33 Control of Pain in Children with Chronic and Terminal Disease

33 Control of Pain in Children with Chronic and Terminal Disease
The Massachusetts General Hospital Handbook of Pain Management

Control of Pain in Children with Chronic and Terminal Disease

Alyssa A. LeBel and Christine N. Sang

Infants do not cry without some legitimate cause.
—Omnibonus Fenarius

I. Presentation of chronic and terminal pain in children

1. Children with cancer

2. Children with other chronic and terminal illnesses
II. Developmental issues and the pain system

1. Maturity of the nervous system

2. Cognitive development
III. Assessment of pain

1. General principles

2. Self-report

3. Pain behavior and physiologic variables
IV. Pain management

1. Pharmacologic treatment

2. Regional anesthesia and analgesia

3. Other techniques
V. Conclusion
Selected Readings

Pain is the overwhelming concern in children with terminal disease. These patients have complex presentations of acute and chronic somatic, visceral and neuropathic pain associated with severe illnesses: cancer, acquired immunodeficiency syndrome (AIDS), cystic fibrosis, congenital heart disease, neuromuscular disease, and neurodegenerative disorders. Treatment and procedurerelated pain is prominent and includes such problems as mucositis, pleurisy, pathologic fracture, phantom limb pain, chemotherapyassociated neuropathy, prolonged postdural puncture headache, abdominal pain from intractable vomiting, and radiation dermatitis. As well, the child’s sensory experience is accompanied by emotional and behavioral responses modified by parental fears and beliefs, social context, and past experiences.
1. Children with cancer
A prospective study assessing the prevalence and etiology of pain in children and young adults with cancer treated by the pediatric branch of the National Cancer Institute over a 6-month period demonstrated that pain was present in 54% of hospitalized patients and 25% of outpatients. The individual frequencies of the various causes of pain differed markedly from those reported in a similar adult series. Tumor-related pain accounted for 34% of the pain experienced by hospitalized children and only 18% of the pain experienced by outpatients. Treatment-related pain was commonly reported in both inpatient and outpatient children. Even in patients with active malignancy, tumor-associated pain accounted for only 46% of the pain experienced, and therapy-related pain accounted for 39%; pain from both causes was reported by 14% of the patients.
Several obvious differences between adult and pediatric malignancies contribute to these reported differences:

The spectrum of malignancies seen in children is different from that in adults. The most common malignancies seen in children (acute lymphoblastic leukemia, primary brain tumors, rhabdomyosarcoma, neuroblastoma, and other soft-tissue and bone sarcomas) are rarely seen in adults, whereas carcinoma, the most common adult malignancy, rarely occurs in children.

Most pediatric malignancies become widely metastatic and are rapidly fatal once they become refractory to standard therapy. An adult, on the other hand, may survive for many years with advanced disease.

Most pediatric cancers are initially managed with aggressive multimodal treatment regimens that combine surgery, radiation therapy, and chemotherapy. These treatments are highly effective in inducing tumor remission, but they also result in considerable morbidity.

When conventional therapy is no longer effective, many children continue to receive anticancer treatment (often investigational treatment) until shortly before their death. This approach is designed to test new treatment strategies; however, it inevitably leads to an increase in treatment-related morbidity and pain for children.
2. Children with other chronic and terminal illnesses
In other chronic and terminal illnesses in children, such as AIDS, cystic fibrosis, and congenital heart disease, pediatric patients may have the more “adult” experience of prolonged disability with superimposed acute exacerbations and intervention-related distress.
1. Maturity of the nervous system
Until recently, many clinicians assumed that “neurologic immaturity” prevents very young children from experiencing pain. Current research disputes this contention. Pain transmission pathways develop during fetal life. Nerve tracts in the spinal cord and brainstem begin to myelinate around the gestational age of 22 weeks and are completely myelinated by 28 to 30 months after birth. More specifically, myelination is complete up to the thalamus by 30 weeks’ gestation, and the thalamocortical pain connections to the cortex are myelinated by 37 weeks’ gestation. Thus, pathways that conduct noxious information from nociceptor to cortex are present in the newborn infant.
The majority of neurotransmitters and neuromodulators are present in the fetus. Calcitonin gene-related peptide (CGRP) and substance P are present at 8 to 10 weeks’ gestation, and others such as enkephalin and vasoactive intestinal peptide (VIP) appear 2 to 4 weeks later. Catecholamines are present in late gestation, and, in the human fetus, serotonin has been found at 6 postnatal weeks. Neurotransmitters that enhance the perception of pain are produced earlier in the fetus than are endogenous opioids.
It appears, therefore, that pain processing in the mature fetus and newborn is adequately developed so that the infant may exhibit behavioral and physiologic responses to noxious stimuli and may even have enhanced nociception. The misconception that neonates and infants do not feel pain, combined with a fear of using opioids in very young children, has resulted in gross undertreatment of pain in this population. Recent research has emphasized the importance of providing adequate pain control in newborns and young infants. It is now clear that the undertreatment of pain can have both short- and long-term adverse psychological and pathologic effects on these young patients.
2. Cognitive development
Piagetian theory is often used to describe the developmental levels of understanding pain in school-age children; these levels are listed in Table 1. Speculations about younger children have been extrapolated from that framework. However, recent findings have shown that younger children have a more sophisticated understanding of pain than was previously reported. Children of 18 months of age can express and localize pain. Although younger children may recover more frequently from surgery and report less pain after surgery, they typically have more pain from needle procedures than older children. Young children’s limited cognitive development may preclude an understanding of the context of the needle pain, the realization that the pain will be over quickly, and the use of effective cognitive coping strategies.

