Gabapentin Successfully Manages Chronic Unexplained ...

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

Julie M. Hauer, Beverly S. Wical and Lawrence Charnas
Pediatrics 2007;119;e519-e522
DOI: 10.1542/peds.2006-1609

The online version of this article, along with updated information and services, is
located on the World Wide Web at:

http://www.pediatrics.org/cgi/content/full/119/2/e519

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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, Lawrence Charnas, MD, PhDc

cDivision of Pediatric Clinical Neuroscience, aDepartment of Pediatrics, University of Minnesota, Minneapolis, Minnesota; bGillette Children’s Specialty Healthcare, St Paul,
Minnesota

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

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 hyper-
algesia 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.

NONVERBAL, SEVERELY NEUROLOGICALLY impaired therapy and Nissen fundoplication. All patients had gas-
children with recurrent pain and irritability pose a trointestinal motility and/or sensory abnormalities. Of
significant challenge in defining the etiology and identi- the 14 patients, 12 showed a low gastric-volume thresh-
fying interventions that improve symptoms. Common old for retching. Five patients showed no motility disor-
recognized pain sources in these children include gastro- ders, but reduced gastric threshold for retching ex-
esophageal reflux (GER), constipation, feeding difficul- plained their symptoms. Seven patients demonstrated
ties from delayed gut motility, positioning, spasticity, hip both motility disorders and decreased gastric-volume ca-
pain, and dental pain. A pain source may not be identi- pacity. Tricyclic antidepressants and gabapentin success-
fied or, if identified, not fully explain the irritability. One fully managed the symptoms of visceral hyperalgesia.
commonly held belief is that an abnormal brain may be
the explanation for irritability in some children with Neurologically impaired children with chronic, unex-
neurologic impairment. In the differential diagnosis of plained irritability commonly have feeding intolerance
“irritability/excessive crying,” “neurologic impairment” despite management of motility disorders. We observed
is included with the statement “children who are neu- that irritability in our patients often correlated with feed-
rologically impaired, for various reasons, may be exces- ing, defecation, and flatus. We hypothesized that visceral
sively irritable.”1 Parents commonly identify the gastro- hyperalgesia may manifest as either feeding intolerance
intestinal tract as a source of pain in neurologically or recurrent irritability and that medical management
impaired children.2 directed toward the neurosensory cause of symptoms
might improve the irritability. We used this to explore
Visceral hyperalgesia, an increased sensitivity to vis- novel approaches to management of recurrent pain and
ceral stimulation with resulting discomfort or pain,
seems to be the mechanism of symptoms for children Key Words: irritability, pain, visceral hyperalgesia, gabapentin, neurological
with functional abdominal pain.3 Visceral hypersensitiv- impairment
ity caused by gastrointestinal sensory input with result- Abbreviation: GER, gastroesophageal reflux
ing pain, irritability, or feeding intolerance seemed to be
a viable explanation for neurologically impaired children www.pediatrics.org/cgi/doi/10.1542/peds.2006-1609
as well. Zangen et al4 identified visceral hyperalgesia as a
source of feeding difficulty in 12 of 14 neurologically doi:10.1542/peds.2006-1609
impaired children with refractory, persistent food refusal
and retching and vomiting despite maximal medical Accepted for publication 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: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics

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irritability. In this report, we describe the successful Parents requested discontinuation of gabapentin for 1
management of severe, unexplained, and disruptive ir- child despite excellent symptom control because of nys-
ritability in 9 patients identified in a retrospective chart tagmus. Symptoms returned within 1 week after discon-
review. tinuation of gabapentin and persisted for several
months. This child was then treated with amitriptyline,
CASE SERIES as previously reported,4 with elimination of symptoms
After institutional review board approval, we identified for Ͼ14 months. The parents of another child requested
the medical charts of children we had treated empirically gabapentin taper and discontinuation after 2 years of
with gabapentin for recurrent irritability that was dis- symptom control. Symptoms returned after removal of
ruptive to daily life. Episodes were variable in duration gabapentin and then resolved with reinitiation of gaba-
and frequency, but all children experienced recurrent, pentin therapy. No other complications of gabapentin
often daily crying episodes that lasted at least 1 hour. therapy were noted. Sleepiness, if noted, was transient
Gabapentin was initiated when no etiology for irritabil- and not considered significant by parents. The patients
ity had been identified or if management for the identi- remained symptom free on gabapentin for 3 months to 3
fied sources of irritability was not successful in alleviat- years (mean: 11.6 months).
ing symptoms. Common signs reported by parents
included crying, arching, disrupted sleep, and feeding DISCUSSION
intolerance, with descriptors including irritability, pain, Children with neurologic impairment experience pain
and agitation. more frequently than the general pediatric population.
In a large community-based survey of nonneurologically
RESULTS impaired Dutch children aged 0 to 18 years, 54% expe-
Nine individuals, 4 males and 5 females, aged 9 months rienced pain within the past 3 months, 25% reported
to 22 years, were identified. All were nonverbal, nonam- chronic pain (defined as recurrent or continuous pain
bulatory with severe global neurologic impairment. Five for more than 3 months), and 12% indicated a fre-
children had identified etiologies for neurologic impair- quency of at least once a week.6 In marked contrast,
ment: hypoxic ischemic encephalopathy (3), cryptogenic caregivers of children aged 3 to 18 years with severe
infantile spasms (1), and presumed fat emboli syndrome cognitive impairment reported pain episodes occurring
with bilateral middle cerebral artery infarct (1). No eti- weekly, on average, with 44% of children experiencing
ology was identified in 4 children. Six were fed predom- pain each week over a 4-week interval. Pain frequency
inantly or exclusively by gastrostomy feeding tube, and was higher in the most impaired group of children.2
a seventh was scheduled for gastrostomy feeding-tube Caregivers of children with moderate-to-severe cerebral
placement at the time that gabapentin was initiated. palsy reported over a 4-week interval that 26% experi-
enced pain or discomfort once or twice, 19% a few
GER was evaluated by an upper gastrointestinal series times, 10% fairly often, 2.5% very often, and 8% every/
for all patients, with additional gastrointestinal studies almost every day.7 In a study of nonverbal cognitively
including pH probe (6), gastric emptying (6), upper en- impaired children, caregivers reported that 73.5% expe-
doscopy (5), and colonoscopy (1). Documented abnor- rienced pain on at least 1 day over a 2-week time period,
malities were infrequent and included mild chronic in- 62% experienced Ն5 separate days of pain, and 23.5%
flammation at distal esophagus by biopsy only (normal experienced pain almost daily.8
visualization with upper endoscopy) in 1 patient. Mild
gastritis and nonspecific colonic cryptitis were identified Identifying a source of pain in the nonverbal neuro-
in another patient, and treatment with prednisone/sul- logically impaired child poses a unique and significant
fasalazine correlated with worse symptoms. All children challenge. Breau et al9 surveyed caregivers for sources of
were treated empirically with a proton-pump inhibitor pain in children with severe cognitive impairments. Pa-
and showed no improvement in symptoms. Eight indi- tient characteristics (age, gender, tube feeding, visual
viduals were on successful management for constipa- and motor impairments, and medication use) were cor-
tion. related with pain sources (accidental, musculoskeletal,
infection, gastrointestinal, or “common childhood”
Parents/caregivers reported marked improvement in sources). Their models were more specific than sensitive
all individuals after gabapentin dose titration. The titra- and seemed more useful at eliminating pain sources.9
tion schedule was flexible but typically began with 5 We are not aware of any prospective study that has
mg/kg per dose at bedtime and increased every 3 to 7 systematically evaluated chronic irritability in nonverbal
days, with the final dose ranging from 15 to 35 mg/kg neurologically impaired children.
per day divided 3 or 4 times a day.5 Commonly noted
improvements included decreased irritability, decreased Our patients’ irritability was temporally related to
crying, improved comfort, improved feeding tolerance, bowel function, with persistence of symptoms despite
better sleep initiation and maintenance, and increased successful management of gastrointestinal disorders.
responsiveness. Breau et al2,9 reported that gastrointestinal pain was the

