Long-term Effects of Cannabidiol and/or Fentanyl Exposure in Rats Submitted to Neonatal Pain.

The current study aimed to evaluate anxiety behavior, hippocampal ionized calcium-binding adaptor molecule 1 (Iba1) and cannabinoid receptor 1 (CB1) gene expression, and nociceptive response in adulthood after a combination of fentanyl and cannabidiol (CBD) for nociceptive stimuli induced during the first week of life in rats. Complete Freund's adjuvant-induced inflammatory nociceptive insult on postnatal day (PN) 1 and PN3. Both fentanyl and CBD were used alone or in combination from PN1 to PN7. Behavioral and nociceptive tests were performed at PN60 and PN62. The expression of the microglial calcium-binding proteins Iba1 and CB1 was detected in the hippocampus using reverse Quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Our results suggest that the anxiety behavior response and immune activation in adult life depend on the CBD dose combined with fentanyl for the nociceptive stimuli induced during the first week of life. Treatment of neonatal nociceptive insult with CBD and opioids showed significant dose-dependent and male-female differences. The increased gene expression in the hippocampus of the analyzed cannabinoid gene supports this data. In addition, treatment with fentanyl led to an increase in CB1 protein expression. Moreover, the expression of Iba1 varied according to the administered dose of CBD and may or may not be associated with the opioid. A lower dose of CBD during the inflammatory period was associated with enhanced anxiety in adult life. PERSPECTIVE: The treatment of nociceptive stimuli with CBD and opioids during the first week of life demonstrated significant sex differences in adult life on anxiety behavior and supraspinal pain sensitivity.

Effects of repetitive pinprick stimulation on preterm offspring: Alterations in nociceptive responses and inflammatory hypersensitivity in adulthood.

INTRODUCTION: This study investigates the effects of repetitive pinprick stimulation on preterm offspring and its impact on nociceptive responses and inflammatory hypersensitivity in adulthood. OBJECTIVES: The objective is to shed light on the potential long-term consequences of neonatal pain and prematurity on sensory processing. METHODS: Term and preterm rats were subjected to repetitive pinprick (PP) stimulation or control (CC) during the neonatal period. Adult rats received CFA injection to induce inflammatory hypersensitivity, and mechanical hypersensitivity was measured. Gender differences in inflammatory hypersensitivity were also examined. Maternal behavior, litter weight, and offspring growth were monitored to assess any potential influences of the stimulation on these parameters. RESULTS: In preterm rats, the PP stimulation did not affect baseline thresholds to mechanical stimuli, but increased mechanical hypersensitivity after CFA injection in adult rats. Females exhibited greater inflammatory hypersensitivity compared to males. Maternal behavior, litter weight, and offspring growth were not influenced by the stimulation. PP stimulation during the neonatal period led to changes in nociceptive responses in adulthood, potentially altering sensory processing. CONCLUSION: PP stimulation in preterm rats during the neonatal period resulted in changes in nociceptive responses in adulthood, leading to increased inflammatory hypersensitivity. The study emphasizes how early development can significantly impact sensory processing and further highlights the potential long-term consequences of prematurity and neonatal pain on this processing.

Newborn self-regulation and mother comfort in kangaroo position versus sucrose during repeated heel punctures: randomized clinical trial / Autorregulação e conforto materno ao recém-nascido em posição canguru versus sacarose submetidos a punções de calcâneo: ensaio clínico randomizado

ABSTRACT BACKGROUND AND OBJECTIVES: Self-regulation is the ability to control mental functions, satisfying physical, social and emotional needs. The objective of this study was to compare self-regulatory actions in newborns submitted to kangaroo position or 25% sucrose for analgesia during two heel punctures in the first hours of life, and to describe the comfort actions offered by mothers to their infants in kangaroo position. METHODS: Randomized equivalence clinical trial with newborns submitted to two heel punctures and their mothers. The kangaroo position group remained in contact with the mother for three minutes before, during and three minutes after the punctures. The sucrose group received 25% sucrose orally two minutes before the punctures and remained in a common crib, without manipulation. The self-regulation actions and maternal comfort were microanalytically analyzed in the two punctures (18 data collection phases). The percentages of self-regulation/comfort actions duration were compared between intragroup and between groups. RESULTS: The sample consisted of 80 newborns (40 per group) and 40 mothers (kangaroo position group). Sucking fingers/fist/tongue was the only self-regulation action that statistically differed in the two punctures (p<0.001), being higher in the sucrose group. In the kangaroo position group, mothers offered comfort actions to the child at all stages of collection, especially rocking and caressing. CONCLUSION: Self-regulation actions of the newborns were observed in all phases of collection in both groups, such as sucking and taking hand to mouth. In the kangaroo position group, there were maternal comfort actions, especially hugging and caressing.

