Analgesic Therapy and Palliative Care in Children

SUMMARY

In this chapter we outline approaches to pain and symptom management, supportive care, and palliative care for children with life-threatening illnesses. Much of the literature on palliative care in adults and children concerns cancer; we focus in large measure on cancer in this chapter but also address a range of other life-threatening conditions, including neurodegenerative disorders, acquired immunodeficiency syndrome, and more rapidly progressive cases of cystic fibrosis. Each of the latter conditions differs from cancer in its natural history, clinical course, patterns of symptoms, and prognosis; these differences are important for instituting individualized approaches to palliative care. Curative, supportive, and palliative care should be regarded as a continuum. Aspects of a supportive care approach should be incorporated into the care of all children with life-threatening illnesses, even while curative or life-prolonging therapies continue.

Pediatric analgesic pharmacology has received extensive study in the past 20 years, and there is now a basis for safe and effective prescription of opioids and other classes of analgesics for infants and children. The majority of children with cancer can be made comfortable by using the World Health Organization analgesic “ladder” approach, with weight-based adjustments in dosing. Much less information is available regarding the prescription of adjuvant medications, anticonvulsants, and antidepressants for neuropathic pain in children; most prescribing is currently based on extrapolation from adult studies. Although pain is a prominent symptom in many cases, it should be emphasized that palliative care efforts must address the full spectrum of non-painful symptoms, as well as the emotional and spiritual suffering of patients at the end of life ( ). Surveys of parents’ impressions following the death of their child with cancer reinforces the need to improve efforts to address these broader issues ( , ).

Cancer in Children: Epidemiology and Prognosis

Treatment of childhood cancer has seen much more dramatic improvements in survival than most adult cancers have. More than 60% of children in whom malignancy is diagnosed in developed countries and who have access to state-of-the-art treatment will have long-term disease-free survival. Acute lymphoblastic leukemia, the most common childhood cancer, was uniformly fatal in the early 1950s; now, disease-free long-term survival rates exceed 70%. The prognosis is less optimistic with some of the primary central nervous system neoplasms, although recent advances have improved survival.

When compared with adults, multimodal treatment consisting of chemotherapy, radiation therapy, and surgery is performed more commonly with curative intent. Cancer therapy in children can be arduous and require a year or longer of repetitive cycles of chemotherapy and frequent diagnostic and therapeutic procedures, along with associated medical complications, pain, nausea, and other symptoms.

Many children with widely advanced cancer participate in experimental protocols of chemotherapeutic agents and other novel treatment approaches. They and their families are often willing to undertake treatments with low a priori probability of cure.

The gains in survival from childhood cancer are not shared worldwide. Many developing countries lack the resources to provide the medications, blood products, radiation therapy, surgical expertise, and intensive medical support required to deliver curative therapy. It was with recognition of these economic realities that the World Health Organization Cancer Unit emphasized straightforward, cost-effective, non-technological methods of palliative care. Regulatory barriers continue to limit access to effective analgesics ( ).

Pain and Distress at the Time of Initial Diagnosis of Cancer

At initial diagnosis, many children report tumor-related pain ( ) that commonly involves bone, viscera, soft tissues, and nerves. Bone pain may be due to periosteal stretch, as with bone sarcomas. Leukemias and other malignancies that proliferate in bone marrow can cause pain as a result of filling and compression of the bone marrow spaces. Leukemias, lymphomas, and neuroblastomas proliferate in the abdominal viscera, especially in the liver and spleen, and cause pain because of capsular stretch. Headache is common in children with brain tumors, although others initially have neurological deficits. The majority of children with spinal cord tumors have back or neck pain at diagnosis ( ). Metastatic spinal cord compression is unusual at diagnosis and is more likely to occur later in the child’s illness ( ). Back pain as a sign of spinal cord compression in children usually occurs before abnormal neurological signs or symptoms become apparent ( ).

Analgesics are often required for short periods following the initial diagnosis. Initiation of cancer therapy brings relief of pain in the majority of cases, typically within 2 weeks. Resolution of bone marrow and visceral pain is particularly rapid with hematological malignancies and somewhat slower with solid tumors. Headache from brain tumors may improve with corticosteroid therapy or with relief of increased intracranial pressure, either from surgical resection or from shunting of cerebrospinal fluid.

