Oral administration of a very small dose of sucrose (0.1 ml) appears to be equally effective at reducing pain in neonates during a single painful procedure as larger doses. Sucrose administration in the clinical setting was associated with very few adverse events. This trial was more closely aligned with a pragmatic design on the continuum between pragmatic and exploratory trials . Unlike explanatory trials that test interventions under optimal conditions, pragmatic trials are more generalizable; however, they are also more prone to co-intervention.
Although site was controlled for in the primary outcome analyses, there was a difference in PIPP-R scores across sites (Table 3) that may be partially explained by organizational contextual factors that were not controlled for or assessed in the analyses. For example, although we enrolled neonates in the first 30 of days of life and collected information on exposure to painful procedures and sucrose received since birth, it is possible that sucrose administration and documentation practices differed due to clinical practice guidelines or organizational contextual factors (e.g., workload/staff ratios, unit culture, and the research or clinical experience of the bedside nurses) . We also found higher pain scores were associated with more preterm neonates (P < .001; Table 3) and they experienced a slightly greater proportion of adverse events (3 versus 2 in neonates > 29 weeks GA), although total numbers were very small. Despite higher pain scores with lower GA, there was no difference in the number of rescue doses across GA, which might be explained by site differences in sucrose administration practices.
We could think of two possible explanations for why PIPP-R scores were significantly higher in the least mature group of neonates: (a) the PIPP-R measure inherently scores younger GA higher, or b) sucrose is less effective in these babies (e.g., they are less able to mount an endogenous opioid response that is the underlying mechanism of action of sweet taste ). Differences seen in mean pain intensity were not thought to be due to additional weighting in the PIPP-R measure by GA [< 28 weeks (+ 3), 28–31 weeks and 6 days (+ 2), 32 weeks to 35 weeks and 6 days (+ 1), and ≥ 36 weeks (0)], as there were no corresponding incremental differences seen by GA group. In terms of the latter explanation (b), this needs to be further researched with an adequate sample size of extremely premature neonates (< 28 weeks GA).
Our findings are consistent with past research (primarily in animals) that demonstrated that the analgesic effects of sucrose were primarily mediated by exposure and not dose [10, 22]. Although there was no difference in pain intensity at 30 and 60 s, pain was not fully eliminated during the heel lance procedure. Mean pain intensity scores equated to mild pain (Table 2), or approximately 3/10 if converted to the more common 10-point scale metric. As pain intensity was measured on a continuum, and treatment failure was not defined, the incidence of treatment failure was not determined. However, severe pain could definitely be considered a treatment failure and this occurred in 7.5 to 11.3% of neonates (Table 4) across sucrose doses. These results are similar to systematic reviews of other behavioral interventions, including breastfeeding  and skin-to-skin care . Given that the majority of previous studies have used a single procedure, it is uncertain if the wide variably in neonatal pain response is attributed to the intervention or other factors which remain unknown . Future work in the repeated use of interventions is warranted. In the meantime, we would recommend that if the initial dose of sucrose does not appear to be ameliorating the pain that additional rescue doses be provided during the procedure up to a specified amount. We would also recommend that multiple non-pharmacologic strategies be implemented simultaneously including swaddling, facilitated tucking, skin-to-skin/kangaroo care, breastfeeding, and/ or pacifiers.
Knowledge is lacking on the long-term effects of sucrose with repeated administration. Of the studies that have evaluated repeated doses of sucrose [26,27,28,29,30], none have evaluated long-term outcomes of using sucrose for all painful procedures performed throughout the neonate’s stay in the NICU. Johnston [26, 31] reported that 107 preterm infants < 31 weeks GA who were exposed to > 10 doses of sucrose per day in the first 7 days of life, after which time no pain relief was used, were more likely to exhibit poorer attention and motor development on the Neurobehavioral Assessment of Preterm Infants (NAPI) scale in the early months of life. Conversely, Banga  reported that of 93 neonates randomized to either repeated doses of sucrose or water for painful procedures for 7 consecutive days, there were no significant differences in NAPI scores or adverse events. Stevens  found no statistically significant differences between sucrose plus pacifier, water plus pacifier, or the standard care group on neurobiological risk status outcomes. Future research needs to address the repeated use of minimally effective doses of sucrose on the neurodevelopment of neonates and effectiveness over time.
Approximately 2% of neonates suffered adverse events. These all resolved spontaneously without medical intervention or with minimal caregiver intervention (e.g. positioning). Most adverse events occurred at one site, where the highest proportion of the sickest neonates is cared for, although this is not represented in the study sample. This adverse event rate is consistent with the 2016 Cochrane sucrose review . Although researchers are becoming more vigilant in observing and reporting adverse events, it remains unclear how adverse events are reported (i.e., chart review is considerably different from careful direct observation of every newborn infant who is receiving the intervention).
A few study limitations need mention. Pain intensity did not differ significantly between the 30 and 60-s time points. Although these time intervals have been used in multiple research studies of acute procedural pain, they are arbitrary and designed based on mean behavioral response time; observing neonates for longer periods of time may demonstrate additional responses of less typical responders or other types of responses (e.g. physiologic, cortical). Although there has been significant validation and updating of the PIPP-R measure, there remains no gold standard for measuring pain in infants that may influence the determination of the effectiveness (or lack thereof) of pain relieving interventions. The future, which includes novel strategies for better understanding of the developing cortical pain circuitry, will pave the way for better prevention and treatment of pain in this vulnerable population.
Finally, we were limited by the documentation in the medical records, which may not have included all pain relieving strategies such as sucrose and non-pharmacologic interventions. Although we believe infants should receive some form of intervention for all painful procedures, it is difficult to speculate on whether the discrepancy between number of documented painful procedures and pain-relieving interventions is an administration or documentation issue. As the number of painful procedures included since birth was extensive (e.g., tape removals, bloodwork, injections, vascular access attempts/insertions, NG/OG tube insertions and suctioning, chest tube attempts/insertions, lumbar punctures, eye exams, and urinary catheterizations), it is possible oral sucrose is not routinely administered for each of these types of procedures, depending on unit standards/practices.