A framework for individualized splice-switching oligonucleotide therapy.

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

Rescue designs in analgesic trials from 0 to 2 years of age: scoping review.

Pediatric analgesic trials are challenging, especially in newborns and infants. Following an FDA-academic consensus meeting, we analyzed pragmatic rescue designs in postoperative trials of local anesthetics, acetaminophen, opioids, and NSAIDs involving children ages 0-2 years and assessed surgical volumes to provide trial design recommendations. Searches of PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science were conducted. A scoping approach identified trends in analgesic trials with an emphasis on randomized controlled trials (RCTs) utilizing immediate rescue designs. Age-specific surgical volumes were estimated from French national databases. Of 3563 studies identified, 23 RCTs used study medication(s) of interest and immediate rescue paradigms in children ages 0-2 years. A total of 270 studies met at least one of these criteria. Add-on and head-to-head designs were common and often used sparing of non-opioid or opioid rescue medication as a primary outcome measure. According to French national data, inguinal and penile surgeries were most frequent in ages 1 month to 2 years; abdominal and thoracic surgeries comprise approximately 75% of newborn surgeries. Analgesic trials with rescue sparing paradigm are currently sparse among children ages 0-2 years. Future trials could consider age-specific surgical procedures and use of add-on or head-to-head designs. IMPACT: Clinical trials of analgesic medications have been challenging in pediatrics, especially in the group from newborns to 2 years of age. Following an FDA-academic workshop, we analyzed features of completed analgesic trials in this age group. Studies using immediate rescue in placebo control, add-on, and head-to-head trial designs are pragmatic approaches that can provide important information regarding clinical effectiveness, side effects, and safety. Using a French national dataset with a granular profile of inpatient, outpatient, and short-stay surgeries, we provide information to future investigators on relative frequencies of different operations in neonates and through the first 2 years of life.

The Risk of Kidney Injury in Patients With Sickle Cell Disease Treated With Ketorolac for Acute Pain.

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P =0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P =0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.

Ketamine use for management of vaso-occlusive pain in pediatric sickle cell disease.

BACKGROUND: Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. OBJECTIVES: This study aimed to characterize ketamine use for VOE management in pediatric SCD. METHOD: This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. RESULTS: Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0 µg/kg/min; median maximum dose 3.0 µg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n = 34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. CONCLUSION: Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.

The Comfort Ability Pain Management Workshop: A Preliminary, Nonrandomized Investigation of a Brief, Cognitive, Biobehavioral, and Parent Training Intervention for Pediatric Chronic Pain.

Objective: Psychological intervention is widely recognized as an integral part of the recovery process from pediatric chronic pain, but service acquisition is often limited by resource barriers. The aim of this study was to assess the feasibility, acceptability, and satisfaction of a brief, structured, skills-based, group intervention designed expressly to address gaps in service delivery. Exploratory outcomes were also assessed. Method: Adolescents with chronic pain (n = 102; ages 10-17 years) and their mothers (n = 105) completed self-report questionnaires at baseline, 1-week, 1-month, and 3-month posttreatment. Results: This study demonstrated feasibility, and overall high acceptability and satisfaction among adolescents and parents. Exploratory analyses within this nonrandomized design suggest that adolescents demonstrate improvement in functionality (p = .0012), depression symptoms (p < .0001), and pain catastrophizing (p < .0001) by 1-month posttreatment and continued making gains over time. Parents made significant changes in parenting practices (p-values < .01) and in their beliefs about their adolescent's ability to manage pain (p < .001) by 1-week posttreatment and continued making gains over time. Conclusions: This brief intervention is both feasible and acceptable. Although small effect sizes were found for all outcome measures, parents and adolescents made significant gains postintervention. In the absence of a direct comparison group, we cannot determine if these improvements are exclusively attributable to the intervention. Future research will be needed to understand the degree to which this brief intervention may effectively enhance the attainment of evidence-based psychoeducation and cognitive behavioral skills that are known to foster adaptive parent and adolescent responses to chronic pain.

Clinical signs and electroencephalographic patterns of emergence from sevoflurane anaesthesia in children: An observational study.

