PEDIATRICS Vol. 115 No. 4 April 2005, pp. 1004-1007 (doi:10.1542/10.1542/peds.2004-1189)
The Role of Endogenous Opioids in Mediating Pain Reduction by Orally Administered Glucose Among Newborns
From the Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. It has been demonstrated clearly that sweet-tasting solutions given before a painful intervention can reduce pain among newborns. There is no fully accepted explanation for this effect, but activation of endogenous opioids has been suggested as a possible mechanism. The aim of this study was to obtain deeper knowledge of the underlying mechanism by investigating whether administration of an opioid antagonist would reduce the effect of orally administered glucose at heel stick among term newborns.
Design. A randomized, placebo-controlled, double-blind trial with a validated, neonatal, pain-rating scale.
Participants. The trial included 30 term newborns undergoing heel stick, who were assigned randomly to 1 of 2 groups, ie, group I, with naloxone hydrochloride (opioid antagonist) 0.01 mg/kg administered intravenously before oral administration of 1 mL of 30% glucose, or group II, with a corresponding amount of placebo (saline solution) administered intravenously before oral administration of glucose.
Outcome Measures. Pain-related behavior during blood sampling was measured with the Premature Infants Pain Profile. Crying time and heart rate were also recorded.
Results. The 2 groups did not differ significantly in Premature Infant Pain Profile scores during heel stick. The median crying time during the first 3 minutes was 14 seconds (range: 0–174 seconds) for the naloxone group and 105 seconds (range: 0–175 seconds) for the placebo group. There was no significant difference in heart rate between the 2 groups.
Conclusion. Administration of an opioid antagonist did not decrease the analgesic effect of orally administered glucose given before blood sampling.
Key Words: neonate • pain • glucose • opioid antagonist
Abbreviations: PIPP, Premature Infant Pain Profile
A number of well-conducted studies have shown that highly concentrated, sweet-tasting solutions given orally before the intervention can reduce pain among newborns undergoing heel stick, venipuncture, or other painful cutaneous procedures.1–7 Sucrose and glucose are the most commonly used sweet-tasting solutions; they are effective and simple to use and have no documented side effects. The use of orally administered, sweet-tasting solutions for managing neonatal pain in the clinical setting is widespread and is recommended in both national and international guidelines.8,9 There is no fully accepted explanation for the pain-reducing effect of sweet-tasting solutions, but activation of endogenous opioids has been suggested as a possible mechanism.10 This possibility is supported by the findings that newborn infants of women maintained on methadone during pregnancy were not calmed by administration of sweet-tasting solution11 and that the analgesic effect in a rat model could be reversed with opioid antagonists.12
An opioid antagonist counteracts the effects of opioids by binding to opioid receptors. Naloxone is a competitive antagonist and appears to be effective at all 3 types of opioid receptors. It is free of agonist activity of its own. When naloxone is administered intravenously, the onset of action is apparent within 2 minutes. The duration of effect of naloxone is 
1 to 2 hours but is dependent on the dose and route of administration.13 The aim of this study was to clarify the mechanism underlying the pain-reducing effect of orally administered glucose by attempting to determine whether administration of an opioid antagonist would reduce the effect of orally administered glucose at heel stick among term newborns.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Participants
This prospective, randomized, placebo-controlled study was designed to include term neonates treated in the NICU of Örebro University Hospital during the period of October 2002 to March 2004. The hospital committee for research ethics approved the study, and informed consent was obtained from the parents of each neonate before the infant participated in the study procedure.
Term neonates who were in their first 10 days of life, had a peripheral venous catheter for treatment of suspected infection, had been treated with antibiotics for 3 days and/or had a C-reactive protein level of <30 mg/L, and were judged to be in clinically stable condition by the attending neonatologist were eligible to participate. Infants were not eligible for the study if they were receiving intensive care or analgesics or had neurologic symptoms.
On the basis of data from a previous study,4 a mean difference of 3 in Premature Infant Pain Profile (PIPP) score, a SD of 2.5, a P value of <.05, and a sample of 25 infants per group would yield a power of 80% to detect a difference. To minimize the number of subjects recruited for the study, for ethical reasons, an interim analysis was planned when a total of 30 infants had been randomized.
