1. Ann Naughton, Kelli MSN, NNP-BC


Many agents, both pharmacologic and nonpharmacologic, have been studied to alleviate neonatal pain, and the research is extensive. The 2 most commonly studied nonpharmacologic agents studied have been sucrose and nonnutritive sucking (NNS). There is increasing evidence that the synergistic effect of sucrose and NNS is more effective than the effect of sucrose or NNS alone. The purpose of this integrative review of the literature was to determine whether there is a relationship between the synergistic effect of combining sucrose and NNS administered before and during painful procedures, and reducing procedural pain in both preterm and term neonates. This integrative review indicates that the combination of sucrose and NNS is a safe, effective, and clinically significant means of providing procedural pain relief in neonates, both term and preterm.


Article Content

The recognition, management, and clinical importance of neonatal pain and stress have been slow to progress over time. During the 1970s and 1980s, there were many achievements and breakthroughs made in increasing the survivability of critically ill neonates. We are now able to help neonates of increasingly lower gestational age and more advanced diseases survive to discharge from the neonatal intensive care unit (NICU). During this time and in earlier decades, the effects of noxious stimuli in neonates were being researched and beginning to become better understood. During the 1990s, there was a push for more developmental care to be instituted into the care plans of critically ill neonates. Along with developmental care initiatives, new therapies, technologies, and techniques aimed at reducing unnecessary stress and pain in neonates were developed. These developments continue today.1-3


The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."1(p124),3(p61),4(p106),5(p3) Being unable to communicate verbally in no way negates the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment.1,4,5 This definition can be applied to neonates because research suggests that neonates, full-term and preterm, display both physiologic and behavioral cues to pain and stress and these cues are valid indicators of neonatal pain.5 When discussing pain in neonates, the term nociception is often used because it better describes the experience of pain in neonates. One researcher4 showed preference for the term nociception because it refers to "the physiologic process of transduction, transmission, perception and modulation of specific stimuli through the nervous system rather than only the behavioral and social components of pain."(p106) The author4 later stated "the detection of a noxious stimulus and the transduction and transmission of information about the presence and the quality of that stimulus from the site of stimulation to the brain."(p106) Another researcher1 described the term nociception as being "used to describe the effects of a stimulus independent of any judgment of higher consciousness, memory or possible emotional effects or suffering."(p124)


In the developing fetus, the anatomic maturation of the nociceptive pathways from the peripheral receptors to the cerebral cortex is usually complete by the middle to the end of the second trimester. Neonates manifest similar physiologic changes in their endocrine and metabolic systems, cardiovascular and respiratory systems, and behavioral responses, in response to pain and distress as older children and adults do.1-3,5 However, newborns have been shown to exhibit a more prolonged stress response than adults as measured by an increase in cortisol.


Nociception is measured by various biologic components that assess pain as opposed to assessing only external, physical signs of pain. A group of researchers4 defines several biologic markers for stress and therefore pain in the neonate. Neonates display a change in hormonal response, including an increase in the catecholamines, epinephrine and norepinephrine, cortisol levels, and [beta]-endorphins. The production of insulin is suppressed and glucagon is released from the pancreas. Growth hormone and prolactin are secreted more frequently when pain management is not used in neonates.4 In addition, nociception is measured by increased heart rate, blood pressure, and respiratory rate, intracranial pressure and sweating, and decreased oxygen saturation and vagal tone. A neonate's behavioral response to pain or nociception is similar to an adult's but is more exaggerated. These behavioral responses to pain include crying, facial grimacing, chin quivering, eye squeezing, nasolabial furrowing, taught tongue, open and/or stretched mouth, lip purse, and agitation alone or in combination.1-5 Another researcher1 suggests that newborns may experience an increased sensitivity to pain and preterm neonates may have a more pronounced sensitivity than term neonates.


