Every year between 400 and 450 new cases of cancer among children between the age of 0 and 18 years are registered in Israel. Approximately 75% to 80% of these children will be eventually cured with modern treatment modalities. The rest of them, between 20% and 25%, will eventually die despite all efforts. Often combined with medical treatments aimed at curing the illness (such as chemotherapy), palliative services are developed for the benefit of individuals and their families during the difficult periods of living with the disease, dying from it and grieving. The delicate intricacies involved in supporting children suffering from terminal cancer and their grief-stricken families call for specialized services by a well-balanced team of interdisciplinary professionals trained in palliative care.
THE PEDIATRIC PALLIATIVE CARE UNITSINISRAEL
There are 6 major centers receiving 50 to 150 new patients per year, each center has the authorization of the health Ministry to educate fellows in pediatric hematology oncology and in pediatrics. Four other satellites institutions treat children with cancer between 5 and 10 per year generally together with the center, which is located in proximity.
Children who are in palliative care are treated by the staff of the centers and approximately 70% to 80% of the children are dying in the Pediatric Hematology Oncology department. Each center has a multidisciplinary team including: a Pediatrician who is dedicated to and highly specialized in Pediatric Oncology or Hematology, a pediatric hematologist oncologist with special knowledge in palliative care, qualified pediatric oncology nurses, social workers, clinical psychologist, music therapist, art therapists, physiotherapists, medical clown. Approximately 20% to 30% of the children are spending their last days at home and daily/weekly visits at home are organized by the staff including a nurse, a physician, social worker, psychologist; most of the parents are educated to deliver supportive care at home including total parenteral nutrition, patient control analgesia morphine, oxygen mask ventilation. There is no pediatric palliative care units in the Health Care Medical Community Clinic, therefore the staff of the hospital is particularly involved and when the burden for the parents in terms of nursing and psychological strains is too high, and often parents turn to hospital in times of symptoms crises or in anticipation of a tragic dying process (suffocation, bleedings).
PALLIATIVE CARE IN ADOLESCENTS
Special efforts are made in the pediatric departments to better treat adolescents in terminal phases, including Do Not Ressuscitate orders, help from the school, friends, and volunteers, still specific spiritual, ethical, and legal issues have to be taken into account. The Israeli health ministry is studying now the possibility to decrease the age of the informed consent from 18 years old to 14-16 years, including the assent or consent of children with regard to Do Not Ressuscitate, experimental therapy. Most of the efforts of the palliative care team are centralized on the best interest for the child who is not necessary always the best interest of the parents.
PALLIATIVE CARE EDUCATION PROGRAMINISRAEL
Together with adult palliative care specialists the Israeli pediatric oncologists wrote guidelines aimed to educate the pediatric department staff in palliative care. Ben-Gurion University of the Negev, UJA Federation of New York, the Israel Cancer Association, and the “Support” organization (a multidisciplinary organization for palliative care in Israel) worked together to implement a nationwide palliative training program.
The program was initiated in 2005 and during the first 3 years of its implementation, 15 courses were conducted all over Israel. Some 400 participants took part; the majority were nurses, but also social workers, and physicians.
Since then, several courses in palliative care are conducting in the Israeli universities and institutions with a special session in pediatric palliative care. Two Israeli palliative care associations are organizing annual meetings in palliative care where every centers present their researches and protocols. An Israeli Journal in palliative care is published quarterly. Two years ago, the Israel Society of Pediatric Hematology Oncology started a program for education of the fellows in pediatric Hematology Oncology with a focus on medical and psychosocial approaches in children dying from cancer. This program includes teaching on pharmacology of opioids, and symptoms management. In addition, 2 children's hospitals created a special pain Unit, to treat children with terminal diseases, including education for the pediatric nurses and fellows. The focus of the education program is on expertize in integrating palliative care in the intensive care environment, with an extensive teaching service that provides both academic and clinical education, mentoring and practicum experiences to pediatricians. The guidelines in pain management are similar to the one published by the European association for palliative care International Meeting for Palliative Care in Children, Trento1 and will be described in the following chapters.
