Propofol is an intravenous agent used commonly for induction and maintenance of anesthesia, procedural and critical care sedation in children. The mechanisms of action on the central nervous system involve interactions at various neurotransmitter receptors, especially gamma-aminobutyric acid A receptor. Approved for use in the United States by the Federal Drugs and Administration (FDA) in 1989, its use for induction of anesthesia in children less than 3 years of age still remains off-label. Despite its wide use in pediatric anesthesia, there is conflicting literature about its safety and serious adverse effects in particular subsets of children. Particularly as children are not “little adults”, in this review, we emphasize the maturational aspects of propofol pharmacokinetics. Despite the myriad of propofol pharmacokinetic-pharmacodynamic studies and the ability to use allometrical scaling to smooth out differences due to size and age, there is no optimal model that can be used in target controlled infusion pumps for providing closed loop total intravenous anesthesia in children. As the commercial formulation of propofol is a nutrient-rich emulsion, the risk for bacterial contamination exist despite the FDA mandating addition of antimicrobial preservative, calling for manufacturers’ directions to discard open vials after six hours. While propofol has advantages over inhalation anesthesia like less postoperative nausea and emergence delirium in children, pain on injection remains a problem even with newer formulations. Propofol is known to depress mitochondrial function by its action as an uncoupling agent in oxidative phosphorylation. This has implications for children with mitochondrial diseases and the occurrence of propofol-related infusion syndrome, a rare but seriously life-threatening complication of propofol. At the time of this review, there is no direct evidence in humans for propofol induced neurotoxicity to the infant brain; however, current concerns of neuroapoptosis in developing brains induced by propofol persist and continue to be a focus of research.

Background Chronic postsurgical pain (CPSP) affects half a million children annually in the United States, with dire socioeconomic consequences, including long-term disability into adulthood. The few studies of CPSP in children are limited by sample size, follow-up duration, non-homogeneity of surgical procedure and factors evaluated. Methods In a prospective study of 144 adolescents undergoing a single major surgery (spine fusion), we evaluated demographic, perioperative, surgical and psychosocial factors as predictors of a continuum of postsurgical pain: immediate, pain maintenance at 2–3 months (chronic pain/CP) and persistence of pain a year (persistent pain/PP) after surgery. Results We found an incidence of 37.8% and 41.8% for CP and PP. CP and acute pain were both significant predictors for developing PP (p-value <0.001 and 0.003). Preoperative pain and higher postoperative opioid requirement was significantly associated with CP (p = 0.015, p = 0.002), while Childhood Anxiety Sensitivity Index (p = 0.002) and surgical duration (p = 0.014) predicted PP. The final regression models had reasonable predictive accuracy (c-statistic of 0.73 and 0.83 for CP and PP, respectively). Anxiety scores and catastrophizing for child and parent were found to be significantly correlated (p = 0.005, p = 0.013 respectively). Pain trajectories revealed that 65% of patients who developed PP reported CP and high pain trends; however, 33% of those who developed PP could not be identified using solely pain criteria. Conclusion Persistent postsurgical pain in children is a significant problem. It can be predicted in part by combinations of psychological and clinical variables, which may provide evidence-based measures to prevent development of CPSP in the future. Significance In a homogeneous cohort of adolescents undergoing spine fusion, we report a high incidence of persistent postsurgical pain (41.8%) predicted by child anxiety, perioperative pain, and surgical duration. Our results stress timely preventive and therapeutic strategies.

BACKGROUND: Interindividual variability in pain perception and analgesic response is a major problem in perioperative practice. Adult studies suggest pain management is influenced by patient’s race. The objective of this study is to evaluate the influence of race on perioperative pain treatment in children. METHODS: Prospective observational study evaluating effect of race on analgesia and opioid related adverse effects after tonsillectomy in African American and Caucasian children. A sample of 194 healthy children between 6 and 15 years of age were included. Race was self-identified by parents. All participants received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine. Analgesia outcomes included maximum postoperative pain scores, postoperative opioid requirement, and analgesic interventions. Safety outcomes included incidences of opioid related adverse effects. RESULTS: African American children experienced significantly more postoperative pain than Caucasian children as measured by postoperative opioid requirement (P = .0011), maximum postoperative pain scores (P &lt; .0001), and analgesic interventions (P &lt; .0001) in the recovery room. Although Caucasian children received relatively less opioids perioperatively, they had significantly higher opioid related adverse effects (P = .039). African American children with obstructive sleep apnea were more likely to have prolonged post anesthesia recovery unit stay due to inadequate pain control. CONCLUSIONS: After similar uses of intraoperative morphine for tonsillectomy, there was an unequal burden of increased pain in African American children and increased opioid adverse effects in Caucasian children in the recovery room. Though Caucasian children received relatively less opioids perioperatively, they had higher incidences of opioid related adverse effects than African American children.