e520 HAUER et al
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second most frequently identified source in 94 children tin therapy, titrated to standard doses, produced marked
with severe cognitive impairment, with 22% of care- symptom improvement in a small group of neurologi-
givers indicating such pain. Approximately half with cally impaired children with significant unexplained
gastrointestinal pain experienced episodes classified as pain and irritability. Gabapentin is used for a number of
“digestive” resulting from “gas” or “gastrointestinal” prob- pain syndromes, including diabetic neuropathy, trigem-
lems without identification of cause/location, and a sim- inal neuralgia, and other neuropathic pain syndromes
ilar number experienced pain classified as “bowels” but and is thought to act by downregulation of the ␣2␦
not caused by constipation. Similar to our observations, subunit of voltage-gated calcium channels.20–22 Gabapen-
pain of unknown cause was the most intense, followed tin has been shown to inhibit central sensitization in a
by pain attributed to the bowels or the gastrointestinal human model of hyperalgesia23 and reduced rectal sen-
tract and digestive pain. Houlihan et al7 reported signif- sory thresholds through decreased rectal sensitivity to
icantly higher rates of pain in children with a gastros- distention and enhanced rectal compliance in diarrhea-
tomy tube and those taking medications for feeding, predominant irritable bowel syndrome.24
GER, or gastrointestinal motility. Higher rates of pain
despite management of motility and reflux suggest vis- Our study has several limitations. It is a retrospective
ceral hyperalgesia as a missing component of manage- study with a small sample size and lacks a standardized
ment, as identified in patients by Zangen et al.4 medical evaluation of potential pain sources for each
patient, standardized evaluation to demonstrate visceral
Visceral hyperalgesia or hypersensitivity, an alter- hyperalgesia as the cause of symptoms and response to
ation in the response to bowel sensory input, is a viable therapy in each patient, and standardized assessment to
hypothesis for symptoms in our population. The devel- score irritability. These will need to be addressed in a
opment of visceral hypersensitivity seems to be a multi- prospective study in a new patient population. Finally,
step, heterogeneous process that is incompletely under- we chose gabapentin over tricyclic antidepressants or
stood. Injury or inflammation in the viscera10,11 is other medications because of its safety profile, ease of
followed by a nociceptive nervous system response,12 use, and lack of significant drug-drug interactions, al-
with a cascade of chemical mediators,13 spinal cord hy- though other agents could have been used.4,22,25
persensitization, and cortical responsiveness to visceral
sensation.14 CONCLUSIONS
Recurrent irritability and/or pain in neurologically im-
In animal models, persistent stimulation of afferent paired children must be assessed thoroughly. When no
fibers reshapes the peripheral nociceptor and central etiology can be identified or if symptoms persist despite
neuron responses with hyperalgesia and altered motili- management of the identified etiologies, visceral hyper-
ty.14 Gastrointestinal tract inflammation can cause local algesia should be considered as a source of symptoms
hyperexcitability of nociceptor neurons, which persist and a trial of gabapentin or other centrally acting agents
after removal of the inflammatory stimulus.15 In new- considered.25
born but not adult rats, colonic distention produced
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e522 HAUER et al
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Gabapentin Successfully Manages Chronic Unexplained Irritability in Children
With Severe Neurologic Impairment

Julie M. Hauer, Beverly S. Wical and Lawrence Charnas
Pediatrics 2007;119;e519-e522
DOI: 10.1542/peds.2006-1609

Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/119/2/e519
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