Pain in the neonate has both short- and long-term adverse effects on physical and developmental outcomes, which are more pronounced in the very-low-birth-weight (VLBW) preterm neonate. In the short term, the physiologic signs of pain and distress, including increased heart rate, blood pressure, respiratory rate, and crying, can be physiologically detrimental in the VLBW preterm neonate. This instability alters metabolic demand and oxygenation and may contribute to intraventricular hemorrhage. In the older preterm and full-term neonates, pain and distress, in the short term, can manifest itself in sleep and feeding disruptions and disruptions in interaction patterns.1,3,5 There are conflicting data as to the long-term effects repeated painful stimuli as a neonate. Some older infants and children have exaggerated responses to painful stimuli, while others have decreased responses.1,3,4


There are multiple lines of evidence showing that neonates who are hospitalized undergo multiple painful procedures during their stay. Even full-term neonates in the standard newborn nursery are subject to painful procedures. These procedures are medically necessary for their care but may become quite extensive. These procedures include-but are not limited to-intubation and mechanical ventilation, nasal, tracheal, and nasopharyngeal suctioning, heel sticks, intravenous catheter insertion, nasogastric tube insertion, arterial puncture, lumbar puncture, venipuncture, central catheter insertion, intramuscular injections, chest tube insertion, circumcision, and surgical interventions. Many of these procedures are routine for certain disease states or are routine newborn care. Quite often these procedures are performed multiple times to account for failed attempts.2,5,6


Many agents, both pharmacologic and nonpharmacologic, have been studied to alleviate neonatal pain, and the research is extensive. The 2 most commonly studied nonpharmacologic agents have been sucrose and nonnutritive sucking (NNS).1,2,4,5,7 Although these agents have been extensively studied, there is a gap in knowledge as to the appropriate dosing of sucrose and in the safety and efficacy of long-term repeated doses of sucrose. There is increasing evidence that the synergistic effect of sucrose and NNS is more effective than the effect of sucrose alone. Numerous studies have also shown that although there is evidence-based research regarding sucrose and NNS, they are not always used in routine neonatal care and pain management. This may be due to the gaps in knowledge stated previously. This integrative review of the literature studies the body of evidence surrounding the use of combining 2 nonpharmacologic techniques for reducing neonatal pain, sucrose in combination with NNS. For this integrative review of the literature, reports were included that studied both preterm and full-term neonates, and various measures of nonpharmacologic pain management that included sucrose and NNS as variables. No exclusions were made on the basis of year of publication or country in which the studies were conducted but only articles printed in English were included. Both qualitative and quantitative studies were included. The purpose of this integrative review of the literature was to determine whether there is a relationship between the synergistic effect of combining sucrose and NNS administered before and during painful procedures, and reducing procedural pain in both preterm and term neonates.



In conducting this integrative review of the literature, it is necessary to search multiple databases using several key words and key word combinations. This search was done solely using computer databases. This author used both the SUNY Stony Brook HSC Library and the library in the hospital and medical school where employed, which is the Mount Sinai Levy Library, as well as an Internet search. The Internet search allowed for identification of what articles were at least in part relevant to the topic and then those articles were searched for using various databases in these libraries. For the relevant articles that were obtained, a citation search was conducted to attempt to find more relevant articles. Initially, no exclusion criteria were imposed, except for searching for only English language research, regardless of the country of origin, and the availability of the article in full text. In further conducting the search, this author decided to exclude articles specifically related to the use of sucrose and NNS for neonatal pain for specific procedures, such as circumcision and retinopathy of prematurity examinations because a more general body of research is desired, as opposed to research on specific procedures. If the article contained these specific procedures as well as other procedures such as heel lance or venipuncture, they were included. All research types, quantitative, qualitative, and review, were considered for inclusion. The vast majority of research available is quantitative as well as several reviews. There were no limits placed on the year of publication of the research to allow for primary research. The following databases were searched: CINAHL, PubMed/MEDLINE, and ISI Web of Knowledge-Web of Science, The Cochrane Database including the Cochrane Database of Systemic Reviews and PSYCHinfo, as well as Google Scholar. The key words used were "neonatal," "pain," "procedural pain," "sucrose," and "nonnutritive sucking" in various combinations.


