This is the first clinical trial to report on the comperative influence of the time interval following sucrose administration prior to heel lance on behavioral and physiological responses used to calculate a composite pain score in premature infants. A recent Cochrane review revealed that high-quality evidence for the beneficial effect of 0.5-1 ml of 24% sucrose orally for minor painful procedures in preterm and term infants [13]. Accordingly, we included healthy late preterm (postconceptional age of 34–37 weeks) infants who are able to respond properly to a painful stimuli in the study. However, our patients’ low mean pain scores equated to mild pain for the majority of neonates suggest that 1 ml of 24% sucrose provided adequate pain control during blood glucose monitoring by heel lance. Even though, there was an appreciable difference in the PIPP-R scoring during 1 minute with the patients who receive the heel lance following a 2 minute time interval having a mild decrease in the pain score compared to infants who have no time interval, but it was not a statistically significant decrease. Similar results have been attained in terms of seconder results including crying incidence, crying time, and heart rate during 1 minute between groups. Our findings demonstrate that the time interval prior to heel lance did not produce a statistically significant reduction in the behavioural and physiological responses of newborns who underwent minor painful procedures and a lack of statistically significant effect on the PIPP-R scoring.
To achieve to reach at least the predetermined postconceptional age (34–37 weeks) and increase the number of subjects, neonates with a gestational age of < 32 weeks included in the study. Additionally, the postnatal ages of the patients who are more immature were older than the other subjects. Mean pain intensity scores during 1 minute were inversely associated with gestational age, corrected age, birth weight, and actual weight. These findings suggest that the analgesic properties of sucrose affected by gestational, and chronological age, and actual weight. But, however, our findings are in contrast with previous studies of Johnston and collegues that have characterized the odds of demonstrating pain responses were 0.9351 times greater per week of postconceptual age at birth, and 0.9988 times greater per hour of postnatal age [14]. These authors have argued that pain response of newborns seems gestational week and postnatal age related. At the end of 1 minute the heart beat rate of the patients were associated with postnatal age at data collection day. Furthermore, more mature infants reached lower pain scores than those infants who are < 32 weeks GA at the end of 1 minute and discrepancy with the findings of Johnston et al may be related to the older postnatal age of the patients in our study.
Interventions in two groups resulted in a similar rate of adverse events or safety concerns, and most of them were obsereved in patients who were born prior to 32 weeks GA. These findings are comparable with previous studies reporting on the safety of using sucrose on pain management in premature infants [10, 15]. All of the adverse events were short term and resolved spontaneously.
Once, in rats, the pain-relieving effect of sucrose had been blocked via administration of naloxone or naltrexone [16]. Accordingly, it was proposed that sucrose mediate the release of beta endorphins and regulate the communication of pain signals. Beta endorphin being an endogenous opioid peptide neurotransmitter that acts as an opioid agonist and that has been used to evaluate the efficacy of analgesics[17]. On the other hand, in a small sample of preterm infants, changes in plasma β endorphin did not increase after treatment with sucrose[18]. Furthermore, in the study of Gradin et al, they failed to show the decrease the effects of glucose during the heel lance after a morphine antagonist administration in term infants [19]. There may be the mechanisms other than those mediated by opioid pathways involved in the effects of sucrose. Given the immediate onset of the action of sucrose and comparable results between groups can not be solely explain with opioid pathway theory in our study. Indeed, intraoral administration of sucrose has been found useful for pain relieving in preterms, but, it had not generate the same effect when given directly into the stomach [20]. It may simply be that sensory stimulation derived from the sucrose itself. Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor cells (gustatory cells) located on taste buds in the oral cavity, mostly on the tongue. The taste receptor cells send information detected by clusters of various receptors and ion channels to the gustatory areas of the brain. Sweet tastes causes depolarization of the gustatory cells, although different mechanisms are applied, and provide the perception [21]. The sweet taste of sucrose is proposed to promote analgesia through activation of endogenous opioids that attenuate nociceptive information at the level of dorsal horn[22–24], but it has not been fully proven. Administering sucrose in the mouth and perception by gustatory cells may block perception of pain. The act of ingestion of sucrose may also divert the infant’s attention from the painful stimulus. The molecular basis for the neural systems change observed after presentation of natural reward of sucrose and pain, however, remains incompletely understood. The nucleus accumbens (NAc) is a key component of brain reward circuitry [25]. A number of foods stimulate dopamine release in the NAc, including sugar [26, 27].
The investigators who are convinced by opioid mediated hypothesis have been concluded that a 2 min interval prior to heel lance is required to inhibit nociceptive impulses following stimulating taste receptors in the mouth, and mediating opioid responses. Although, lack of satisfactory studies on time interval and scheduling of orally administered sucrose prior to heel lance, but, therefore, there is a compelling allegation of the time interval-2-minute after sucrose ingestion prior to painful procedure. Regardless of the fact that taste-induced analgesia in animal, and human newborns is rapid, enduring and dependent on the ability to detect sweet taste [16, 28], the studies have been focused on the type and concentration of sweeting solution rather than the time of administration prior to heel lance. As yet, various time intervals prior to heel lance have been used in two studies of human subjects [11, 12]. Time delays between oral sucrose intake and the initiation of painful procedures ranged from 4 minutes to immediately before the procedure. But, however, following initial several studies, there is a paucity of studies comparing different time intervals between sucrose intake and heel lance for relieving procedural pain in neonates. In the experiment of Blass et al., a delay of 30, 60, 90, 120 or 240 s was imposed between sucrose intake and the initiation of blood collection in term healthy newborns and declared that the most effective time delay was 120 s. They speculated that the effectiveness of the 2-min interval accords with previous findings of endogenous opioid release caused by sucrose taste. But, the infants in that study was term neonates and, however, the primary outcome was crying [11]. Afterwards, Meesters et al [12], prospectively studied with variable time intervals between sucrose administration and heel stick in preterm and critically ill infants. No correlation was found between pain intensity and time interval prior to heel stick procedure. They concluded that 2 minute waiting is unnecessary after sucrose administration. The validated PIPP-R which was not yet present at the time of the initial study and we employed healthy preterm infants and test with it and our finding is aligned with the second study of showing lack of correlation between various time intervals and PIPP-R scoring.