Table 1. Development sequence of children’s understanding of pain

Coping strategies are influenced by cognitive development. Children as young as 18 months indicate, through structured play sessions, the awareness of ways to eliminate their pain, generally by seeking hugs and kisses and asking for medicine. Children who are 3 to 4 years of age spontaneously use distraction and also report that play makes them feel better. Although they may use this technique spontaneously, children cannot deliberately distract themselves or use self-initiated cognitive strategies to decrease pain before the age of about 5 years. Cognitive and behavioral strategies, such as relaxation, are generally beyond their capabilities.
Communicating pain is also influenced by cognitive development (see the following section).
1. General principles
The assessment of pain in children should be systematic, and it requires reevaluation throughout the course of the illness. Because infants cannot communicate verbally, behavioral and physiologic responses can be used to assess pain in the very young, including facial expression, tachycardia, and stress-related hormones. However, these signs may not be specific to pain. The child’s cognitive development and ability to understand pain influence the choice of suitable measurement tools.
In children, pain measurement must take the following into account (taken from McGrath and Craig 1989):

The child’s report of pain is the best indicator of pain.

Pain that appears to be unexplained by known causes may indicate disease progression or other factors and should be investigated.

The denial of pain when there is evidence of tissue damage should be investigated.

Neonates and infants feel pain.

Developmental factors should be considered before selecting the appropriate measures of pain intensity (this is more difficult younger than 2½ years).
2. Self-report
Children as young as 18 months can indicate their pain and give a location, but it is not possible to obtain a self-report of intensity of pain before about 3 years of age. Children who are 3 years of age can give a gross indication, such as “no pain,” “a little pain,” and “a lot of pain.” Similarly, many children at this age can use concrete measures such as “poker chips” of “pieces of hurt” to convey the intensity of their pain. The use of more abstract self-report instruments, such as the “smiling faces scale” (see Fig. 1 of Chapter 6), are generally not valid for use in children under 5 years of age.
Simple self-report measures are recommended for children older than 6 years of age. Among the most useful scales for measuring intensity of pain are visual analog scales, either vertical or horizontal, and simple numeric scales. For example, “If 0 means no hurt or pain and 10 means the biggest pain you ever have, what is your pain now?” The use of adjectival categorical scales such as “mild,” “moderate,” “severe,” and “excruciating” are not recommended for children younger than 13 years of age.
3. Pain behavior and physiologic variables
Behavioral observations should not be used in lieu of self-report. However, behavioral observations are invaluable when self-report is not available—for example, in children younger than 2 years of age or in children without verbal ability as a result of disability or disease. In the presence of noxious stimuli, behavioral pain indicators may arouse suspicion and prompt investigations even in the absence of a verbal report of pain. Behavioral indicators of pain are listed in Table 2.

