Non-Pharmacology Pain Management on Neonate: A Systematic Review

Introduction: Neonates undergoing treatment often experience pain and painful procedures. Proper pain management needs to be done considering various cases in neonates with different pain experiences and causes. This study aimed to review the effect of non-pharmacological pain interventions on neonates. Methods: A systematic review was conducted to investigate the effect of non-pharmacology pain management in neonates. Studies were obtained from Proquest, Clinical Key for Nursing, Science Direct, and EBSCO databases. This study was limited to Randomized Control Trial studies published between 2015 and 2022, using subject headings and synonyms as


INTRODUCTION
Exposure to pain in neonates is related to neuronal development. Exposure to pain obtained during treatment will have an acute or chronic impact on subsequent development. Pain experienced by premature babies is also a fundamental problem because the sensory development of pain is not perfect. Premature babies with exposure to pain are at risk for allodynia and inappropriate pain response and can also experience hyperalgesia, where the neonate experiences an excessive pain response. Neonates also felt discomfort during the procedure for taking venous blood. Venous blood sampling is a routine invasive procedure performed on hospitalized neonates. Neonates are particularly vulnerable to the adverse effects of this routine procedure. Some studies say that discomfort will affect heart rhythm, cortisol levels, crying behavior, decreased oxygen, and increased motoric excess. According to anatomical studies, nociceptors receiving pain stimuli in neonates have the same or even denser density than adults. More than 90% of hospitalized neonates undergo invasive procedures such as venous blood. The results of data at the University of Muhammadiyah Malang Hospital in 2017, of 115 neonates, 93% were taken for venous blood collection at least once and a maximum of 6 times during hospitalization. The room nurse does not yet have the right action to manage the discomfort caused by the venous blood sampling procedure.
The first year of the study showed that the average comfort level was 22.5, where the lowest score was five while the highest score in patients not using a ventilator was 25; if using a ventilator, the highest score was 30. The NIPS pain scale obtained an average result of 4.94 from the value range 1-7. The results of this study showed data that infants who were treated at the hospital experienced pain when taking venous blood and experienced discomfort with an average close to the maximum value. The results of another study showed that 50.3% of neonates experienced pain, and only 32% had pain management, both pharmacological and nonpharmacological. This finding shows that almost 70% of neonates do not receive pain management during treatment.
Efforts to prevent the long-term impact of discomfort and pain are significant. The study of non-pharmacological pain management, especially in neonates, has not been widely discussed, so this topic is needed to strengthen the study of non-pharmacological particular interventions in newborns who experience pain.

Study Design and Literature Search Strategy
The research design used in this study is a systematic review. The literature search strategy and selection criteria are as follows: In obtaining references in this study, the researchers searched for articles from several search sites, including Science Direct, Proquest, Clinical Key For Nursing, and EBSCO. The articles were searched based on the research title entitled Non-Pharmacology Pain Management on Neonate, so to get the desired journal, the researcher used keywords as described in table 1 below:

Selection Criteria, Screening and Quality Evaluation
The topic of this study is Non-Pharmacology Pain Management on Neonate based on literature studies. This study used data filtering to select articles by the following provisions: articles from the last eight years (2015-2022), reputable international journals, accessible full text, experimental study, and randomized controlled trial study. In this study, quality assessment uses JBI critical appraisal tools. The assessment process must include information that matches the predetermined assessment criteria and at least meets the criteria of more than 50% (Aromataris & Munn, 2020). The literature search and screening process flow are generally described in figure 1.