BACKGROUND: Few studies have systematically described relationships between clinical-behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE: To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical-behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical-behavioural signs. DESIGN: An observational study. SETTING: A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS: Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES: Time-course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS: Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION: Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical-behavioural signs in children more than 3 months.

Electroencephalographic discontinuity during sevoflurane anesthesia in infants and children.

BACKGROUND: Deep anesthesia in adults may be associated with electroencephalographic (EEG) suppression and higher rates of postoperative complications. Little is known about the impact of anesthetic depth on short- or long-term outcomes in pediatrics. Brain activity monitoring may complement clinical signs of anesthetic depth. This prospective observational study aimed to assess the frequency and degree of profound EEG suppression using multichannel EEG in children during sevoflurane general anesthesia. METHODS: Children aged 0-40 months who required general anesthesia for elective surgery were included. Continuous EEG recordings were performed starting from when anesthesia began and until recovery. Discontinuity was defined as EEG amplitude <25 uV, lasting ≥2 s, and observed in all electrodes across the scalp. Frequency, duration, and inter-event interval of discontinuity events were measured. Relationships between discontinuity events and postnatal age, endtidal sevoflurane concentration (etSEVO), and multiple clinical parameters were analyzed. RESULTS: Discontinuity events were observed in 35/68 children, with a median duration of 10 s (95%CI: 8-12) and a median of 4 events per patient (95%CI: 2-7). Children who had discontinuity events were younger (5.5 months, 95%CI: 3.6-6.5) compared to children who did not have discontinuity events (10.2 months, 95%CI: 6.1-14); (difference between medians, 4.7 months, 95%CI: 2.3-8, P = 0.0002). Younger infants exhibited a higher number of discontinuity events, and the incidence decreased with postnatal age (r68 = -0.53, P < 0.0001). The majority of discontinuity events were observed during the first 30 min of anesthesia (66.4% total events), where etSEVO was >3%. Few discontinuity events were observed during maintenance and none during emergence. Blood pressure, heart rate, tissue oxygen saturation, and endtidal CO2 partial pressure did not change during these events. CONCLUSIONS: Electroencephalographic monitoring may complement clinical signs in providing information about brain homeostasis during general anesthesia. The impact of discontinuity events on immediate and long-term outcomes merits further study.

Immediate rescue designs in pediatric analgesic trials: a systematic review and meta-analysis.

BACKGROUND: Designing analgesic clinical trials in pediatrics requires a balance between scientific, ethical, and practical concerns. A previous consensus group recommended immediate rescue designs using opioid sparing as a surrogate measure of analgesic efficacy. The authors summarize the performance of rescue analgesic designs in pediatric trials of four commonly used classes of analgesics: opioids, nonsteroidal antiinflammatory drugs, acetaminophen, and local anesthetics. METHODS: MEDLINE, Embase, CINAHL, The Cochrane Library, and Web of science were searched in April 2013. The 85 studies selected were randomized or controlled clinical trials using immediate rescue paradigms in postoperative pain settings. A random-effects meta-analysis was used to synthesize predefined outcomes using Hedges' g. Difference between the means of the treatment arms were also expressed as a percentage of the corresponding value in the placebo group (placebo-treatment/placebo). Distributions of pain scores in study and control groups and relationships between opioid sparing and pain scores were examined. RESULTS: For each of the four study drug classes, significant opioid sparing was demonstrated in a majority of studies by one or more of the following endpoints: (1) total dose (milligram per kilogram per hour), (2) percentage of children requiring rescue medication, and (3) time to first rescue medication (minutes). Pain scores averaged 2.4/10 in study groups, 3.4/10 in control groups. CONCLUSIONS: Opioid sparing is a feasible pragmatic endpoint for pediatric pain analgesic trials. This review serves to guide future research in pediatric analgesia trials, which could test whether some specific design features may improve assay sensitivity while minimizing the risk of unrelieved pain.

A Phase 1, Dose-escalation, Double-blind, Block-randomized, Controlled Trial of Safety and Efficacy of Neosaxitoxin Alone and in Combination with 0.2% Bupivacaine, with and without Epinephrine, for Cutaneous Anesthesia.

BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine. METHODS: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 µg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 µg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 µg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia. RESULTS: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 µg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). CONCLUSION: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.

Sensory processing sensitivity in adolescents reporting chronic pain: an exploratory study.

Introduction: Sensory processing sensitivity (SPS) describes a genetically influenced trait characterized by greater depth of information processing, lower sensory threshold, and ease of overstimulation. It is hypothesized that SPS plays a crucial role in the context of chronic pain.Objectives: This exploratory study examined SPS as a correlate of pain intensity and pain-related disability in a sample of adolescents reporting chronic pain. Methods: Adolescents reporting chronic pain were contacted through social media and through specialized pain clinics. Participants completed online questionnaires on their levels of SPS, pain features, emotion regulation, and quality of life. A series of analysis of variances (ANOVAs) were calculated to detect differences between 3 SPS groups (ie, high, medium, and low sensitivity) regarding emotion regulation, quality of life, and pain features. Multiple linear regressions were conducted to predict pain intensity, pain-related disability, and quality of life. Results: In total, 103 participants completed the survey (68.9% female, Mage 17.9). Back pain was the most frequently reported pain location. Proportion of highly sensitive individuals was large (45.68%). The ANOVA revealed significant differences between sensitivity groups related to quality-of-life subscales, namely, for physical (F(2, 100) = 7.42, P < 0.001), emotional (F(2, 100) = 6.11, P < 0.001), and school functioning (F(2, 100) = 3.75, P = 0.03). High sensitivity was not predictive of pain but of health-related quality of life. Conclusions: Our results indicate that SPS is an important and prevalent characteristic to consider in the context of chronic pain in adolescents, specifically regarding the quality of life.

Patient Controlled Analgesia for Vaso-Occlusive Episodes in Children: A Retrospective Study.

OBJECTIVE: To describe Patient-Controlled Analgesia (PCA) administration in pediatric patients admitted with sickle cell vaso-occlusive episode (VOE). METHODS: This single-center retrospective study included all inpatient hematology admissions for VOE between 2014 and 2020. PCA-ratio was calculated as the ratio of bolus over continuous IV opioids dose, and time to PCA adjustment as time between first PCA order and a subsequent order that increased dosing or changed opioid medication. RESULTS: A total of 866 encounters (172 unique patients) with PCA for VOE were included. The mean age was 15.4 years old (SD = 5.0). On average, after admission (hospital arrival), the first opioid dose was given at 1 hour, PCA started at 3.5 hours, and mean length of stay was 4.3 days (SD = 2.5). The mean initial PCA-ratio was 1.7 (SD = 0.6). There were no significant associations between age, gender, initial pain score, or admission hemoglobin and PCA-ratio (linear regression model P = 0.443). In 24.7% of encounters, the PCA was adjusted within 6 hours. After adjusting by age and gender, lower admission pain scores (OR = 1.15, P = 0.004), lower PCA-ratio (OR = 2.1, P = 0.003), longer time to PCA start (OR = 1.2, P = 0.001), and no adjuvant ketamine (OR = 2.4, P < 0.001) were associated with PCA unadjusted within 6 hours. CONCLUSION: At our institution, patients with VOE received opioids and PCA within the first hours of admission. PCAs were started at a ratio of 1.5-1.8, considered normal continuous. While no specific PCA-ratio was clearly superior for pain control, lower ratios (high continuous infusion) were associated with not requiring PCA adjustments at 6 hours. Prospective studies are needed.

Clinical Characterization of Pediatric Erythromelalgia: A Single-Center Case Series.

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

Modified Sensory Testing in Non-verbal Patients Receiving Novel Intrathecal Therapies for Neurological Disorders.

