The use of ibuprofen and acetaminophen for acute headache in the postconcussive youth: A pilot study.

OBJECTIVE: Acute postconcussive headaches are problematic for children after mild traumatic brain injury. There are no evidence-based guidelines for their management. This pilot study aims to assess the feasibility and efficacy of routine analgesia administration. METHODS: A four-arm open-label randomized controlled trial pilot/feasibility study was conducted: (i) acetaminophen, (ii) ibuprofen, (iii) alternating acetaminophen and ibuprofen and (iv) a control group. Children and youth 8 to 18 years of age presenting to emergency department with headache within 48 hours of their first concussion were recruited consecutively and sequentially randomized. Children with abnormal neuroimaging, history of previous concussions and bleeding disorder were excluded. A headache survey was administered at recruitment. All participants were provided with standard concussion management education and were also instructed on how to use the headache diary for the 1-week study follow-up period. The diary captures (i) headache days, (ii) number of headaches, (iii) headache intensity and (iv) return-to-school information. Feasibility was assessed based on study recruitment and compliance. RESULTS: There were no feasibility concerns with the recruitment and no major compliance issues. Patients on acetaminophen, ibuprofen or both had significantly less headache days, episodes of headache and lower headache intensity than did the standard care group. Patients on both ibuprofen and acetaminophen (79.0%) and on ibuprofen alone (61.0%) were more likely to be back at school 1 week postinjury as compared with the acetaminophen group (33.3%) and the standard care group (21.1%). CONCLUSION: Results showed routine analgesia administration was feasible and effective for postconcussive headache management. A larger full-scale randomized controlled trial is required to further assess the efficacy with longer follow-up, a wider variety of patients and more concussion related outcomes.

OBJECTIF: Les céphalées postcommotionnelles posent problème chez les enfants après une légère commotion cérébrale. Il n'y a pas de lignes directrices factuelles sur leur prise en charge. La présente étude pilote vise à évaluer la faisabilité et l'efficacité de l'administration systématique d'analgésiques. MÉTHODOLOGIE: Les chercheurs ont réalisé une étude pilote et de faisabilité ouverte, aléatoire et contrôlée en quatre volets : i) acétaminophène, ii) ibuprofène, iii) alternance entre l'acétaminophène et l'ibuprofène et iv) groupe témoin. Des enfants et des adolescents de huit à 18 ans qui ont consulté à l'urgence à cause de céphalées dans les 48 heures suivant une première commotion ont été recrutés de manière consécutive, séquentielle et aléatoire. Les enfants dont la neuro-imagerie était anormale ou qui avaient des antécédents de commotion ou des troubles hémostatiques étaient exclus. Les enfants ont répondu à un sondage sur les céphalées au moment de leur recrutement. Tous les participants ont reçu une formation normale sur la prise en charge des céphalées et ont également appris à utiliser un journal des céphalées pendant la période de suivi d'une semaine. Le journal a permis de saisir : i) les journées comportant des céphalées, ii) le nombre de céphalées, iii) l'intensité des céphalées et iv) l'information sur le retour à l'école. Les auteurs ont évalué la faisabilité d'après le recrutement dans l'étude et la compliance aux directives. RÉSULTATS: Le recrutement ne soulevait aucune inquiétude quant à la faisabilité et aucun problème de compliance important. Les patients qui prenaient de l'acétaminophène, de l'ibuprofène ou ces deux médicaments présentaient beaucoup moins de journées comportant des céphalées, moins d'épisodes de céphalées et une intensité de céphalée plus faible que le groupe témoin. Les patients qui prenaient à la fois de l'ibuprofène et de l'acétaminophène (79,0 %) ou de l'ibuprofène seul (61,0 %) étaient plus susceptibles d'avoir repris l'école une semaine après leur commotion que ceux qui prenaient de l'acétaminophène (33,3 %) et le groupe témoin (21,1 %). CONCLUSION: Les résultats ont démontré qu'il était possible d'administrer systématiquement des analgésiques pour prendre en charge les céphalées postcommotionnelles et que ce traitement était efficace. Une étude aléatoire et contrôlée à plus grande échelle s'impose pour mieux évaluer l'efficacité de ces traitements dans le cadre d'un suivi plus long, auprès d'un plus vaste éventail de patients et de patients présentant plus de résultats cliniques liés aux commotions.

