Noxious-evoked Brain Activity Research Articles

Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK

Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. Wellcome Trust and Bliss.

Multicentre, randomised controlled trial to investigate the effects of parental touch on relieving acute procedural pain in neonates (Petal)

IntroductionNewborn infants routinely undergo minor painful procedures as part of postnatal care, with infants born sick or premature requiring a greater number of procedures. As pain in early life can...

Premature infants display discriminable behavioral, physiological, and brain responses to noxious and nonnoxious stimuli.

Pain assessment in preterm infants is challenging as behavioral, autonomic, and neurophysiological measures of pain are reported to be less sensitive and specific than in term infants. Understanding the pattern of preterm infants’ noxious-evoked responses is vital to improve pain assessment in this group. This study investigated the discriminability and development of multimodal noxious-evoked responses in infants aged 28–40 weeks postmenstrual age. A classifier was trained to discriminate responses to a noxious heel lance from a nonnoxious control in 47 infants, using measures of facial expression, brain activity, heart rate, and limb withdrawal, and tested in two independent cohorts with a total of 97 infants. The model discriminates responses to the noxious from the nonnoxious procedure with an overall accuracy of 0.76–0.84 and an accuracy of 0.78–0.79 in the 28–31-week group. Noxious-evoked responses have distinct developmental patterns. Heart rate responses increase in magnitude with age, while noxious-evoked brain activity undergoes three distinct developmental stages, including a previously unreported transitory stage consisting of a negative event-related potential between 30 and 33 weeks postmenstrual age. These findings demonstrate that while noxious-evoked responses change across early development, infant responses to noxious and nonnoxious stimuli are discriminable in prematurity.

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

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 (electroencephalography)-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 an 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.

Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT

Background Identifying better pain management strategies for painful procedures performed in neonatal care is a clinical priority. Retinopathy of prematurity screening and heel-lance blood tests are essential clinical procedures, but adequate pain relief is not currently provided because of a lack of evidence-based analgesia. Morphine provides effective analgesia in older children and adults, but efficacy in infants is controversial. Morphine is, however, commonly used intravenously for sedation in ventilated infants. Objective The primary objective was to investigate whether or not a single 100 µg/kg morphine sulphate dose administered orally prior to painful clinical procedures provides effective analgesia. Design Single-centre, prospective, randomised controlled trial. Setting John Radcliffe Hospital, Oxford, UK. Participants Thirty-one infants of 34–42 weeks’ gestational age, requiring a heel lance and retinopathy of prematurity screening on the same test occasion. Interventions The study interventions were 100 µg/kg of oral morphine sulphate (intervention arm) or placebo (control arm) 1 hour before the clinically required procedures. Main outcome measures There were two co-primary outcomes: Premature Infant Pain Profile-Revised score (a higher score implies more nociceptive processing) during the 30-second period after retinopathy of prematurity screening, and the magnitude of noxious-evoked brain activity (a higher activity implies more nociceptive processing) following the heel lance. Physiological stability and safety were secondary outcomes. Results After 31 participants were randomised (30 studied and one withdrew), the predefined safety stopping boundary was passed as 3 of the 15 infants who received morphine had apnoeas requiring resuscitation with non-invasive positive-pressure ventilation in the 24 hours after drug administration, compared with 0 of the 15 infants who received placebo [difference in proportion 0.2, 80% confidence interval (adjusted to allow for planned multiple analyses) 0.05 to 1.00; p = 0.085]. The trial was therefore stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. There was no significant difference between the trial arms for either primary outcome (Premature Infant Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – morphine: 11.1 ± 3.2; Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening mean score ± standard deviation – placebo: 10.5 ± 3.4; mean difference in Premature Infant Pain Profile-Revised score following retinopathy of prematurity screening score 0.5, 95% confidence interval –2.0 to 3.0, p = 0.66; noxious-evoked brain activity following heel lancing median activity – morphine: 0.99, interquartile range 0.40–1.56; noxious-evoked brain activity following heel lancing median activity – placebo: 0.75, interquartile range 0.33–1.22; and median difference in noxious-evoked brain activity following heel lancing 0.25, 95% confidence interval –0.16 to 0.80, p = 0.25). Limitations The trial lacked power for the primary outcome measures because of early cessation. However, there was a trend across modalities favouring placebo, suggesting that it was unlikely that a clinically significant analgesic benefit would have been detected in the original proposed sample of 156 infants. Conclusions The administration of 100 µg/kg of oral morphine to non-ventilated premature infants has the potential for harm without analgesic benefit. Oral morphine is not recommended for retinopathy of prematurity screening, and caution is strongly advised if this is being considering for other acute painful procedures in non-ventilated premature infants. Future work Further clinical trials are essential to ascertain effective pain management for retinopathy of prematurity screening. Using multimodal measures with detailed physiological recordings provides a rigorous approach to assess analgesic efficacy and adverse effects, leading to greater mechanistic understanding of the drug effects. This is essential in future clinical trials of analgesics in infants. Patient and public involvement The research team worked closely with an on-site charity during the trial design, conduct, oversight and dissemination. Trial registration Clinical Controlled Trials ISRCTN82342359; EudraCT 2014-003237-25. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Funding was also received for the trial from the Wellcome Trust (reference numbers 095802 and 102076). The report will be published in full in Efficacy and Mechanism; Vol. 6, No. 9. See the National Institute for Health Research’s Journals Library website for further project information.