Table 2. Behavioral indicators of pain

Neonates and infants feel pain, and neonates are no less sensitive to noxious stimulation than are older children and adults. Therefore, assessment of pain, although more complex than in older children, should be considered essential in the care of neonates and infants. In infants, reliance on facial expression, crying, posture, and physiologic variables such as heart rate, respiratory rate, blood pressure, and palmar sweating are important as potential indicators of pain, and scoring systems, such as the CRIES scale described by Krechel and Bildner (1995) are useful. There are currently no physiologic measures that reliably indicate pain, and pain treatment should never be withheld because of a lack of physiologic evidence alone.
The administration of analgesics to children with cancer and terminal illness follows the general principles of the WHO analgesic ladder, a stepwise approach to prescribing analgesics depending on the intensity of pain (see Chapter 32).
1. Pharmacologic treatment
Table 3 lists the pediatric dosages for common pain medications.

Table 3. Analgesic medications in children

(i) Acetaminophen and the nonsteroidal anti-inflammatory drugs
Acetaminophen has been shown to be safe even for newborns, in whom the immature hepatic metabolism system is protective, with decreased production of toxic metabolites. In children who are unable to take acetaminophen by mouth, the rectal route is the next option. However, in the child with cancer, bacterial seeding is a concern.
Aspirin, salicylates (such as choline magnesium trisalicylate), and several nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen (Motrin) and naproxen (Naprosyn), are used, particularly for children with pain of inflammatory origin. Early experience with the use of the selective cyclooxygenase-2 (COX-2) inhibitors, such as rofecoxib (Vioxx) and celecoxib (Celebrex), is promising. The use of these medications, however, is limited in the child with thrombocytopenia, coagulopathy, or gastritis.
(ii) Opioids
Although there is a history of avoidance of opioids in the treatment of newborns and infants, our current understanding dictates that there are few contraindications to opioid treatment in the very young. Physiologic factors, such as the immaturity of the nervous system, liver, and kidneys, force us to alter the method of providing opioid analgesia but do not preclude the use of these important and effective analgesics.
As in adults, opioid analgesics are the drugs of choice for moderate to severe pain. For infants 3 to 6 months of age, clearance and analgesic effects of morphine, fentanyl, sufentanil, and methadone resemble those for young adults. Six-month-old infants show no more respiratory depression from fentanyl than do adults. All opioids, including morphine, appear to have a wide margin of safety and excellent efficacy for most children older than 6 months with cancer pain and resistant chronic pain.
Premature and term infants show reductions in clearance of most opioids. The sensitivity of newborns to morphine is the result, in part, of kinetic factors, including a smaller volume of distribution, diminished clearance, and, possibly, increased entry through the blood–brain barrier. An increased sensitivity on a pharmacodynamic basis, associated with immaturity of ventilatory responses to hypoxemia and hypercarbia, may also be present.
For nonintubated infants younger than 3 to 6 months, opioids must be used with caution and only with close observation. The dose should be approximately one third to one fourth of that used for children. In contrast to respiratory effects, the cardiovascular depressant effects of opioids in newborns are mild and may actually be beneficial in some situations.
For children with cancer, the oral route is most effective. However, the use of this route may be limited by nausea, mucositis, and difficulty with swallowing pills or elixirs. The principles of opioid therapy (see Chapter 9) apply equally to adults and children. Longacting preparations are used as the basis of chronic opioid therapy, and short-acting opioids are reserved for breakthrough pain. However, in small children (<20 kg), the use of long-acting preparations is limited by the lack of availability of low-dose preparations. Tramadol (Ultram), a weak opioid agonist (chiefly at the mu receptor) with additional norepinephrine and serotonin reuptake inhibition, is an option for oral analgesia with somewhat fewer side effects than pure opioid agonists. However, the concomitant use of standard opioids, or use in opioid-dependent patients, should be avoided because of unpredictable interactions.
When parenteral administration is required, the intravenous or subcutaneous route can be used. Intramuscular injections should not be used because they are painful and frightening, and children may accept pain in preference to asking for a “shot.” In cases of severe pain in a patient whose dose requirement is unknown, 0.05 to 0.1 mg/kg of morphine can be given; the patient is reassessed every 15 minutes, and additional increments of 0.05 mg/kg are administered until relief is obtained. Intermittent bolus injections of morphine can then be provided around the clock. Continuous infusions of morphine may begin at a starting dose of 0.01 to 0.05 mg/kg per hour for children older than 6 months of age. Occasionally, an alternative opioid may be indicated, in which case equianalgesic doses can be substituted for morphine (see Appendix VIII). Patientcontrolled analgesia (PCA) is effective for children and adolescents aged 5 years and older (see Chapter 22). However, some children and adolescents may not have the cognitive, emotional, or physical resources to use PCA.
