Acute pain management in children: challenges and recent improvements.

PURPOSE OF REVIEW: The evidence regarding the efficacy of analgesics available to guide postoperative pain treatment in pediatric patients is limited. Opioid medications are very often an important component of pediatric postoperative pain treatment but have been associated with perioperative complications. We will focus on initiatives aiming to provide effective treatment minimizing the use of opioids and preventing the long-term consequences of pain. RECENT FINDINGS: Interpatient variability in postoperative pain is currently managed by applying protocols or by trial and error, thus often leading to patients being either undertreated or overtreated. Few evidence-based reports are available to guide the use of opioid medications in children, including the prescription of opioids after hospital discharge. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids, thus decreasing the risk of toxicity and dose-related side effects. There is a lack of adequate research in this field, and more specifically on identifying which patient is at higher risk of poor postoperative pain management. SUMMARY: Treatment options have evolved in recent years, including the combinations of multimodal regimens and regional anesthetic techniques. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids.

Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine.

STUDY OBJECTIVE: To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN: Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION: Canadian Task Force Classification I. SETTING: University hospitals in Italy. PATIENTS: One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS: Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS: One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION: Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation.

Emergence delirium, pain or both? A challenge for clinicians.

BACKGROUND: Children commonly display early postoperative negative behavior (e-PONB) after general anesthesia, which includes emergence delirium (ED), discomfort, temperament, and pain. However, it is often difficult for the caregiver to discriminate between various aspects of e-PONB. OBJECTIVE: This prospective observational study evaluates the possibility to distinguish between ED and pain in young children using validated pediatric observational scales in the early postoperative phase. METHODS: Following institutional approval and written consent, children undergoing elective adenoidectomy and/or tonsillectomy were enrolled. Following standardized anesthesia, two trained observers simultaneously evaluated children's behavior with the Paediatric Anaesthesia Emergence Delirium Scale (PAED) and with the Face, Legs, Activity, Cry, Consolability scale (FLACC) at extubation, and at 5, 10, and 15 min. RESULTS: Of 150 children that completed the study, 32 (21%) had ED, 7 (5%) had pain, and 98 (65%) had simultaneously both ED and pain. The association of 'No eye contact', 'No purposeful action' and 'No awareness of surroundings' (ED1) had a sensitivity of 0.96 and a specificity of 0.80 (PPV 0.97, NPV 0.78) to identify ED. 'Inconsolability' and 'Restlessness' (ED2) had a sensitivity of 0.69 and a specificity of 0.88 (PPV 0.83 and NPV 0.78) to identify pain. CONCLUSION: It is difficult to differentiate between ED and pain using FLACC and PAED scores. 'No eye contact', 'No purposeful action', and 'No awareness of surroundings' significantly correlated with ED. 'Inconsolability' and 'Restlessness' are not reliable enough to identify pain or ED in the first 15 min after awakening.

The effect of fentanyl and clonidine on early postoperative negative behavior in children: a double-blind placebo controlled trial.

BACKGROUND: Early negative postoperative behavior (e-PONB) is common in children and manifests itself as emergence agitation (EA), emergence delirium (ED), and pain. The objective of this prospective double blind, randomized, placebo-controlled trial was to determine whether IV clonidine or IV fentanyl prior to surgery modifies e-PONB in children. METHODS: Ninety children scheduled for subumbilical surgery under sevoflurane anesthesia supplemented with regional anesthesia were randomized to either receive IV clonidine 2 mcg·kg(-1) , IV fentanyl 2 mcg·kg(-1) or placebo (IV saline) before surgery. Primary outcome measures were the incidence of EA, ED and pain during the first hour after awakening. Secondary outcome measures were side effects such as nausea and vomiting and delayed discharge from PACU. RESULTS: Eighty-seven children (n = 29 per group) completed the study. EA was present in 10 children (six clonidine, none fentanyl, and four placebo, P = 0.04) whereas ED was observed in 20 children (nine clonidine, three fentanyl, and eight placebo P = 0.13). Sixteen children who received placebo had a CHIPPS score of ≥4 compared with nine children in fentanyl group and 18 children receiving clonidine (P = 0.04). Ten children receiving fentanyl vomited during the first postoperative day, compared with six children in placebo group and none in clonidine group (P = 0.003). Discharge from PACU was not affected. CONCLUSIONS: IV fentanyl before surgery but not IV clonidine modifies e-PONB in children undergoing lower abdominal surgery under general anesthesia supplemented with regional anesthesia. The use of fentanyl in this population was also associated with reduced pain scores after awakening but with significantly greater incidence of PONV.