Nociception and the neonatal brain

Measuring brain activity in infants provides an objective surrogate approach with which to infer pain perception following noxious events. Here we discuss different approaches which can be used to measure noxious-evoked brain activity, and discuss how these measures can be used to assess the analgesic efficacy of pharmacological and non-pharmacological interventions. We review factors that can modulate noxious-evoked brain activity, which may impact infant pain experience, including gestational age, sex, prior pain, stress, and illness.

Birth experience in newborn infants is associated with changes in nociceptive sensitivity

Vaginal birth prepares the fetus for postnatal life. It confers respiratory, cardiovascular and homeostatic advantages to the newborn infant compared with elective cesarean section, and is reported to provide neonatal analgesia. We hypothesize that infants born by vaginal delivery will show lower noxious-evoked brain activity a few hours after birth compared to those born by elective cesarean section. In the first few hours of neonatal life, we record electrophysiological measures of noxious-evoked brain activity following the application of a mildly noxious experimental stimulus in 41 infants born by either vaginal delivery or by elective cesarean section. We demonstrate that noxious-evoked brain activity is related to the mode of delivery and significantly lower in infants born by vaginal delivery compared with those born by elective cesarean section. Furthermore, we found that the magnitude of noxious-evoked brain activity is inversely correlated with fetal copeptin production, a surrogate marker of vasopressin, and dependent on the experience of birth-related distress. This suggests that nociceptive sensitivity in the first few hours of postnatal life is influenced by birth experience and endogenous hormonal production.

Use of morphine before retinopathy of prematurity examinations

Use of morphine before retinopathy of prematurity examinations

Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial

SummaryBackgroundInfant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain.MethodsIn this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 μg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34–42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile–Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25).FindingsBetween Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI −2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40–1·56) with morphine and 0·75 (0·33–1·22) with placebo (median difference 0·25, 95% CI −0·16 to 0·80; p=0·25).InterpretationAdministration of oral morphine (100 μg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants.FundingWellcome Trust and National Institute for Health Research.

Optimising neonatal fMRI data analysis: Design and validation of an extended dHCP preprocessing pipeline to characterise noxious-evoked brain activity in infants

The infant brain is unlike the adult brain, with considerable differences in morphological, neurodynamic, and haemodynamic features. As the majority of current MRI analysis tools were designed for use in adults, a primary objective of the Developing Human Connectome Project (dHCP) is to develop optimised methodological pipelines for the analysis of neonatal structural, resting state, and diffusion MRI data. Here, in an independent neonatal dataset we have extended and optimised the dHCP fMRI preprocessing pipeline for the analysis of stimulus-response fMRI data. We describe and validate this extended dHCP fMRI preprocessing pipeline to analyse changes in brain activity evoked following an acute noxious stimulus applied to the infant's foot. We compare the results obtained from this extended dHCP pipeline to results obtained from a typical FSL FEAT-based analysis pipeline, evaluating the pipelines' outputs using a wide range of tests. We demonstrate that a substantial increase in spatial specificity and sensitivity to signal can be attained with a bespoke neonatal preprocessing pipeline through optimised motion and distortion correction, ICA-based denoising, and haemodynamic modelling. The improved sensitivity and specificity, made possible with this extended dHCP pipeline, will be paramount in making further progress in our understanding of the development of sensory processing in the infant brain.

The influence of the descending pain modulatory system on infant pain-related brain activity.

The descending pain modulatory system (DPMS) constitutes a network of widely distributed brain regions whose integrated function is essential for effective modulation of sensory input to the central nervous system and behavioural responses to pain. Animal studies demonstrate that young rodents have an immature DPMS, but comparable studies have not been conducted in human infants. In Goksan et al. (2015) we used functional MRI (fMRI) to show that pain-related brain activity in newborn infants is similar to that observed in adults. Here, we investigated whether the functional network connectivity strength across the infant DPMS influences the magnitude of this brain activity. FMRI scans were collected while mild mechanical noxious stimulation was applied to the infant's foot. Greater pre-stimulus functional network connectivity across the DPMS was significantly associated with lower noxious-evoked brain activity (p = 0.0004, r = -0.86, n = 13), suggesting that in newborn infants the DPMS may regulate the magnitude of noxious-evoked brain activity.

Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography.

Pain is an unpleasant sensory and emotional experience. In non-verbal patients, it is very difficult to measure pain, even with pain assessment tools. Those tools are subjective or determine secondary physiological indicators which also have certain limitations particularly when exploring the effectiveness of analgesia. As cortical processing is essential for pain perception, brain activity measures may provide a useful approach to assess pain in infants. Here we present a method to assess nociception with electrophysiological brain activity recordings optimized for the use in newborn infants. To produce highly standardized and reproducible noxious stimuli we applied mechanical stimulation with a flat-tip probe, e.g., PinPrick, which is not skin-breaking and does not cause behavioral distress. The noxious-evoked potential allows the objective measurement of nociception in non-verbal patients. This method can be used in newborn infants as early as 34 weeks of gestational age. Moreover, it could be applied in different situations such as measuring the efficacy of analgesic or anesthetic drugs.

Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography

Electrophysiological Measurement of Noxious-evoked Brain Activity in Neonates Using a Flat-tip Probe Coupled to Electroencephalography