A randomized controlled trial of amitriptyline versus gabapentin for complex regional pain syndrome type I and neuropathic pain in children.

BACKGROUND: Treatment of neuropathic pain in children is challenging, and requires a multimodal approach of pharmacologic, physical, and psychological therapies; however there is little evidence to guide practice. Amitriptyline and gabapentin are first-line drugs for treating neuropathic pain in adults, yet no studies have examined their efficacy, or compared them directly, to determine which might be better for pain relief and sleep disturbance in children. METHODS: After informed consent was obtained, 34 patients aged 7-18 years diagnosed with complex regional pain syndrome type I (CRPS I) or a neuropathic pain condition were randomly allocated to receive either amitriptyline or gabapentin. Patients were followed for 6 weeks and assessed for pain intensity, sleep quality and adverse events. We blinded study personnel, including health-care providers, participants, parents, the research coordinator and the data analyst. Patients then completed quantitative sensory testing (QST) and a psychosocial pain assessment with the team psychologist, within 1-3 days of the start of the trial. RESULTS: At the end of the 6-week trial, patients on both drugs had important reductions in pain, having surpassed the minimally important difference (MID) of 1. The difference between the groups however was not statistically significant. For the secondary outcomes, we found no statistically significant difference between the two drugs in sleep score or adverse events suggesting that both drugs improve sleep score to a similar degree and are equally safe. CONCLUSIONS: Amitriptyline and gabapentin significantly decreased pain intensity scores and improved sleep. There were no significant differences between the two drugs in their effects on pain reduction or sleep disability. IMPLICATIONS: Although larger, multi-centred trials are needed to confirm our findings, including long-term follow-up, both drugs appear to be safe and effective in treating paediatric patients in the first-line treatment of CRPS I and neuropathic pain over 6-weeks.

Decreased sensitivity to thermal stimuli in adolescents with autism spectrum disorder: relation to symptomatology and cognitive ability.

UNLABELLED: Social communication deficits and repetitive behaviors are established characteristics of autism spectrum disorder (ASD) and the focus of considerable study. Alterations in pain sensitivity have been widely noted clinically but remain understudied and poorly understood. The ASD population may be at greater risk for having their pain undermanaged, especially in children with impaired cognitive ability and limited language skills, which may affect their ability to express pain. Given that sensitivity to noxious stimuli in adolescents with ASD has not been systematically assessed, here we measured warm and cool detection thresholds and heat and cold pain thresholds in 20 high-functioning adolescents with ASD and 55 typically developing adolescents using a method-of-limits quantitative sensory testing protocol. Adolescents with ASD had a loss of sensory function for thermal detection (P < .001, both warm and cool detection thresholds) but not pain threshold (P > .05, both heat and cold pain thresholds) in comparison to controls, with no evidence for significant age or sex effects (P > .05). Intelligence quotients and symptomatology were significantly correlated with a loss of some types of thermal perception in the ASD population (ie, warm detection threshold, cool detection threshold, and heat pain threshold; P < .05). Decreased thermal sensitivity in adolescents with ASD may be associated with cognitive impairments relating to attentional deficits. Our findings are consistent with previous literature indicating an association between thermal perception and cortical thickness in brain regions involved in somatosensation, cognition, and salience detection. Further brain-imaging research is needed to determine the neural mechanisms underlying thermal perceptual deficits in adolescents with ASD. PERSPECTIVE: We report quantitative evidence for altered thermal thresholds in adolescents with ASD. Reduced sensitivity to warmth, coolness, and heat pain was related to impaired cognitive ability. Caregivers and clinicians should consider cognitive ability when assessing and managing pain in adolescents with ASD.

Assessing pain intensity in children with chronic pain: convergent and discriminant validity of the 0 to 10 numerical rating scale in clinical practice.