The databases searched and the initial search results for each are depicted in Table 1. The Google Scholar search was more of a guide to see the various articles that may be available and produced very large numbers of results that were unmanageable. In Google Scholar, for the key word combination "neonatal pain AND sucrose AND nonnutritive sucking," results were sorted by relevance, the first 100 articles scanned and the most relevant articles marked to determine whether these articles were also found in the various databases. Because of the often very large number of results in each database for the key word combinations "neonatal pain" and "neonatal procedural pain," the results were sorted by relevance to the key words and availability of full text. This still produced a large number of results, so these were scanned through the first 100 articles after sorting and the most relevant articles were placed into a folder for these key words. The searches of the key word combinations "neonatal pain and sucrose," "neonatal pain and nonnutritive sucking," and "neonatal pain and sucrose and nonnutritive sucking" yielded more manageable search results. For each database and each key word combination, the results were sorted by relevance and availability of full text. The most relevant of these articles were placed in a second folder. Both folders were compared to determine whether they contained the same articles. There were a total of 75 relevant articles that were then placed in a third folder, which combined the first 2 folders. On further review of the 75 articles, it was noted that about 50 of the articles researched only the use of sucrose for neonatal pain relief and the safety and efficacy of the use of sucrose. Since this literature review is studying the combination of sucrose and NNS for neonatal pain relief, the results were further narrowed down in this folder to 25 articles. In the search of full-text articles within this folder, 22 of the 25 articles were able to be obtained. Each of the 22 articles was obtained and reviewed. For the article found from The Cochrane Database of Systemic Reviews, only the section pertaining to the use of sucrose and NNS in combination was reviewed as the article is upward of 160 pages and discusses many different methods of relieving neonatal pain. After careful review of each of these articles, it was decided that only research that explored the combination of sucrose and NNS was to be included so as to satisfy the purpose of this integrative review. Studies that did not include this combination were excluded. Of the 22 articles, 10 articles were chosen for inclusion for analysis and interpretation in this integrative review.

Table 1 - Click to enlarge in new windowTABLE 1. Databases Searched and Key Words Used to Show Search Results


The purpose of this integrative review of the literature was to determine whether there is a relationship between the synergistic effect of combining sucrose and NNS administered before and during painful procedures, and reducing procedural pain in both preterm and term neonates. This integrative review studies 10 research articles, including quantitative and review research (see Tables 2 and 3). Seven of these articles fall into the category of quantitative or experimental and 3 of these articles are reviews of the literature. The articles chosen for inclusion are exhaustive of the research available for the specific inclusion criteria for this integrative review. The following section discusses these articles in accordance with the research purpose.

TABLE 2-a. Evidence ... - Click to enlarge in new windowTABLE 2-a. Evidence for Quantitative Studies Regarding the Use of Sucrose and Nonnutritive Sucking (NNS) for Procedural Pain in Neonates
TABLE 3-a. Evidence ... - Click to enlarge in new windowTABLE 3-a. Evidence for Included Reviews Regarding the Use of Sucrose and NNS for Procedural Pain in Both Term and Preterm Neonates

Some of the earliest research, dating back to only 1990,8 focused on the different pathways of orogustatory and orotactile stimulation using sucrose and pacifiers (Table 2). One of the 3 experiments included sucrose infused through a pacifier that produced a calming effect compared with water infused through a pacifier and these results reached statistical significance. In this study, statistical significance was also reached in another of the experiments that tested sucrose administration with water administration. A pacifier alone was found to calm but did not have a lasting effect. This research did not study a specific "painful" stimulus, but it used the stimulus itself to conduct the experiments, nor did it use a reliable, valid tool for measuring "pain" or "discomfort" (Table 2). This study demonstrated high interrater reliability and claimed randomization but did not state the method used to employ this randomization. The findings of this study show that orogustatory and orotactile stimulation operate through different pathways to calm a 1- to 3-day-old full-term infant. Suggestions were made to use this study to guide future research on how ingestion and contact influence coping with stress and pain in infants.8