Children and their families experience an array of emotions at diagnosis, including among others, fear, anxiety, anger, denial, and panic. Explanations should be simple, forthright, and stated calmly. Patients and parents may not process or remember instructions or descriptions. Psychological support should be provided and individualized with consideration of the child’s development and coping style and the family’s cultural and spiritual values. A range of interventions for emotional and spiritual support should be available. Many children express their fears and emotions through play, art, or music. Child life programs have taken a lead in advocating the emotional support of children and families facing illness ( , ).

Pain Secondary to Cancer Treatment

As treatment progresses, treatment-related rather than tumor-related causes of pain predominate ( ), including postoperative and procedure-related pain, mucositis, phantom limb pain, infection, and pain from chemotherapy.

Painful Diagnostic and Therapeutic Procedures

Needle procedures are a major source of distress for children with cancer ( ). Common procedures include venipuncture, venous cannulation, lumbar puncture, bone marrow aspirate and biopsy, and removal of central venous lines. Radiation therapy is not painful per se but often requires sedation or general anesthesia to facilitate cooperation and immobility.

It is crucial to treat the pain and distress associated with the initial diagnostic procedures very effectively. Children need adequate preparation before needle procedures to minimize their fear and anxiety. Such preparation includes involving the child’s parents to obtain insight into their child’s coping style, to explain to them the nature of the procedure, and to enlist their support. Children’s distress during painful procedures is strongly influenced by the adult behavior related to reassurance, which has complex components, including parental facial expression, tone, and verbal content during painful medical procedures ( ). An age-appropriate explanation to the child should follow, with consideration of a particular child’s previous experience and coping style ( ).

Effective initial treatment will set a pattern of trust and confidence for patients and families. Conversely, if the first bone marrow aspiration or lumbar puncture is a horrific experience, there will be a carryover effect of persistent fear and distress to future procedures. A follow-up study of children in a clinical trial supports this belief. A randomized controlled trial compared a method of rapid opioid delivery—oral transmucosal fentanyl citrate—with placebo for the pain of lumbar puncture and bone marrow aspiration ( ). The group that received the active agent for the first procedure showed less distress and pain at subsequent procedures, thus implying a persistent carryover effect of inadequately treated pain ( ).

Management of painful and distressing procedures is best done by a combination of non-pharmacological and pharmacological approaches individualized to the particular child’s developmental level, coping style, medical and psychological condition, and type of procedure ( ). Some aspects of the non-pharmacological approach are commonsense, as outlined in Box 74-1 .

Box 74-1

Commonsense but Frequently Forgotten Aspects of Pediatric Procedures

Minimize unnecessary procedures, especially repeated venipuncture.
Use age-appropriate explanations.
Involve the parents to support the child and be allies, not to assist or to restrain the child.
In most cases, use a treatment room rather than the patient’s room so that the patient’s own room remains a “safe” place.
Skilled and expeditious but not rushed performance shortens the period of distress. Get all supplies and equipment prepared beforehand so that the procedure is completed as quickly as possible.
Assign practitioners’ pagers (“beepers”) to other clinicians during the procedure whenever possible to minimize interruptions.
When feasible, trainees should learn first by watching, by using models, and in some cases by supervised performance of procedures on anesthetized patients.

In addition to these commonsense measures, there are a number of specific psychological techniques for managing the pain and distress associated with procedures, including hypnosis, relaxation training, and guided imagery ( , ). Other cognitive–behavioral interventions include preparatory information, positive coping statements, modeling, and behavioral rehearsal. There are many variations of these methods, and the optimal techniques depend on the experience of the practitioners and the developmental level and personal style of the child.

Evidence supports the efficacy of psychological techniques for managing painful procedures in children with cancer ( ). In our opinion, these techniques should be taught to children with cancer whenever possible. They have several advantages. They are exceedingly safe, and the child can develop a sense of mastery and confidence that can be generalized to new situations. Conversely, hypnosis should not be used as an excuse to withhold adequate analgesics for moderate to severe pain. Some children may be too traumatized to use these techniques or may have developmental or cognitive limitations that prevent their use.