Several neurological disorders may be amenable to treatment with gene-targeting therapies such as antisense oligonucleotides (ASOs) or viral vector-based gene therapy. The US FDA has approved several of these treatments; many others are in clinical trials. Preclinical toxicity studies of ASO candidates have identified dose-dependent neurotoxicity patterns. These include degeneration of dorsal root ganglia, the cell bodies of peripheral sensory neurons. Quantitative sensory testing (QST) refers to a series of standardized mechanical and/or thermal measures that complement clinical neurologic examination in detecting sensory dysfunction. QST primarily relies on patient self-report or task performance (i.e., button-pushing). This brief report illustrates individualized pragmatic approaches to QST in non-verbal subjects receiving early phase investigational intrathecal drug therapies as a component of clinical trial safety protocols. Three children with neurodevelopmental disorders that include Neuronal Ceroid Lipofuscinosis Type 7, Ataxia-Telangiectasia, and Epilepsy of Infancy with Migrating Focal Seizures are presented. These case studies discuss individualized testing protocols, accounting for disease presentation, cognitive and motor function. We outline specific considerations for developing assessments for detecting changes in sensory processing in diverse patient groups and safety monitoring trials of early phase investigational intrathecal drug therapies. QST may complement information obtained from the standard neurologic examination, electrophysiologic studies, skin biopsies, and imaging. QST has limitations and challenges, especially in non-verbal subjects, as shown in the three cases discussed in this report. Future directions call for collaborative efforts to generate sensory datasets and share data registries in the pediatric neurology field.

Standardizing Opioid Prescribing in a Pediatric Hospital: A Quality Improvement Effort.

BACKGROUND: Opioids are indicated for moderate-to-severe pain caused by trauma, ischemia, surgery, cancer and sickle cell disease, and vaso-occlusive episodes (SCD-VOC). There is only limited evidence regarding the appropriate number of doses to prescribe for specific indications. Therefore, we developed and implemented an opioid prescribing algorithm with dosing guidelines for specific procedures and conditions. We aimed to reach and sustain 90% compliance within 1 year of implementation. METHODS: We conducted this quality improvement effort at a pediatric academic quaternary care institution. In 2018, a multidisciplinary team identified the need for a standard approach to opioid prescribing. The algorithm guides prescribers to evaluate the medical history, physical examination, red flags, pain type, and to initiate opioid-sparing interventions before prescribing opioids. Opioid prescriptions written between January 2015 and September 2020 were included. Examples from 2 hospital departments will be highlighted. Control charts for compliance with guidelines and variability in the doses prescribed are presented for selected procedures and conditions. RESULTS: Over 5 years, 83 037 opioid prescriptions in 53 804 unique patients were entered electronically. The encounters with ≥1 opioid prescription decreased from 48% to 25% between 2015 and 2019. Compliance with the specific guidelines increased to ∼85% for periacetabular osteotomies and SCD-VOC and close to 100% for anterior-cruciate ligament surgery. In all 3 procedures and conditions, variability in the number of doses prescribed decreased significantly. CONCLUSION: We developed an algorithm, guidelines, and a process for improvement. The number of opioid prescriptions and variability in opioid prescribing decreased. Future evaluation of specific initiatives within departments is needed.

Nusinersen for Patients With Spinal Muscular Atrophy: 1415 Doses via an Interdisciplinary Institutional Approach.

BACKGROUND: Spinal deformity and prior spinal fusion pose technical challenges to lumbar puncture (LP) for nusinersen administration for patients with spinal muscular atrophy (SMA). In this retrospective study over two study phases, we evaluated (1) factors associated with difficult LP or unscheduled requirement for image guidance and (2) effectiveness of a triage pathway for selective use of image guidance and nonstandard techniques, particularly for patients with spinal instrumentation/fusion to the sacrum. METHODS: With institutional review board approval, electronic health records, imaging, and administrative databases were analyzed for patients receiving nusinersen from January 2012 through September 2021. Descriptive statistics and univariate analyses were used. RESULTS: From January 2012 to March 2018 (phase 1), among 82 patients with SMA, 461 of 464 (99.4%) LP attempts were successful. Univariate analyses associated difficulty with prior spinal instrumentation, higher body mass index, and severity of the spinal deformity. Based on this experience, starting in April 2018 (phase 2), 125 patients were triaged selectively for ultrasound, fluoroscopy, or Dyna computed tomography. Patients with spinal instrumentation/fusion to the sacrum were treated primarily via intrathecal ports (137 doses) or transforaminal LP (55 doses). From April 2018 through September 2021, 704 of 709 (99.3%) LPs were successful. In total from January 2012 to September 2021, 1415 doses were administered. Over 50% of LPs were performed by neurology nurse practitioners without image guidance. Safety outcomes were excellent. CONCLUSIONS: A stratified approach resulted in successful intrathecal nusinersen delivery and efficient resource allocation for patients with SMA, with or without complex spinal anatomy.