TABLE 2-b. Evidence ... - Click to enlarge in new windowTABLE 2-b. Evidence for Quantitative Studies Regarding the Use of Sucrose and Nonnutritive Sucking (NNS) for Procedural Pain in Neonates
TABLE 2-c. Evidence ... - Click to enlarge in new windowTABLE 2-c. Evidence for Quantitative Studies Regarding the Use of Sucrose and Nonnutritive Sucking (NNS) for Procedural Pain in Neonates
TABLE 3-b. Evidence ... - Click to enlarge in new windowTABLE 3-b. Evidence for Included Reviews Regarding the Use of Sucrose and NNS for Procedural Pain in Both Term and Preterm Neonates

There was a span of 9 years noted between the earliest researchers8 and the next published article studying the combination of sucrose and NNS. This is reflective of the lack of substantive research on neonatal pain itself before the 1990s. This study9 (Table 2) studied how taste- and sucking-induced analgesia combated pain in healthy term neonates during a mandatory heel stick procedure and blood collection. This study used crying, grimace, and heart rate to measure pain during the heel stick procedure and blood collection.9 With the exception of heart rate, the tools to rate pain are not clinically reliable or valid. Heart rate is not a clinically reliable or valid tool, but neonatal response to pain can be seen by an increase in heart rate, so physiologically heart rate can indicate a response to a painful procedure. This experiment used 40 subjects randomized into 1 of 4 study groups. There is some question raised about the actual randomization procedure. This is because the study stated that 17 of the subjects were exclusively breastfed, for 8 of the subjects it was not their first heel stick, and 10 subjects were circumcised the previous day, and for each, these infants were distributed equally among the groups with no mention of assignment of random study numbers. There was some control for variability because one phlebotomist was used for 36 of the 40 heel stick procedures and blood collection. This study found the synergistic effect of sucrose and NNS to yield remarkable analgesia.9


French researchers10 (Table 2) studied the synergistic effect of sucrose and pacifiers, using the behavioral acute pain rating scale for neonates, Douleur Aique du Nouveau-ne (DAN). This scale had recently been validated as a clinically valid scale. This was a randomized and controlled study, and the sampling procedure and the randomization procedure were clearly explained. This study found that the association of sucrose and a pacifier showed a trend toward lower pain scores compared with a pacifier alone, but this did not reach statistical significance.10 This study acknowledged its limitations and weaknesses such as the observer being blinded to the solution administered but not to the use of a pacifier since this was impossible in this study, its small sample size, the design of the study being only able to detect a 2-point difference in the DAN scores and lacked power to detect a 1-point difference, and the DAN scale not being able to assess the degree of the perception of pain. There is strength in that the study employed a clinically valid tool. This study finds that sucrose and a pacifier, among other interventions, are safe and effective ways to reduce pain in neonates during minor painful procedures.10


In 1999, a group of researchers11 (Table 2) were the first to study developmentally sensitive interventions (including a pacifier dipped in sucrose) for procedural pain in VLBW preterm neonates. These VLBW preterm neonates are rarely studied and most likely experience the most amount of procedural pain in the course of their NICU stay. In this trial, each infant served as its own control because they received all 4 of the interventions in random order. This study clearly defined its standardization and randomization procedures and used the Premature Infant Pain Profile (PIPP) pain tool, a clinically reliable and valid tool, to measure procedural pain in these VLBW preterm neonates. This study identified its limitation in that these researchers only evaluated for pain-reducing or relieving effects during a single painful procedure, for which they implied that and recommended future research on the safety and efficacy of sucrose and NNS in repeated doses and over time. This study found that a pacifier dipped in sucrose, of all the other variables tested, was the most efficacious means of pain reduction for a single painful procedure.11


