Pain is a frequent and significant problem for many children with severe neurological impairment (NI).1–4 Unfortunately, these children remain vulnerable to undertreatment of pain, especially given the challenge of identifying the presence and source of pain, as well as the persistence of symptoms in some despite treatment of identified causes. This article outlines assessment and management strategies, focusing on children with NI who are unable to articulate their pain, given the inherent challenges in this group. This information is relevant to a range of static and progressive disorders, in which the condition may be indicated by a developmental level (cerebral palsy, severe cognitive impairment), the result of an insult to the central nervous system (hypoxic ischemic encephalopathy), or as a result of a medical disorder with associated impairment of the central nervous system (genetic disorder, congenital anomaly, structural brain malformation, metabolic disorder).
Identifying Presence and Severity of Pain
The options for assessing presence and severity of pain in those unable to give self-report include observational assessment of behaviors associated with pain and assessment of physiological markers. Specific distress behaviors associated with pain include the following:
- vocalizations (crying, moaning);
- facial expression (grimacing);
- interactivity (withdrawn);
- eating and sleeping;
- protective actions;
- tone and posture (arching, stiffening); and
- physiological responses.
Observational pain assessment tools assist with identifying presence of pain and monitoring for improvement in pain when an intervention is introduced. Tools that have been validated to differentiate pain from non-pain events in children with severe NI are indicated in Table 1 (see page 200).4,6,7,10,11 These pain assessment tools cannot replace the input of a parent or caregiver involved with the child on a daily basis. Behavioral measurement must be assessed in the context of sources of distress, such as hunger, along with knowledge of the child’s baseline, and experience with how a child responds to different sources of discomfort. This is important because specific behaviors indicating pain are different from one child to another, although the listed classes of distress behaviors are common to almost all children. These assessment tools are best used to supplement caregiver input and to allow monitoring of severity before interventions to treat pain are administered.
Table 1. Pain Assessment Tools for Children with NI Who Cannot Self-Report
Studies of physiological measures, such as vital signs, diaphoresis, and hormone levels, such as cortisol, are best correlated with acute pain associated with invasive and surgical procedures. None has proved to be reliable, sensitive, or specific for chronic pain.7 In addition, such measures may be altered by autonomic dysfunction in children with NI. Physiological measures may have a role in monitoring pain when used to supplement more reliable information.
Searching for Causes of Pain and Discomfort
Figure 1 (see page 200) contains a schematic of the types of pain and distress in children with NI, including nocioceptive pain, neuropathic pain, visceral hyperalgesia, and central pain.
Figure 1. Schematic — Sources of Discomfort and Distress in Children with NI.
Common recognized pain sources in children with NI include acute sources, such as fracture, urinary tract infection, or pancreatitis,12 and chronic sources, such as gastroesophageal reflex disorder (GERD), constipation, feeding difficulties from delayed gut motility, positioning, spasticity, hip pain, or dental pain. Table 2 (see page 202) outlines etiologies of acute and chronic pain to consider.
Table 2. Sources of Pain/irritability in Children with NI
Neuropathic pain conditions are those associated with injury, dysfunction, or altered excitability of portions of the peripheral or central nervous system. Features of neuropathic pain conditions may include motor findings, such as spasms, dystonia, and tremor, and autonomic disturbances, such as erythema, mottling, and increased sweating.13
There are many reasons to consider neuropathic pain in children with NI. Experience shows that a nocioceptive pain source may not be identified, or pain may continue despite treatment of an identified source. “Screaming of unknown origin,” was used to describe children with neurologic disorders, severe developmental delay, neurodegeneration, or severe motor impairments with persistent agitation, distress, or screaming, acknowledging that evaluation often does not identify a specific nociceptive cause.14
Neuropathic pain may occur in children with NI after repeated injury or surgery.15 Persistent pain is reported in 10–50% of adults after common surgeries, becoming severe in 2% to 10% of these patients, with iatrogenic neuropathic pain probably the most important cause of long-term postsurgical pain.16 Neuropathic pain was identified in six children with cerebral palsy after multilevel orthopedic surgery.17 Onset of symptoms ranged from 5 to 9 days. Interventions included gabapentin, amitriptyline, and transcutaneous electrical nerve stimulation, with improvement in symptoms over variable periods of time. Hunt et al7 identified that a significant portion in the high pain group had a history of surgical interventions.