BACKGROUND: In clinical practice, children are often asked to rate their pain intensity on a simple 0 to 10 numerical rating scale (NRS). Although the NRS is a well-established measure for adults, no study has yet evaluated its validity for children with chronic pain. OBJECTIVES: To examine the convergent and discriminant validity of the NRS as it is used within regular clinical practice to document pain intensity for children with chronic pain. Interchangeability between the NRS and an analogue pain measure was also assessed. METHODS: A cohort of 143 children (mean [± SD] age 14.1±2.4 years; 72% female) rated their pain intensity (current, usual, lowest and strongest levels) on a verbally administered 0 to 10 NRS during their first appointment at a specialized pain clinic. In a separate session that occurred either immediately before or after their appointment, children also rated their pain using the validated 0 to 10 coloured analogue scale (CAS). RESULTS: NRS ratings met a priori criteria for convergent validity (r>0.3 to 0.5), correlating with CAS ratings at all four pain levels (r=0.58 to 0.68; all P<0.001). NRS for usual pain intensity differed significantly from an affective pain rating, as hypothesized (Z=2.84; P=0.005), demonstrating discriminant validity. The absolute differences between NRS and CAS pain scores were small (range 0.98±1.4 to 1.75±1.9); however, the two scales were not interchangeable. CONCLUSIONS: The present study provides preliminary evidence that the NRS is a valid measure for assessing pain intensity in children with chronic pain.

Thermal pain and sensory processing in children with sickle cell disease.

OBJECTIVES: Early tissue injury and recurrent pain in sickle cell disease (SCD) may alter pain and sensory processing. In this study, we evaluate thermal pain and sensory processing for 27 children aged 10.3 to 18.3 years with SCD and 28 African-American control patients. MATERIALS AND METHODS: Outcome measures included heat and cold detection thresholds, heat and cold pain thresholds, and thermal perceptual sensitization at the volar surface of the dominant forearm and thenar eminence of the nondominant hand. RESULTS: Children with SCD were less sensitive to heat detection (P=0.006) and cold detection (P=0.015) stimuli at the thenar eminence compared with controls. At the forearm, no difference was found between groups for cold (P=0.58) or heat (P=0.07) detection thresholds. Children with SCD had increased sensitivity to cold pain at the forearm (P=0.03) compared with controls, but not when measured at the thenar eminence (P=0.084). There was no evidence that children with SCD had altered heat pain thresholds compared with controls. There was no difference between groups for perceptual sensitization at the thenar eminence (41% vs. 39%) (χ=0.15, P>0.1) or at the forearm (30% vs. 36%) (χ=0.23, P>0.5). DISCUSSION: Three of ten quantitative sensory tests were found to differ between groups. These results suggest that SCD may influence pain and sensory processing in children, but our interpretation is necessarily cautious. Due to the small differences in measures found between groups, further investigation is required to confirm our findings. If confirmed, the development of population-specific reference standards for quantitative sensory testing may emerge as a useful clinical tool for pain physicians in identifying and quantifying pain and sensory processing in children with SCD.

Use of zebrafish apoptosis assays for preclinical drug discovery.

INTRODUCTION: Apoptosis has become an important target for drug discovery. Although the mouse remains the animal model of choice for the preclinical assessment of drug toxicity and efficacy, zebrafish are increasingly used for early drug studies. Here, we describe approaches for assessing drug effects on apoptosis in transparent zebrafish. AREAS COVERED: In this review, the authors discuss the drug effects on developmentally regulated apoptosis using microscopy. They also discuss the effects of neuroprotectants in a chemical induced disease model using morphometric image analysis. Finally, the authors review the effects of radioprotectants in irradiated whole animals using a conventional 96-well microplate format. EXPERT OPINION: Several challenges have limited more widespread use of zebrafish as the organism of choice for drug screening. However, zebrafish do have a number of compelling inherent advantages including: rapid organogenesis, transparency, statistically significant numbers of animals per experiment and adaptability of cell-based methods.

Risk factors associated with self-injurious behaviors in children and adolescents with autism spectrum disorders.

While self-injurious behaviors (SIB) can cause significant morbidity for children with autism spectrum disorders (ASD), little is known about its associated risk factors. We assessed 7 factors that may influence self-injury in a large cohort of children with ASD: (a) atypical sensory processing; (b) impaired cognitive ability; (c) abnormal functional communication; (d) abnormal social functioning; (e) age; (f) the need for sameness; (g) rituals and compulsions. Half (52.3%, n = 126) of the children (n = 241, aged 2-19 years) demonstrated SIB. Abnormal sensory processing was the strongest single predictor of self-injury followed by sameness, impaired cognitive ability and social functioning. Since atypical sensory processing and sameness have a greater relative impact on SIB, treatment approaches that focus on these factors may be beneficial in reducing self-harm in children with ASD.

