Pain panacea for opiophobia in infants?

INTRAVENOUS ACETAMINOPHEN (PARACETAMOL) IS SUGgested for use as an opioid-sparing analgesic for children requiring surgery or emergency care, despite limited data on its efficacy and toxicity in infants and children. In this issue of JAMA, the randomized trial by Ceelie and colleagues addresses this evidence gap by showing clinically significant reductions in morphine use among neonates or infants receiving postoperative analgesia. Among patients randomized to receive acetaminophen (n=33) or morphine (n=38) postoperatively, the cumulative morphine dose during the first 48 hours following surgery was 121 g/kg (interquartile range, 99-264) vs 357 g/kg (interquartile range, 220-605), respectively—a 66% relative reduction between groups (P .001). There were no differences in the number of patients requiring morphine rescue doses or in pain scores. These findings merit consideration because of the careful study design, well-matched study groups, and the magnitude of effects observed. However, in addition to the limitations of small sample size, single-center study site, and lack of safety data, these findings also should be interpreted in light of several other considerations. First, given the brief duration of exposure to morphine (48-72 hours) in the trial, it is unlikely that patients in the morphine group developed opioid tolerance, although opioidinduced hyperalgesia could have increased their analgesic requirements. Careful clinical evaluations can differentiate opioid-induced hyperalgesia from opioid tolerance, although standardized clinical tests or biomarkers for opioidinduced hyperalgesia are currently unavailable for this age group. It is possible that some patients in the morphine group may have developed opioid-induced hyperalgesia, partly explaining the wide range of morphine requirements in this group. Another possibility is the accumulation of morphine3-glucuronide, a metabolic product formed preferentially in infants and associated with behavioral excitability and hyperalgesia. These effects were less likely in the group receiving intravenous acetaminophen, perhaps accounting for some of its opioid-sparing effects. Second, synergism between morphine and acetaminophen cannot be ruled out, because all patients received morphine (100 g/kg) before leaving the operating room. The mechanism(s) of acetaminophen analgesia are currently unclear, but several mechanisms could potentiate opioid analgesia. Oral acetaminophen preparations are frequently combined with opioids. However, a randomized trial studying the interactions between intravenous morphine and acetaminophen in 90 adult postoperative patients found additive but not synergistic effects (clinicaltrials.gov Identifier: NCT1366313). In the study by Ceelie et al, some findings suggest that acetaminophen may have been more effective in older infants. In stratified analysis, the cumulative morphine dose in the acetaminophen group compared with the morphine group was 49% lower among neonates aged 0 through 10 days (median dose, 111 g/kg per 48 hours vs 218 g/kg per 48 hours, respectively) and was 73% lower among infants aged 11 through 365 days (median dose, 152 g/kg per 48 hours vs 553 g/kg per 48 hours). For a study designed to investigate the efficacy of acetaminophen, it is arguable that collapsing the age-related strata should have been based on the pharmacokinetics of acetaminophen rather than morphine. Nevertheless, reporting data on morphine dose reductions according to the age-group strata originally designed in this study will be of interest for clinicians. Third, although the age distribution of opioid-related adverse effects in this study population was not reported, an age-related susceptibility to opioid adverse effects is well known with regard to respiratory depression and possibly hypotension. The study by Ceelie et al was designed to focus on the adverse effects of opioids, whereas the toxicity or possible adverse effects of acetaminophen were not evaluated. Hepatic toxicity following intravenous acetaminophen is not uncommon and has been reported following 10-fold dosing errors in infants but also can occur after therapeutic oral doses. Other possible adverse effects include systemic anaphylaxis or localized effects and pain at the site of injection (in one study, this occurred in 15% of patients receiving acetaminophen and in 33% of those receiving propacetamol). However, given the dose and time of exposure in this study, those adverse effects would be unlikely.