Visceral hyperalgesia is an altered response to visceral stimulation resulting in a decreased activation threshold for pain in response to a stimulus, such as intraluminal pressure.18 It is noteworthy that the gastrointestinal tract is commonly identified by parents as a source of pain in children with NI.1,3,4,19 Breau et al1 identified “gastrointestinal” as the most frequent source of all episodes of pain in children with severe cognitive impairment. Pain of unknown cause was the most intense, with a mean severity score of 8.7 on a 0 to 10 numerical scale (0 = no pain, 10 = worst pain), followed by pain attributed to the bowels, gastrointestinal tract and digestive pain, with a mean score of 7.5. Houlihan et al3 reported significantly higher rates of pain in children with a gastrostomy tube and those taking medications for feeding, GERD, or GI motility. Although not described in detail, children in these studies had continued pain despite receiving treatment for common GI sources such as GERD and constipation.
In a case series of 14 medically fragile children with continued retching and vomiting despite medical treatment and Nissen fundoplication, visceral hyperalgesia was identified in 12 children as a source of symptoms.20 Tricyclic antidepressants (TCAs), gabapentin, cyproheptadine, and dicyclomine were used in various combinations depending on evaluation results, with 11 children reported as “better” or “much better” and a decrease in the mean number of retching episodes per day from 14 to 1.5. A case series of nine neurologically impaired children with symptoms indicating pain, feeding intolerance, and disrupted sleep identified significant improvement after use of gabapentin.21 This suggests that pain associated with GI symptoms may improve with medical management directed toward visceral hyperalgesia when symptoms persist despite management of the more commonly recognized problems.
Information that may suggest visceral hyperalgesia in children with NI includes:
- pain and feeding intolerance associated with feedings by gastrostomy tube (G-tube), suggesting decreased gastric volume threshold;
- pain associated with intestinal gas and feedings by jejunostomy tube (J-tube), suggesting pain at times of normal intestinal distention;
- excessive response to a noxious stimulus, such as prolonged crying spells associated with GERD; and
- pain associated with flatus and bowel movements, suggesting pain associated with colonic distention.
Central pain, also referred to as thalamic pain syndrome, is a recognized source of pain in adults with insults to the central nervous system, such as after a cerebral vascular accident or multiple sclerosis. Descriptors by adults of pain symptoms include burning, aching, throbbing, and the sensation of pins and needles. Associated symptoms include visceral pain, such as an exaggerated sensation of painful fullness from bladder, and visceral distention. Interventions with reported benefit include nortriptyline, gabapentin, lamotrigine, with lack of benefit from carbamazepine.22,23 Central pain as a source of pain has not been described in children, although it is likely a source for consideration in children with NI.
Treatment Strategies for Persistent Unidentified Pain
Good pain management starts with an assessment for treatable sources of pain, such as urinary tract infection, GERD, and pancreatitis. This often includes maximizing management of common chronic problems, such as constipation with use of MiraLAX or lactulose along with suppositories and enemas, and GERD, with an empiric trial of a proton pump inhibitors.
Spasticity is another commonly considered source of pain in children with NI. Factors that can exacerbate spasticity include acute illness, discomfort (such as from constipation), and pain. Spasticity is a potential source of pain and an indicator of pain including behaviors, such as arching, posturing, and stiffening. For this reason, neuropathy may be a poorly recognized contributing factor to spasticity in children with NI.
Various therapeutic interventions to reduce excessive muscle tone are available, including physical therapy, medications, and surgery. There are few randomized controlled trials of oral drugs, especially in children, and weak evidence demonstrating the efficacy of medications, such as benzodiazepines, baclofen, dantrolene, and alpha2-adrenergic agonists (clonidine and tizanidine).24,25 Two trials comparing drugs (tizanidine versus diazepam and tizanidine versus baclofen) found no significant differences between medications in either trial.26,27 Adverse drug reactions are common, and the highest rates are seen with dantrolene (64% to 91%).25 Side effects commonly seen with all medications include sedation, drowsiness, and muscle weakness. Side effects tend to be dose-related and often disappear when doses are reduced. In patients with multiple sclerosis, gabapentin resulted in a significant decrease in spasticity without sedation.28 This may indicate a potential benefit to children with demyelinating or other neurodegenerative conditions. Primary care clinicians can assist by searching for factors that can exacerbate spasticity, such as pain, and offer therapeutic symptom management trials, rather than increasing or adding other interventions for spasticity.