Clinical impact and evidence base for physiotherapy in treating childhood chronic pain.

PURPOSE: As part of the special series on pain, our objectives are to describe the key features of chronic pain in children, present the rationale for interdisciplinary treatment, report a case study based on our biopsychosocial approach, and highlight the integral role of physiotherapy in reducing children's pain and improving function. We also evaluate the evidence base supporting physiotherapy for treating chronic neuropathic pain in children. SUMMARY OF KEY POINTS: Chronic pain affects many children and adolescents. Certain challenging pain conditions begin primarily during adolescence and disproportionately affect girls and women. Children with these conditions require an interdisciplinary treatment programme that includes physiotherapy as well as medication and/or psychological intervention. Converging lines of evidence from cohort follow-up studies, retrospective chart reviews, and one randomized controlled trial support the effectiveness of physiotherapy within an interdisciplinary programme for treating children with chronic pain. CONCLUSIONS: Evidence-based practice dictates that health care providers adopt clear guidelines for determining when treatments are effective and for identifying children for whom such treatments are most effective. Thus, additional well-designed trials are required to better identify the specific physiotherapy modalities that are most important in improving children's pain and function.

Reducing distress for children during invasive procedures: randomized clinical trial of effectiveness of the PediSedate.

BACKGROUND: Procedural pain control remains problematic for young children, especially during anxiety-causing procedures for which children should not be deeply sedated. The PediSedate was designed to address this problem by delivering nitrous oxide in oxygen through a simple nosepiece, combined with an interactive video component, so that children can use attention and distraction with drug delivery. OBJECTIVES: We conducted a randomized clinical trial to evaluate the effectiveness of the PediSedate for reducing children's behavioral distress in comparison with standard care in the emergency department. Secondary objectives were to assess children's acceptance, cooperation, and pain. METHODS: Thirty-six children, aged 3-9 years old, who required invasive procedures associated with high levels of anxiety and low levels of pain such as sutures, IVs, and lumbar punctures were randomized to receive either the standard care or the PediSedate. The primary outcome was children's distress (observational scale of behavioral distress) that was monitored before and during the procedure. RESULTS: Children randomized to the PediSedate group had significantly less distress during invasive procedures (mean = 1.8, sd = 3.2) than children receiving standard care (mean = 9.3, SD = 5.6; anova, P < 0.0001). Also, children in the PediSedate group were more cooperative [chi(2)(1) = 22.05, P < 0.0001] and fewer children reported pain [chi(2)(1) = 14.45, P < 0.001]. CONCLUSIONS: Previous studies have demonstrated the effectiveness of nitrous oxide sedation alone for minimizing pain and distress during invasive procedures. We have found that delivering nitrous oxide sedation via a system combined with an interactive video component is also effective. Further studies should determine which factors are dominant and determine the specific failure rate for this delivery system in comparison with other systems.

The complex minds of teenagers: neuroanatomy of personality differs between sexes.

Extraversion and neuroticism influence behaviour and mood. Extreme expressions of these personality traits may predispose individuals to developing chronic functional pains and mood disorders that predominantly affect women. We acquired anatomical MRI scans and personality scores from healthy male and female adolescents and measured gray matter volume (GMV) and cortical thickness to test the hypothesis that neuroticism and extraversion contribute to sex differences in fronto-limbic cortical development during a crucial period of social and biological maturation. In females, extraversion correlated negatively with medial frontal gyrus GMV and neuroticism correlated positively with subgenual anterior cingulate cortex GMV and cortical thickness. Interestingly, correlations between GMV and personality in males showed an opposite effect. Given the association of these cortical areas with social cognition and emotional processing, we suggest that a neuro-maturational divergence during adolescence accounts for the higher prevalence of specific chronic pains and mood disorders in females.

Zebrafish: a predictive model for assessing drug-induced toxicity.

The zebrafish model organism is increasingly used for assessing drug toxicity and safety and numerous studies confirm that mammalian and zebrafish toxicity profiles are strikingly similar. This transparent vertebrate offers several compelling experimental advantages, including convenient drug delivery and low cost. Although full validation will require assessment of a large number of compounds from diverse classes, zebrafish can be used to eliminate potentially unsafe compounds rapidly in the early stages of drug development and to prioritize compounds for further preclinical and clinical studies. Adaptation of conventional instrumentation combined with new nanotechnology developments will continue to expand use of zebrafish for drug screening.

