[Challenges in pain assessment and management among individuals with intellectual and developmental disabilities : German version]. / Herausforderungen der Schmerzerfassung und -therapie bei Personen mit Intelligenzminderung und Entwicklungsstörungen : Deutsche Fassung.

INTRODUCTION: Intellectual and developmental disabilities (IDD) include conditions associated with physical, learning, language, behavioural, and/or intellectual impairment. Pain is a common and debilitating secondary condition compromising functional abilities and quality of life. OBJECTIVES: This article addresses scientific and clinical challenges in pain assessment and management in individuals with severe IDD. METHODS: This Clinical Update aligns with the 2019 IASP Global Year Against Pain in the Vulnerable and selectively reviews recurring issues as well as the best available evidence and practice. RESULTS: The past decade of pain research has involved the development of standardized assessment tools appropriate for individuals with severe IDD; however, there is little empirical evidence that pain is being better assessed or managed clinically. There is limited evidence available to inform effective pain management practices; therefore, treatment approaches are largely empiric and highly variable. This is problematic because individuals with IDD are at risk of developing drug-related side effects, and treatment approaches effective for other populations may exacerbate pain in IDD populations. Scientifically, we are especially challenged by biases in self-reported and proxy-reported pain scores, identifying valid outcome measures for treatment trials, being able to adequately power studies due to small sample sizes, and our inability to easily explore the underlying pain mechanisms due to compromised ability to self-report. CONCLUSION: Despite the critical challenges, new developments in research and knowledge translation activities in pain and IDD continue to emerge, and there are ongoing international collaborations.

A Randomized Controlled Trial Evaluating a Pain Training for Respite Workers Supporting Children With Disabilities Part Two: Training Evaluations and the Impact of Training on Knowledge Application.

Within a parallel-group randomized control trial, pain training's impact on Respite Workers' (RW) care approaches and training evaluations was explored. RW (n = 158) from 14 organizations received pain or control training following randomization. Researchers were blind until randomization; allocations were not shared explicitly with organizations/participants. Participants completed a strategy use questionnaire immediately before and an evaluation immediately after training completion. Four-to-6 weeks later, participants completed the strategy use questionnaire and semistructured focus groups. No differences in pain approaches were noted in strategy use questionnaires. Per focus groups, both groups acquired a "knowing" about pain and applied pain-related care approaches in similarly. Pain training participants identified need for "growing and strengthening" pain knowledge. Training endorsements were favorable. RW pain training has value and may impact practice.

A Randomized Controlled Trial Evaluating a Pain Assessment and Management Program for Respite Workers Supporting Children With Disabilities Part One: Pain-Related Knowledge and Perceptions.

This parallel group randomized controlled trial tested effectiveness of the Let's Talk About Pain training on respite workers' (RW) pain-related knowledge and feasibility-confidence-skill ratings using between-group and within-group analyses. Fourteen children's respite organizations were randomized to pain or control training. Participants (nintervention = 66; ncontrol = 92) underwent a 3-3.5 hour training and completed measures at pre-, post-, and 4-6 week follow-up. Intention-to-treat (nintervention = 65; ncontrol = 92) and per-protocol (nintervention = 26-38; ncontrol = 40-57) analyses were conducted. Pain training participants demonstrated significantly higher pain knowledge and feasibility-confidence-skill ratings post-follow-up versus control group and significant increases in knowledge from pre-post. Significant gains were maintained from post-follow-up. Results represent a promising step towards enhancing pain-related care for children with IDD.

The importance of feasible outcome evaluations: Developing stakeholder-informed outcomes in a randomized controlled trial for children's respite workers receiving pain training.

Objective: Pain is common for children with intellectual and developmental disabilities. It is critical that caregivers have adequate pain assessment and management knowledge. The Let's Talk About Pain program has shown promise to provide pain-related knowledge and skills to respite workers; however, more systematic evaluation of the program is needed. This study aims to support Let's Talk About Pain's RCT development by using stakeholder input to help determine a feasible approach for collecting behaviorally based outcomes. A secondary aim is to discuss relevant considerations and implications for others in the disability field conducting similar work. Methods/Design: Four employees in children's respite organizations completed telephone interviews lasting approximately fifteen minutes and a questionnaire about feasible data collection approaches. Results: The use of questionnaire and focus group methodology was determined to be the most feasible method to evaluate participants' pain-related approaches in practice. Conclusions: Special consideration should be made when making methodological-related choices during study development to help ensure study feasibility. The iterative approach described in this paper may also be helpful in clinical settings when designing program evaluations to enhance feasibility and suitability; it is particularly important for multifaceted organizations supporting individuals with complex needs including those with intellectual and developmental disabilities.