CANCER PAIN MANAGEMENT IN CHILDREN WITH TERMINAL DISEASES
Despite the advancement in the knowledge and skills in treating cancer pain in children, there are still many reports indicating suboptimal treatment. We still witness many barriers for treatment among parents and in medical teams.2 For many parents the words morphine or methadone mean: the situation is serious or terminal, we are giving up, fear of addiction and concern that when there will be a need for strong pain medications they will not be effective.3 Among many medical teams morphine mean—addiction, risk of shortening life, respiratory depression, confusion, tolerance, side effects, and fear from pain medications as most physicians and nurses do not receive structured training in pain management during their studies.4,5
THE PATHOPHYSIOLOGIC CLASSIFICATIONOFPAIN
Neuropathic pain is caused by an injury to the transmission system: the injury may be a result of a tumor infiltration, chemotherapy medications, radiation, mechanical reasons (such as surgery), or infection (eg, herpes zoster). Nociceptive pain derives from stimulation of the peripheral receptors as in a fracture or bone tumor.6,7 Pain can be treated by both pharmacological and nonpharmacological methods. At our disposal, there are many drugs: acetaminophen, nonsteroidal anti-inflammatory, opioids, tramadol, anticonvulsants, antidepressants.
The World Health Organization ladder has 3 steps according to the increasing pain intensity.6,7 The severity of pain determines the type and dose of medication we choose. For mild pain step 1, we will prescribe simple analgesia nonopioids such as paracetamol, anti-inflammatory antipyretic,for step 2 moderate pain, we recommend minor dose opioids±adjuvants, and for severe pain step 3 major opioids±adjuvants are indicated.
In each stage, if the patient has neuropathic pain caused by compression or outright damage of a peripheral nerve, steroids may relieve the neuropathic pain, but formore durable pain, tricyclic antidepressants, anticonvulsants are required.8
How to Evaluate Pain Severity?
Children aged 5 years and older will know how to relate to the Visual Analog Scale of 0 to 10. Younger children, 3 to 5 years old, will relate to the faces scale. For children who cannot express themselves we will rely on observation or other commonly used tools such as the Face Leg Activity Cry Consolability observing faces expressions, leg movements, activity, crying, and consolability.
Opioids are the corner stone for the treatment of pain. They bind to 5 types of receptors (μ, κ, σ, δ, ε), on the peripheral nerve system or spinal level. Opioids modify the transmission signal and decrease pain perception. In addition, on the supraspinal level opioids send inhibitory signals and affect the limbic system that modifies the emotional response to pain.9
Each opioid has different effects on the different receptors and on the different levels, such that there is great variability between children. These differences are specific and individual for each child. Thus, there is no correlation in the analgesic sensitivity to the different opioids and in the side effects for individuals. A child can develop significant sedation with morphine and no sedation with oxycodone. In addition, there might be a child that will need minimal doses of an opioid to achieve an analgesic effect and another with the same pathology will need very high doses. Another interesting phenomenon of opioids is that there is no ceiling effect. Thus, there is no maximal dose for any opioid.10,11
Opioids are divided into 2 groups: immediate release (IR) and extended release (ER) medications. The IR opioids are: morphine, codeine, oxycodone, hydromorphone, hydrocodone, fentanyl, and methadone.
Morphine is the most widely used medication. Taken orally (per oral), activity begins within 30 minutes and peaks within an hour, ending after approximately 4 hours. Administered subcutaneously, the peak activity is reached within 30 minutes, and intravenously within 5 to 10 minutes. Hydromorphone and oxycodone pharmacokinetics are similar. Oxycodone is 1.5 to 2.0 times more potent than morphine with similar pharmacokinetics. Oxycodone has 2 metabolites: Noroxycodone, which is partly active and the other oxymorphone, which is active though its quantity is minimal. It clears in children very quickly and thus, can be used in high doses, but only per oral.
Fentanyl is a very potent lipophilic opioid, 80 to 100 times more potent than morphine in adults but only 13 to 20 times in children. Fentanyl activity is quicker and is active for a shorter time than morphine given parenterally. It does not have any active metabolites. According to different studies, its pharmacokinetics in children is similar to adults.12 Fentanyl is provided as a patch, which releases regular doses for 48 to 72 hours. This is a very convenient preparation to be used in children as it increases compliance rate dramatically.
From the analgesic point of view, there is no preference of one opioid over another. Although for patients with kidney function problems, there is an advantage for fentanyl and methadone that do not have active metabolites.
