Ethics of trial of effect of parental touch on relieving acute procedural pain in neonates

The multicentre randomised controlled trial (RCT) of effect of parental touch on relieving acute procedural pain in neonates recently published in the Lancet Child and Adolescent Health (1) is a perfect example of a well-designed well conducted rigorous experimental trial of a neonatal pain reduction intervention, conducted at two sites in the United Kingdom. Indeed the quality of the trial was praised in a commentary associated with the publication (2). The study was considered in line with family centred care, as parents of the newborns, of which 35% were fathers, were involved in the delivery of the intervention (stroking the leg). However, this study raises a number of considerations for the optimal standards of trial design and conduct in acute pain in newborns. Considerations include the use of what needs to be considered ‘usual care’ based on current best evidence and recommendations for practice and processes, the principle of equipoise (3,4), and processes of obtaining informed consent.

In this trial (1), the standard of care reported was as per ‘local practice guidelines’, which were swaddling and non-nutritive sucking. However these interventions have been reported to be less effective on their own compared to breastfeeding (5,6), skin to skin care (7) and small volumes of sweet tasting solutions, either sucrose or glucose (8-12). These three strategies have long been recommended for needle-related procedures in newborns in national and international clinical practice guidelines and standards (13-15), and have moderate to high levels of evidence based on their respective GRADE status as reported in systematic reviews (6,7,9). These strategies should therefore be considered as standard of care/usual care in neonatal pain studies. Yet, very little information on the extensive body of literature on these strategies has been included in this published study. Specifically, none of the systematic reviews of sucrose or glucose published over the years were discussed or cited in the reference list despite the extensive evidence from hundreds of trials and multiple systematic reviews (8-12). The lack of the use of known evidence-based pain management practices as standard of care in such newborn procedural pain studies calls into question the principle of equipoise, for this study as well as neonatal pain studies being conducted and published. The principle of equipoise involves “the state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in the trial.” (page 141) (16). In fact, it has been argued that we have had too many newborn procedural pain studies for well over a decade (17-19). Over a decade ago, Pediatrics published an ethics rounds on this exact question, titled “Should an IRB Approve a Placebo-Controlled Randomized Trial of Analgesia for Procedural Pain in Neonates?” (20). At that time, Bellini stated “In conclusion, this trial is to be rejected because it exposes infants to avoidable pain, a behavior that is anachronistic for modern medicine” (page 551) (20). Yet, trials continue to be conducted and published. This commentary explores the bigger picture of the use of evidence by researchers in their quest to build further evidence.

Unit practices versus best standard of care

Firstly, as above, the authors of this study under discussion (1) state that the practice in the participating unit is swaddling and non-nutritive sucking. However, using normal unit practices as standard of care in a trial, when there are known more effective treatments, needs to be questioned. The value of new trials compared to implementation interventions or policy interventions, always needs to be weighed up. However, usual practices should always be based on the best available evidence where feasible and possible.

This lack of use of best evidence for newborns undergoing painful procedures is not new to this single publication. In fact, there has been very little change in pain management practices during painful procedures for hospitalized newborns over the last 30 years (21). Responsibility needs to be moved from individual healthcare providers to the healthcare organisation or system level on implementing strategies that will facilitate changing pain practices and improving outcomes (21). Such system level strategies include ChildKind, Solutions for Kids in Pain (SKiP), and Comfort Promise (22). Researchers and clinicians need to address the knowledge-to-practice gap in neonatal pain management and demonstrate the societal and population health impact of their research. It is therefore crucial to engage in dissemination and implementation (D&I) strategies. The development and use of various D&I strategies (e.g., social media posts, plain language summaries, webinars, guidelines, evidence-based interventions) tailored to different audiences (e.g., decision-makers, clinicians, families, institutions) may lead to change in knowledge, attitudes, and behaviors.

Parental informed consent

Written informed consent from the parents was obtained after parents were verbally informed about the study and given written information. However, the processes of informed consent may not be considered as ‘fully informed’. Is it the role of investigators to inform participants/caregivers of all alternative effective treatments? In this case, is it necessary for the investigators to inform parents that there was already evidence of analgesic effects of breastfeeding or holding their babies skin to skin? Parents were involved in this study, however, were they given opportunities to hold their babies, rather than just stroking one leg? Lack of parents’ understanding, information and time to discuss the studies have been previously identified in a systematic review of ethical issues regarding consent to participate in neonatal clinical trials (23).

Finally, we recognize the persistent challenges of pain assessment in neonates and infants due to the lack of standardized, universally accepted pain assessment tools. Incorporating new technologies into pain assessment, such as neuroimaging and artificial intelligence, may overcome the limitations of subjective observation and offer a more reliable and consistent method for assessing pain in this population.