From One Pain to Many: The Emergence of Overlapping Pains in Children and Adolescents.

OBJECTIVES: The objective of this study was to compare children and adolescents with overlapping chronic pains (OCP) to those with single chronic pains (SCP) among youth presenting in specialized clinical settings, in an effort to identify potential risk factors for developing overlapping pains. METHODS: A total of 1235 youth ages 8 to 18 seen in a tertiary care multidisciplinary pain clinic or a multidisciplinary headache clinic completed self-report measures of pain, disability, psychological functioning and clinical history and characteristics at the time of initial clinic visit. Information was captured in a chronic pain data repository and accessed for the current study. RESULTS: Subsequent pain symptoms developed on average 11.9 months (SD=24.5 mo) after onset of the first pain symptom. Compared with patients with SCP, patients with OCP report more medical comorbidity, more developmental issues, and poorer current sleep and school functioning. They also scored significantly higher than patients with SCP on self-reported functional disability, pain catastrophizing, fear of pain, depression, anxiety, and psychological stress and lower quality of life (all Ps<0.001). In multivariate analysis, variables most strongly associated with presenting with OCP were age (odds ratio [OR]: 1.1, P<0.001), having a clinically significant high functional disability (OR: 1.4, P=0.3), and low quality of life (OR: 2.5, P<0.001). DISCUSSION: Given their tendency toward more psychological and medical comorbidities, patients with OCP may require more intense and diverse treatment approaches. Some early life experiences may be a risk factor for development of OCP. Longitudinal studies are needed to fully evaluate the heightened risk for OCP associated with some of these factors.

Trends in Gabapentin and Pregabalin Prescribing in a Tertiary Pediatric Medical Center.

OBJECTIVES: Analgesic medications are commonly prescribed in pediatrics, with prescribing practices frequently extrapolated from adult trials. Gabapentinoids (gabapentin and pregabalin) are widely used as analgesics but are labeled in pediatrics only for epilepsy. We aim to (1) define trends in pediatric gabapentinoid prescribing (label and off-label) over 7 years, and (2) evaluate use in chronic pain clinic (CPC) patients during 2018. METHODS: Retrospective data from a tertiary-care pediatric hospital were collected between 2013 and 2019. Annual numbers of gabapentinoid prescriptions were stratified by prescriber specialty. Additional information about gabapentinoid prescribing in the CPC was manually collected from initial clinic notes in 2018. RESULTS: There were 15 808 outpatient prescriptions for gabapentinoids among 5172 patients over 7 years. Of these, 93% were gabapentin and 7% were pregabalin. Numbers of patients receiving gabapentin and pregabalin prescriptions increased by 1.4- and 1.3-fold, respectively, between 2013 and 2019. Few prescriptions were done for patients with a previous epilepsy diagnosis (in 2019, 16% for gabapentin and 13% for pregabalin). Approximately 28% of 650 CPC new patients were prescribed gabapentin or pregabalin before referral. Among those, 44% had discontinued the medication because of adverse events (35%), inefficacy (46%), or both (5%). Most side effects reported were mild to moderate. Diagnoses at first visit were diverse, not limited to neuropathic pain conditions, and did not differ between patients receiving or not receiving gabapentinoid prescriptions. CONCLUSIONS: In our hospital, gabapentinoids are commonly prescribed off-label for diverse indications, including chronic pain. Future research is needed to evaluate gabapentinoid efficacy in these indications.

