Contrarily to past practices and beliefs, newborns can indeed feel and understand pain stimulus, with premature infants been even more susceptible to pain [11]. Heavy pain for the newborn can affect physiologically all the main organ systems with potential severe consequences in later on [11]. Neonatal nervous systems are in continuous development, thus, they are prone to neurodevelopmental changes from painful stimuli [12], with effects evident even in adult life [13,14]. Even more so for premature neonates that are put into neonatal intensive care units (NICU) in order to become fully grown infants. Their requirements for stimuli and nutrients are at the foetus level and need to be highly regulated to reach the appropriate level of development [15]. NICU has seen many advance in the past years but, accommodation in one does not secure the required development especially for very low birth weight (<1500 g) infants [16,17]. Stunted growth is directly linked to neurodevelopmental problems [18,19] that in turn are linked to worse sensory management for preterm neonates, making them more sensitive to pain [20].

Nutritional practices in NICU are increasingly incorporate breast feeding in their regimes considering it a medical intervention for the correct development of the neonate [21,22,23,24]. Human milk is not the only milk supplied nor breast feeding the only delivery method. Cow’s milk and enriched milk products are also utilized but human milk has many health inductive properties that make it more that nutritional and indeed more medicinal in nature [25,26,27,28]. Breastfeeding releases antioxidant and anti-inflammatory substances to the infant [29], helps establish the gut microbiome and the immune system [30,31] while promoting neurological development [32]. An additional and equally important reason is the required parental presence enhancing the parental-infant interaction that is also an indicator for a succesful outcome after NICU [28].

Non-pharmacological methods, such as non-nutritive sucking [71], skin-to-skin care [72,73], swaddling/facilitated tucking [74], rocking/holding [73,75], and music [76,77] have been recently found to be effective as pain relief strategies in infants in the NICU. In addition, Shah, et al. (2012) found administering glucose/sucrose offered similar pain relief to breastfeeding in neonates [76].

Table 1 summarizes all the common pain management methods in NICU.

Non-nutritive sucking (NNS), is the provision of a pacifier or the sucking of the fingers or the hand in neonates of NICU. NNS is considered a safe and effective method of pain relief during the pinprick procedure in neonates [71]. But it is more effective in conjunction with sucrose/glucose sucking [94]. A randomized controlled clinical trial with cross-over design [97] in an Iranian NICU with 60 infants demonstrated the effectiveness of using oral dextrose for pain management during a heel prick in comparison to facilitated tucking. They did find also that facilitated tucking is effective compared to no management and can be utilized in constrained situations or in combination with oral dextrose [97]. According to a recent study [98], where sucrose was compared with non-nutritive suction, it appeared that with the help of the NIPS scale, sucrose was superior in reducing the duration of crying when removing adhesive patches from newborn wounds. But it was noted that sucrose alone is not superior to behavioral pain management compared to the combination of methods [98]. A significant reduction in pain scores was found in neonates with NNS as well as sucrose administration compared to NNS or sucrose alone in a 2022 study [94] albeit for mild pain caused. Short duration of the sucrose administration pain relief effect has been reported previously [95,96]. NNS usage in the contex of Point of care quality improvement method (POCQI) using a commercially fixed dosage oral sucrose solution gave a 96% rise in NNS use, in a level 3 NICU in India [99].

Breastfeeding in NICU has to be initiated and then established for the neonates to automate the process by tube and then progress to oral feeding after they are developed enough [21,100,101]. When established bottle-feeding and breastfeeding are the most common delivery methods for maternal milk even though exclusive breastfeeding is the gold standard recommended for at least first six months [102,103].

Breastfeeding utilization in the NICU becomes highly important, as studies are published daily with the properties and benefits of breast milk [104,105]. Newborns undoubtedly need their mother’s contact and proper nutrition for their future development. Breastfeeding for a duration of more than 2 min prior to a painful procedure [85] is a valid non pharmacological pain management method. While, the presence of the mother to breastfeed, especially in very premature infants is not applicable, it is a valid option in more grown infants [85].