After inclusion in the study, each infant was allocated randomly to receive naloxone hydrochloride (Narcanti; Bristol-Myers Squibb, Bromma, Sweden) at 0.01 mg/kg, administered intravenously, or a corresponding amount of placebo (saline solution) before oral administration of 1 mL of 30% glucose before blood sampling. The dose of Narcanti was the dose recommended for complete reversal of the opioid effect among newborns.13 An assistant not involved in the study performed the randomization in blocks, and the treatment allocations were inserted into identical sealed envelopes marked only with a number. All blood sampling in the study was performed for clinical purposes, and the neonates could be included only once.
Procedure
Two experienced research nurses, trained with respect to this particular project, performed the blood sampling procedure in a standardized manner. The infant was placed on a nursing table in a quiet observation room, and a pulse oximeter probe (Datex-Ohmeda 3800; Datex-Ohmeda, Helsinki, Finland) was attached to the infant's foot. The infant and the pulse oximeter were filmed during the study period with 2 cameras (Panasonic digital video camera NV-DS15; Panasonic Svenska AB, Stockholm, Sweden), and the films were mixed into 1 tape. An assistant who was not involved in the study opened the numbered envelope that contained the treatment assignment and prepared the injection. The research nurse injected the assigned solution and waited for 2 minutes, to ensure the full effect of Narcanti. One milliliter of 30% glucose was instilled into the infant's mouth, in the same manner for both groups; after an additional 2 minutes, the heel stick was performed with a lancet (Microtainer safety flow lancet; Becton Dickinson, Franklin Lakes, NJ). When enough blood had been collected, an adhesive bandage was applied and the infant rested on the nursing table for 3 minutes. If >1 stick was needed to obtain the correct amount of blood, the second stick was performed after the completion of data collection.
Outcome Measures
One experienced observer (M.G.), who was not aware of the assignments to the study groups, analyzed the videotapes. Crying was measured continuously during the blood sampling, as the presence of audible distressed vocalization. The latency and duration of the first cry were also measured. The pain response was measured with the PIPP during the first 30 seconds after the skin puncture. PIPP is a 7-indicator composite scale scoring for the occurrence of facial action (brow bulge, eye squeeze, and nasolabial furrow), changes in heart rate and oxygen saturation, and 2 contextual indicators of pain (gestational age and behavioral state).
Statistical analyses were conducted with the SPSS for Windows software program (SPSS, Chicago, IL). Significance in comparisons between the groups was assessed with the Mann-Whitney U test for PIPP scores and crying time. Student's t test was used to assess differences in PIPP scores and heart rate. P values of <.05 were considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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An interim analysis was performed when 30 infants had been randomized. A statistician performed this analysis independently of the research team. The analysis was conducted with a modification of the P value criterion to .029, to comply with a total level of significance of .05.14 The crying time was found to be substantially longer in the placebo group than in the naloxone group (P = .096 with the Mann-Whitney U test, P = .028 with Student's t test). Because this finding was quite opposite the a priori hypothesis and there was no difference in PIPP scores between the 2 groups (P = .94), inclusion of additional patients was discontinued.
Thirty-five infants met the selection criteria during this study period. Parents of 5 of the 35 infants withheld their consent. No infant was excluded after randomization. Data were missing for 2 infants, ie, PIPP score for 1 and the end of the procedure for 1, because of equipment failure. The infant was excluded from that particular analysis but was included in other analyses that did not involve the missing variable.
Characteristics of the studied infants are presented in Table 1. There were no substantial differences between the groups with respect to these characteristics.
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Group medians and means are reported for PIPP scores and cry variables in Table 2. There was no statistically significant difference in PIPP scores between the naloxone group and the placebo group during heel stick. Analysis of the latency of the first cry showed no difference between the naloxone group and the placebo group. The duration of the first cry did not differ between the groups. The median crying time during the first 3 minutes was 14 seconds for the naloxone group, compared with 105 seconds for the placebo group. The difference was not statistically significant.