Cutaneous analgesia can be provided by several local anesthetic formulations and delivery systems, including a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA), tetracaine gel (amethocaine, Ametop), and lidocaine iontophoresis. EMLA ( , ) is available as either a patch or a cream that is applied under an occlusive dressing. Although the standard recommendation is to apply EMLA for 60 minutes, the depth and reliability of analgesia increase with longer application times, for example, 90–120 minutes ( , ). EMLA has been proved to be safe, with low plasma local anesthetic concentrations and a negligible risk for methemoglobinemia. Tetracaine (amethocaine) gel appears to be similarly effective as EMLA and may have a more rapid onset ( ).

Topical cooling with ice or fluorocarbon coolant sprays has been used with some success ( ). Both skin cooling and EMLA may produce vasoconstriction, which may make venous cannulation more difficult. Iontophoresis involves the use of an electrical current to accelerate penetration of the drug through the skin. Iontophoresis can produce skin analgesia rapidly and with good depth of penetration ( ). There are a number of ongoing approaches to improve the efficacy and reduce the time of onset for non–needle-based methods of cutaneous anesthesia. Both local heating ( ) and ultrasound ( ) can dramatically accelerate the onset of topical local anesthetic formulations. Topical local anesthetics are useful and should be widely available, but they are not a panacea. Children who have experienced repeated distressing procedures will probably remain anxious despite the use of EMLA because of their fear and lack of trust.

Local anesthetic infiltration can reduce the pain that occurs with deeper needle procedures. Prior use of topical anesthesia can reduce the discomfort of the infiltrating needle. The pain of infiltration can be reduced by neutralizing commercially supplied acidic local anesthetic solutions immediately before use with sodium bicarbonate in the following ratios: 1 part sodium bicarbonate (8.4% wt/vol) to either 9 parts 1% lidocaine (lignocaine) or 25 parts 0.25% bupivacaine ( ).

Conscious Sedation and General Anesthesia

For painful or extensive procedures or for children who have limited ability to cope or cooperate, conscious sedation and general anesthesia should both be readily available ( Box 74-2 ). Conscious sedation refers to the administration of anxiolytics and analgesics to render the child sedated and comfortable but still able to respond to stimuli and maintain airway reflexes and ventilation. For both conscious sedation and general anesthesia, safe practice necessitates administration by practitioners with expertise in airway management and with knowledge of the relevant pharmacology and medical issues. Protocols for monitoring and drug dosing can help reduce risk ( ). Monitoring with oximetry is widely recommended.

Box 74-2

Recommendations for Conscious Sedation in Children

Establish protocols, education programs, and an assessment program to track efficacy and complications. Efficacy should be judged by patients, as well as by practitioners.
Standardize the choice of drugs and doses for the majority of procedures so that practitioners are comfortable with a consistent approach.
Reduce doses in patients with risk factors for hypoventilation.
Observe fasting guidelines for solids and clear liquids to reduce the risk for aspiration.
Use an observer whose only job is to assess the level of consciousness and adequacy of respiration.
Use pulse oximetry to assess oxygenation.
Keep available an oxygen delivery source, suction, a bag and mask, and an airway management cart with a proper range of equipment.
Keep available reversal agents, especially naloxone and flumazenil.
Recognize that conscious sedation is a continuum and that in some patients standard doses may produce deep sedation.
Recognize that conscious sedation does not permit complete lack of responses to events; it is not general anesthesia.
Refer higher-risk patients and more extensive procedures for management by pediatric anesthesiologists or similar specialists.

Pure sedatives, such as pentobarbital, chloral hydrate, and midazolam, are extensively used for painless procedures that require immobility, such as radiation therapy. When procedures involve significant pain that cannot be relieved by local anesthesia, such as bone marrow aspiration, we generally prefer combining a sedative–anxiolytic, such as midazolam ( ), with an analgesic, either an opioid or ketamine. The combination of midazolam with either fentanyl or low-dose ketamine is generally safe and effective ( , , ). The intravenous route is useful because of rapid onset, complete bioavailability, and the ability to titrate incremental doses to effect.

Ketamine has received widespread use because it produces analgesia, dissociation, and stable respiration in most children. Even though ketamine is useful, it is not free of risk or devoid of adverse reactions. Although respiration is generally well maintained, perhaps better than with opioids dosed to comparable effect, ketamine has the disadvantage of no pharmacological reversal agent, and complications of respiratory depression have been reported ( , , , ). Ketamine should be used primarily in a setting where personnel with advanced airway skills are readily available. The incidence of dysphoria, bad dreams, or prolonged sedation remains in dispute ( ). Co-administration of ketamine with benzodiazepines appears to diminish this risk.

