Original Article
Comparative Safety Evaluation of Non-narcotic Analgesics

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Abstract

Both spontaneous reports and single outcome studies may distort the overall safety evaluation of drugs. We identified epidemiologic studies, published from January 1970 to December 1995, that investigated the association of serious adverse effects with aspirin, diclofenac, acetaminophen, and dipyrone to determine and compare the excess mortality associated with short-term drug use. The estimated excess mortality due to community-acquired agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal complications was 185 per 100 million for aspirin, 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen, and 25 per 100 million for dipyrone. The estimates were largely influenced by the excess mortality associated with upper gastrointestinal complications. A relative risk estimate of 300 or more for the association of dipyrone with agranulocytosis would have been necessary for the excess mortality of dipyrone to be comparable to that of aspirin or diclofenac. Based on published epidemiologic evidence used to determine the excess mortality associated with short-term use of these four non-narcotic analgesics, the current regulatory ranking of the drugs appears inappropriate.

Introduction

Comprehensive risk evaluations should include comparisons of the safety of the agent to other drugs with similar indications. Comparative evaluations are of particular importance to avoid regulatory and clinical decisions based on single adverse events that are uncommon (e.g., those events with a low baseline incidence).

A comparative safety evaluation of drugs should employ an objective measure to incorporate and quantify the impact of a range of drug-specific adverse effects, with varying degrees of seriousness. For those effects that are life-threatening, an appropriate estimate for the comparative assessment is the excess mortality.

We reviewed the published epidemiologic literature to estimate and compare the excess mortality of four agents indicated for the short-term relief of pain: aspirin, diclofenac, acetaminophen, and dipyrone. In the 1970s, dipyrone was banned in the United States and several European nations, after reports of fatal agranulocytosis among users [1]. At the time dipyrone was banned, little information was available to quantify the risk associated with its use. In addition, no standards were established to compare agent-specific adverse effects.

Since the 1970s, considerable epidemiologic data have been published on the safety of non-narcotic analgesics. The association of the nonsteroidal anti-inflammatory drugs, such as aspirin and diclofenac, with serious upper gastrointestinal complications has been well documented 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, but has not affected their availability. In the United States, diclofenac is available with a prescription, and aspirin and acetaminophen are available over the counter. Because these agents are representative of non-narcotic analgesics commonly administered for pain, they are appropriate agents for comparison of safety with dipyrone. We sought to determine the appropriateness of the current regulation of these agents through a comparative evaluation of the number of deaths over a 1-week period attributable to a short-term course of therapy with each agent.

Section snippets

Methods

We performed a search of the English language literature using the Medline database to locate all epidemiologic studies published from January 1970 to December 1995 that investigated the association of potentially fatal adverse effects with aspirin, diclofenac, acetaminophen, and dipyrone. Life-threatening, drug-related adverse events that are predominantly reported were reviewed through the database, searching for the following terms: adverse effects, toxicity, gastropathy, peptic ulcer,

Results

We selected nine case-control studies that assessed the risk of agranulocytosis (one study) [13], aplastic anemia (one study) [13], anaphylaxis (one study) [15], or serious gastrointestinal complications (seven studies) 4, 5, 6, 7, 8, 9, 10 associated with aspirin, diclofenac, acetaminophen, or dipyrone. Of the seven studies examining gastrointestinal complications, six studies investigated the association with aspirin 5, 6, 7, 8, 9, 10, three the association with diclofenac 4, 6, 9, three the

Overall excess mortality

The overall excess mortality from agranulocytosis, aplastic anemia, anaphylaxis, and upper gastrointestinal complications was 185 per 100 million for aspirin, 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen, and 25 per 100 million for dipyrone, using the median estimates of excess mortality due to gastrointestinal complications for each agent and the higher estimate of excess mortality due to agranulocytosis for dipyrone (Figure 1). The excess mortality associated with

Discussion

The absolute risk of mortality associated with dipyrone appears to be similar to acetaminophen and substantially lower than the risk associated with aspirin and diclofenac, other agents commonly used for short-term pain relief. The estimated excess mortality due to agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal complications was 185 per 100 million for aspirin, 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen, and 25 per 100 million for

Acknowledgements

This study was supported by Hoechst AG, Frankfurt, Germany. Presented in part at the 10th International Conference on Pharmacoepidemiology, Stockholm, August 30, 1994.

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