Challenges in pain assessment and management among individuals with intellectual and developmental disabilities.

INTRODUCTION: Intellectual and developmental disabilities (IDD) include conditions associated with physical, learning, language, behavioural, and/or intellectual impairment. Pain is a common and debilitating secondary condition compromising functional abilities and quality of life. OBJECTIVES: This article addresses scientific and clinical challenges in pain assessment and management in individuals with severe IDD. METHODS: This Clinical Update aligns with the 2019 IASP Global Year Against Pain in the Vulnerable and selectively reviews recurring issues as well as the best available evidence and practice. RESULTS: The past decade of pain research has involved the development of standardized assessment tools appropriate for individuals with severe IDD; however, there is little empirical evidence that pain is being better assessed or managed clinically. There is limited evidence available to inform effective pain management practices; therefore, treatment approaches are largely empiric and highly variable. This is problematic because individuals with IDD are at risk of developing drug-related side effects, and treatment approaches effective for other populations may exacerbate pain in IDD populations. Scientifically, we are especially challenged by biases in self-reported and proxy-reported pain scores, identifying valid outcome measures for treatment trials, being able to adequately power studies due to small sample sizes, and our inability to easily explore the underlying pain mechanisms due to compromised ability to self-report. CONCLUSION: Despite the critical challenges, new developments in research and knowledge translation activities in pain and IDD continue to emerge, and there are ongoing international collaborations.

A Comparison of Hip Spica Casting to Short Leg Casts and Bar after Hip Reconstruction in Cerebral Palsy.

Background Immobilization after hip reconstruction in children with cerebral palsy varies according to surgeon preference. The effect of postoperative immobilization on postoperative pain is unknown. Success in achieving hip stability and complications may also differ depending on the immobilization technique utilized. Questions/purposes Using retrospective data, we aimed to evaluate: (a) what effect does postoperative immobilization with hip spica casting versus short leg casts and bar (SLCaB); have on pain and pain management in children with quadriplegic cerebral palsy undergoing femoral and/or pelvic osteotomy? and (b) Do complications and radiographic outcomes differ between those treated postoperatively with hip spica casting and those in short leg casts? Materials and Methods Children with quadriplegic cerebral palsy (GMFCS IV-V, mean age 7.8 years [range: 3-15 years]) undergoing femoral or pelvic osteotomy between 2012 and 2014 in the treatment of spastic hip subluxation were reviewed. Modes of immobilization were compared, between spica casting (n=15) and SLCaB (n=12). Preoperative, perioperative, and postoperative pain was quantified between groups. In-hospital epidural dosage, morphine equivalent dosages (MED), adjunctive medications, early maintenance of radiographic hip stability, and all complications were noted and analyzed. Results Children were more likely to have spica cast immobilization if they were younger. Postoperative pain scores were similar between groups, with comparable patterns of epidural and MED administered during hospitalization. Spica casts were often flared up during hospitalization, but skin ulcers were uncommon and comparable between the two groups. Within 12 months of surgery, more ipsilateral femur fractures were observed distant to implants in the hip spica group, although the incidence of fractures did not meet statistical thresholds. Conclusion Spica casting and SLCaB after neuromuscular hip reconstruction did not show a difference in hip stability, narcotic pain medication usage or complication profile.

Study protocol for a multi-centre parallel two-group randomized controlled trial evaluating the effectiveness and impact of a pain assessment and management program for respite workers supporting children with disabilities.