Anxiety sensitivity, fear of pain and pain-related disability in children and adolescents with chronic pain.

BACKGROUND: Converging lines of evidence suggest that anxiety sensitivity and fear of pain may be important vulnerability factors in the development of avoidance behaviours and disability in adults with chronic pain. However, these factors have not been evaluated in children with chronic pain. OBJECTIVES: To examine the relationships among anxiety sensitivity, fear of pain and pain-related disability in children and adolescents with chronic pain. METHODS: An interview and five questionnaires (Childhood Anxiety Sensitivity Index, Pain Anxiety Symptoms Scale, Functional Disability Inventory, Multidimensional Anxiety Scale for Children, and Reynolds Child or Adolescent Depression Scale) were administered to 21 children and adolescents eight to 17 years of age (mean +/- SD 14.24+/-2.21 years) who continued to experience pain an average of three years after discharge from a specialized pain clinic for children. RESULTS: Anxiety sensitivity accounted for 38.6% of the variance in fear of pain (F[1,20]=11.30; P=0.003) and fear of pain accounted for 39.9% of the variance in pain-related disability (F[1,20]=11.95; P=0.003), but anxiety sensitivity was not significantly related to pain disability (R2=0.09; P>0.05). CONCLUSIONS: These findings indicate that children with high levels of anxiety sensitivity had a higher fear of pain, which, in turn, was linked to increased pain disability. The results of this study suggest that anxiety sensitivity and fear of pain may play important and distinct roles in the processes that maintain chronic pain and pain-related disability in children.

Children with chronic pain: impact of sex and age on long-term outcomes.

The present study examined the long-term pain and disability outcomes of a pediatric chronic pain clinic cohort and evaluated whether these outcomes differed by age and sex. Patients were interviewed a mean of 3 years after their last appointment at a pediatric pain clinic. The cohort comprised 95 females and 48 males, aged 5-23 years when interviewed. Of the cohort, 62.2% (67 females, 22 males) reported continuing pain. Females were significantly more likely than males to report continuing pain (OR=2.9, 95% CI=1.4-5.8, p=.005), use of health care (OR=5.1, 95% CI=1.4-18.5, p=.01), medication (OR=4.7, 95% CI=1.3-16.9, p=.02) and non-drug methods of pain control (OR=3.4, 95% CI=1.3-9.2, p=.02). For patients whose pain had associated psychosocial factors, females (76.4%) were significantly more likely than males (21.4%) to report continuing pain (OR=13.8, 95% CI=3.3-58.4, p=.005). Finally, among patients still experiencing pain, the frequency of pain episodes increased significantly with age (OR=1.3, 95% CI=1.0-1.5, p=.02). Results indicate that chronic pain persists for many children despite treatment at specialized clinics. Females may be at higher risk for continuing pain and report greater use of health care, medication, and non-drug methods of pain control.

Neurotoxicity assessment using zebrafish.

INTRODUCTION: Transparency is a unique attribute of zebrafish that permits direct assessment of drug effects on the nervous system using whole mount antibody immunostaining and histochemistry. METHODS: To assess pharmacological effects of drugs on the optic nerves, motor neurons, and dopaminergic neurons, we performed whole mount immunostaining and visualized different neuronal cell types in vivo. In addition, we assessed neuronal apoptosis, proliferation, oxidation and the integrity of the myelin sheath using TUNEL staining, immunostaining and in situ hybridization. The number of dopaminergic neurons was examined and morphometric analysis was performed to quantify the staining signals for myelin basic protein and apoptosis. RESULTS: We showed that compounds that induce neurotoxicity in humans caused similar neurotoxicity in zebrafish. For example, ethanol induced defects in optic nerves and motor neurons and affected neuronal proliferation; 6-hydroxydopamine caused neuronal oxidation and dopaminergic neuron loss; acrylamide induced demyelination; taxol, neomycin, TCDD and retinoic acid induced neuronal apoptosis. DISCUSSION: Effects of drug treatment on different neurons can easily be visually assessed and quantified in intact animals. These results support the use of zebrafish as a predictive model for assessing neurotoxicity.

