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Objective: We studied the reliability and validity of the COMFORTneo scale, designed to measure neonatal prolonged pain., Study Design: This prospective observational study evaluated four clinimetric properties of the COMFORTneo scale from NICU nurses' assessments of neonates' pain. Intra-rater reliability was determined from three video fragments at two time points. Inter-rater reliability and construct validity were determined in five neonates per nurse with the COMFORTneo and numeric rating scales (NRS) for pain and distress. Pain scores using N-PASS were correlated with COMFORTneo scores to further evaluate construct validity., Result: Intra-rater reliability: Twenty-two nurses assessed pain twice with an intraclass correlation coefficient (ICC) of 0.70. Inter-rater reliability: The ICC for 310 COMFORTneo scores together with 62 nurses was 0.93. Construct validity: Correlation between COMFORTneo and NRS pain, distress, and N-PASS was 0.34, 0.72, and 0.70, respectively., Conclusion: The COMFORTneo can be used to reliably and validly assess pain in NICU patients., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Inadequate pain and/or stress management in preterm- and term-born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long-term effects on the developing human brain and neuropsychological functioning are reviewed., (© 2018, The American College of Clinical Pharmacology.)

Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also - and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Several functional magnetic resonance imaging (fMRI) studies use thermal pain stimuli to determine brain activation patterns during pain. Studies use either a standard temperature condition for all participants or an individualized temperature condition based on the individually determined pain threshold of the participant. The aim of the present study was to compare both conditions in the same participants., Methods: Eighteen healthy participants (21-29 years) underwent four fMRI runs, in each of which they received three types of thermal stimuli: neutral (32 °C), warm (37 °C) and painfully hot. In two runs, the painfully hot stimulus was set at a standard temperature of 46 °C; in the other two runs, the temperature was set at the subject's individual pain threshold (46-48 °C). fMRI (blood oxygen level dependent) was performed on a 1.5 T MR scanner (GE Signa). Pre-processing and statistical analyses were performed using Statistical Parametric Mapping (SPM8) software., Results: While the stimulation temperatures were lower in the standard temperature condition, both conditions activated the same brain regions. When comparing the conditions directly to each other, we did not find significantly different grey matter activation patterns., Conclusions: The similar activation patterns between the two conditions suggest that it is not necessary to use individualized stimuli per se. The temperature of 46 °C appeared to be an adequate temperature for standardized stimulation to observe significant brain activations related to thermal pain., (© 2013 European Federation of International Association for the Study of Pain Chapters.)

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4-20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3-6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Newborns admitted to the neonatal intensive care unit (NICU) regularly undergo painful procedures and may face various painful conditions such as postoperative pain. Optimal management of pain in these vulnerable preterm and term born neonates is crucial to ensure their comfort and prevent negative consequences of neonatal pain. This entails accurate and timely identification of pain, non-pharmacological pain treatment and if needed administration of analgesic therapy, evaluation of treatment effectiveness, and monitoring of adverse effects. Despite the widely recognized importance of pain management, pain assessment in neonates has thus far proven to be a challenge. As self-report, the gold standard for pain assessment, is not possible in neonates, other methods are needed. Several observational pain scales have been developed, but these often rely on snapshot and largely subjective observations and may fail to capture pain in certain conditions. Incorporation of biomarkers alongside observational pain scores holds promise in enhancing pain assessment and, by extension, optimizing pain treatment and neonatal outcomes. This review explores the possibilities of integrating biomarkers in pain assessment in the NICU. [ABSTRACT FROM AUTHOR]

Aims: To investigate the pharmacokinetics and safety of prolonged paracetamol use (>72 h) for neonatal pain. Methods: Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed‐effects model. Results: Forty‐eight neonates were enrolled (38 received paracetamol for >72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable >30 h after dose. There was no significant difference (P >.05) between alanine aminotransferase and bilirubin measures at <72 h or >72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81‐kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady‐state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half‐life was 3.55 h (range 2.41–5.65). Conclusion: Our study did not provide evidence of paracetamol‐induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates. [ABSTRACT FROM AUTHOR]

Less invasive surfactant administration (LISA) is an effective, minimally invasive technique of administering surfactant to infants with respiratory distress syndrome. While termed less invasive, LISA still requires airway instrumentation with direct laryngoscopy, thus may be considered painful. However, the issue of whether or not to routinely sedate infants for LISA remains contentious, with significant variation in practice between centres. Proponents for giving pharmacological analgesia and/or sedation predominantly focus on patient comfort during the procedure. However, those who favour non-pharmacological measures of pain management focus on the potential for procedural success without the risk of adverse events, such as respiratory depression and potentially the need for escalation to intubation, which may occur with pharmacological agents. The neonatal population who may benefit from LISA is varied. Due to this variety in presentation type, gestational age, and unit experience, there is a need to provide an individualized, tailored approach to sedation and analgesia for these infants. Using a blanket approach to sedation will lead to infants being exposed to sedative medications on the assumption of potential distress, rather than in response to signs of actual distress. This places the infant at risk of the adverse reactions, potentially without them ever having needed the beneficial effect of the medications. This seems an unnecessary risk. This article explores the ethical arguments pertaining to analgesia and sedation during the LISA technique, concluding that a standardized approach to the usage of pharmacological sedation is undesirable. Moreover, we maintain that procedural analgesia and sedation should be based on individualized, infant-centred assessment, rather than on a rigid, standardized approach. [ABSTRACT FROM AUTHOR]