Although many children with cancer have indwelling central venous lines or easy peripheral venous access, others do not. For these children, needle-free routes of administration are helpful. Oral benzodiazepine–opioid or benzodiazepine–ketamine mixtures can be effective, although absorption varies and oral–parenteral ratios are only approximations ( , ). If oral sedation is used, sufficient time should elapse to achieve the peak drug effect. Because of variability in onset and offset, children need to be observed for the development of deep sedation or respiratory depression. Some children will become restless or try to get up and walk and may injure themselves if unattended. Oral–transmucosal fentanyl has rapid absorption and good efficacy for bone marrow aspiration and lumbar puncture despite the frequent occurrence of nausea and itching ( ).

Nitrous oxide 30–50% in oxygen can be used for sedation ( , ) with good safety, rapid onset and offset, no requirement for intravenous access, and good analgesia. Some children will resist the mask, will report bothersome dreams (particularly with concentrations in excess of 50%), or will find nitrous oxide inadequate for portions of more painful procedures. Combining nitrous oxide with other sedatives or analgesics requires experience; responses vary greatly ( ).

The development of shorter-duration general anesthetic agents has greatly facilitated these procedures, both in operating room areas and in remote locations. If intravenous access is available, propofol is widely favored because of its rapid onset, rapid pleasant emergence, and antiemetic effects ( , ). If inhalational anesthesia is required, the vapor anesthetic sevoflurane has become popular because of its sweet smell and extremely rapid onset and offset. Some children fear the mask or dislike the pungent aroma of volatile anesthetics, especially halothane and isoflurane ( ).

There is considerable controversy regarding the relative risks and benefits of brief deep sedation or general anesthesia provided by anesthetists ( ) versus conscious sedation provided by non-specialists ( , ). Many pediatric centers use a two-tiered approach, with conscious sedation for certain procedures performed by oncologists and other non-anesthetists according to protocol guidelines and with a sedation service staffed by pediatric anesthetists for higher-risk patients, for more extensive or demanding procedures, or in cases of failed sedation by non-anesthetists ( ). It is essential that there be close communication and collaboration between pediatricians and anesthetists and recognition of each other’s practice constraints. We believe that it is important for pediatric residents to receive experience and training in the use of conscious sedation in preparation for a wide range of subsequent practice settings.

Lumbar Puncture

The distress of lumbar puncture is related in part to the required body position and the necessity to remain still, as well as pain from contact of the needle with skin, bony spinous processes, or laminae. Topical anesthesia can facilitate deeper infiltration ( ). The distress of lumbar puncture may be diminished by using cognitive and behavioral techniques, conscious sedation, or in some cases, general anesthesia.

Lumbar puncture may produce a sustained cerebrospinal fluid leak and lead to a low–intracranial pressure headache. The risk for post–dural puncture headache can be reduced by using smaller-gauge needles with non-cutting points. Treatment involves simple analgesics, adequate hydration, and the supine position. In adults, caffeine ( ) and sumatriptan have produced mixed results ( ). In refractory cases, an epidural blood patch (injection of autologous blood into the epidural space) may be required. Because of the theoretical concern for injecting circulating malignant cells into the neuraxis, we reserve epidural blood patches for prolonged and severe headaches in patients with no evidence of circulating blast cells.

Bone Marrow Aspiration

Bone marrow aspiration produces pain both with passage of a large needle through the periosteum and with application of suction in the marrow space. The former pain is only partially relieved by local anesthetic infiltration near the periosteum; the latter pain is not relieved with local anesthetics. Bone marrow aspiration is a source of severe distress in children ( , ). Guided imagery, relaxation, hypnosis, conscious sedation, and general anesthesia have been shown to be effective modalities for reducing distress in this setting ( ).

Removal of Central Venous Lines

Tunneled central venous lines require removal, either electively when treatment courses are completed or more urgently in cases of infection or occlusion. Brief general anesthesia and conscious sedation are widely used for these procedures.

As noted earlier, the choice among treatments depends on the child’s age, temperament, preferences, previous experience with procedures, and the local availability of services. For example, a 12-year-old who is an excellent hypnotic subject and who experiences severe nausea or dysphoria with sedation or general anesthesia may prefer hypnosis over pharmacological measures. Conversely, a 3-year-old who has had severely traumatic experiences with previous procedures may do better with a brief general anesthetic. Options should be tailored to individual needs ( ). Pharmacological and psychological approaches should be seen as complementary, not mutually exclusive.