A Turkish study12 (Table 2) examined sucrose and dextrose with and without a pacifier and compared the analgesic effects for minor procedural pain in healthy term neonates. This study tools were crying time and pain scores using the Neonatal Facial Coding System before, during, and after a heel lance. The study was randomized, but the randomization process was not explained. This study included the limitation that the observer was not blinded to the administration of a pacifier to the infants but this blinding was not possible in the study. The researchers found that of all interventions made, sucrose followed by a pacifier had lower pain scores and crying time than dextrose followed by a pacifier, but this difference was not statistically significant, concluding that an enhanced analgesic effect was obtained with a combination of either sugar with a pacifier.12


Another group of researchers13 conducted a randomized controlled trial, using the Gate Control Theory of Pain, whose purpose was to compare the safety and efficacy of sucrose with NNS to sucrose alone, controlled by water and NNS, for decreasing procedural pain associated with heel lances in both term and preterm neonates. This trial used the PIPP, a clinically reliable, valid, and widely used pain-rating tool. The PIPP scores according to gestational age due to the assumption that premature neonates can actually feel more pain and are not yet developmentally able to show many of the classic pain symptoms seen in neonates. These researchers13 were very specific in describing their sample size and collection methods, standardization, as well as their randomization procedures and showed high interrater reliability. This study also assessed for adverse effects of the procedure, which was not seen in many of the other studies included in this integrative review. These researchers13 recognized that a limitation of this study was the lack of data on the ability to suck efficiently. This trial found that the PIPP scores were significantly lower in the sucrose with NNS group than the sucrose alone and sterile water with NNS, whose scores showed no significant difference in PIPP scores.


A 2009 Saudi Arabian study14 researched the analgesic effects of sucrose versus water alone or with a pacifier in preterm neonates. They used the PIPP as the pain-rating tool due to its clinical reliability and validity, as well as crying time, before, during, and after a venipuncture procedure. This trial used a control of standard care or no treatment. This study did not clearly describe its randomization and standardization procedures. This study resulted in the combination of sucrose and NNS having the lowest pain scores of all groups for all measurements, which was found to be statistically significant. They found no side effects in the administration of sucrose to preterm neonates. This study implies that the synergistic effect of the combination of sucrose and NNS is statistically and clinically effective and safe intervention for relieving pain during simple procedures in term and preterm neonates. Future research was recommended.14


Three review studies were chosen for inclusion for this integrative review. These reviews were extensive and discussed numerous types of pain relief measures for neonates, so the results are discussed here with reference to the specific purpose of this integrative review. Two authors15 reviewed the literature concerning the use of sucrose with preterm infants. The literature included physiologic mechanisms for sucrose action, current recommendations for sucrose use, and a critique of published studies involving the use of sucrose with preterm neonates (Table 3). They identified the limitation that less research has been done concerning preterm neonates and recommended additional research to determine the most effective approaches for the administration of sucrose, to examine the effectiveness with additional types of painful procedures as most research has been conducted using heel sticks and venipuncture, and to examine the effects of the long-term, repeated use of sucrose. The review concluded that the administration of oral sucrose is effective as a simple and safe method of pain relief for neonates, and that oral sucrose may be combined with NNS to provide significant pain relief.15 Another article16 reviewed complementary and alternative medicine approaches for distress and pain related to medical procedures among neonates up to 6 weeks of age (Table 3). The focus was to review the empirical literature on sucrose with and without NNS for procedural pain in infancy. This review recognized that in many studies, validated behavioral pain tools were not used and recommended future well-controlled investigations using validated behavioral tools. Their findings were that on the whole, sucrose, NNS, and sweetened solutions hold considerable promise for reducing neonatal procedural pain. The findings of this study extend to both minor (heel stick) and major (circumcision) procedures. Their findings also revealed that it appeared that sucrose administered before a procedure on a pacifier to induce NNS may be the most consistent form of pain relief.16 An extensive Cochrane review17 was also included in this integrative review to determine whether the findings of this review were similar or not to the Cochrane review. The purpose of this Cochrane review was to determine the efficacy, effect of dose, and safety of oral sucrose for relieving procedural pain in neonates (Table 3). This review found that sucrose is safe and effective for reducing procedural pain for single events with minimal to no side effects. An optimal dose could not be determined because of the inconsistencies in effective sucrose dosing among studies. They also found that other pain-relieving measures, such as NNS, should be considered in combination with sucrose to significantly reduce or eliminate pain in neonates.17 This extensive Cochrane review recommends further research on repeated administration of sucrose in neonates and the use of sucrose in combination with other nonpharmacologic (eg behavioral, physical) and pharmacologic interventions. Sucrose use in extremely low-birth-weight and unstable and/or ventilated neonates also needs to be investigated.17