Data Extraction and Analyze
This study extracted data related to the population, intervention, and outcomes (PIO components). To standardize this process and increase the validity of the results, researchers will compile data extraction tables and classify the data collected from research results based on research identities: title, year, author, research methods, and research results (Saltikov, 2012). Furthermore, the data analysis process is carried out using thematic analysis to saturate the information obtained from selected research journals. The data extraction and JBI score assessment areas are presented in Table 1 below. The results of the hammock position group showed increased pain compared to the traditional position group (Premature Infant Pain Profile score, 2.62 ± 1.89 vs. 2.31 ± 1.97, P = .008) and sleep-wake status score (2.08 ± 0.64 vs 1.23 ± 0.44, P < .001), decreased heart rate (151.69 ± 5.44 vs 142.77 ± 5.18 beats/min, P < 0.001), respiratory rate ( 52.31 ± 4.05 vs 50.23 ± 2.55 beats/min, P = .024), and increased peripheral S pO 2 (94.69 ± 2.14 vs 98.00 ± 1.22%, P < .001) .

3
Monica Rita  The results showed no significant difference between gender, weight, and baseline pain scores in the four groups (p: 0.904). The results of the lowest pain score were found in the breastfeeding group when compared to other groups, breast milk feeding (5.52 ± 2.22), Oral dextrose (6.45 ± 1.88), KMCM (6.84 ± 1.96), and KMCM ointment (7.37 ± 1.95) in data collection after heel-picked and there was a significant difference with p-value = 0.001 It was found that the intervention of white noise and facilitated tucking applied was more effective in relieving infants before the endotracheal suctioning procedure (p < 0.05 ). No significant differences were found between groups in reducing pain during the endotracheal suctioning procedure (p > 0.05 ). The score analysis using PIPP-R in premature infants was divided into four groups: the group with breast mil smell, white noise, facilitated tucking applied, and control groups before the endotracheal suctioning procedure. While there was no significant difference between the groups in terms of measurements obtained 3 and 5 min before the procedure, there was a significant difference between the groups at 1 min (p = 0.048). After the procedure, the intervention group breast mil smell, white noise, and facilitated tucking applied and the control group while there was no difference between mean scores of premature infants were determined at 1 and 5 min on the PIPP-R; there was a significant difference between the mean scores of the PIPP-R determined at 3 min (p = 0.047). found that the results of a high maturity significance between differences regarding physiological, behavioral, and neurological outcomes of premature infants concerning temperature, oxygen saturation (SaO2), infant crying, sleep, and juveniles' activity between the study and control groups. Regarding the physiological functioning of premature babies, it shows that 90%, 97.5% & 85% compared to 40%, 60% & 0% of mature babies, their temperature is normal in the supine position, side-lying, and prone positions in the study group and control group, respectively, which exhibited maturity difference insignificance (X2 = 23.14,20.57 & 14.06 at p-values 0.00 , 0.00, & 0.00) respectively. As regards respiratory rate, the analysis also explained that 80% of infants were premature compared to 57.5%. They had normal respiratory rates during the supine position of the study group and control group, respectively, with a maturely significant difference (X2 = 5.33, at a p-value of 0.05). Regarding SaO2 during prone position, it was found that 100% and 90% of premature babies had a SaO2 level of 95% in both. Regarding the behavior of premature infants, the responses in the form of a sleep/awake state stated that 82.5%, 87.5% & 100% were had a better sleep in supine, side-lying and prone positions compared to 20%, 20% & 10% in both study and control groups respectively. These results also showed that 80% and 90% of the premature infants were awake in the study group compared to 62.5% and 30% of those in the control group during the recumbent and prone positions, respectively, reflecting the significant difference in premature ( X2 = 21.37 &10.14, at P-values of 0.00, 0.006) respectively. Minority (5%) mature infants in the study group cry on their stomachs potition. 