Conclusions

The ethics of conducting neonatal pain trials in the face of abundant evidence of strategies with known analgesic effects, needs to be carefully examined. There is a need to call for cessation of newborn pain trials where sick and healthy newborns do not receive the best evidence. This includes all trials with placebo/non treatment arms and trials where already known ineffective interventions or new interventions are being studied without standard care using either breastfeeding or skin-skin contact, when possible, feasible and culturally acceptable, or sucrose or glucose. Organisational standards need to reflect current evidence, ensure newborns receive the best pain management, including involving parents in all aspects of care and reject ethics application submissions where best standard of care is not used. There are ways to reduce pain in newborns during commonly performed needle procedures—we need to use the evidence.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-324/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-324/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Hauck AGV, van der Vaart M, Adams E, et al. Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK. Lancet Child Adolesc Health 2024;8:259-69. [Crossref] [PubMed]
2. Guinsburg R. The touch of science: the Petal trial. Lancet Child Adolesc Health 2024;8:246-7. [Crossref] [PubMed]
3. Ashcroft R. Equipoise, knowledge and ethics in clinical research and practice. Bioethics 1999;13:314-26. [Crossref] [PubMed]
4. Bueno M, Harrison D. What happened to the principle of equipoise in the planning, designing and conducting of placebo-controlled trials for neonatal procedural pain? Pediatr Neonatol 2019;60:479-80. [Crossref] [PubMed]
5. Benoit B, Martin-Misener R, Latimer M, et al. Breast-Feeding Analgesia in Infants: An Update on the Current State of Evidence. J Perinat Neonatal Nurs 2017;31:145-59. [Crossref] [PubMed]
6. Shah PS, Torgalkar R, Shah VS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev 2023;8:CD004950.
7. Johnston C, Campbell-Yeo M, Disher T, et al. Skin-to-skin care for procedural pain in neonates. Cochrane Database Syst Rev 2017;2:CD008435. [Crossref] [PubMed]
8. Bueno M, Yamada J, Harrison D, et al. A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates. Pain Res Manag 2013;18:153-61. [Crossref] [PubMed]
9. Yamada J, Bueno M, Santos L, et al. Sucrose analgesia for heel-lance procedures in neonates. Cochrane Database Syst Rev 2023;8:CD014806. [Crossref] [PubMed]
10. Huang RR, Xie RH, Wen SW, et al. Sweet Solutions for Analgesia in Neonates in China: A Systematic Review and Meta-Analysis. Can J Nurs Res 2019;51:116-27. [Crossref] [PubMed]
11. Lin T, Qiu HF, Huang RR, et al. There are already enough studies on sweet solutions for neonatal procedural pain and more would be unethical and unnecessary. Acta Paediatr 2023;112:1434-6. [Crossref] [PubMed]
12. Harrison D, Larocque C, Bueno M, et al. Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis. Pediatrics 2017;139:e20160955. [Crossref] [PubMed]
13. Prevention and Management of Procedural Pain in the Neonate. An Update. Pediatrics 2016;137:e20154271. [Crossref] [PubMed]
14. Eccleston C, Fisher E, Howard RF, et al. Delivering transformative action in paediatric pain: a Lancet Child & Adolescent Health Commission. Lancet Child Adolesc Health 2021;5:47-87. [Crossref] [PubMed]
15. Health Standards Organization. Pediatric Pain Management. 2023. Available online: https://healthstandards.org/standard/pediatric-pain-management-can-hso-13200-2023-e/
16. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-5. [Crossref] [PubMed]
17. Harrison D, Bueno M, Yamada J, et al. Analgesic effects of sweet-tasting solutions for infants: current state of equipoise. Pediatrics 2010;126:894-902. [Crossref] [PubMed]
18. Bellieni CV, Buonocore G. Recommendations for an ethical treatment of newborns involved in clinical trials. Acta Paediatr 2010;99:30-2. [Crossref] [PubMed]
19. Guinsburg R. In reply. Pediatrics 2010;125:e709-10. [Crossref] [PubMed]
20. Bellieni CV, Taddio A, Linebarger JS, et al. Should an IRB approve a placebo-controlled randomized trial of analgesia for procedural pain in neonates? Pediatrics 2012;130:550-3. [Crossref] [PubMed]
21. Bueno M, Rao M, Aujla P, et al. A scoping review of the epidemiology and treatment of painful procedures in hospitalized neonates: What has changed in the past three decades? Eur J Pain 2024;28:1468-85. [Crossref] [PubMed]
22. Harrison D, Bueno M. Translating evidence: pain treatment in newborns, infants, and toddlers during needle-related procedures. Pain Rep 2023;8:e1064. [Crossref] [PubMed]
23. Wilman E, Megone C, Oliver S, et al. The ethical issues regarding consent to clinical trials with pre-term or sick neonates: a systematic review (framework synthesis) of the empirical research. Trials 2015;16:502. [Crossref] [PubMed]