Incidence of pain after craniotomy in children.

BACKGROUND: There is very few information regarding pain after craniotomy in children. OBJECTIVES: This multicentre observational study assessed the incidence of pain after major craniotomy in children. METHODS: After IRB approval, 213 infants and children who were <10 years old and undergoing major craniotomy were consecutively enrolled in nine Italian hospitals. Pain intensity, analgesic therapy, and adverse effects were evaluated on the first 2 days after surgery. Moderate to severe pain was defined as a median FLACC or NRS score ≥ 4 points. Severe pain was defined as a median FLACC or NRS score ≥ 7 points. RESULTS: Data of 206 children were included in the analysis. The overall postoperative median FLACC/NRS scores were 1 (IQR 0 to 2). Twenty-one children (16%) presented moderate to severe pain in the recovery room and 14 (6%) during the first and second day after surgery. Twenty-six children (19%) had severe pain in the recovery room and 4 (2%) during the first and second day after surgery. Rectal codeine was the most common weak opiod used. Remifentanil and morphine were the strong opioids widely used in PICU and in general wards, respectively. Longer procedures were associated with moderate to severe pain (OR 1.30; CI 1.07-1.57) or severe pain (OR 1.41; 1.09-1.84; P < 0.05). There were no significant associations between complications, pain intensity, and analgesic therapy. CONCLUSION: Children receiving multimodal analgesia experience little or no pain after major craniotomy. Longer surgical procedures correlate with an increased risk of having postoperative pain.

Markers of Tissue Deterioration and Pain on Earth and in Space.

Purpose: Pain is an understudied physiological effect of spaceflight. Changes in inflammatory and tissue degradation markers are often associated with painful conditions. Our aim was to evaluate the changes in markers associated with tissue deterioration after a short-term spaceflight. Patients and Methods: Plasma levels of markers for systemic inflammation and tissue degeneration markers were assessed in two astronauts before and within 24 h after the 17-day Axiom Space AX-1 mission. Results: After the spaceflight, C-reactive protein (CRP) was reduced in both astronauts, while INFγ, GM-CSF, TNFα, BDNF, and all measured interleukins were consistently increased. Chemokines demonstrated variable changes, with consistent positive changes in CCL3, 4, 8, 22 and CXCL8, 9, 10, and consistent negative change in CCL8. Markers associated with tissue degradation and bone turnover demonstrated consistent increases in MMP1, MMP13, NTX and OPG, and consistent decreases in MMP3 and MMP9. Conclusion: Spaceflight induced changes in the markers of systemic inflammation, tissue deterioration, and bone resorption in two astronauts after a short, 17-day, which were often consistent with those observed in painful conditions on Earth. However, some differences, such as a consistent decrease in CRP, were noted. All records for the effect of space travel on human health are critical for improving our understanding of the effect of this unique environment on humans.

The effects of propofol and ketamine on the cytokine levels of children with acute lymphoblastic leukemia.

The immune system of children with acute lymphoblastic leukemia (ALL) is affected by both the underlying disease and the chemotherapy. Children with ALL receive sedation for diagnostic and therapeutic procedures, which may contribute to immune competence alteration. The effects of propofol-ketamine combination on the immune system of children with ALL have not been investigated. This cohort study was designed to assess the immunomodulatory activity of the propofol-ketamine combination on proinflammatory and anti-inflammatory cytokines of children with ALL undergoing painful procedures. We enrolled 20 children with ALL undergoing bone marrow aspiration (BMA) and lumbar puncture with methotrexate. All children received sedation with IV ketamine (0.5 mg/kg) and propofol (3±2 mg/kg). Plasma concentration of cytokines interleukin (IL)-1ß, IL-2, IL-6, IL-10, IL-8, IL-12p70, and interferon-γ before sedation for BMA was represented as T0, during lumbar puncture with methotrexate sedation 6 hours after T0 was represented as T1, and 24 hours after BMA was represented as T2. Sedation with propofol-ketamine combination did not modify the plasma concentration of the most measured cytokines and the T helper 1/2 ratio in children with ALL. There was a significant reduction in IL-8 concentration 24 hours after BMA associated with the concomitant administration of steroids and methotrexate. These data suggest that sedation with propofol-ketamine combination may not affect the immediate outcome of children with ALL.