8 Sibel Kucukoglu, Sirin Kurt and Aynur Aytekin. (2015). The effect of the facilitated tucking position in reducing vaccinationinduced pain in newborns (Kucukoglu et al., 2015). Results of comparing the descriptive characteristics of newborns in the control and treatment groups were found. There were no significant differences in maturity between the groups in terms of sex, gestational age, weight, height, method of delivery, and the number of previous children submitted by the child's mother. The mean NIPS pain score of infants in the treatment group (2 .83 ± 1.18) was significantly lower than that of infants in the control group (6.47 ± 1.07, p < 0.05). While 50% of the infants in the treatment group had no pain, 93.4 % of the infants in the treatment and control groups experienced pain. When the physiological parameters of the newborn changed in the care and control groups the groups were examined, no differences were found between the groups in terms of fever, pulse, respiration, and oxygen saturation before and after the procedure (p > 0.05) The respiration rate of newborns in the control group was significantly higher than that of newborns in the treatment group during the procedure (p < 0.05) in the prone position during heel pike and 86.63 in the supine position. Average SatO2 increased significantly during prone positioning (p= 0.000). Furthermore, the average SatO2 increased significantly during the prone position five minutes before heel spear, 30 minutes before heel spear, and 30 min after heel spear (p < 0.05), which means heart rate (HR) was 146.09 during the prone positioning and 145.48 during the supine position, with no significant difference between the positions (p= 0.166); premature infants in the supine position cried because of longer time during heel spearing than those who were prone position (p=0.003). Crying time was not significantly different in body weight, sex, and gestational age (p> 0.05). NIPS scores show significantly lower scores in the prone position than in the supine position (p=0.000). The COMFORT neo scale scores showed a significant decrease in scores in the prone position compared to the supine position. The NRS COMFORT neo pain score shows significantly lower scores in the prone position than in the supine position (p = 0.000). The median salivary cortisol level during the prone position five minutes before the heel spear was significantly lower than in the supine position (p= 0.006). Thirty minutes after heel spearing, the salivary cortisol level during the prone position was significantly lower than in the supine position (p= 0.001). Five minutes before and 30 minutes after heel spearing, Median salivary melatonin levels during the prone position did not show a significant difference compared to the supine position (p= 0.445) 10 Hsueh The pain was measured by watching videotapes of infants undergoing heel-stick procedures and assessing pain at 1-minute intervals with premature PIPP. Data were collected through eight phases: baseline (phase 1, 10 min without stimulation before heel stick), during heel stick (phases 2 and 3), and 10 min recovery (phase 4-8). For infants receiving suckling and breast milk, the change in pain score from baseline in phases 2-8 was 2.634, 4.303, 2.812, 2,271, 1,465, 0.704, and 1,452 units lower than the change in the corresponding pain score in infants receiving routine care (all p-value < 0.05 except for phases 6 and 7). Similarly, for infants who received sucking, breastfeeding, and tucking, the pain scores from baseline were 2.652, 3.644, 1.686, 1.770, 1,409, 1.165, and 2,210 units lower than the corresponding changes in pain scores in infants receiving routine care in the second phase. 2-8 (all p values < 0.05 except for phase 4). After receiving suckling, breast milk, sucking, and sucking breast milk, the baby's risk of experiencing mild pain (pain score 6) was significantly decreased by 67.0% and 70.1%, respectively, compared with infants receiving routine care. The results showed no significant difference in premature infants who underwent intervention in each group, both on the pain scale, saturation, duration of crying, and heart rate before, during, and after the procedure. However, the average value of the duration of crying in the amniotic odor group got the lowest score. Due to amniotic odor, there was a significant difference in oxygen saturation in term infants in each group. respectively (P = 0.012). In addition, the mean PIPP scores in groups A, B, and C were 6.6 ± 1.3, 10 ± 2, and 11.4 ± 1.9, respectively (P < 0.001). No significant difference was found between groups in mean Sa02, systolic, and diastolic blood pressure after intervention (P > 0.05) 14 Dilek Kucuk  In the study, it was found that no significant difference was found between the three groups in the mean ± SD HR, BP, and Sao2 before intervention (P > 0.05 ). However, after the intervention, the mean heart rates in groups A, B, and C were (A = 146 ± 14.3 ), (B = 153 ± 17.5), and (C = 155 ± 17.7), respectively. -respectively (P = 0.012). In addition, the mean PIPP scores of groups A, B and C were (A = 6.6 ± 1.3 ), (B = 10 ± 2), and (C = 11.4 ± 1.9), respectively. respectively (P < 0.001). There was no significant difference between the groups in mean SaO2, systolic blood pressure, and premature after intervention (P > 0.05 ).