The Effectiveness of Cancer Pain Management in a Tertiary Hospital Outpatient Pain Clinic in Thailand: A Prospective Observational Study.

Objectives: The objective was to examine the effectiveness of the updated approach. Methods: With IRB approval, outpatients with cancer were enrolled from January to December 2018. Assessments were recorded at baseline and three consecutive visits (BL, FU1, FU2, and FU3), including Numerical Rating Scale (NRS), the Brief Pain Inventory (BPI), the Edmonton Symptom Assessment System (ESAS), side effects, and analgesic use. The primary outcome was a favorable response, defined as an NRS decrease more than 30% or NRS <4. Secondary outcomes included trends over time in BPI, ESAS, side effects, and analgesic use. Pain response predictors at FU3 were analyzed using logistic regression. Results: Among 150 patients, 72 (48%) completed follow-ups. Of these, 61% achieved a favorable response at FU3. Pain interference diminished at all visits relative to baseline (p < 0.05). Median morphine equivalent daily dosage (MEDD) at BL was 20 mg/day, with a statistically significant, but clinically modest increase to 26.4 mg/day at FU3. Radiation therapy during pain care was a predictor of pain responders. Conclusion: The current Siriraj multidisciplinary approach provided effective relief of pain and stabilization of other cancer-related symptoms. Radiation therapy during pain care can be used to predict pain outcomes. Ongoing improvement domains were identified and considered in the context of cultural, economic, and geographic factors.

Developing a pediatric pain data repository.

The management of pediatric pain typically consists of individualized treatment plans and interventions that have not been systematically evaluated. There is an emerging need to create systems that can support the translation of clinical discoveries, facilitate the assessment of current interventions, and improve the collection of patient-centered data beyond routine clinical information. We present the development of the pediatric pain data repository, a custom-built system developed at Boston Children's Hospital by a multidisciplinary pain treatment service. The Repository employs a web platform to collect standardized patient-reported outcomes and integrates this with electronic medical record data. To date, we have collected information on 2577 patients and anticipate adding approximately 500 new patients per year. Major strengths of the Repository include collection of extensive longitudinal patient-reported outcomes, automated clinical data abstraction, and integration of the system into clinical workflows to support medical decision making.

Exposure to Parental Depressive Symptoms: A Longitudinal Analysis on the Association with Adolescents' Depressive Symptoms and Adjustment Problems.

OBJECTIVE: Parental depressive symptoms have been associated with depressive symptoms and adjustment problems in adolescents. However, longitudinal studies assessing both mothers' and fathers' depressive symptoms over time and their association with adolescents' outcomes are sparse. METHODS: Data were obtained from the Study of Early Child Care and Youth Development. A total of 1364 children and families were followed from the child's birth until the age of 15 years. Adolescents' depressive symptoms were evaluated via self-reported questionnaire at ages 11 to 15 years. Adjustment problems at 15 years of age were defined as high internalizing and/or externalizing problems. Parental depressive symptoms were assessed several times during the study period. Trajectories created using partitional clustering analyses were entered in logistic regression models to predict adolescents' outcomes. RESULTS: After adjusting for sociodemographic variables, adolescents' outcomes were associated with every additional time point of reported maternal (depressive symptoms: odds ratio [OR] = 1.2, p = 0.001; adjustment problems: OR = 1.1, p = 0.003) and paternal depressive symptoms (adjustment problems: OR = 1.2, p = 0.027). When maternal and paternal depressive symptom trajectories were combined, we found adolescents' depressive symptoms to be significantly associated with mother elevated and stable subclinical father scores (OR = 3.3, p = 0.003) and girls (OR = 5.4, p < 0.001). Adjustment problems were associated with father elevated and stable subclinical mother (OR = 1.9, p = 0.003) and mother elevated and stable subclinical father (OR = 2.1, p = 0.001) trajectories. CONCLUSION: Parental depressive symptoms are an important risk factor for adolescents' outcomes. This highlights the importance of continuously evaluating parents' mental status across child development. The cumulative effect of recurrent depressive symptoms and the combined parental trajectories are especially predictive for the development of adolescents' outcomes.