Objective: Pain is common and complex for children with intellectual and developmental disabilities (I/DD). Secondary caregivers such as respite workers are lacking important pain-related information which can impact care. Here, we outline a randomized controlled trial (RCT) protocol testing the effectiveness of a pain training for respite workers supporting children with I/DD. Methods/design: Organizations enrolled in the RCT were randomly assigned to receive a 3-3.5 hours pain or family-centered care training. Data were collected immediately before, after, and 4-6 weeks following completion of the training. Outcomes are as follows: pain knowledge (primary), pain assessment and management perceptions (secondary), training evaluations (secondary), and use of pain assessment and management skills (tertiary). Both quantitative and qualitative methodologies are being used including questionnaires, rating scales, a standardized vignette, and focus groups. Conclusions: Results from this trial will be used to further understand the impact of the pain training and inform next steps related to implementation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03421795.

Musculoskeletal Pain Outcomes Pre- and Post Intrathecal Baclofen Pump Implant in Children With Cerebral Palsy: A Prospective Cohort Study.

OBJECTIVE: To characterize musculoskeletal pain intensity, duration, frequency, and interference with activities of daily living in children with cerebral palsy (CP) before and after intrathecal baclofen pump placement. DESIGN: Prospective cohort study. SETTING: Children's tertiary hospital. PARTICIPANTS: Participants were children with CP (N=32; 53% male; mean age, 9.9y; age range, 4-17y). The majority of participants had a CP diagnosis of quadriplegia (76%) and relied on wheeled mobility (91%). INTERVENTIONS: Assessments were completed pre- and post intrathecal baclofen pump implant. MAIN OUTCOME MEASURES: Because of considerable patient heterogeneity, both pain measures (Brief Pain Inventory, Dalhousie Pain Interview) were completed by proxy (parent) report at the time of the procedure and approximately 6 months after intrathecal baclofen (ITB) pump placement. RESULTS: Prior to implant, 31% of participants were living with constant pain, which reduced to 6% post ITB implant (P<.001). Based on Wilcoxon signed rank tests, pain duration significantly decreased post ITB pump implant (P<.01). CONCLUSIONS: This prospective analysis supports the anecdotal and retrospective evidence that musculoskeletal pain decreases in CP following ITB pump implant. The greatest effect appears to be on the duration of pain experience. Pain did not decrease for all individuals, and it would be worth further investigation to better understand the relation between patient characteristics and pain outcomes.

Preliminary Evidence That Resting State Heart Rate Variability Predicts Reactivity to Tactile Stimuli in Rett Syndrome.

Patients with Rett syndrome may manifest altered pain perception/experience and are vulnerable to conditions associated with chronic pain. Pain response is difficult to measure, however, because of severe communicative impairment. There is also documented autonomic dysfunction, including decreased heart rate variability. Given the relation between pain and the autonomic nervous system, we tested the feasibility of using resting heart rate variability to predict nonverbal pain/discomfort behavior during a standardized modified quantitative sensory test in Rett syndrome. All stimulus applications resulted in increased behavioral reactivity compared to baseline, with repeated von Frey significantly greater than all other stimuli. Resting heart rate variability predicted behavioral reactivity to repeated von Frey. These preliminary findings provide feasibility evidence for an integrated autonomic-sensory measurement approach and are consistent at a construct level with preclinical evidence in Rett syndrome. Further work is needed to determine how heart rate variability changes during stimulus application.

Investigating the Feasibility of a Modified Quantitative Sensory Testing Approach to Profile Sensory Function and Predict Pain Outcomes Following Intrathecal Baclofen Implant Surgery in Cerebral Palsy.

OBJECTIVES: Intrathecal baclofen (ITB) pumps used to manage spasticity in children with cerebral palsy (CP) also improve pain outcomes for some but not all patients. The purpose of this clinical feasibility study was to explore whether a quantitative sensory testing approach could a) be modified and used to subgroup individuals into sensory profiles and b) test whether the profiles were related to postimplant pain outcomes (i.e., pain responsive or pain persistent). SUBJECTS: A purposeful clinical sample of nine children with CP (mean age = 12.5 years, male = 56%) and complex communication needs participated. METHODS: A prospective within-subject design was used to measure proxy-reported pain before and after ITB implant. Pain response status was determined by proxy-reported pain intensity change (>50% change in maximum rated intensity). A modified quantitative sensory testing (mQST) procedure was used to assess behavioral responsivity to an array of calibrated sensory (tactile/acute nociceptive) stimuli before surgery. RESULTS: Seven individuals with presurgical pain had mQST differentiated sensory profiles in relation to ITB pain outcomes and relative to the two individuals with no pain. Presurgically, the ITB pain responsive subgroup (N = 3, maximum rated pain intensity decreased >50% after ITB implant) showed increased behavioral reactivity to an acute nociceptive stimulus and cold stimulus, whereas the ITB pain persistent subgroup (N = 4) showed reduced behavioral reactivity to cold and repeated von Frey stimulation relative to the no pain individuals. CONCLUSION: Implications for patient selection criteria and stratification to presurgically identify individuals with CP "at risk" for persistent postprocedure pain are discussed.