Pain prevalence in nine- to 13-year-old schoolchildren.

BACKGROUND: Despite significant progress in the epidemiology of chronic pain in adults, major gaps remain in our understanding of the epidemiology of chronic pain in children. In particular, the incidence, prevalence and sensory characteristics of many types of pain in Canadian children are unknown. OBJECTIVES: A study to obtain the lifetime and point prevalence of common acute pains, recurrent pain syndromes and chronic pains was conducted in a cohort of 495 school children, nine to 13 years of age, in eastern Ontario. METHODS: Children reported their pain experiences and described the intensity, affect and duration of the pains experienced over the previous month by completing the Pain Experience Interview -- Short Form. RESULTS: The majority of children (96%) experienced some acute pain over the previous month, with headache (78%) being most frequently reported. Lifetime prevalence for certain acute pains differed significantly by sex (P<0.05). Fifty-seven per cent of children reported experiencing at least one recurrent pain, while 6% were identified as having had or currently having chronic pain. DISCUSSION: The prevalence of acute pain in this Canadian cohort is consistent with international estimates of acute pain experiences (ie, headache) and recurrent pain problems (ie, recurring headache, abdominal pain and growing pains). However, 6% of children reported chronic pain. The self-completed Pain Experience Interview--Short Form provides a feasible administration technique for obtaining population estimates of childhood pain, and for conducting longitudinal studies to identify risk and prognostic factors for chronic pain.

Human melanoma cells transplanted into zebrafish proliferate, migrate, produce melanin, form masses and stimulate angiogenesis in zebrafish.

In this research, we optimized parameters for xenotransplanting WM-266-4, a metastatic melanoma cell line, including zebrafish site and stage for transplantation, number of cells, injection method, and zebrafish incubation temperature. Melanoma cells proliferated, migrated and formed masses in vivo. We transplanted two additional cancer cell lines, SW620, a colorectal cancer cell line, and FG CAS/Crk, a pancreatic cancer cell line and these human cancers also formed masses in zebrafish. We also transplanted CCD-1092Sk, a human fibroblast cell line established from normal foreskin and this cell line migrated, but did not proliferate or form masses. We quantified the number of proliferating melanoma and normal skin fibroblasts by dissociating xenotransplant zebrafish, dispensing an aliquot of CM-DiI labeled human cells from each zebrafish onto a hemocytometer slide and then visually counting the number of fluorescently labeled cancer cells. Since zebrafish are transparent until approximately 30 dpf, the interaction of labeled melanoma cells and zebrafish endothelial cells (EC) can be visualized by whole-mount immunochemical staining. After staining with Phy-V, a mouse anti-zebrafish monoclonal antibody (mAb) that specifically labels activated EC and angioblasts, using immunohistology and 2-photon microscopy, we observed activated zebrafish EC embedded in human melanoma cell masses. The zebrafish model offers a rapid efficient approach for assessing human cancer cells at various stages of tumorigenesis.

A zebrafish assay for identifying neuroprotectants in vivo.

In this study, we developed an in vivo method to determine drug effects on oxidation-induced apoptosis in the zebrafish brain caused by treatment with L-hydroxyglutaric acid (LGA). We confirmed that LGA-induced apoptosis was caused by oxidation by examining the presence of an oxidative product, nitrotyrosine. Next, we examined the effects of 14 characterized neuroprotectants on LGA-treated zebrafish, including: D-methionine (D-Met), Indole-3-carbinol, deferoxamine (DFO), dihydroxybenzoate (DHB), deprenyl, L-NAME (N(G)-nitro-L-arginine methyl ester), n-acetyl L-cysteine (L-NAC), 2-oxothiazolidine-4-carboxylate (OTC), lipoic acid, minocycline, isatin, cortisone, ascorbic acid and alpha-tocopherol. Eleven of 14 neuroprotectants and 7 of 7 synthetic anti-oxidants exhibit significant protection in zebrafish. Buthionine sulfoximine (BSO), used as a negative control, exhibited no significant protective effects. In addition, three blood-brain barrier (BBB) impermeable compounds exhibited no significant effects. Our results in zebrafish were similar to results reported in mammals supporting the utility of this in vivo method for identifying potential neuroprotective anti-oxidants.