Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial.

Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 µg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective: This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 µg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants.

Five-year follow-up of effects of neonatal intensive care and morphine infusion during mechanical ventilation on diurnal cortisol rhythm.

OBJECTIVE: To test the hypothesis that the diurnal cortisol secretion rhythm of children who as neonates had been hospitalized differs from that of children without a history of neonatal hospital admission and that this rhythm differs between these hospitalized children treated with either continuous morphine infusion or placebo. STUDY DESIGN: A follow-up cohort study was performed with 5-year-old children who as neonates participated in a randomized controlled trial of continuous morphine infusion (born 24-42 weeks' gestation), and a control group of healthy term born (≥ 37 weeks' gestation) children. Five saliva samples over a school day were assayed for cortisol concentrations. The diurnal cortisol rhythm was analyzed with random regression analysis for repeated measurements. RESULTS: Compared with the healthy controls, the trial participants had greater cortisol levels (P = .002) after adjustment for sex and socioeconomic status. The administration of morphine did not affect the cortisol concentrations (P = .66) after adjustment for sex, socioeconomic status, and gestational age at birth. CONCLUSIONS: The finding that former trial participants had greater cortisol levels at 5 years of age supports the concept of long-lasting programming of the hypothalamic-pituitary-adrenal axis. Morphine infusion in the neonatal period did not alter cortisol secretion at 5 years of age.

Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 µg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

Thermal detection thresholds in 5-year-old preterm born children; IQ does matter.

BACKGROUND: Experiencing pain at newborn age may have consequences on one's somatosensory perception later in life. Children's perception for cold and warm stimuli may be determined with the Thermal Sensory Analyzer (TSA) device by two different methods. AIM: This pilot study in 5-year-old children born preterm aimed at establishing whether the TSA method of limits, which is dependent of reaction time, and the method of levels, which is independent of reaction time, would yield different cold and warm detection thresholds. The second aim was to establish possible associations between intellectual ability and the detection thresholds obtained with either method. STUDY DESIGN: A convenience sample was drawn from the participants in an ongoing 5-year follow-up study of a randomized controlled trial on effects of morphine during mechanical ventilation. METHODS: Thresholds were assessed using both methods and statistically compared. Possible associations between the child's intelligence quotient (IQ) and threshold levels were analyzed. RESULTS: The method of levels yielded more sensitive thresholds than did the method of limits, i.e. mean (SD) cold detection thresholds: 30.3 (1.4) versus 28.4 (1.7) (Cohen'sd=1.2, P=0.001) and warm detection thresholds; 33.9 (1.9) versus 35.6 (2.1) (Cohen's d=0.8, P=0.04). IQ was statistically significantly associated only with the detection thresholds obtained with the method of limits (cold: r=0.64, warm: r=-0.52). DISCUSSION: The TSA method of levels, is to be preferred over the method of limits in 5-year-old preterm born children, as it establishes more sensitive detection thresholds and is independent of IQ.

Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial.

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.

Taking up the challenge of measuring prolonged pain in (premature) neonates: the COMFORTneo scale seems promising.

OBJECTIVES: Pain assessment is essential to tailor intensive care of neonates. The present focus is on acute procedural pain; assessment of pain of longer duration remains a challenge. We therefore tested a modified version of the COMFORT-behavior scale-named COMFORTneo-for its psychometric qualities in the Neonatal Intensive Care Unit setting. METHODS: In a clinical observational study, nurses assessed patients with COMFORTneo and Numeric Rating Scales (NRS) for pain and distress, respectively. Interrater reliability, concurrent validity, and sensitivity to change were calculated as well as sensitivity and specificity for different cut-off scores for subsets of patients. RESULTS: Interrater reliability was good: median linearly weighted Cohen kappa 0.79. Almost 3600 triple ratings were obtained for 286 neonates. Internal consistency was good (Cronbach alpha 0.84 and 0.88). Concurrent validity was demonstrated by adequate and good correlations, respectively, with NRS-pain and NRS-distress: r=0.52 (95% confidence interval 0.44-0.59) and r=0.70 (95% confidence interval 0.64-0.75). COMFORTneo cut-off scores of 14 or higher (score range is 6 to 30) had good sensitivity and specificity (0.81 and 0.90, respectively) using NRS-pain or NRS-distress scores of 4 or higher as criterion. DISCUSSION: The COMFORTneo showed preliminary reliability. No major differences were found in cut-off values for low birth weight, small for gestational age, neurologic impairment risk levels, or sex. Multicenter studies should focus on establishing concurrent validity with other instruments in a patient group with a high probability of ongoing pain.