The pharmacologic approach to the management of side effects is similar to that in adults. However, children may have difficulty communicating subjective symptoms that reflect difficulties with pruritus, nausea, and dysphoria. Therefore, if an infant or child becomes restless or irritable with an increased opioid dose, treatment of side effects is suggested empirically, as is a change to an alternative opioid. For acute respiratory depression, as dictated by professional judgment, children may receive naloxone titrated to the desired effect. The initial dose of naloxone in a child is 0.5 to 1.0 µg/kg.
(iii) Adjuvant medications
Adjuvant medications such as tricyclic antidepressants and stimulants are beneficial as co-analgesics in children with cancer pain, with dosages extrapolated from the adult dosage by weight (see Chapter 32 and Appendix VIII). In general, the starting dose is low, approximately 0.2 mg/kg of amitriptyline (Elavil), with an increase to approximately 1 to 3 mg/kg per day. A baseline electrocardiogram may be useful in patients who have received other cardiotoxic medications. Neuropathic pain may respond to anticonvulsant or sodium channel blocking agents such as gabapentin (Neurontin), up to 45 mg/kg/day, titrating from every hour of sleep (5 mg/kg) to three times daily, and mexiletine, 2 to 3 mg/kg, two to three times a day. The starting dose for stimulants, such as dexamphetamine and methylphenidate, is 0.05 mg/kg. Corticosteroids are helpful because of their anti-inflammatory, antiemetic, and mood-altering effects.
2. Regional anesthesia and analgesia
Regional blockade techniques have been developed for children of all ages, including newborns, and are generally performed with sedation or light general anesthesia because of patients’ fear of needles. Regional, caudal epidural, and lumbar epidural blockade provide excellent analgesia with wide margins of safety. Hemodynamic and respiratory effects of epidural or subarachnoid blockade in infants are mild. The distribution and clearance of bupivacaine and lidocaine following regional blockade in children older than 6 months resemble those in adults. Bupivacaine clearance is mildly delayed in newborns. Epidural and subarachnoid infusions of opioid and local anesthetics have been effectively used in infants and children who have refractory cancer pain, deafferentation pain, and complex regional pain syndrome, type I (CRPS-I). It is important to administer local anesthetic slowly in children, with constant assessment for clinical signs of intravascular effect.
Infants and children may also receive viscous lidocaine for mucosal analgesia. A single mucous dose of lidocaine should not exceed 4 mg/kg; a repeated oral administration of up to 2 mg/kg is generally safe. Infants and young children should receive dilute lidocaine sprays, such as 1% in neonates and 2% in children (compared to the 4% to 10% used in adults). A transdermal 5% lidocaine patch (Lidoderm) applied to dermal areas of localized peripheral neuropathic pain (one to three patches per 12 hours) is currently being studied in children.
3. Other techniques
Children are excellent subjects for hypnosis, relaxation, and biofeedback training, all of which are especially useful for recurrent pain such as headache and for brief painful medical procedures. Some of these techniques are described in Chapter 22. Children over the age of 7 years generally benefit from such programs, but some behavioral treatment strategies have applied to children as young as 3 to 4 years.
Thankfully, chronic pain and serious illness are rare in the pediatric population of the Western world. However, when they occur, their effects are devastating, not only to the children but also to their families and caregivers. Pain treatment in this population is challenging for many reasons, including caregivers’ insecurity over pediatric dosing, difficulties in assessing pain, and resistance to opioid use because of misguided fears. It is, however, critically important to give the benefit of adequate analgesia to these vulnerable patients, even though this may require the involvement of experts in developing safe and effective treatment regimens.

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Berde CB, Ablin A, Glazer J, et al. Report of the Subcommittee on Disease Related Pain in Childhood Cancer. Pediatrics 1990;86:818–825.

Beyer JE, Wells N. Assessment of cancer pain in children. In: Patt RB, ed. Cancer Pain. Philadelphia: Lippincott, 1993:57–84.

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McCarthy PJ, Beyer J, Cleeland C, et al. Report of the Subcommittee on Assessment and Methodologic Issues in the Management of Pain in Childhood Cancer. Pediatrics 1990;36:814–817.

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