Alyssa Lebel

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Patterns of spread in complex regional pain syndrome, type I (reflex sympathetic dystrophy)

&NA; There are reports that complex regional pain syndrome, type I (reflex sympathetic dystrophy; CRPS‐I/RSD) can spread from the initial site of presentation, but there are no detailed descriptions of the pattern(s) of such spread. We describe a retrospective analysis of 27 CRPS‐I/RSD patients who experienced a significant spread of pain. Three patterns of spread were identified. ‘Contiguous spread (CS)’ was noted in all 27 cases and was characterized by a gradual and significant enlargement of the area affected initially. ‘Independent spread (IS)’ was noted in 19 patients (70%) and was characterized by the appearance of CRPS‐I in a location that was distant and non‐contiguous with the initial site (e.g. CRPS‐I/RSD appearing first in a foot, then in a hand). ‘Mirror‐image spread (MS)’ was noted in four patients (15%) and was characterized by the appearance of symptoms on the opposite side in an area that closely matched in size and location the site of initial presentation. Only five patients (19%) suffered from CS alone; 70% also had IS, 11% also had MS, and one patient had all three kinds of spread. Our results suggest that CRPS‐I/RSD spread may not be a unitary phenomenon. In some it may be due to a local spread of pathology (CS); in others it may be a consequence of a generalized susceptibility (IS). In the MS case, spread may be due to abnormal neural functioning spreading via commissural pathways. Alternatively, we discuss the possibility that all three kinds of spread may be due to aberrant CNS regulation of neurogenic inflammation.

The Young Brain and Concussion: Imaging as a Biomarker for Diagnosis and Prognosis

Concussion (mild traumatic brain injury (mTBI)) is a significant pediatric public health concern. Despite increased awareness, a comprehensive understanding of the acute and chronic effects of concussion on central nervous system structure and function remains incomplete. Here we review the definition, epidemiology, and sequelae of concussion within the developing brain, during childhood and adolescence, with current data derived from studies of pathophysiology and neuroimaging. These findings may contribute to a better understanding of the neurological consequences of traumatic brain injuries, which in turn, may lead to the development of brain biomarkers to improve identification, management and prognosis of pediatric patients suffering from concussion.

Neuropathic pain in children: Special considerations.

Neuropathic pain is relatively uncommon in children. Although some syndromes closely resemble those found in adults, the incidence and course of the condition can vary substantially in children, depending on developmental status and contextual factors. There are some neuropathic pain syndromes that are rare and relatively unique to the pediatric population. This article discusses the array of neuropathic pain conditions in children and available treatment strategies. Data are limited by small numbers and few randomized controlled trials. Research and clinical implications are discussed.

Pediatric Analgesic Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

Mapping pain activation and connectivity of the human habenula.

The habenula, located in the posterior thalamus, is implicated in a wide array of functions. Animal anatomical studies have indicated that the structure receives inputs from a number of brain regions (e.g., frontal areas, hypothalamic, basal ganglia) and sends efferent connections predominantly to the brain stem (e.g., periaqueductal gray, raphe, interpeduncular nucleus). The role of the habenula in pain and its anatomical connectivity are well-documented in animals but not in humans. In this study, for the first time, we show how high-field magnetic resonance imaging can be used to detect habenula activation to noxious heat. Functional maps revealed significant, localized, and bilateral habenula responses. During pain processing, functional connectivity analysis demonstrated significant functional correlations between the habenula and the periaqueductal gray and putamen. Probabilistic tractography was used to assess connectivity of afferent (e.g., putamen) and efferent (e.g., periaqueductal gray) pathways previously reported in animals. We believe that this study is the first report of habenula activation by experimental pain in humans. Since the habenula connects forebrain structures with brain stem structures, we suggest that the findings have important implications for understanding sensory and emotional processing in the brain during both acute and chronic pain.

The responsive amygdala: Treatment-induced alterations in functional connectivity in pediatric complex regional pain syndrome

Summary Amygdala connectivity is altered in children with chronic neuropathic pain and is responsive to intensive interdisciplinary treatment, with an associated decrease in pain‐related fear. ABSTRACT The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear, and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age‐sex matched control subjects before and after intensive physical‐biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared with control subjects, with differences predominantly in the left amygdala in the pretreated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy control subjects from time 1 to time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain‐related fear scores; and (4) decreases in pain‐related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity after an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response.

Intrinsic brain networks normalize with treatment in pediatric complex regional pain syndrome

Pediatric complex regional pain syndrome (P-CRPS) offers a unique model of chronic neuropathic pain as it either resolves spontaneously or through therapeutic interventions in most patients. Here we evaluated brain changes in well-characterized children and adolescents with P-CRPS by measuring resting state networks before and following a brief (median = 3 weeks) but intensive physical and psychological treatment program, and compared them to matched healthy controls. Differences in intrinsic brain networks were observed in P-CRPS compared to controls before treatment (disease state) with the most prominent differences in the fronto-parietal, salience, default mode, central executive, and sensorimotor networks. Following treatment, behavioral measures demonstrated a reduction of symptoms and improvement of physical state (pain levels and motor functioning). Correlation of network connectivities with spontaneous pain measures pre- and post-treatment indicated concomitant reductions in connectivity in salience, central executive, default mode and sensorimotor networks (treatment effects). These results suggest a rapid alteration in global brain networks with treatment and provide a venue to assess brain changes in CRPS pre- and post-treatment, and to evaluate therapeutic effects.

Transient and persistent pain induced connectivity alterations in pediatric complex regional pain syndrome.

Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS.

Relations Between Pain Characteristics, Child and Parent Variables, and School Functioning in Adolescents With Chronic Headache: A Comparison of Tension-Type Headache and Migraine

OBJECTIVE To assess for differences in headache characteristics and psychosocial factors based on headache diagnosis, and to evaluate whether headache diagnosis moderates relations between psychosocial factors and school difficulties. METHODS Retrospective chart review was conducted with 262 adolescents with chronic tension-type headache (TTH; N = 153) and migraine evaluated at a pediatric headache clinic. Adolescents completed measures of anxiety, depression, and pain coping. Parents completed a measure of parental protective behavior and school functioning. RESULTS Adolescents with TTH reported greater depression symptoms, and their parents endorsed greater school difficulties, whereas parents of adolescents with migraine reported more protective parenting. Protective parenting was positively associated with school difficulties in both groups, but the relation was significantly stronger in adolescents with TTH. Headache duration and depression symptoms were significant predictors of school functioning in both groups. CONCLUSIONS Headache duration and depression may impact school functioning independent of headache diagnosis. Protective parenting, in particular, seems to be linked to school-related disability in adolescents with TTH, and this link may be important to consider in assessment and treatment.