The purpose of this integrative review of the literature is to determine whether there is a relationship between the synergistic effect of combining sucrose and NNS administered before and during painful procedures, to reduce procedural pain in neonates. All of the studies included in this review researched the combination of sucrose and NNS to determine whether there was a synergistic effect between the 2 nonpharmacologic means of procedural pain relief. With the exception of 2 studies, sucrose in combination with NNS for the neonatal population provided the most effective and significant procedural pain relief. The Cochrane review17 is the most recent study and recommended that sucrose combined with other pain-relieving methods, such as NNS, be used for procedural pain in neonates.


The calming and pain-relieving effects of sucrose are thought to be mediated by endorphin-releasing pathways activated by sweet taste. The orogustatory effects of sucrose have been demonstrated in animal studies and in preterm and term human neonates during painful procedures.18 In contrast to sucrose, the analgesic effects of NNS are hypothesized to be activated through non-endorphin-releasing pathways by orotactile stimulation. The combination of orogustatory effects and orotactile effects appears to be superior in the management of neonatal pain.8 The evidence is sufficient to support the efficacy of combining the 2 interventions for procedural pain relief in neonates.18 This integrative review supports the practice of a synergistic effect utilizing both sucrose and NNS for procedural pain relief in term and preterm neonate, as a safe and effective means of providing procedural pain relief.



This integrative review of the literature is limited in that it included only studies that tested the combination of sucrose and NNS. Although this was the purpose of the review, other sweet solutions, such as dextrose or glucose, were not studied. This review is also limited in that the included studies used several different doses, concentrations, and intervals of dosing for sucrose. Further research is warranted to determine the most safe and effective concentration, dose, and interval of dosing of sucrose. Of all the studies researched, both included and excluded from this review, none discussed the impact that offering a pacifier or other nonlactating nipple to a neonate has on breastfeeding. This subject area would be an interesting one to explore. Another recommendation is to conduct more studies with clinically validated pain assessment tools and larger sample sizes and include VLBW, ill neonates. This review provides implications for clinical practice in that sucrose and NNS can be considered for standard care policy for procedural pain in NICUs with the confidence that it is safe and effective. Sucrose has been widely studied and found to produce a calming effect and reduce procedural pain. Sucking is well known to be calming in neonates, but the calming effect is often lost once the stimulus is removed. The combination of sucrose and NNS increases the calming effect in neonates during procedural pain. Neonates, both full-term and preterm, undergo multiple painful procedures during a hospital stay, whether it be a routine healthy newborn hospital stay or an extended NICU stay.2,5,6 Studies have demonstrated that neonates feel pain as older children and adults do, and pain in the neonate can lead to both short- and long-term effects physically and developmentally.1,5,10 Because of this, it is imperative to provide relief to these neonates during painful procedures. The direct care nurse should use this substantial evidence in clinical practice. They should inquire as to whether or not there is a policy in place on their unit and if there is not one, they should work to create a policy. Sucrose in combination with NNS is a safe and effective nonpharmacologic means of relieving pain in neonates and should be used regularly in clinical practice for painful procedures.




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For more than 69 additional articles related to neonatal topics, go to


neonate; nonnutritive sucking; nonpharmacologic; pain management; preterm neonates; procedural pain; sucrose; term neonates