Assessment of cortisol as a neonatal pain biomarker in the application of non-pharmacological analgesia therapies: systematic review and meta-analysis.

Background: In the history of Neonatology, decades ago pain has been little studied because it was believed that newborns didn't have the capacity to experience pain. Nowadays, there is enough evidence for the existence of neonatal pain but its adequate treatment is an aspect that is continuously evolving. The objective of this study was to evaluate the effectiveness of non-pharmacological analgesia therapies used to alleviate pain in newborns by analysing neonatal cortisol levels as biological markers of pain.

Methods: A systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the Cochrane Collaboration Handbook. Searches were performed in databases such as PubMed, Web of Science, Scopus, CINAHL, Cochrane Library and Science Direct until the end of May 2024. The search identified 1075 articles, of which 10 studies met the inclusion criteria and had the necessary data to develop the meta-analysis. Furthermore, in each meta-analysis, subgroups were performed: non-pharmacological analgesia vs. placebo, and pre-post intervention by gestational age.

Results: The meta-analysis found that breastfeeding exhibited a moderate effect size (SMD = -0.63; 95% CI = -1.07 to -0.19), sucrose showed a small effect (SMD = -0.15; 95% CI = -0.55 to 0.26), and skin to skin contact exhibited a large effect (SMD = -1.34; 95% CI = -2.21 to -0.46). Patients under 28 weeks have less post-intervention pain and showed a large effect (SMD = 1.44; 95% CI = 0.47 to 2.40), between 28 and 32 weeks they have more post-intervention pain and presented a small effect (SMD = -0.43; 95% CI = -0.86 to -0.0), and over 32 weeks they have an increased post-intervention pain and exhibited a large effect (SMD = -1.08; 95% CI = -1.65 to -0.51).

Conclusions: Non-pharmacological therapies showed efficacy in pain reduction based on neonatal cortisol levels. Skin to skin contact is the most effective method to reduce pain from invasive procedures, such as heel pricks in preterm infants under 28 weeks. Breastfeeding also demonstrated to be an effective and safe alternative to use for pain relief and to reduce cortisol levels. However, the cortisol results indicate that sucrose was not effective in reducing neonatal pain.

Trial registration: PROSPERO: CRD42023463831.