Direct-breastfeeding is the direct suckling on the breast regardless of the delivery of milk to the infant [106], while expressed breast feeding is the extraction and storage of milk for later delivery with a bottle [107]. Direct breastfeeding is the unequivocal best practice in non-pharmacological pain management methods since it has been compared to all other methods and has been found more effective [61]. It fared much better compared to swaddling [76,86], maternal holding [87] or skin-to-skin care [88,89], topical anesthetics [90] and cooling sprays [91], non-nutritive sucking [92] and music [93] in pain management.

A well-known Cochrane systematic review and meta-analysis [76] from 20 studies (1075 direct and 996 expressed breast feeding infants) established the pain management effectiveness of breastfeeding either direct or in full-term infants. A later systematic review [108] for 15 studies with 1908 infants in total, was more explicit in their results.

Direct breast-feeding was stated as the best method of non-pharmacological pain management compared to all other (holding, skin-to-skin contact, topical anesthetics, and music), and was preferable even to administration of glucose/sucrose in full-term infants [76]. While they did not recommend expressed breast milk as they deemed it not effective enough for pain relief [76].

Despite the effectiveness of non-pharmacological methods for procedural pain management in infants, being evident [109], researchers know precious little about the actual methods the NICU infant parents use. Campbell-Yeo et al. (2011) believed that such strategies are mostly used by nurses to hold on to NICU authority over infant caregiving, despite parents wishing to be more engaged in comforting their infants [85]. Parental involvement in infant pain management in NICU has been previously addressed and needs to be higher [110,111].

A unique cross-sectional and descriptive study of 178 parents whose newborns were placed in NICUs in Finland [112] found that most parents almost exclusively used physical methods, such as touching, holding, and positioning. Very few used other established NICU strategies such as breastfeeding, with only 2% of the parents utilizing it and NNS with oral sucrose (6%). They stated that parental pain management was relate to newborn condition and gestational age [112]. Parents did not use many valid strategies, such as swaddling, facilitated tucking/kangaroo care, music, breastfeeding, and NNS/sucrose [112]. Parents used easy to copy and perform methods that did not require to be taught by the nursing staff, clearly lacking training and knowledge on these effective, yet more difficult to master, strategies [112]. They concluded with a plea to extend parents’ use and knowledge of non-pharmacological pain management methods to manage their infants’ procedural pain in the NICU [112].

The majority of non-pharmacological pain management methods are more effective performed by the parents rather than NICU staff [85]. Thus, NICU staff and healthcare professionals must enable parents to follow such methods, by providing guidance and training for a more active involvement into their child’s care while in NICU [113,114].

Historically, several accepted pain management methods over the years have changed due to undesirable clinical results [6]. It is generally accepted that the use of pharmacological methods in NICU is a controversial issue, as the goal of the medical and nursing staff is not only to deal with short term pain, but also to properly manage the incident, in order to mitigate the subsequent consequences in the long term [115]. In addition, it is worth noting that most non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended for infants < 6 months of age, due to established adverse side effects [80]. The most widely used NSAID is paracetamol [77] for mild to moderate pain relief, and to reduces the need to use morphine [116], thus reducing the risk of opioid addiction. Intubation and mechanical ventilation are usually the procedures that opioids such as fentanyl and morphine are used for, since they are causes for persistent pain [6]. Recent research is inconclusive whether opioids have an effect on pain and neurodevelopmental outcomes at later age [117,118]. Also morphine or fentanyl usage probably has limited effectiveness on reducing the duration of mechanical ventilation and neonatal mortality [119].

Midazolam, and its family of substances benzodiazepines are in use in NICU especially for sedation. As they are found to strengthen opioid effectiveness in causing respiratory depression and hypotension safety concern have been raised [81]. Several other substances some controlled, methadone [78], ketamine, propofol, and dexmedetomidine, where considered, but very limited data and known side effects have restricted their use [79].

In a recent study it was shown that the use of morphine allowed enhanced pain relief compared to its combination with midazolam in NICU, with a lower cost. Thus, morphine alone stands as a common analgesia strategy especially in neonates with respiratory distress syndrome (RDS) [120]. Figure 1 summarizes the main findings.