Aim Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African–American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1 Methods In 146 children undergoing adenotonsillectomy, 146 concentration–time profiles (2–4 measurements per patient) were available. Population pharmacokinetic ana lysis characterized the profiles in NONMEM® and tested OCT1 variants as covariates. Results Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2–*5/*2–*5 was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2–*5; p < 0.05). Conclusion Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African–American children.

OIRD is an important, albeit mostly preventable, complication of opioid therapy in children. Naloxone use can be used as a measure to track opioid safety in children, identify contributing factors, and formulate preventive strategies to reduce the risk for OIRD.

Aim Large interindividual variability in morphine pharmacokinetics could contribute to variability in morphine analgesia and adverse events. Methods Influence of weight, genetic polymorphisms, race and sex on morphine clearance and metabolite formation from 220 children undergoing outpatient adenotonsillectomy was studied. A nonlinear mixed effects model was developed in NONMEM to describe morphine and morphine glucuronide pharmacokinetics. Results Children with ABCC3 −211C>T polymorphism C/C genotype had significantly higher levels of morphine-6-glucuronide and morphine-3-glucuronide formation (~40%) than C/T+T/T genotypes (p < 0.05). In this extended cohort similar to our earlier report, OCT1 homozygous genotypes (n = 13, OCT1*2–*5/*2–*5) had lower morphine clearance (14%; p = 0.06), and in addition complementing lower metabolite formation (~39%) was observed. ABCB1 3435C>T TT genotype children had lower levels of morphine-3-glucuronide formation though no effect was observed on morphine and morphine-6-glucuronide pharmacokinetics. Conclusion Our data suggest that besides bodyweight, OCT1 and ABCC3 genotypes play a significant role in the pharmacokinetics of intravenous morphine and its metabolites in children.

Inadequate pain relief and adverse effects from analgesics remain common in children and adults during the perioperative period. Opioids are the most commonly used analgesics in children and adults to treat perioperative pain. Narrow therapeutic index and a large interpatient variability in response to opioids are clinically significant, with inadequate pain relief at one end of the spectrum and serious side effects, such as respiratory depression and excessive sedation due to relative overdosing, at the other end. Personalizing analgesia during the perioperative period attempts to maximize pain relief while minimizing adverse events from therapy. While various factors influence response to treatment among surgical patients, age, sex, race and pharmacogenetic differences appear to play major roles in predicting outcome. Genetic factors include a subset of genes that modulate the proteins involved in pain perception, pain pathway, analgesic metabolism (pharmacokinetics), transport and receptor signaling (pharmacodynamics). While results from adult genetic studies can provide direction for pediatric studies, they have limited direct applicability, as children's genetic predispositions to analgesic response may be influenced by developmental and behavioral components, altered sensitivity to analgesics and variation in gene-expression patterns. We have reviewed the available evidence on improving and personalizing pain management with opioids and the significance of individualizing analgesia, in order to maximize analgesic effect with minimal adverse effects with opioids. While the early evidence on individual genotype associations with pain, analgesia and opioid adverse outcome are promising, the large amount of conflicting data in the literature suggests that there is a need for larger and more robust studies with appropriate population stratification and consideration of nongenetic and other genetic risk factors. Although the clinical evidence and the prospect of being able to provide point-of-care genotyping to enable clinicians to deliver personalized analgesia for individual patients is still not available, positioning our research to identify all possible major genetic and nongenetic risk factors of an individual patient, advancing less expensive point-of-care genotyping technology and developing easy-to-use personalized clinical decision algorithms will help us to improve current clinical and economic outcomes associated with pain and opioid pain management.

IntroductionThe perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP).MethodsA prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2–3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2–3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P<0.05) nongenetic variables.ResultsMajority (83%) of the patients reported no pain preoperatively, while CPSP occurred in 36% of the subjects (44/121). Regression on dichotomized preoperative pain outcome showed association with methylation at six CpG sites (1, 3, 4, 9, 11, and 17) (P<0.05). Methylation at CpG sites 4, 17, and 18 was associated with higher AUC after adjusting for opioid consumption and preoperative pain score (P<0.05). After adjusting for postoperative opioid consumption and preoperative pain score, methylation at CpG sites 13 and 22 was associated with CPSP (P<0.05).DiscussionNovel CPSP biomarkers were identified in an active regulatory region of the OPRM1 gene that binds multiple transcription factors. Inhibition of binding by DNA methylation potentially decreases the OPRM1 gene expression, leading to a decreased response to endogenous and exogenous opioids, and an increased pain experience.