Evidence of altered salivary cytokine concentrations in Rett syndrome and associations with clinical severity.

Background: Immune dysregulation may play a role in the development of Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations of the MECP2 gene. Abnormal cytokine concentrations have been documented in the serum of individuals with RTT. Measurement of salivary cytokines has been investigated as a potential alternative approach to measurement in blood and serum, but it is unclear whether salivary cytokine concentrations can provide valid information about systemic immune function in neurodevelopmental disorders. The goal of this study was to evaluate the potential validity of salivary cytokines as biomarkers of immune dysregulation in RTT. Methods: Saliva samples from 16 individuals with RTT (all female; age range 2-40 years) and 16 healthy control females (age range 2-40 years) were analyzed for concentrations of 12 cytokines. Between-group differences in concentrations, and correlations with clinical severity in the RTT group were evaluated. Results: Concentrations of several salivary cytokines (IL-1ß, IL-6, IL-8, IL-10, GM-CSF, TNF-α, and VEGF) were increased in RTT compared to controls. The same cytokines showed significant positive correlations with clinical severity scores. There were no differences in concentrations of IL-2, IL-4, IL-5, IL-12p70, and IFN-γ. Conclusion: The results suggest that salivary cytokines may be a possible indicator of immune dysregulation in RTT. Future research should investigate whether these results can be applied to other neurodevelopmental disorders.

A clinical case-control comparison of epidermal innervation density in Rett syndrome.

INTRODUCTION: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10-15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. METHODS: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12-19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11-17). RESULTS: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. CONCLUSIONS: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.

Psychometric properties of the brief pain inventory modified for proxy report of pain interference in children with cerebral palsy with and without cognitive impairment.

INTRODUCTION: Cerebral palsy (CP) is the most common cause of physical disability in children and is often associated with secondary musculoskeletal pain. Cerebral palsy is a heterogeneous condition with wide variability in motor and cognitive capacities. Although pain scales exist, there remains a need for a validated chronic pain assessment tool with high clinical utility for use across such a heterogeneous patient population with and without cognitive impairment. OBJECTIVES: The purpose of this study was an initial assessment of several psychometric properties of the 12-item modified brief pain inventory (BPI) pain interference subscale as a proxy-report tool in a heterogeneous sample of children with CP with and without cognitive impairment. METHODS: Participants (n = 167; 47% male; mean age = 9.1 years) had pain assessments completed through caregiver report in clinic before spasticity treatment (for a subgroup, the modified BPI was repeated after procedure). To measure concurrent validity, we obtained pain intensity ratings (Numeric Rating Scale of pain) and pain intensity, duration, and frequency scores (Dalhousie Pain Interview). RESULTS: Modified BPI scores were internally consistent (Cronbach α = 0.96) and correlated significantly with Numeric Rating Scale intensity scores (rs = 0.67, P < 0.001), Dalhousie Pain Interview pain intensity (rs = 0.65, P < 0.001), pain frequency (rs = 0.56, P = 0.02), and pain duration scores (rs = 0.42, P = 0.006). Modified BPI scores also significantly decreased after spasticity treatment (pretest [scored 0-10; 3.27 ± 2.84], posttest [2.27 ± 2.68]; t (26) = 2.14, 95% confidence interval [0.04-1.95], P = 0.04). CONCLUSION: Overall, the modified BPI produced scores with strong internal consistency and that had concurrent validity as a proxy-report tool for children with CP.