Objective: To assess thermal-sensory thresholds and psychosocial factors in children with Complex Regional Pain Syndrome Type 1 (CRPS-I) compared to healthy children. Methods: We conducted quantitative sensory testing on 34 children with CRPS-I and 56 pain-free children. Warm, cool, heat, and cold stimuli were applied to the forearm. Children with CRPS-I had the protocol administered to the pain site and the contralateral-pain site. Participants completed the self-report Behavior Assessment System for Children. Results: Longer pain durations (>5.1 months) were associated with decreased sensitivity to cold pain on the pain site (P =.04). Higher pain-intensity ratings were associated with elevated anxiety scores (P =.03). Anxiety and social stress were associated with warmth sensitivity (both P <.05) on the contralateral-pain site. Conclusions: Pain duration is an important factor in assessing pediatric CRPS-I. Hyposensitivity in the affected limb may emerge due to degeneration of nociceptive nerves. Anxiety may contribute to thermal-sensory perception in childhood CRPS-I. [ABSTRACT FROM AUTHOR]

Recent years have seen the increasing use of noninvasive respiratory support in preterm infants with the aim of minimizing the risk of mechanical ventilation and subsequent bronchopulmonary dysplasia. Respiratory distress syndrome is the most common respiratory diagnosis in preterm infants, and is best treated by administration of surfactant. Until recently, this has been performed via an endotracheal tube using premedication, which has often included opiate analgesia; subsequently, the infant has been ventilated. Avoidance of mechanical ventilation, however, does not negate the need for surfactant therapy. Less invasive surfactant administration (LISA) in spontaneously breathing infants is increasing in popularity, and appears to have beneficial effects. However, laryngoscopy is necessary, which carries adverse effects and is painful for the infant. Conventional methods of premedication for intubation tend to reduce respiratory drive, which increases the likelihood of ventilation being required. This has led to intense debate about the best strategy for providing appropriate treatment, taking into account both the respiratory needs of the infant and the need to alleviate procedural pain. Currently, clinical practice varies considerably and there is no consensus with respect to optimal management. This review seeks to summarize the benefits, risks, and challenges associated with this new approach. [ABSTRACT FROM AUTHOR]

Background. Patients treated in neonatal/pediatric intensive care units (N/PICUs) are frequently exposed to pain. To assess its severity, several behavioral and behavioral-physiological scales are used, but their usefulness is limited. It is therefore justified to search for additional methods to assess the adequacy of analgesia and sedation in these patients. Objectives. To evaluate the usefulness of skin conductance (SC) measurement in the assessment of analgosedation quality in infants requiring mechanical ventilation treated in N/PICUs. Material and methods. Thirty infants aged 6--208 days treated in 6 N/PICUs, mechanically ventilated and receiving analgosedation, were included for the study. Simultaneous COMFORT-B assessment and SC measurement using SCA (skin conductance algesimeter) monitor were performed. Due to technical problems, not all of the SC records could be interpreted, and finally 412 simultaneous assessments on the COMFORT-B scale and SC measurements in 29 patients were analyzed. Results. We found a statistically significant correlation between the COMFORT-B scoring and the SC measurements. Additionally, SC was significantly lower when the behavioral score indicated deep sedation, in comparison to periods when it indicated moderate or insufficient analgosedation. Conclusions. Skin conductance measurements are comparable with the COMFORT-B rating in mechanically ventilated infants receiving analgosedation. The SCA monitor may be of value in the assessment of analgosedation quality, and in particular may identify the situation where sedation is deep. Further research is needed regarding the suitability of this device in clinical practice. [ABSTRACT FROM AUTHOR]