Emergence delirium in children: a comparison of sevoflurane and desflurane anesthesia using the Paediatric Anesthesia Emergence Delirium scale.

OBJECTIVES/AIM: This randomized control trial was designed to evaluate the incidence of emergence delirium (ED) in preschool children receiving sevoflurane or desflurane anesthesia combined with an effective caudal block. BACKGROUND: While ED has been described in children receiving sevoflurane or desflurane anesthesia, a direct comparison between the two agents using a validated ED assessment tool has not been reported previously. METHODS/MATERIALS: Two hundred and sixty preschool children scheduled for elective sub-umbilical surgery were randomized to receive sevoflurane or desflurane anesthesia combined with a caudal block. ED was defined as a Paediatric Anesthesia Emergence Delirium scale (PAED) ≥ 10 points. A delirium-specific score (ED I) was calculated from the first three items of the PAED score (eye contact, purposeful actions, awareness of the surroundings) and a nonspecific score (ED II) from the last two items on the PAED score (restlessness and inconsolability) to test the hypothesis that some items of the PAED scale may better reflect clinical ED than others. RESULTS: Thirty-one (25%) children in each group demonstrated ED after awakening with ED being of shorter duration in the desflurane group than the sevoflurane group. An ED I score of nine points had a sensitivity of 0.93 and a specificity of 0.94 for ED. An ED II score of five points had a sensitivity of 0.34 and specificity of 0.95 for ED. CONCLUSION: Sevoflurane and desflurane anesthesia were associated with similar incidences of ED in children undergoing sub-umbilical surgery and receiving effective regional anesthesia. High scores on the first three items of the PAED scale were highly correlated with ED. The items restlessness and inconsolability had lower sensitivity for the diagnosis of ED.

Evaluation of Nociception during Pediatric Surgery: A Topical Review.

The association between intraoperative nociception and increased patient's morbidity is well established. However, hemodynamic parameters, such as heart rate and blood pressure, may result in an inadequate monitor of nociception during surgery. Over the last two decades, different devices have been marketed to "reliably" detect intraoperative nociception. Since the direct measure of nociception is impractical during surgery, these monitors measures nociception surrogates such as sympathetic and parasympathetic nervous systems responses (heart rate variability, pupillometry, skin conductance), electroencephalographic changes, and muscular reflex arc. Each monitor carries its own advantages and disadvantages. The manuscript aims to give an overview of the most up-to-date information available in the literature on current nociceptor monitors available in clinical practice, with particular focus on their applications in pediatrics.

Pain Experience and Sensory Changes in Astronauts During and After Short-Lasting Commercial Spaceflight: A Proof-of-Concept Study.

Space travel has been associated with musculoskeletal pain, yet little is known about the nociceptive changes and pain experience during spaceflight. This preliminary study aims to investigate the pain experience and sensory alterations in astronauts following a 17-day mission to the International Space Station (ISS) on Axiom Space's AX-1 commercial space flight. Two participants were enrolled, and data were collected pre-flight, in-flight, post-flight, and three-month post-flight. Validated pain questionnaires assessed anxiety, catastrophizing, impact on physical and mental health, disability, and overall pain experience. Qualitative interviews were conducted post-landing and conditioned pain modulation (CPM) and quantitative sensory testing (QST) were performed. Both astronauts reported musculoskeletal pain during and after the flight, which was managed with anti-inflammatories and stretching techniques. Pain levels returned to baseline after three months. Pain questionnaires revealed heightened pain experiences in-flight and immediately post-flight, although their adequacy in assessing pain in space is uncertain. Qualitative interviews allowed astronauts to describe their pain experiences during the flight. Sensory changes included increased mechanical touch detection thresholds, temporal pain summation, heat pain thresholds, and differences in conditioned pain modulation post-flight. This preliminary study suggested that spaceflight may affect various aspects of sensory perception and regulation in astronauts, albeit in a variable manner. More data are needed to gain insight of on gain and loss of sensory functions during space missions. Further investigation into the multifactorial stressors affecting the somatosensory system during space travel could contribute to advancements in space and pain medicine.

The Psychosocial Characteristics and Somatosensory Function of Children and Adolescents Who Meet the Criteria for Chronic Nociplastic Pain.

