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.

Data availability

Source data to produce figures 2-5 are provided with the paper. The data that support the findings of this study are available upon reasonable request from the corresponding author. Due to ethical restrictions, we consider appropriate to monitor the access and usage of the data as it includes highly sensitive information. Data sharing requests should be directed to rebeccah.slater@paediatrics.ox.ac.uk.Code availability: The magnitude of noxious-evoked brain activity in response to the experimental noxious stimuli and clinically-required procedures was calculated using the template of noxious evoked brain activity previously validated for experimental and clinical stimuli and available from (Hartley et al., 2017). The code to perform simulations to compare the sample size needed to assess an intervention effect with and without taking into account individual nociceptive sensitivity presented in study 2 are available from https://gitlab.com/paediatric_neuroimaging/simulating_power_nociceptive_sensitivity.git

Article and author information

Author details

  1. Maria M Cobo

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3961-1568
  2. Caroline Hartley

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7981-0836
  3. Deniz Gursul

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Foteini Andritsou

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4408-167X
  5. Marianne van der Vaart

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Gabriela Schmidt Mellado

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Luke Baxter

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9548-7162
  8. Eugene P Duff

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8795-5472
  9. Miranda Buckle

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Ria Evans Fry

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Gabrielle Green

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Amy Hoskin

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Richard Rogers

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Eleri Adams

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Fiona Moultrie

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1431-791X
  16. Rebeccah Slater

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    For correspondence
    rebeccah.slater@paediatrics.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1595-4846

Funding

Wellcome Trust (Senior Fellowship Award,207457/Z/17/Z)

  • Rebeccah Slater

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethical approval was obtained from the National Research Ethics Service (reference 12/SC/0447) and informed written parental consent was obtained prior to each study.

Reviewing Editor

  1. Markus Ploner, Technische Universität München, Germany

Publication history

  1. Received: November 27, 2020
  2. Accepted: March 17, 2021
  3. Accepted Manuscript published: April 13, 2021 (version 1)
  4. Version of Record published: April 30, 2021 (version 2)

Copyright

© 2021, Cobo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Maria M Cobo
  2. Caroline Hartley
  3. Deniz Gursul
  4. Foteini Andritsou
  5. Marianne van der Vaart
  6. Gabriela Schmidt Mellado
  7. Luke Baxter
  8. Eugene P Duff
  9. Miranda Buckle
  10. Ria Evans Fry
  11. Gabrielle Green
  12. Amy Hoskin
  13. Richard Rogers
  14. Eleri Adams
  15. Fiona Moultrie
  16. Rebeccah Slater
(2021)
Quantifying individual noxious-evoked baseline sensitivity to optimise analgesic trials in neonates
eLife 10:e65266.
https://doi.org/10.7554/eLife.65266

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