Mucositis

Cancer chemotherapy and radiation therapy attack the rapidly dividing cells of the epithelial lining of the oral cavity and gastrointestinal tract. Mucosal injury and cell death impair barrier function and produce the pain and inflammation known as mucositis. Topical therapies that have been used widely include diphenhydramine, kaolin, sodium bicarbonate, hydrogen peroxide, sucralfate, clotrimazole, nystatin, lidocaine (lignocaine), and dyclonine, but data on efficacy are limited ( ). Excessive use of topical local anesthetics can occasionally block protective airway reflexes, thereby resulting in aspiration, or can cause systemic accumulation with a risk for seizures. When pain persists despite topical therapies, opioids should be used.

The mucositis following bone marrow transplantation is more intense and prolonged than that associated with routine chemotherapy. Mucositis in transplant patients has a continuous component, along with sharp exacerbation during mouth care and swallowing. Preventive strategies may reduce the incidence and severity of mucositis ( , ). Opioids are generally partially effective, but for some patients the pain can preclude talking, eating, and on occasion, swallowing. Continuous opioid infusions, patient-controlled analgesia (PCA), and nurse-controlled analgesia via a PCA pump are commonly used ( ). PCA appears to be safe and effective for mucositis pain following bone marrow transplantation in children ( , ). In one comparison, the PCA group required less morphine and had less sedation and less difficulty concentrating but analgesia equivalent to that in the group receiving staff-controlled continuous infusion of morphine; in other comparisons, PCA groups have had lower opioid use and side effects, as well as lower pain scores ( ). There is a need for further study of the optimal methods of management.

Graft-versus-Host Disease

Donor-derived immune cells attack host tissues following bone marrow transplantation and create a multiorgan inflammatory process known as graft-versus-host disease. Abdominal pains and limb pains are common. Abdominal pain may arise from both hepatic and intestinal inflammation and from veno-occlusion. Despite pre-emptive anti–T-cell therapies in transplant protocols, this problem remains common and is a frequent source of pain, which is usually treated with opioids for the management of severe pain.

Infection

Immunocompromised children are susceptible to bacterial, viral, fungal, and protozoal infections, which may produce pain in a range of sites, including mouth sores, perirectal abscesses, and skin infection. Analgesics may be required until antimicrobial therapies reduce the inflammation.

Acute herpes zoster can be quite painful and merits the use of opioids as needed. Zoster infection in children is less likely to produce prolonged post-herpetic neuralgia than in adults; a small subgroup of children may experience long-term post-herpetic burning pain, episodic shooting pain, itching, and skin hypersensitivity. Early antiviral therapy should be encouraged ( ). Therapies for post-herpetic neuralgia are adapted from those used in adults and include tricyclic antidepressants ( , ); anticonvulsants ( ); topical, regional, and systemic local anesthetics; and opioids ( ).

Acute Abdominal Emergencies

Oncology patients may have any of the causes of acute abdomen that afflict other patients, such as appendicitis, a perforated ulcer, or bowel obstruction. Neutropenic patients may suffer acute bowel inflammation known as typhlitis. Although they have the signs of an acute surgical abdomen, this condition is usually treated conservatively, and surgical exploration is generally restricted to cases of overt bowel perforation or severe bleeding. Many of these patients are quite ill and require opioids despite the effects of these drugs on bowel motility.

Pre-emptive treatment of constipation is important in all patients taking opioids, but it is especially important in sick neutropenic patients. Delayed administration of oral laxatives for mild ileus and constipation can lead to a difficult situation with severe abdominal distention, emesis, and suspicion of typhlitis. Treatment options then become limited; enemas or rectal laxatives are contraindicated because of their risk of producing bacteremia or perforation.

Recent pharmaceutical research has led to development of novel peripheral opioid antagonists for the treatment of opioid-induced bowel dysfunction. One, methylnaltrexone, is administered parenterally; its quaternary amine group renders it relatively impermeable across the blood–brain barrier ( ). A second, alvimopan, is administered enterally ( ). Its action is predominantly on the gastrointestinal tract, primarily because of very poor absorption into the portal venous circulation and efficient first-pass clearance in the liver and, secondarily, because of relative exclusion by the blood–brain barrier. Both these drugs, which are currently far advanced in the drug approval process, may have a unique role in the prevention and treatment of opioid-induced bowel dysfunction in oncology patients ( ).