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The mean heart rate for the naloxone group before the test was 126 beats per minute, that during the test was 128 beats per minute, and that immediately after the test was 130 beats per minute. The corresponding figures for the placebo group were 121, 113, and 118 beats per minute. There were no significant differences between the 2 groups. No adverse effects were observed for any of the participants.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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As far as we know, this is the first study to address the question of whether administration of an opioid antagonist reduces the analgesic effect among human newborns of a sweet solution given orally before blood sampling. These results showed that the pain-reducing effect of glucose administered orally before heel stick for newborns was not diminished by previous intravenous injection of the opioid antagonist naloxone hydrochloride.
This finding is inconsistent with that in a rat study that suggested that the calming effect of sucrose is mediated through release of endogenous opioids.12 However, in a recently published study, Taddio et al15 did not find a significant difference in the serum ß-endorphin concentrations among preterm infants before and after a single dose of sucrose. In another study, no opioid-like tolerance was observed when glucose was given repeatedly, at normal pain-relieving doses, to newborn infants.16 These findings could appear in favor of our results and against an endogenous opioid-mediated mechanism of effect of sweet solutions.
It is possible that the lack of difference in pain reactions between the study groups was attributable to the use of an improper subtherapeutic dose of naloxone hydrochloride. This seems unlikely, because the dose used was the dose that is officially recommended to reduce an opioid effect in this population.13 Another possible explanation for the lack of difference could be that a sweet solution causes activation of a group of endogenous opioids that cannot be reversed with naloxone.
The sample size might also explain the result. However, the interim analysis showed that it was highly unlikely that a significant difference in PIPP score would be detected with additional accrual, and a tendency to a longer duration of crying was noted in the placebo group, compared with the naloxone group, a result that goes in the direction opposite the a priori hypothesis.
The tendency toward a significantly shorter latency of first cry and longer duration of crying in the placebo group is confusing. One possible explanation could be that naloxone has a calming effect, decreasing the crying but not the pain. However, there is no evidence showing this, making the explanation unlikely. Another explanation could be unknown differences between the groups, causing crying for reasons other than pain (for example, hunger or wet diapers). The fact that only the crying time and not the pain score was affected supports this.
The possibility that naloxone hydrochloride might exert an agonistic effect has been discussed. There is extensive pharmacologic evidence that naloxone is a pure opioid antagonist that does not have the agonistic characteristics of other narcotic antagonists. In the absence of opioids, it exhibits essentially no pharmacologic activity.13 However, there are a few studies suggesting the opposite, namely, that naloxone in small doses produces analgesic effects in some groups of human adults17 and rats.18 If naloxone in small doses has an agonistic effect among newborns, then it would confound our results. Because we used an adequate dose of naloxone and there were no differences in pain scores, this explanation seems unlikely.
Orally administered glucose has a clearly demonstrated pain-reducing effect among newborns. The question of the mechanisms underlying this effect, however, remains unresolved. It has been speculated that mechanisms other than endogenous opioids may be involved in this analgesic effect of sweet solutions. Activation of the pleasure center of the brain, including release of dopamine, is a conceivable explanation. Endogenous pain-inhibiting systems not involving opioids and basic feeding-related behaviors are other possibilities. To date, no studies have addressed these issues.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We found that intravenous injection of an opioid antagonist did not diminish the analgesic effect of orally administered glucose given before blood sampling among newborns infants.
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ACKNOWLEDGMENTS |
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The Capio Research Foundation, the Samariten Foundation, the Research Committee of the County of Örebro, the Foundation for Medical Research at Örebro University Hospital, and the Research Unit at Örebro University Hospital supported this study.
We thank the assistant nurses Ewy Conradsson and Kerstin Sonesson-Svensson for excellent help with the performance of the study.
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FOOTNOTES |
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Accepted Sep 1, 2004.
Address correspondence to Maria Gradin, RN, BScN, Department of Pediatrics, Örebro University Hospital, S-701 85 Örebro, Sweden. E-mail: maria.gradin{at}orebroll.se
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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