Purpose: Nociplastic pain distinguishes individuals with pain and hypersensitivity in body regions with apparently normal tissues, without any signs of neuropathy, but with contribution of central and/or peripheral sensitization. There is a lack of literature describing nociplastic pain in the pediatric population. The objective of this study was to investigate the differences between pediatric patients with nociplastic pain compared with patients with non-nociplastic pain. Patients and Methods: This study included 414 pediatric patients followed at an interdisciplinary centre for complex pain. All patients underwent an exhaustive pain assessment consisting of face-to-face interviews, validated self-report questionnaires and quantitative sensory testing. Recently established criteria for chronic nociplastic pain, and quantitative sensory testing was used to describe and stratify our cohort. Results: One hundred and sixty-five patients (40%) were stratified as having possible nociplastic pain and two hundred and forty-nine (60%) patients, as non-nociplastic pain. Patients with nociplastic pain displayed pain hypersensitivity in the region of pain, more symptoms of panic and social phobia, and worse sleep quality than patients with non-nociplastic pain. The proportion of patients achieving a meaningful clinical outcome after completion of their treatment (medications, physiotherapy, psychology, nursing, social worker, and/or interventional procedures) was lower in patients with nociplastic pain (62%) than those without nociplastic pain (86%). Conclusion: Our results suggest that patients who meet the criteria for nociplastic pain can be identified in a population of children and adolescents being treated in a center for complex pain. Combining screening with validated questionnaires and quantitative sensory testing facilitates the phenotyping and graded severity of patients with nociplastic pain in daily clinical practice.

Experience and Management of the Adverse Effects of Analgesics After Surgery: A Pediatric Patient Perspective.

After surgery, the adverse effects (AEs) of analgesics are common and critical factors influencing the postoperative experience of pediatric patients. Inadequate management of AEs has been found to prolong hospital stay, increase readmission rates and decrease satisfaction with care. The aim of this qualitative descriptive study was to better understand the AEs of analgesics from the perspective of adolescent patients with idiopathic scoliosis after spinal surgery. A total of 7 patients participated in the study. Semistructured interviews were conducted at discharge and 1 week after discharge. Transcribed data were analyzed using qualitative content analysis and themes were identified. Overall, participants most frequently reported gastrointestinal and cognitive AEs, with constipation being the most persistent and bothersome. The pediatric participants used a combination of 3 strategies to mitigate analgesic AEs, namely pharmacologic, nonpharmacologic, and reduction of analgesic intake. Participants demonstrated a lack of understanding of AEs and involvement in their own care. Future studies should be conducted to evaluate the efficacy of nonpharmacological strategies in managing analgesic AEs for pediatric patients after surgery.

Phenotyping Chronic Musculoskeletal Pain in Male and Female Adolescents: Psychosocial Profiles, Somatosensory Profiles and Pain Modulatory Profiles.

PURPOSE: A major limitation in treatment outcomes for chronic pain is the heterogeneity of the population. Therefore, a personalized approach to the assessment and treatment of children and adolescents with chronic pain conditions is needed. The objective of the study was to subgroup pediatric patients with chronic MSK pain that will be phenotypically different from each other based on their psychosocial profile, somatosensory function, and pain modulation. PATIENTS AND METHODS: This observational cohort study recruited 302 adolescents (10-18 years) with chronic musculoskeletal pain and 80 age-matched controls. After validated self-report questionnaires on psychosocial factors were completed, quantitative sensory tests (QST) and conditioned pain modulation (CPM) were performed. RESULTS: Three psychosocial subgroups were identified: adaptive pain (n=125), high pain dysfunctional (n=115), high somatic symptoms (n=62). Based on QST, four somatosensory profiles were observed: normal QST (n=155), thermal hyperalgesia (n=98), mechanical hyperalgesia (n=34) and sensory loss (n=15). Based on CPM and temporal summation of pain (TSP), four distinct groups were formed, dysfunctional central processing group (n=27) had suboptimal CPM and present TSP, dysfunctional inhibition group (n=136) had suboptimal CPM and absent TSP, facilitation group (n=18) had optimal CPM and present TSP, and functional central processing (n=112) had optimal CPM and absent TSP. A significant association between the psychosocial and somatosensory profiles. However, no association was observed between the psychosocial or somatosensory profiles and pain modulatory profiles. CONCLUSION: Our results provide evidence that adolescents with chronic musculoskeletal pain are a heterogenous population comprising subgroups that may reflect distinct mechanisms and may benefit from different treatment approaches. The combination of screening self-reported questionnaires, QST, and CPM facilitate subgrouping of adolescents with chronic MSK pain in the clinical context and may ultimately contribute to personalized therapy.

