Published online February 1, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. e519-e522 (doi:10.1542/peds.2006-1609)
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EXPERIENCE & REASON

Gabapentin Successfully Manages Chronic Unexplained Irritability in Children With Severe Neurologic Impairment

Julie M. Hauer, MDa,b, Beverly S. Wical, MDb,c and Lawrence Charnas, MD, PhDc

c Division of Pediatric Clinical Neuroscience
a Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
b Gillette Children's Specialty Healthcare, St Paul, Minnesota

ABSTRACT

Neurologically impaired children have an increased frequency of recurrent pain and irritability that persist in some despite comprehensive evaluation and management of possible pain sources. We hypothesized that visceral hyperalgesia was a source of chronic unexplained irritability and report the outcome of gabapentin treatment in 9 severely neurologically impaired children. Caregivers reported marked improvement after treatment ranging from 3 months to 3 years. Nystagmus in 1 child was the only noted adverse effect. Visceral hyperalgesia may be a source of unexplained irritability in the neurologically impaired child. Symptoms may improve with gabapentin treatment.

Key Words: irritability • pain • visceral hyperalgesia • gabapentin • neurological impairment

Abbreviations: GER, gastroesophageal reflux

Nonverbal, severely neurologically impaired children with recurrent pain and irritability pose a significant challenge in defining the etiology and identifying interventions that improve symptoms. Common recognized pain sources in these children include gastroesophageal reflux (GER), constipation, feeding difficulties from delayed gut motility, positioning, spasticity, hip pain, and dental pain. A pain source may not be identified or, if identified, not fully explain the irritability. One commonly held belief is that an abnormal brain may be the explanation for irritability in some children with neurologic impairment. In the differential diagnosis of "irritability/excessive crying," "neurologic impairment" is included with the statement "children who are neurologically impaired, for various reasons, may be excessively irritable."1 Parents commonly identify the gastrointestinal tract as a source of pain in neurologically impaired children.2

Visceral hyperalgesia, an increased sensitivity to visceral stimulation with resulting discomfort or pain, seems to be the mechanism of symptoms for children with functional abdominal pain.3 Visceral hypersensitivity caused by gastrointestinal sensory input with resulting pain, irritability, or feeding intolerance seemed to be a viable explanation for neurologically impaired children as well. Zangen et al4 identified visceral hyperalgesia as a source of feeding difficulty in 12 of 14 neurologically impaired children with refractory, persistent food refusal and retching and vomiting despite maximal medical therapy and Nissen fundoplication. All patients had gastrointestinal motility and/or sensory abnormalities. Of the 14 patients, 12 showed a low gastric-volume threshold for retching. Five patients showed no motility disorders, but reduced gastric threshold for retching explained their symptoms. Seven patients demonstrated both motility disorders and decreased gastric-volume capacity. Tricyclic antidepressants and gabapentin successfully managed the symptoms of visceral hyperalgesia.

Neurologically impaired children with chronic, unexplained irritability commonly have feeding intolerance despite management of motility disorders. We observed that irritability in our patients often correlated with feeding, defecation, and flatus. We hypothesized that visceral hyperalgesia may manifest as either feeding intolerance or recurrent irritability and that medical management directed toward the neurosensory cause of symptoms might improve the irritability. We used this to explore novel approaches to management of recurrent pain and irritability. In this report, we describe the successful management of severe, unexplained, and disruptive irritability in 9 patients identified in a retrospective chart review.

CASE SERIES

After institutional review board approval, we identified the medical charts of children we had treated empirically with gabapentin for recurrent irritability that was disruptive to daily life. Episodes were variable in duration and frequency, but all children experienced recurrent, often daily crying episodes that lasted at least 1 hour. Gabapentin was initiated when no etiology for irritability had been identified or if management for the identified sources of irritability was not successful in alleviating symptoms. Common signs reported by parents included crying, arching, disrupted sleep, and feeding intolerance, with descriptors including irritability, pain, and agitation.