Bircan Tasci and Tolay Kuxlu
Ayyildz (2020)  The findings show that newborns in both groups were similar in sex, mode of delivery, weeks of gestation, birth weight, head circumference, length, Apgar score, and no premature difference. At the same time, in both groups, prematurely significant differences were detected between NIPS scores before, during, and after sampling (breastfeeding group, p = 0.001 and formula-fed group, p = 0.001). Although no prematurely significant differences were detected between the heart rates of the groups before sampling (p = 0.571), newborns in the breastfed group had a lower heart rate remit during (p = 0.001) and after (p = 0.001) sampling compared to the formula milk group. At the same time, in both groups, a prematurely significant difference was detected between heart rates before, during, and after sampling (breast milk group, p = 0.001 and formula milk group, p = 0.001. Although no significant differences were detected prematurely between the SpO2 levels of the two groups before sampling (p=0.099), newborns in the breast milk group had higher SpO2 levels during and after sampling compared to newborns in the formula milk group (p = 0.001). The duration of the crying of newborns sniffing milk formula was significantly longer during sampling than newborns who sniffed breast milk (p = 0.001). There was no prematurely significant difference between the groups in terms of salivary cortisol measurements prior to sampling (p = 0.820); the salivary cortisol levels of newborns in the breastfed group after sampling were found to be premature significantly lower than those of newborns in the breastfed group formula (p = 0.004 Profile-Revised (PIPP-R) pain score 5. Analysis: a statistically significant (p<0.05) difference between two groups in terms of PIPP-R score during and after the sampling ( p= 0.008 and p= 0.03 ) A total of 61 infants were analyzed in the study, consisting of 29 girls (47.5%) and 32 boys (52.5%) aged 2-25 days (mean age 5.31 -4.86 days). No significant difference was seen between the two groups regarding gestational age, birth weight, age at intervention, or mode of delivery (p>0.05). There was no difference in gender between groups (p = 0.029). In total, 20 (66.7%) and 12 (38.7%) infants were men in CG and LOG, respectively; it compares PIPP-R scores. There is a significant difference between the two groups regarding PIPP-R scores both during and after sampling (p = 0.008 and p = 0.03, respectively). PIPP-R scores at the start of the procedure were not found to be significantly different between groups (p > 0.05 A Mann-Whitney U test was performed to test the difference in the PIPP score between both groups. The calculated p-value was 0.76. The median duration of total audible cry after venipuncture was 4 seconds for the sucrose group and 5.5 seconds for the honey-treated group. It gives a median difference of 1.5 seconds between both groups. The Mann Whitney U test showed a p-value of 0.803 when performed to test for the difference between both groups with the duration of crying time Based on a review of 19 journals related to pain management in neonates, the most journals were in 2020, with as many as five journals (28%). While the research design used was a randomized controlled trial of as many as 11 journals (64%). The sample characteristics are 61% are preterm newborn infants, the most instrument used is PIPP (33%), and the most common pain management is odor stimulation (39%). Based on data analysis, the intervention proved to be effective (72%), and five others (28%) obtained different trials that are equally effective, or there are no differences with other interventions in the journal so that they can be recommended as appropriate pain management for this treatment.

Result of Data Analysis
We generated the reviews' findings into groups and subgroups themes, as shown in the Tabel Table 3 above shows that the most common interventions for non-pharmacological pain management in neonates are odor stimulation in breast milk, mother odor, vanilla odor, and amnion odor. Next is the position set at the time of the action that causes pain in as many as six articles. Six articles discuss combination intervention, while three discuss sound stimulation. Articles that discuss the intervention of sound stimulation, oral stimulation, and modification of the treatment environment are two articles each.