Canadian surveillance study of complex regional pain syndrome in children.

ABSTRACT: This study describes the minimum incidence of pediatric complex regional pain syndrome (CRPS), clinical features, and treatments recommended by pediatricians and pain clinics in Canada. Participants in the Canadian Paediatric Surveillance Program reported new cases of CRPS aged 2 to 18 years monthly and completed a detailed case reporting questionnaire from September 2017 to August 2019. Descriptive analysis was completed, and the annual incidence of CRPS by sex and age groupings was estimated. A total of 198 cases were reported to the Canadian Paediatric Surveillance Program, and 168 (84.8%) met the case definition. The minimum Canadian incidence of CRPS is estimated at 1.14/100,000 (95% confidence interval 0.93-1.35/100,000) children per year. Incidence was highest among girls 12 years and older (3.10, 95% confidence interval 2.76-3.44/100,000). The mean age of CRPS diagnosis was 12.2 years (SD = 2.4), with the mean time from symptom onset to diagnosis of 5.6 months (SD = 9.9) and no known inciting event for 19.6% of cases. Most cases had lower limb involvement (79.8%). Nonsteroidal anti-inflammatory drugs (82.7%) and acetaminophen (66.0%) were prescribed more commonly than antiepileptic drugs (52.3%) and antidepressants (32.0%). Referrals most commonly included physical therapy (83.3%) and multidisciplinary pain clinics (72.6%); a small number of patients withdrew from treatment because of pain exacerbation (5.3%). Pain education was recommended for only 65.6% of cases. Treatment variability highlights the need for empiric data to support treatment of pediatric CRPS and development of treatment consensus guidelines.

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia.

ABSTRACT: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Intraperitoneal ropivacaine nebulization for pain management after laparoscopic cholecystectomy: a comparison with intraperitoneal instillation.

BACKGROUND: Studies evaluating intraperitoneal local anesthetic instillation for pain relief after laparoscopic procedures have reported conflicting results. In this randomized, double-blind study we assessed the effects of intraperitoneal local anesthetic nebulization on pain relief after laparoscopic cholecystectomy. METHODS: Patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive either instillation of ropivacaine 0.5%, 20 mL after induction of the pneumoperitoneum, or nebulization of ropivacaine 1%, 3 mL before and after surgery. Anesthetic and surgical techniques were standardized. Degree of pain at rest and on deep breathing, incidence of shoulder pain, morphine consumption, unassisted walking time, and postoperative nausea and vomiting were evaluated at 6, 24, and 48 hours after surgery. RESULTS: Of the 60 patients included, 3 exclusions occurred for conversion to open surgery. There were no differences between groups in pain scores or in morphine consumption. No patients in the nebulization group presented significant shoulder pain in comparison with 83% of patients in the instillation group (absolute risk reduction -83, 95% CI -97 to -70, P<0.001). Nineteen (70%) patients receiving nebulization walked without assistance within 12 hours after surgery in comparison with 14 (47%) patients receiving instillation (absolute risk reduction -24, 95% CI -48 to 1, P=0.04). One (3%) patient in the instillation group vomited in comparison with 6 (22%) patients in the nebulization group (absolute risk reduction -19%, 95% CI -36 to -2, P=0.03). CONCLUSIONS: Intraperitoneal ropivacaine nebulization was associated with reduced shoulder pain and unassisted walking time but with an increased incidence of postoperative vomiting after laparoscopic cholecystectomy.

The Pittsburgh Sleep Quality Index: Reliability, Factor Structure, and Related Clinical Factors among Children, Adolescents, and Young Adults with Chronic Pain.

This study is aimed at assessing the psychometric properties and the factorial structure of the Pittsburgh Sleep Quality Index (PSQI) in a clinical sample of children, adolescents, and young adults with chronic pain. Data of 482 participants (aged 8-21 years) from two crosssectional studies and a chronic pain services outpatient clinic were analyzed. Exploratory and confirmatory factor analysis and reliability analysis of PSQI component scores were performed. Relationships between the PSQI global score and various clinical measures were investigated to assess external validity. The findings exhibit the reliability and validity of a single-factor model of the PSQI in a clinical sample of youth with chronic pain and support the relationship in this specific population between poor sleep quality and important clinical measures of well-being. These results support an informed decision regarding its use with this specific population and underscore the clinical relevance of assessing sleep quality.