Postoperative Pain and Perioperative Care

It is to be expected that children with cancer and their parents will have considerable preoperative anxiety and fear. Heavy premedication may be required, and early anticipation of the need for larger than average doses for premedication may prevent unpleasant scenes and distress in the preoperative waiting area.

Children who are opioid tolerant may have a higher risk for intraoperative awareness during anesthesia, particularly if a nitrous oxide–opioid–relaxant–based anesthetic technique is used without adjustment for these increased opioid requirements. Unless severe hemodynamic instability is present, we recommend the incorporation of either volatile anesthetic agents or adequate doses of hypnotics (e.g., propofol infusions) to ensure unconsciousness during surgery.

Postoperatively, patients who have been receiving opioids preoperatively should have their daily dose of opioids calculated and this dose used as a baseline to which additional opioids are added for the purpose of postoperative pain control. This principle is commonly ignored, which leads to insufficient medication of oncology patients postoperatively. Cancer resection can be especially painful postoperatively because of the need to cut across tissues to obtain clear margins rather than dividing the tissue in natural planes.

Epidural analgesia can be used with very good effect for cancer surgery in children ( ). As with systemic opioids, it is our experience that the initial dosing of epidural infusions in children with cancer is often too conservative. Rapid and aggressive bedside titration should be used to relieve their pain. Maximum weight-based local anesthetic dosing is limited by strict guidelines, whereas dosing of epidural opioids should be titrated upward to clinical effect. Placement of the tip of the epidural catheter at the level of the dermatomes innervating the surgical field permits optimal use of local anesthetic–opioid synergism. If epidural catheter tips are below the level of the surgical dermatomes or if analgesia with combinations of local anesthetics and lipid-soluble opioids (e.g., fentanyl) is inadequate, clinicians should not hesitate to switch the opioid component of the epidural mixture to a water-soluble drug such as morphine or hydromorphone to achieve adequate neuraxial spread. Clonidine is being used increasingly as a useful adjunctive medication in pediatric epidural infusions ( ). Clonidine enhances the analgesia from local anesthetics and opioids and may provide an improved side effect profile because it does not produce ileus, itching, or urinary retention and it appears to provide some antiemetic effects in postoperative patients.

Post-surgical Neuropathic Pain

Damage to peripheral nerves is unavoidable in many types of tumor resections, particularly with limb sarcomas, and nerve injury may produce prolonged neuropathic pain. Studies of the pre-emptive effects of regional blockade in preventing neuropathic pain are controversial at best. We favor the use of perioperative regional blockade whenever feasible for resection of limb sarcoma, in part because it may provide very good postoperative analgesia, even if the more prolonged benefits are controversial. If a child shows signs and symptoms of neuropathic pain following cancer surgery, we make early use of tricyclic antidepressants and anticonvulsants ( Table 74-1 ). In many cases they appear to be beneficial and are required for several weeks to months. With tricyclics, we typically begin with nortriptyline in doses of 0.1–0.2 mg/kg at nighttime and increase the dosing every few days until either there is relief, side effects occur, or full antidepressant levels are achieved, often with the addition of a smaller morning dose.

Table 74-1

Dosing Recommendations for Non-opioid Analgesics in Children

DRUG	RECOMMENDED DOSING	COMMENTS
Acetaminophen (paracetamol)	Single doses of 15–20 mg/kg; repeated doses of 10–15 mg/kg q4h orally, up to 90 mg/kg/day in children and 60 mg/kg/day in infants	Generally safe; does not cause gastric irritation or bleeding
Choline magnesium salicylate	10–15 mg/kg q8–12h orally	Lower gastric and bleeding risk than with most NSAIDs
Ibuprofen	8–10 mg/kg q6–8h orally	Largest pediatric experience among NSAIDs; potential for bleeding and gastritis limits use in children with cancer
Naproxen	5–7 mg/kg q8–12h orally	Risks similar to those with ibuprofen; longer duration permits less frequent dosing
Amitriptyline or nortriptyline	Begin at 0.1–0.2 mg/kg at bedtime; increase incrementally as limited by side effects and as needed for efficacy up to 2 mg/kg day	Clearance is variable, so some patients will benefit from a small morning dose in addition; plasma concentrations may be a helpful guide at higher dose ranges
Gabapentin	Begin at 100 mg orally at bedtime or with 50 mg (half of the smallest capsule’s contents) in younger children; if tolerated, advance to twice daily and then three times daily over a period of several days; if tolerated, escalate as needed and tolerated up to 60 mg/kg/day divided in three doses	These recommendations are provisional because current experience is limited

NSAIDs, non-steroidal anti-inflammatory drugs.