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Infants in neonatal intensive care units frequently experience clinically necessary painful procedures, which elicit a range of behavioral, physiological, and neurophysiological responses. However, the measurement of pain in this population is a challenge and no gold standard exists. The aim of this study was to investigate how noxious‐evoked changes in facial expression, reflex withdrawal, brain activity, heart rate, and oxygen saturation are related and to examine their accuracy in discriminating between noxious and non‐noxious stimuli. In 109 infants who received a clinically required heel lance and a control non‐noxious stimulus, we investigated whether combining responses across each modality, or including multiple measures from within each modality improves our ability to discriminate the noxious and non‐noxious stimuli. A random forest algorithm was used to build data‐driven models to discriminate between the noxious and non‐noxious stimuli in a training set which were then validated in a test set of independent infants. Measures within each modality were highly correlated, while different modalities showed less association. The model combining information across all modalities had good discriminative ability (accuracy of 0.81 in identifying noxious and non‐noxious stimuli), which was higher than the discriminative power of the models built from individual modalities. This demonstrates the importance of including multiple modalities in the assessment of infant pain. [ABSTRACT FROM AUTHOR]

Summary: Background: Temporomandibular disorder (TMD) is a multifactorial condition involving environmental, psychological and genetic factors. Objective: The aim of this case‐control study was to evaluate the influence of genetic polymorphisms in 5HTT and COMT on TMD and anxiety in adolescents. Methods: TMD was diagnosed and classified according to the RDC/TMD criteria. For case group, the following TMD categories were used: myofascial pain, disc displacement, arthralgia and painful TMD (myofascial and arthralgia). Anxiety levels were assessed according to the State‐Trait Anxiety Inventory. Genomic DNA was extracted, and genetic polymorphisms were genotyped by TaqMan chemistry and endpoint analysis. Logistic multivariate regression was used to analyse the associations between TMD types and genotypes, anxiety level and genotypes, using an adjusted odds ratio (ORa; CI 95%) that considered the gender. Results: In 5HTT, the rs1042173 was associated with painful TMD (arthralgia and myofascial pain) (ORc = 1.97; CI 95%: 1.02‐3.77; P = 0.04). Polymorphisms in COMT rs4818 were significantly associated with myofascial pain (ORc = 2.15; CI 95%: 1.08‐4.29; P = 0.02) and were borderline for painful TMD (ORc = 1.85; CI 95%: 0.97‐3.51; P = 0.06) and disc displacement (ORc = 2.42; CI 95%: 1.00‐5.87; P = 0.05). The rs6269 was borderline for myofascial pain (ORc = 1.82; CI 95%: 0.92‐3.59; P = 0.08) and disc displacement (ORc = 2.38; CI 95% 0.95‐5.97; P = 0.06) and also was associated with anxiety (ORa = 2.34; CI 95% 1.04‐5.25; P = 0.03). Conclusion: Polymorphisms in 5HTT and COMT are associated with TMD in adolescents. Moreover, polymorphism in COMT is associated with anxiety in adolescents. [ABSTRACT FROM AUTHOR]

Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following reinjury in adulthood. Spinal microglia contribute to this persistent effect, and microglial inhibition at the time of adult reincision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult reincision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation (Emr1) and transformation to a reactive phenotype (Irf8). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to reincision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following reincision in adulthood was prevented in males but unaffected in females. Similarly, reincision induced Emr1 and Irf8 gene expression was downregulated in males, but not in females, following neonatal incision with minocycline. To evaluate the distribution of reincision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was reincised, and was increased following prior incision at ipsilateral, but not contralateral, sites, supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state span developmental stages. [ABSTRACT FROM AUTHOR]

Objectives To propose approaches tailored to the specific needs of neonates, such as structured product development programmes, with the ultimate goal to improve the safe and effective use of analgosedatives in these fragile patients. Key findings The feasibility and relevance of a structured product development programme in neonates (optimal study design based on preliminary data; model development; internal, external and prospective evaluation; an individualized dosing regimen; long-term safety; pharmacogenetics) are illustrated for the use of morphine. Based on changes in clinical practices, similar development plans are in progress for short-acting analgosedatives such as propofol, but are in need of tailored pharmacodynamic tools to assess and quantify effects. Furthermore, for drugs like paracetamol where there is already sufficient clinical pharmacology knowledge, attention needs to be given to long-term safety aspects. Finally, new covariates such as pharmacogenetics might further improve neonatal pain management, but clearly need to be integrated with other well-established covariates like age or weight. Summary Product development programmes for analgosedatives in neonates are needed. These programmes should be tailored to their specific needs (short-acting sedation, pain relief), should include long-term safety and should incorporate the exploration of newer covariates like pharmacogenetics. [ABSTRACT FROM AUTHOR]