A Case-Controlled Investigation of Tactile Reactivity in Young Children With and Without Global Developmental Delay.

Assessing tactile function among children with intellectual, motor, and communication impairments remains a clinical challenge. A case control design was used to test whether children with global developmental delays (GDD; n = 20) would be more/less reactive to a modified quantitative sensory test (mQST) compared to controls (n = 20). Reactivity was indexed by blinded behavioral coding across vocal, facial, and gross motor responses during the mQST. On average the children with GDD were significantly more reactive than controls to most tactile sensory modalities including light touch (p = .034), pin prick (p = .008), cool (p = .039), pressure (p = .037), and repeated von Frey (p = .003). The results suggest the mQST approach was feasible and highlights the GDD sample was more reactive than controls to a range of stimuli.

A case-controlled comparison of postoperative analgesic dosing between girls with Rett syndrome and girls with and without developmental disability undergoing spinal fusion surgery.

BACKGROUND: Rett syndrome is associated with severe motor and communicative impairment making optimal postoperative pain management a challenge. There are case reports documenting reduced postoperative analgesic requirement in Rett syndrome. AIM: The goal of this preliminary investigation was to compare postoperative analgesic management among a sample of girls with Rett syndrome compared to girls with and without developmental disability undergoing spinal fusion surgery. METHOD: The medical records of eight girls with Rett syndrome (mean age = 13.2 years, sd = 1.9), eight girls with developmental disability (cerebral palsy; mean age = 13.1 years, sd = 2.0), and eight girls without developmental disability (adolescent idiopathic scoliosis; mean age = 13.4, sd = 1.8) were reviewed. Data related to demographics, medications, and route of drug administration were recorded. RESULTS: Girls with Rett syndrome received significantly fewer morphine equivalent opioids postoperatively (M = 0.26 mg·kg-1 ·day-1 , sd = 0.10) compared to girls with adolescent idiopathic scoliosis (M = 0.47mg·kg-1 ·day-1 , sd = 0.13; 95% CI -0.34 to -0.08; P = 0.001) and girls with CP (M = 0.40 mg·kg-1 per day, sd = 0.14; 95% CI -0.27 to -0.02; P = 0.01). Girls with Rett syndrome received significantly fewer opioid patient-controlled analgesic (PCA) bolus doses (given by proxy; M = 42.63, sd = 17.84) compared to girls with adolescent idiopathic scoliosis (M = 98.25, sd = 52.77; 95% CI -96.42 to -14.83; P = 0.01). There was also some evidence indicating girls with Rett syndrome received fewer bolus doses compared to girls with CP (M = 80.88, sd = 38.93; 95% CI -79.05 to 2.55; P = 0.06). On average, girls with Rett syndrome also received smaller total doses of acetaminophen, diazepam, and hydroxyzine. CONCLUSION: This study highlights possible discrepancies in postoperative pain management specific to girls with Rett syndrome and suggests further investigation is warranted to determine best practice for postoperative analgesic management for this vulnerable patient population.

Pain experience and expression in Rett syndrome: Subjective and objective measurement approaches.

Rett syndrome (RTT) is associated with myriad debilitating health issues and significant motor and communicative impairments. Because of the former there is concern about the possibility of recurrent and chronic pain but because of the latter it remains difficult to determine what pain 'looks like' in RTT. This study investigated pain experience and expression using multiple complementary subjective and objective approaches among a clinical RTT sample. Following informed consent, 18 participants (all female) with RTT (mean age= 12.8 years, SD= 6.32) were characterized in terms of pain experience and interference, typical pain expression, and elicited pain behavior during a passive range of motion-like examination procedure. Parents completed the Dalhousie Pain Interview (DPI; pain type, frequency, duration, intensity), the Brief Pain Inventory (BPI; pain interference), and the Non-Communicating Children's Pain Checklist - Revised (NCCPC-R; typical pain expression). A Pain Examination Procedure (PEP) was conducted and scored using the Pain and Discomfort Scale (PADS). The majority of the sample (89%) were reported to experience pain in the previous week which presented as gastrointestinal (n=8), musculoskeletal (n=5), and seizure related pain (n=5) that was intense (scored 0-10; M= 5.67, SD= 3.09) and long in duration (M= 25.22 hours, SD= 53.52). Numerous pain-expressive behaviors were inventoried (e.g., vocal, facial, mood/interaction changes) when parents reported their child's typical pain behaviors and based on independent direct observation during a reliably coded pain exam. This study provides subjective and objective evidence that individuals with RTT experience recurring and chronic pain for which pain expression appears intact.