Gabapentin emerged in the late 1990s as the first-line anticonvulsant for the treatment of neuropathic pain in adults ( ). Published pediatric experience is limited to case reports or case series ( ), although anecdotally it is widely used for neuropathic pain in children in pediatric tertiary centers worldwide. Our experience with the use of gabapentin has been somewhat favorable because of both its efficacy and its apparent safety. Occasionally, children will experience headaches, sedation, abdominal upset, and behavioral disturbances.

Pain Caused by Antineoplastic Therapy

Several chemotherapy drugs can produce local necrosis or irritation when a peripheral vein extravasates. Some forms of chemotherapy are painful when injected via peripheral veins, even when no extravasation occurs. Intrathecal chemotherapy can produce backache, headache, and signs of arachnoiditis or meningeal irritation.

Vincristine commonly causes peripheral nerve dysfunction, with hyporeflexia, sensory abnormalities, paresthesias, and gastrointestinal hypomotility; in addition, a small subgroup of children report burning or shooting pains and paresthesias. These conditions are often treated with opioids, tricyclic antidepressants, and anticonvulsants. In the majority of patients these symptoms improve over a period of several months but are likely to recur with repeated cycles of chemotherapy.

Granulocyte colony-stimulating factor accelerates neutrophil production and shortens the duration of neutropenic episodes. It may produce bone marrow pain.

Breakthrough Pain in Children with Cancer

A prospective study determined the prevalence, characteristics, and impact of breakthrough pain in children with cancer ( ). The children responded to a structured interview (Breakthrough Pain Questionnaire for Children) designed to characterize breakthrough pain in children. Of children who experienced breakthrough pain, the majority had one or more episodes of breakthrough pain during the preceding 24 hours, each episode lasting seconds to minutes, occurring several times daily, and most commonly characterized as “sharp” and “shooting” by the children. Younger children (7–12 years) had a significantly higher risk of experiencing breakthrough pain than teenagers did. No statistical difference with regard to anxiety and depression could be shown between children with and without breakthrough pain. Further studies examining the most effective treatment strategies for breakthrough pain in children are necessary.

Chronic Pain in Long-Term Survivors of Childhood Cancer

Long-term survivors of childhood cancer occasionally experience chronic pain. Neuropathic pain includes peripheral neuralgia of the lower extremity, phantom limb pain, post-herpetic neuralgia, and central pain after spinal cord tumor resection. Some patients have chronic lower extremity pain because of a mechanical problem with an internal prosthesis, failure of bony union, or avascular necrosis of multiple joints. Others have long-standing myofascial pain and chronic abdominal pain of uncertain etiology. Some patients treated with shunts for brain tumors have recurrent headaches that appear to be unrelated to intracranial pressure or changes in shunt functioning.

Phantom sensations and phantom limb pain are common in children following amputation for cancer in an extremity ( ). Phantom pain in children tends to decrease with time. Pre-amputation pain in the diseased extremity may be a predictor of subsequent phantom pain. suggested that phantom pain was quite common in children following cancer resection and was often under-recognized by physicians. reported that phantom sensation and pain can occur in children with congenital absence of limbs, although the prevalence of pain is less than in children who received amputations.

Survivors of childhood cancer and their families often worry that pain and other symptoms may imply relapse or a second, treatment-induced malignancy. Care of these children and young adults should be multidisciplinary and include psychological interventions, physical therapy, and efforts to help these children and young adults return to school and work. A small percentage of long-term survivors take oral opioid analgesics on a daily basis for long-term treatment of pain as part of a multidisciplinary program.

Pain Caused by Tumor Progression

Progression of tumor can produce pain, often by infiltration in or pressure on bone, viscera, soft tissues, or nerves. Even where there is no longer curative intent, chemotherapy and radiation therapy may help relieve the pain by shrinking the tumor ( ; ; ; ).

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