no decrease in the incidence of ulcers or other serious GI complications among these patients. In fact, when evaluated as a group, NSAID users who were taking either H2-blockers or antacids for preventive reasons were more than two times as likely to be hospitalized for GI complications than similar patients not taking these medications.

"H2-receptor antagonists can be very effective agents for treating ulcers," said Dr. Singh. "But our analysis suggests that these medications cannot prevent serious GI complications caused by NSAID use, and may actually promote them by masking the early signs of serious GI distress."

A similar study, conducted by Jerry Avorn, MD, associate professor of medicine at Harvard Medical School, compared the incidence of hospitalization among NSAID users who were taking various drugs used as gastroprotective agents. Drawing from a large database of patients in one American state (New Jersey) who received government-reimbursed healthcare, Avorn and his colleagues identified 3,524 NSAID users who were hospitalized for GI complications and 14,096 controls who did not require hospitalization. He found that NSAID users at high risk of GI complications were most likely to be hospitalized if they were taking omeprazole, a proton-pump inhibitor (2 times as likely); followed by sucralfate (1.8 times as likely); and H2-receptor antagonists (1.3 times as likely). Patients taking misoprostol had the lowest incidence of hospitalization for NSAID-induced GI damage; they were 1.05 times as likely to be hospitalized as non-high-risk NSAID users who did not need GI medications.

"As a gerontologist and internist, I am concerned about NSAID use in the elderly; they are more likely to have arthritis and therefore to need these drugs, but they are also much less likely to survive a bleeding ulcer," said Dr. Avorn. "This study measured the impact of various preventive strategies in a real-world setting, in contrast to controlled clinical trials, which must by necessity be small and artificially structured. And it clearly showed that GI medications are not equally effective in protecting patients at high risk of adverse gastrointestinal effects."

Protective NSAID

Misoprostol can be taken as a separate drug along with any NSAID to reduce the risk of GI complications. However, an increasingly popular alternative is an NSAID called Arthrotec® (diclofenac sodium 50/75 mg and misoprostol 200 mcg), which combines misoprostol with diclofenac — one of the world's most popular anti-inflammatory drugs.

Several studies presented at the EULAR symposium provided evidence of the efficacy and safety of this treatment method. The studies documented that the product is at least as effective as diclofenac alone in managing various forms of arthritis and pain, while significantly reducing the risk of GI complications.

Another study — recently published in abstract form in the British Journal of Rheumatology and conducted by David Walker, MD, of Freeman Hospital in Newcastle-upon-Tyne in the United Kingdom — used a special monitoring device to quantify patients' functional level. Through sensors attached to the bodies of participants, the monitor measured patients' posture, the number and amplitude of their steps, and their overall energy expended — all while in their own homes. When compared to their baseline performance, patients taking Arthrotec 75mg were found to have taken 121 percent more steps, have experienced a 24 percent greater amplitude in their steps, and have registered a 161 percent increase in energy used over a 24-hour period. In contrast, patients taking 75 mg of diclofenac alone exhibited a 5 percent decrease in their number of steps, a 2 percent decrease in the amplitude of their steps, and a 9 percent decrease in energy used during the same time period.

"Unlike most arthritis studies that rely on subjective measurements to analyze efficacy, we have developed a system for capturing objective data, in a real-world setting, to evaluate patient improvement while on drug therapy," said Dr. Walker. "These findings must be confirmed in future studies, but the notable difference in patient outcomes between the two drug-therapy regimens suggests either a variance in the diclofenac formulations, or a synergistic relationship with misoprostol."

A separate study, presented this week at EULAR and conducted by D.R. Mehlisch, MD, of Biomedical Research Group in Austin, Texas (U.S.), also suggests a synergistic effect between the misoprostol and diclofenac components of Arthrotec. In 200 patients experiencing dental pain, a consistently higher percentage of patients taking Arthrotec reported at least a 50 percent reduction in pain than those using diclofenac alone. The average duration of pain relief was 5.06 hours for the Arthrotec group and 3.91 hours for patients taking diclofenac alone.

"Though not statistically significant, the consistent numerical superiority of the fixed combination of diclofenac and misoprostol versus diclofenac alone suggests the need for additional research into the possible synergistic analgesic enhancements of misoprostol on diclofenac," concluded Dr. Mehlisch in his research abstract.

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