DISCUSSIONS
This literature review shows that most interventions in overcoming pain in infants use odor stimulation. The journals found related to this topic were at most eight articles that explained the effect of smell with significant results. The odor in reducing pain with the most compelling evidence with the lowest average pain is the smell of breast milk, the smell of the mother, and the smell of the amnion. In contrast, the smell of vanilla and lavender aromatherapy is still less effective for reducing pain than breast milk but affects the duration of crying or calming. Smells that are familiar to babies, such as the smell of one's breast milk and the smell of non-mothers milk, both can significantly reduce pain scale (Alemdar, 2018;Cakirli & Acikgoz, 2021) in addition to having a calming effect on neonates, whereas amniotic odor is more effective in reducing the duration of crying in pain procedures. Breast milk odor can also stabilize the baby's behavior towards pain procedures, heart rate, and oxygen saturation and reduce the duration of crying.
Another intervention that is also quite effective in dealing with pain in neonates is positioning, where the swaddling, holding, Facilitated tacking, Hammock, KMC, Nesting, and prone positions are proven to reduce pain during treatment procedures. The combined position of swaddling, holding, and breastfeeding is more effective in reducing pain. Maternal holding and breastfeeding positions are more effective in reducing pain than holding alone. Nesting in the prone position is more effective in increasing comfort in premature babies exposed to pain than in the supine position; besides that, facilitated tucking is also effective in reducing pain in premature babies vaccinated against newborns or heel-sticks. (Kucukoglu et al., 2015;Peng et al., 2017). As well as the hommock position can also be effective in reducing pain and improving sleep-wake conditions, heart rate and respiratory rate, and oxygen supply in premature infants. It can be concluded that position manipulation such as nesting with a prone position, facilitated tucking, and hammock position can be an option for pain management in premature infants. The above findings also prove that combining more than one position is more effective in reducing pain. Swaddling and holding positions can be alternative pain management options for term infants, combined with breastfeeding to make it more effective.
The results of most journals with interventions that combine positioning, oral stimulation, suction, and the most combination are breastfeeding and smell stimulation, as well as environmental modifications, show evidence of being more effective in reducing pain in both premature and term infants.
Modification of the baby's environment which is part of developmental care by providing a comfortable environment such as in the womb, namely minimizing lighting, installing nesting, closing the incubator, minimizing sound sources, and providing longer rest periods will reduce stress, especially in premature babies and can reduce pain levels due to the procedure. treatment (Alemdar, 2018;El-Nagger & Bayoumi, 2016;Kahraman et al., 2018) . Nurture intervention is also very helpful in improving the quality of life of premature babies in care, where an intervention with a nurturing approach can reduce the baby's stress level. Premature babies with the immaturity of various organ systems are very susceptible to stress levels. Nurture intervention is a combination approach that is quite holistic in managing pain and stress in premature babies. Treatment by mothers with nurture intervention facilitates mothers to do firm, sustained touch, odor exchange, skin-to-skin contact with KMC, eye contact, and vocal shooting, which can effectively improve the quality of development of premature children.
Pain management that is also effective for premature and term babies is a sweet solution by giving 24% sucrose, and 25% dextrose, the type of honey has also been shown to have the same effect in reducing pain due to invasive procedures or other treatment procedures.

CONCLUSIONS
Based on the results of a systematic review, it can be concluded that non-pharmacological pain management is most effective in reducing pain in premature infants and term infants who experience pain due to treatment procedures. The themes obtained from data extraction results in non-pharmacological pain management in neonates were carried out by the smell, sound, oral stimulation, positioning, environmental modification, sweet solution, and interventions. The findings in this study prove that the combination of interventions has a more significant impact on reducing pain due to treatment.

ACKNOWLEDGMENT
The researchers would like to express their deepest gratitude to all leaders of the University of Muhammadiyah Malang at the university level, the Faculty of Health Sciences and Nursing Study Programs for all support, both material and immaterial, as well as to the entire academic community of the Faculty of Nursing, Universitas Airlangga for the support and opportunities that have been given.

CONFLICT OF INTEREST
The principal researcher declares no conflict of interest in this research.