For chronic sources of nociceptive pain that cannot be removed immediately, such as hip subluxation with pain during movement, pain management is guided by the World Health Organization (WHO) analgesic ladder, as seen in Figure 2. When an analgesic in one category is not effective, it is appropriate to utilize an analgesic from the next step of the ladder. It is important to note that codeine is generally not recommended because it is ineffective in some individuals as a result of their inability to metabolize codeine to the active metabolite morphine,29 and it can result in toxicity in others who are ultrarapid-metabolizers.30 Tramadol is an effective option for moderate pain, although it must be used with caution in patients with a seizure disorder, in those taking medications that are inhibitors of cytochrome P450 2D6 isoenzyme (metoclopramide, TCAs), and in combination with medications associated with serotonin syndrome (serotonin reuptake inhibitors, trazadone, risperidone).31,32
Figure 2. World Health Organization Pain Ladder.
Empiric Treatment of Neuropathic Pain, Visceral Hyperalgesia, and Central Pain
In addition to assessment for nociceptive sources of pain, neuropathy should be considered for the reasons previously discussed. For persistent distress that suggests pain, children with NI often benefit from a medication trial that targets neuropathic pain, visceral hyperalgesia, or central pain. Medications best studied for these pain sources are gabapentin and TCAs. Table 3 (see page 203) provides titration schedules for gabapentin and nortriptyline (which have fewer anticholinergic side effects compared with amitriptyline). Gabapentin has a good safety profile in children, including no drug-drug interactions, making it a safe choice for a therapeutic trial in patients with persistent symptoms. Gabapentin has been found to be safe in children at doses up to 78 mg/kg/day.33 Pharmacokinetic data indicate that children under 5 years of age require the highest doses.34
Table 3. Medications, Mechanisms of Action, and Doses
Autonomic dysfunction is a source of discomfort with symptoms including abdominal pain. Autonomic dysfunction, also referred to as dysautonomia, autonomic storm, sympathetic storm, and paroxysmal sympathetic hyperactivity, is common in children with NI. In children with NI, dysautonomia typically reflects hypothalamic impairment. Symptoms include:
- tachycardia or bradycardia;
- hyperthermia or hypothermia;
- skin changes, including pallor, flushing and redness;
- vomiting, retching, bowel dysmotility, and constipation;
- urinary retention;
- abnormal sweating;
- increased salivation; and
- posturing and agitation.
As with other symptoms, evaluation should include a search for factors that may exacerbate dysautonomia, including a review of potential sources of pain. Treatment for dysautonomia in children with NI has been poorly studied. Treatment options that are utilized include benzodiazepines, bromocriptine, clonidine, oral and intrathecal baclofen, beta antagonists, and morphine sulfate. In a summary review of case reports of hypothalamic dysfunction, cyproheptadine was identified to benefit four individuals, including minimizing or eliminating symptoms of temperature instability, diaphoresis, vomiting, and abdominal pain.35 Interventions in this review without benefit included antiepileptics, haloperidol, diazepam, and clonidine. A recent case series of six patients following traumatic brain injury identified improvement with gabapentin, when symptoms of agitation, dysautonomia, and spasticity persisted despite treatment with bromocriptine, clonidine, ITB pump, metoprolol, morphine, and benzodiazepine.36 In a study of familial dysautonomia, 13 of 15 individuals experienced a decrease in symptoms (nausea, retching, tachycardia, and flushing) on pregabalin.37 Most patients were already receiving clonidine and a benzodiazepine.
In children with NI, a therapeutic trial for pain should be considered because it is difficult to determine when features of dysautonomia indicate underlying pain. In addition to scheduled medications, children with intermittent “autonomic storms,” often manifested by an acute onset of facial flushing, sweating, tachycardia, retching, agitation, and stiffening, may benefit from use of clonidine, diazepam, or morphine sulfate during episodes. Table 3 (see page 203) outlines information on cyproheptadine and clonidine.
Retching and Vomiting
Retching and vomiting are also frequent sources of distress in children with NI. Vomiting is often attributed to GERD; visceral hyperalgesia, activation of the emetic reflex, and dysautonomia are likely underrecognized sources of such symptoms in these patients.38 Retching was identified to be improved with alimemazine, a phenothiazine derivative.39 As with other phenothiazine derivatives, various properties may account for this noted benefit, including antihistaminic, anticholinergic, antidopinergic, and antiserotonergic properties. Although alimemazine is not available in the United States, cyproheptadine and other medications that block the receptors that trigger nausea and vomiting may benefit children with NI and retching.
Nonpharmacologic management is a critical part of symptom management in children with NI. Parents often become very adept at identifying comfort strategies, such as touching, stroking, rocking, massaging, and repositioning.19 Assistance includes identifying supportive equipment that minimizes positional pain, such as seating systems and supportive pillows. Use of a pool is often found to be very relaxing for such children, while cuddling and physical therapy are also commonly utilized. Although massage has not been studied in this population, many families report significant benefit for their children. Other modalities for consideration include aromatherapy and acupuncture.