Adverse drug interactions involving common prescription and over-the-counter analgesic agents

Eight analgesic preparations with approved indications for acute pain were among the top 200 drugs prescribed in the United States in 2006. In addition, an estimated 36 million Americans use over-the-counter (OTC) analgesics daily. Given this volume of use, it is not surprising that a number of drug interactions involving analgesic drugs have been reported.

This article examines the pharmacologic factors that enhance the clinical relevance of potential drug interactions and reviews the literature on drug interactions involving the most commonly used analgesic preparations in the United States.

A PubMed search was conducted for English-language articles published between January 1967 and July 2007. Among the search terms were drug interactions, acetaminophen, aspirin, ibuprofen, naproxen, celecoxib, NSAIDs, hydrocodone, oxycodone, codeine, tramadol, OTC analgesics, alcohol, ethanol, antihypertensive drugs, methotrexate, warfarin, SSRIs, paroxetine, fluoxetine, sertraline, citalopram, serotonin syndrome, MAOIs, and overdose. Controlled clinical trials, case-control studies, and case reports were included in the review.

A number of case reports and well-controlled clinical trials were identified that provided evidence of the relatively well known drug-drug interactions between prescription/OTC NSAIDs and alcohol, antihypertensive drugs, high-dose methotrexate, and lithium, as well as between frequently prescribed narcotics and other central nervous system depressants. In contrast, the ability of recent alcohol ingestion to exacerbate the hepatotoxic potential of therapeutic doses of acetaminophen is not supported by either case reports or clinical research. Use of ibuprofen according to OTC guidelines in patients taking cardioprotective doses of aspirin does not appear to interfere with aspirin's antiplatelet activity, whereas chronic prescription use of ibuprofen and other NSAIDs may interfere. Low-dose aspirin intake appears to abolish the gastroprotective effects of cyclooxygenase-2-selective inhibitors, including celecoxib. There is evidence of other less well known and potentially clinically significant drug-drug interactions, including the ability of selective serotonin reuptake inhibitors to inhibit the analgesic activity of tramadol and codeine through inhibition of their metabolic activation, to induce serotonin syndrome when used chronically in the presence of high doses of tramadol through synergistic serotonergic action, and to increase the potential for gastrointestinal bleeding associated with NSAID therapy through additive or supra-additive antiplatelet activity.

Considering the widespread use of analgesic agents, the overall incidence of serious drug-drug interactions involving these agents has been relatively low. The most serious interactions usually involved other interacting drugs with low therapeutic indices or chronic and/or high-dose use of an analgesic and the interacting drug.