RESUMO JUSTIFICATIVA E OBJETIVOS: Autorregulação é a habilidade de controlar as funções mentais, satisfazendo necessidades físicas, sociais e emocionais. O objetivo deste estudo foi comparar ações de autorregulação em recém-nascidos submetidos à posição canguru ou a sacarose 25% para analgesia durante duas punções de calcâneo, nas primeiras horas de vida, e descrever as ações de conforto oferecidas pelas mães aos filhos na posição canguru. MÉTODOS: Ensaio clínico de equivalência randomizado, com recém-nascidos submetidos a duas punções de calcâneo e suas mães. O grupo posição canguru permaneceu em contato materno por três minutos antes, durante e três minutos após as punções. O grupo sacarose recebeu sacarose oral 25% dois minutos antes das punções e permaneceu em berço comum, sem manipulação. As ações de autorregulação e conforto materno foram analisadas microanaliticamente nas duas punções (18 fases de coleta de dados). As porcentagens de duração das ações de autor-regulação/conforto foram comparadas entre as fases intragrupo e entre grupos. RESULTADOS: A amostra foi composta por 80 recém-nascidos (40 por grupo) e 40 mães (grupo posição canguru). Sugar dedos/punho/língua foi a única ação de autorregulação que diferiu estatisticamente nas duas punções (p<0,001), sendo maior no grupo sacarose. No grupo posição canguru, as mães ofereceram ações de conforto ao filho em todas as fases da coleta, especialmente embalar e acariciar. CONCLUSÃO: Foram observadas ações de autorregulação dos recém-nascidos em todas as fases da coleta em ambos os grupos, como sugar e levar mão à boca. No grupo posição canguru, houve ações de conforto materno, especialmente abraçar e acariciar.

Quality Assessment of Neonatal Pain Scales Translated and Validated to Brazilian Portuguese: A Systematic Review of Psychometric Properties.

OBJECTIVES: The objective of this systematic review was to identify and describe the psychometric properties of neonatal pain scales that were translated into Brazilian Portuguese and to verify the methodological quality of these translation, transcultural adaptations and validation. DESIGN: The present study is a systematic review. A systematic search in the literature included studies of development, validation, and transcultural adaptation of neonatal pain scales to Brazilian Portuguese. The instruments must have been developed for health care professionals to evaluate neonatal pain and stress in full-term and preterm newborns. DATA SOURCES: The search strategy was conducted in PubMed, Web of Science, Scopus, and Scielo databases following The PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). REVIEW /ANALYSIS METHODS: A total of 1,479 publications were identified and 5 fulfilled the inclusion criteria, with 4 instruments evaluated. For the methodological quality analysis of the measurement properties of the instruments the Consensus-based Standards for Health Measurement Instruments (COSMIN) Risk of Bias checklist was used. The psychometric properties verified were internal consistency, content validity, reliability, and construct validity. RESULTS: Three instruments reviewed were inadequate and one was doubtful. CONCLUSIONS: The neonatal pain scales wich were cross culturally adapted to Brazilian Portuguese were shown to be of low methodological quality based on COSMIM checklist. Caution should be considered for clinical decisions about pain management judgment coming from these instruments.

Repeated neonatal needle-prick stimulation increases inflammatory mechanical hypersensitivity in adult rats.

BACKGROUND AND AIMS: Newborn infants are vulnerable to procedural stress and pain exposure on the first weeks of life that represents a critical period for the development of nociceptive, sensory, emotional, and social functions. We evaluated the nociceptive behavior of adult male and female rats that were submitted to nociceptive experience in the neonatal period and the maternal behavior in the postnatal period. METHODS: The animals were submitted to repetitive needle pricking from the second to the fifteenth postnatal day (PND 2-15). Maternal behavior and litter weight were evaluated during this period. Mechanical sensitivity to pain was assessed in offsprings during the adulthood by exposing them to inflammatory stimuli, including formalin test or the Freund's complete adjuvant (CFA) injection followed by the electronic von Frey test at 0, 3, 6 and 24 h later. RESULTS: Maternal behavior and litter weight were not altered by pinprick stimuli during PND 2-15. Additionally, pinprick stimulation reduced the paw withdrawal threshold in CFA-injected animals compared to control. In the formalin test, there was a difference between the genders. Female rats are statically more sensitive to formalin stimulation and showed an increased licking time in both the first and second phases and increased number of flinches in second phase. CONCLUSIONS: Experiencing early life repetitive pain exposure increased inflammatory pain sensitivity in adult offspring rats and female rats are more sensitive to chemical stimulation. IMPLICATIONS: Future investigations of the mechanisms involved in this effect may contribute to the improvement of the understanding of inflammatory pain sensitivity differences.

A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates.

OBJECTIVE: To investigate the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-term neonates ≥ 28 to ≤ 44 weeks gestational age. STUDY DESIGN: Forty-two intubated, mechanically ventilated patients (n = 42) were grouped by gestational age into group I (n = 18), ≥ 28 to <36 weeks, and group II (n = 24), ≥ 36 to ≤ 44 weeks. Within each age group, there were 3 escalating dose levels, including a loading dose (LD, µg/kg) followed by a maintenance dose (MD, µg · kg(-1) · h(-1)) for 6-24 hours: level 1, 0.05 LD/MD; level 2, 0.1 LD/MD; and level 3, 0.2 LD/MD. The primary endpoint was the number of patients requiring sedation as determined by the Neonatal Pain, Agitation, Sedation Scale. RESULTS: During dexmedetomidine infusion, 5% of Neonatal Pain, Agitation, Sedation Scale scores were >3, indicating agitation/pain, with 4 patients (10%) requiring more sedation and 17 (40%) requiring more analgesia. Though there was significant variability in pharmacokinetic variables, group I appeared to have lower weight-adjusted plasma clearance (0.3 vs 0.9 L · h(-1) · kg(-1)) and increased elimination half-life (7.6 vs 3.2 hours) compared with group II. Fifty-six adverse events (AEs) were reported in 26 patients (62%); only 3 AEs (5%) were related to dexmedetomidine. There were no serious AEs and no AEs or hemodynamic changes requiring dexmedetomidine discontinuation. CONCLUSION: Dexmedetomidine is effective for sedating preterm and full-term neonates and is well-tolerated without significant AEs. Preterm neonates had decreased plasma clearance and longer elimination half-life.