Background: Quantitative sensory testing (QST) is often used to measure children's and adults' detection- and pain thresholds in a quantitative manner. In children especially the Thermal Sensory Analyzer (TSA-II) is often applied to determine thermal detection and pain thresholds. As comparisons between studies are hampered by the different testing protocols used, we aimed to present a standard protocol and reference values for thermal detection- and pain thresholds in children.Methods: Our standard testing protocol includes reaction time dependent and independent tests and takes about 14-18 min to complete. Reference values were obtained from a sample of 69 healthy term born children and adolescents with a median age of 11.2 years (range 8.2 to 17.9 years old). Seventy-one children were recruited and data of 28 males and 41 females was obtained correctly. We studied possible age and sex differences.Results: This study provides Dutch reference values and presents a standard quantitative sensory testing protocol for children with an age from 8 years onwards. This protocol appeared to be feasible, since only two out of 71 participants were not able to correctly complete the protocol due to attention deficits and were therefore excluded. We found some significant age and sex differences: females were statistically significantly more sensitive for both cold and heat pain compared to males, and the youngest children (8-9 years old) were less sensitive to detect a warm stimulus. The youngest children tend to be more sensitive to heat pain in comparison to older participants, although the difference was not statistically significant.Conclusions: We present a feasible thermal quantitative sensory testing protocol for children and reference values that are easy to interpret and may serve as normative values for future studies. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacologic pain management in newborns and infants is often based on limited scientific data. To close the knowledge gap, drug-related research in this population is increasingly supported by the authorities, but remains very challenging. This review summarizes the challenges of analgesic studies in newborns and infants on morphine and paracetamol (acetaminophen). Areas covered: Aspects such as the definition and multimodal character of pain are reflected to newborn infants. Specific problems addressed include defining pharmacodynamic endpoints, performing clinical trials in this population and assessing developmental changes in both pharmacokinetics and pharmacodynamics. Expert commentary: Neonatal and infant pain management research faces two major challenges: lack of clear biomarkers and very heterogeneous pharmacokinetics and pharmacodynamics of analgesics. There is a clear call for integral research addressing the multimodality of pain in this population and further developing population pharmacokinetic models towards physiology-based models. [ABSTRACT FROM AUTHOR]

Background: Traditionally, 10 years ago, children born preterm often routinely received morphine, especially during mechanical ventilation. Studies in neonatal rats, whose stage of brain development roughly corresponds to that of children born preterm, found negative long-term effects after pain and opioid exposure. Objectives: We studied possible effects of prematurity, procedural pain and opioids in humans 10 years later. We hypothesized that these factors would negatively influence neurobiological, neuropsychological and sensory development later in life. Methods: We included 19 children born preterm who as neonates participated in an RCT on the short-term effects of morphine administration and who previously participated in our follow-up studies at ages 5 and 8/9 years. We assessed associations between brain morphology (n = 11), neuropsychological functioning (n = 19) and thermal sensitivity (n = 17) and prematurity, opioid exposure and neonatal pain. Results: Significant correlations (coefficients 0.60-0.85) of gestational age, number of painful procedures and morphine exposure with brain volumes were observed. Significant correlations between these factors and thermal sensitivity were not established. Neuropsychological outcome was significantly moderately correlated with morphine exposure in only two subtests, and children performed in general 'average' by Dutch norms. Conclusions: Although prematurity, opioid exposure and neonatal pain were significantly associated with brain volume, no major associations with neuropsychological functioning or thermal sensitivity were detected. Our findings suggest that morphine administration during neonatal life does not affect neurocognitive performance or thermal sensitivity during childhood in children born preterm without brain damage during early life. Future studies with larger sample sizes are needed to confirm these findings. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever in children. This drug has multiple mechanisms of action, but its pharmacodynamic is still not well known. The central nervous system is the main site of action and it mirrors the paracetamol effect compartment. The recommended dosages and routes of administration should be different whether paracetamol is used for the treatment of pain or fever. For example, the rectal route, while being efficacious for the treatment of fever, should be avoided in pain management. Paracetamol is a safe drug, but some clinical conditions and concomitant drugs, which are frequent in clinical practice, may increase the risk of paracetamol toxicity. Therefore, it is important to optimize its administration to avoid overdoses and maximize its effect. The principal mediator of the paracetamol toxicity is the N-acetyl- p-benzo-quinone imine (NAPQI), a toxic product of the paracetamol metabolism, which could bind cysteine groups on proteins forming paracetamol-protein adduct in the liver. Conclusion: Although frequently prescribed, the concept of 'effect compartment concentration' and the possible co-factors that could cause toxicity at recommended doses are not familiar to all pediatricians and general practitioners. We reviewed the literature concerning paracetamol mechanisms of action, we highlighted some relevant pharmacodynamic concepts for clinical practice, and we summarized the possible risk factors for toxicity at therapeutic dosages. [ABSTRACT FROM AUTHOR]

Even with the rapid development of pediatric postoperative pain management, pediatric patients have remained undertreated for postoperative pain because of difficulty in pain assessment and concerns regarding side effects of opioid analgesics. Although there are no perfect pain assessment techniques and no absolutely safe analgesics, proper monitoring and an individualized analgesic plan after due consideration of age, operative procedures, and underlying illness, using multimodal analgesics may improve the quality of pain control in children. [ABSTRACT FROM AUTHOR]