Peripheral Innervation in Children With Global Developmental Delay: Biomarker for Risk for Self-Injurious Behavior?

The relation between somatosensory mechanisms and self-injury among children with neurologic impairments associated with developmental delay is not well understood. We evaluated the feasibility of procuring skin biopsies to examine epidermal nerve fiber density and reported self-injury. Following informed parental consent, epidermal skin biopsies were obtained from a distal leg site with no pre-existing skin damage from 11 children with global developmental delay (55% male; mean age = 36.8 months, 17-63 months). Visual microscopic examination and quantitative analyses showed extremely high epidermal nerve fiber density values for some children. Children with reported self-injury (5/11) had significantly (P < .02) greater density values (138.8, standard deviation = 45.5) than children without self-injury (80.5, standard deviation = 17.5). Results from this novel immunohistologic analysis of skin in very young children with neurodevelopmental delays suggest it may be a useful tool to study peripheral innervation as a possible sensory risk factor for self-injury.

A Case-controlled Investigation of Pain Experience and Sensory Function in Neuronal Ceroid Lipofuscinosis.

OBJECTIVES: This case-control study explored pain experience and expression among individuals with neuronal ceroid lipofuscinosis (NCL) through parental report, tactile sensory testing, and infrared thermography (IRT). MATERIALS AND METHODS: Participants with NCL (n=8; M=14.8 y) and their unaffected siblings (n=8; M=23.5 y) were characterized in terms of pain response to a brief tactile sensory test (light touch, Von Frey monofilament). During sensory testing, behavioral expression was measured using the Battens Observational Pain Scale and infrared thermography (IRT) was used to quantify changes in skin/eye temperature. RESULTS: Children with NCL experienced pain frequently and from multiple sources that negatively impacted their lives. Children with NCL were reactive to the sensory testing as indexed by significant increased IRT temperature change (P<0.001). Across combined sensory conditions, individuals with NCL were significantly more reactive (Battens Observational Pain Scale total score) to sensory testing compared with siblings (P<0.05). Similarly, IRT difference scores between sensory conditions revealed a significant increase in temperature for individuals with NCL compared with siblings (P<0.001). DISCUSSION: Ongoing reported pain was a problem for the children with NCL in this sample. Increased pain expression during the repeated Von Frey filament suggests that the pathophysiology of the ongoing pain may be centrally mediated.

Can biomarkers differentiate pain and no pain subgroups of nonverbal children with cerebral palsy? A preliminary investigation based on noninvasive saliva sampling.

OBJECTIVE: Assessing and treating pain in nonverbal children with developmental disabilities are a clinical challenge. Current assessment approaches rely on clinical impression and behavioral rating scales completed by proxy report. Given the growing health relevance of the salivary metabolome, we undertook a translational-oriented feasibility study using proton nuclear magnetic resonance (NMR) spectroscopy and neuropeptide/cytokine/hormone detection to compare a set of salivary biomarkers relevant to nociception. DESIGN: Within-group observational design. SETTING: Tertiary pediatric rehabilitation hospital. SUBJECTS: Ten nonverbal pediatric patients with cerebral palsy with and without pain. METHODS: Unstimulated (passively collected) saliva was collected using oral swabs followed by perchloric acid extraction and analyzed on a Bruker Avance 700 MHz NMR spectrometer. We also measured salivary levels of several cytokines, chemokines, hormones, and neuropeptides. RESULTS: Partial least squares discriminant analysis showed separation of those children with/without pain for a number of different biomarkers. The majority of the salivary metabolite, neuropeptide, cytokine, and hormone levels were higher in children with pain vs no pain. CONCLUSIONS: The ease of collection and noninvasive manner in which the samples were collected and analyzed support the possibility of the regular predictive use of this novel biomarker-monitoring method in clinical practice.