RESULTS

Nine individuals, 4 males and 5 females, aged 9 months to 22 years, were identified. All were nonverbal, nonambulatory with severe global neurologic impairment. Five children had identified etiologies for neurologic impairment: hypoxic ischemic encephalopathy (3), cryptogenic infantile spasms (1), and presumed fat emboli syndrome with bilateral middle cerebral artery infarct (1). No etiology was identified in 4 children. Six were fed predominantly or exclusively by gastrostomy feeding tube, and a seventh was scheduled for gastrostomy feeding-tube placement at the time that gabapentin was initiated.

GER was evaluated by an upper gastrointestinal series for all patients, with additional gastrointestinal studies including pH probe (6), gastric emptying (6), upper endoscopy (5), and colonoscopy (1). Documented abnormalities were infrequent and included mild chronic inflammation at distal esophagus by biopsy only (normal visualization with upper endoscopy) in 1 patient. Mild gastritis and nonspecific colonic cryptitis were identified in another patient, and treatment with prednisone/sulfasalazine correlated with worse symptoms. All children were treated empirically with a proton-pump inhibitor and showed no improvement in symptoms. Eight individuals were on successful management for constipation.

Parents/caregivers reported marked improvement in all individuals after gabapentin dose titration. The titration schedule was flexible but typically began with 5 mg/kg per dose at bedtime and increased every 3 to 7 days, with the final dose ranging from 15 to 35 mg/kg per day divided 3 or 4 times a day.5 Commonly noted improvements included decreased irritability, decreased crying, improved comfort, improved feeding tolerance, better sleep initiation and maintenance, and increased responsiveness.

Parents requested discontinuation of gabapentin for 1 child despite excellent symptom control because of nystagmus. Symptoms returned within 1 week after discontinuation of gabapentin and persisted for several months. This child was then treated with amitriptyline, as previously reported,4 with elimination of symptoms for >14 months. The parents of another child requested gabapentin taper and discontinuation after 2 years of symptom control. Symptoms returned after removal of gabapentin and then resolved with reinitiation of gabapentin therapy. No other complications of gabapentin therapy were noted. Sleepiness, if noted, was transient and not considered significant by parents. The patients remained symptom free on gabapentin for 3 months to 3 years (mean: 11.6 months).

DISCUSSION

Children with neurologic impairment experience pain more frequently than the general pediatric population. In a large community-based survey of nonneurologically impaired Dutch children aged 0 to 18 years, 54% experienced pain within the past 3 months, 25% reported chronic pain (defined as recurrent or continuous pain for more than 3 months), and 12% indicated a frequency of at least once a week.6 In marked contrast, caregivers of children aged 3 to 18 years with severe cognitive impairment reported pain episodes occurring weekly, on average, with 44% of children experiencing pain each week over a 4-week interval. Pain frequency was higher in the most impaired group of children.2 Caregivers of children with moderate-to-severe cerebral palsy reported over a 4-week interval that 26% experienced pain or discomfort once or twice, 19% a few times, 10% fairly often, 2.5% very often, and 8% every/almost every day.7 In a study of nonverbal cognitively impaired children, caregivers reported that 73.5% experienced pain on at least 1 day over a 2-week time period, 62% experienced ≥5 separate days of pain, and 23.5% experienced pain almost daily.8

Identifying a source of pain in the nonverbal neurologically impaired child poses a unique and significant challenge. Breau et al9 surveyed caregivers for sources of pain in children with severe cognitive impairments. Patient characteristics (age, gender, tube feeding, visual and motor impairments, and medication use) were correlated with pain sources (accidental, musculoskeletal, infection, gastrointestinal, or "common childhood" sources). Their models were more specific than sensitive and seemed more useful at eliminating pain sources.9 We are not aware of any prospective study that has systematically evaluated chronic irritability in nonverbal neurologically impaired children.

