Ondansetron may inhibit the analgesic effect of acetaminophen when the two drugs are co-administered, Canadian researchers have found. The recent study looked at children who received either ondansetron or droperidol in conjunction with acetaminophen during tonsillectomy surgery.
“Children who received the two drugs together needed more morphine in the recovery room after the operation,” said Pierre Beaulieu, MD, PhD, associate professor of anesthesiology and pharmacology at the University of Montreal. “Based on our findings, we think the co-administration of these two drugs is deleterious for pain relief.”
The researchers were scheduled to present their findings at the 2013 annual meeting of the Canadian Anesthesiologists’ Society (abstract 1652406), but the conference was cancelled because of severe flooding.
Dr. Beaulieu said his study confirms that acetaminophen and ondansetron engage the same serotonin (5-HT3) receptor. “Because acetaminophen and ondansetron are working on the same receptor, when they are administered together, there is a decrease in pain relief,” he said. Previous research demonstrated the inhibitory effect of ondansetron on acetaminophen in animal and human volunteer studies, but relevant clinical trials in humans had failed to show an effect.
Dr. Beaulieu and his colleagues designed a double-blind parallel group study of 69 children, ages 2 to 7, who underwent elective tonsillectomy and received acetaminophen as an analgesic. The researchers randomly assigned the patients to receive either ondansetron (n=35) or droperidol (n=34) as an antiemetic. The investigators assessed the children’s pain and morphine consumption for 48 hours after surgery.
There was no difference in postoperative nausea and vomiting (PONV) between the two groups, and the primary end point—postoperative pain—did not differ significantly between the two groups during the first 24 hours. Children who received ondansetron, however, were 2.8 times more likely to require morphine (57.1% vs. 20.6%). The amount of morphine administered to the ondansetron group was nearly three times more (279.5 vs. 97.6 mcg) than to children who received droperidol (Figure).
Figure. Morphine titration in the recovery room expressed as median and interquartile range (box) (P=0.01)
Dr. Beaulieu’s conclusions, however, are controversial. Sergio Bergese, MD, chief of neuroanesthesia at Ohio State University, in Columbus, and Suren Soghomonyan, MD, PhD, a research scientist at Ohio State, noted that the study did not include factorial controls, and therefore could not demonstrate a clear interaction. “Increasing numbers of patients receive acetaminophen and ondansetron in combination postoperatively to treat pain and reduce the incidence of PONV. Undoubtedly, clinically important interaction between those drugs, if any, would deserve further research and might have impact on clinical practice,” Dr. Bergese said. “However, in vitro, in vivo and clinical studies specifically designed to test the hypothesis of drug interaction are mandatory before making any conclusions. Any single clinical trial, especially when underpowered in regard of the specific objective, will be inconclusive.”
Furthermore, he stated, droperidol is a sedative and increases opioid effects, which would decrease total opioid consumption. The study may have been further complicated by the nurses’ interpretation of the patients’ need for additional morphine. “The sedative effect of droperidol could easily influence the nurses’ perception of patient pain,” he said.
Dr. Bergese also pointed out that acetaminophen may act on the 5-HT mechanisms primarily via the 5-HT7 receptors, whereas ondansetron is a selective 5-HT3 antagonist. In addition, endocannabinoid and opioid systems are major components of the antinociceptive activity of acetaminophen—and these systems are not engaged by ondansetron. “The overall picture in a clinical setting is more complex,” Dr. Bergese said. “Attempts to explain the cumulative effects of two drugs based on the assumption that these drugs interact on a single receptor level is over-simplification.”
For Dr. Beaulieu, the question is not settled. “We now need to design a large-scale study, ideally multicenter, to determine whether there is an interaction in a larger population,” he said. “If we confirm the interaction, we should change our practice and not give the two drugs together, and that will affect millions of people around the world undergoing surgery.”