The role of pain scales in the design of neonatal acetaminophen clinical trials and their impact on reported outcomes
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Citation
Abstract
BACKGROUND: Over the past two decades, evidence-based guidelines have been published for acute pain pediatric clinical trials involving commonly used analgesics, including acetaminophen. There continues to be discussion about extending these guidelines to the neonatal population. Although the neonatal age cohort is included in the pediatric population, neonates are at a rapid stage of development that necessitates additional considerations when conducting drug research. Analgesic clinical trials inherently pose a risk for experiencing pain, and, because neonates cannot verbalize their pain, accurate pain assessments become a key component of a successful trial design. While dozens of pain scales have been validated for assessing acute pain in this population, there is currently no “gold-standard” method of pain assessment that is used by analgesic trials.
OBJECTIVE: To review the current practices of acetaminophen administration in the neonatal population and investigate the role of pain scales in acetaminophen clinical trials involving neonates and their impact on other elements of trial design, including immediate rescue designs.
METHODS: Electronic literature searches of PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science were conducted in July 2021. Eight randomized controlled trials were included based on defined inclusion criteria. The pain score and rescue analgesic outcomes reported in each of these trials were analyzed. Any potential relationships between reported outcomes and the presence of an increased burden of untreated pain among control groups were also noted. An additional search for related literature among the excluded studies was performed, and notable patterns and reasons for exclusion were summarized.
RESULTS: Among the eight pain scales that were utilized by the included trials, FLACC was the most used observational pain scale. Several parameters, including movement, crying, and facial expression, are conserved across all the included observational pain scales. Considerable heterogeneity exists in the ways that pain scores and rescue analgesic outcomes are reported across the included clinical trials. The expanded search of the excluded studies indicated that the most profound patterns among literature related to acetaminophen administration were (1) a lack of reporting data specifically for the neonatal age group and (2) the prevalent use of retrospective studies.
CONCLUSIONS: Standardizing the methods of reporting outcomes will facilitate the ease of future analyses and can be the subject of future expert consensus discussions. It appears that using multiple pain scales can increases the precision of pain assessment, resulting in favorable outcomes related to pain scores and rescue analgesia. The outcomes indicating the burden among control groups are subject to variation based on the route of administration of tested drugs, components of trial design, and study sponsorship. Retrospective studies may be useful in filling current gaps of knowledge and guiding future research but cannot replace the use of randomized controlled trials for testing drug efficacy in the neonatal age cohort. Data regarding drug efficacy and safety generated from randomized controlled trials should be reported for the neonatal age cohort to account for age-related developmental differences.