Our patients' irritability was temporally related to bowel function, with persistence of symptoms despite successful management of gastrointestinal disorders. Breau et al2,9 reported that gastrointestinal pain was the second most frequently identified source in 94 children with severe cognitive impairment, with 22% of caregivers indicating such pain. Approximately half with gastrointestinal pain experienced episodes classified as "digestive" resulting from "gas" or "gastrointestinal" problems without identification of cause/location, and a similar number experienced pain classified as "bowels" but not caused by constipation. Similar to our observations, pain of unknown cause was the most intense, followed by pain attributed to the bowels or the gastrointestinal tract and digestive pain. Houlihan et al7 reported significantly higher rates of pain in children with a gastrostomy tube and those taking medications for feeding, GER, or gastrointestinal motility. Higher rates of pain despite management of motility and reflux suggest visceral hyperalgesia as a missing component of management, as identified in patients by Zangen et al.4

Visceral hyperalgesia or hypersensitivity, an alteration in the response to bowel sensory input, is a viable hypothesis for symptoms in our population. The development of visceral hypersensitivity seems to be a multistep, heterogeneous process that is incompletely understood. Injury or inflammation in the viscera10,11 is followed by a nociceptive nervous system response,12 with a cascade of chemical mediators,13 spinal cord hypersensitization, and cortical responsiveness to visceral sensation.14

In animal models, persistent stimulation of afferent fibers reshapes the peripheral nociceptor and central neuron responses with hyperalgesia and altered motility.14 Gastrointestinal tract inflammation can cause local hyperexcitability of nociceptor neurons, which persist after removal of the inflammatory stimulus.15 In newborn but not adult rats, colonic distention produced chronic visceral hypersensitivity, with characteristics of allodynia, hyperalgesia, and central neuronal sensitization without peripheral pathology.16 Localized gastric ulceration in rats enhanced development of visceral hyperalgesia and altered gastric motility.17 These experimental models are strikingly similar to the repeated painful gastrointestinal experiences during infancy that are suspected to contribute to sensitization of visceral afferent pathways.4 Children with neurologic impairment have an increased frequency of sensitizing gastrointestinal experiences, including GER, constipation, gastrostomy-tube placement, and fundoplication. Visceral hyperalgesia is likely a result of this sensitization, not of the underlying neurologic impairment. In children with developmental disabilities, 56% were identified as having GER, as documented by 24-hour pH monitoring, with 70% of those children having histologically confirmed esophagitis.18 In children with cerebral palsy, 74% were identified to have chronic constipation, 71% to have abnormal pH monitoring and/or esophagitis, and 32% to have abdominal pain.19

Our retrospective series demonstrated that gabapentin therapy, titrated to standard doses, produced marked symptom improvement in a small group of neurologically impaired children with significant unexplained pain and irritability. Gabapentin is used for a number of pain syndromes, including diabetic neuropathy, trigeminal neuralgia, and other neuropathic pain syndromes and is thought to act by downregulation of the {alpha}2{delta} subunit of voltage-gated calcium channels.20–22 Gabapentin has been shown to inhibit central sensitization in a human model of hyperalgesia23 and reduced rectal sensory thresholds through decreased rectal sensitivity to distention and enhanced rectal compliance in diarrhea-predominant irritable bowel syndrome.24

Our study has several limitations. It is a retrospective study with a small sample size and lacks a standardized medical evaluation of potential pain sources for each patient, standardized evaluation to demonstrate visceral hyperalgesia as the cause of symptoms and response to therapy in each patient, and standardized assessment to score irritability. These will need to be addressed in a prospective study in a new patient population. Finally, we chose gabapentin over tricyclic antidepressants or other medications because of its safety profile, ease of use, and lack of significant drug-drug interactions, although other agents could have been used.4,22,25

CONCLUSIONS

Recurrent irritability and/or pain in neurologically impaired children must be assessed thoroughly. When no etiology can be identified or if symptoms persist despite management of the identified etiologies, visceral hyperalgesia should be considered as a source of symptoms and a trial of gabapentin or other centrally acting agents considered.25

FOOTNOTES

Accepted Sep 13, 2006.

Address correspondence to Julie M. Hauer, MD, University of Minnesota, Department of Pediatrics, MMC 391, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: hauer006{at}umn.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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