Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials

Abstract

Despite the high burden of pain experienced by hospitalised neonates there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.

Early life inflammation is associated with spinal cord excitability and nociceptive sensitivity in human infants

“…The mean (SD) brain activity evoked by a heel lance in a cohort of healthy term infants is 0.72 (0.69) (data published in refs. 52 and 53 ). A sample size of 56 neonates (2:1 Neonatal Control Group to Neonatal Inflammation Group allocation ratio) would be required to observe a 70% increase in noxious-evoked brain activity with a two-sample t-test (80% power and a one-sided 5% significance level).…”

“…The mean (SD) RMS of the reflex withdrawal in a cohort of healthy term infants is 23.3 (17.7) (data published in refs. 52 and 53 ). Assigning the same assumptions as for the noxious-evoked brain activity a lower sample size of 36 neonates would be required for this measure.…”

Toward personalized medicine for pharmacological interventions in neonates using vital signs

“…This could be achieved, for example, by using low level experimental noxious stimuli prior to a painful clinical procedure to gage an individual infant's nociceptive sensitivity. 24 Previous responses to painful procedures could also be used to predict how sensitive an individual might be to a future painful procedure and, therefore, useful for informing future analgesic requirements. Moreover, recent work has demonstrated that resting state brain activity recorded using MRI can predict an individual infant's brain activity response to noxious stimuli, 25 suggesting that baseline measures could be used to predict an individual infant's response to a painful procedure and consequently their analgesic requirements.…”

The impact of premature extrauterine exposure on infants’ stimulus-evoked brain activity across multiple sensory systems

“…Due to the single-trial nature of clinically required noxious procedures, we uniformly applied a template analysis approach to each stimulus modality, which we have formerly developed and validated for the analysis of noxious-evoked brain activity in neonates ( Hartley et al, 2017 , Hartley et al, 2015 ). We have previously shown that a template of noxious-evoked brain activity capturing the dominant evoked waveform is an analysis approach robust enough for successful application to single-trial data, sensitive to a range of biologically interesting demographic and clinical variables ( Cobo et al, 2021 , Green et al, 2019 , Gursul et al, 2018 , Hartley et al, 2021 , Hartley et al, 2016 , Kasser et al, 2019 , Vaart et al, 2019 ), and provides a sensitive primary outcome in analgesic clinical trials ( Hartley et al, 2018 ).…”