Methadone is an opioid with unique characteristics, an “old” nonexpensive drug. Methadone does not have active metabolites and has a long half-life (12 to 200 h) that cannot be predetermined. Conversion from one opioid to methadone depends on the metabolism of the patient and the earlier dose of the opioid received. There are few data on the pharmacokinetics of methadone in children, although from our experience and of other investigators it is an excellent opioid to use for pediatric palliative care—with careful and rational use. Methadone for single dose use can be considered as an IR substance, but for regular chronic use as an ER substance.
Morphine conversion to methadone is 1:5 in low morphine doses up to 100 mg and 1:10 to 20 in high morphine doses.
Morphine, oxycodone, and hydromorphone have ER preparations, given every 8 to 12 hours. In children with usually relatively quick metabolism it should be administered every 8 hours.
Midazolam may be used for its sedative known effects but also as anticonvulsive drug. Children metabolize and excrete midazolam more rapidly than adults do and that adequate sedation safely achieved in the majority of children with a midazolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 μg/L.13,14 Midazolam as adjunct therapy to morphine is recommended in the alleviation of severe dyspnea perception.14
How to Begin the Opioid Treatment
There is no analgesic advantage of one opioid over another. In case a child or a parent is worried about taking opioids, the recommendation is to start with an IR opioid every 4 hours at lowest dose. After several days, ER preparation can be used, fentanyl patches may be a good option in children. Regular around the clock care and addition of a rescue dose if necessary are recommended too. The rescue dose is always given as IR opioids. This dose may be repeated every hour if administered per os, every 30 minutes if administered subcutaneously, and every 5 to 10 minutes if administered intravenously. The rescue dose is calculated at 10% to 20% of the total ER opioids dose in 24 hours.
The requirements for breakthrough pain have to be reviewed after 2 days. The regular dose has to be increased by the amount of breakthrough that has been required (all doses should be converted to milligram equivalents of oral morphine). Children who have a fentanyl patch will receive oral morphine or oxycodone for breakthrough.15
The most common side effects are drowsiness, constipation, urinary hesitancy, pruritus, sedation, nausea, and vomiting. Development of addiction and tolerance is very rare. There is no tolerance to the analgesic effect and the constipation. Tolerance is developed for other side effects as sedation (within 5 to 7 d), nausea/vomiting (within approximately 2 wk).15
Respiratory depression is very rare when opioid is delivered appropriately. It should be noted that the case in respiratory depression is never of sudden cessation in breathing but a gradual depression, which is always preceded by a decrease in conscious state.15
Pain management forms a major part of the care of a child in palliative care but other symptoms may also need to be addressed such as fatigue, neurological symptoms (seizure), respiratory symptoms, especially dyspnea and cough, anorexia and dehydration, constipation, especially due to opioids. For each of those symptoms, the treatment is decided according to the cause and sometimes, cancer-directed therapy may help such as radiotherapy in spinal cord compression, chemotherapy low dose such as oral etoposide, which has an antitumor effect in children with neuroblastoma or other solid tumors. But of cause, communication around this decision is necessary and tailored to the individual family. The aim is to prolong the life of the children and not causing complications, which will decrease quality of life.
DEPRESSION DURING THE TERMINAL PHASE
There are many nonphysical psychological and existential causes of depression in children with terminal diseases, fears of abandonment of separation.16–18 Adolescents suffer from depression caused by many aspects of existential crisis.19–21 Children's concept of death evolves with age and during the period of adolescence, children are able to comprehend the inevitability of death.17 The palliative team has to be aware of those difficulties and recommend intervention of psychiatrist and appropriate medical treatment such as antidepressants.
Shvartzman et al23 carried out a study on opioid use in an Israeli health maintenance organization from 2000 to 2006 showing the growing use of opioids during the 7-year period, a potential indicator of the progress made in improving accessibility and availability of opioids in the health care organization in Israel.
The clinical evidence is now accumulating that major opioids can be used safely and effectively in children with moderate-to-severe pain.
Attentive control of all symptoms in a dying child and special attention to existential, emotional, and social demands of the child and the whole family are the keys of the good quality of care in pediatric oncology. Education of the medical team is imperative, training in pharmacology and metabolism of antalgic drugs is also mandatory to better manage symptom control of the children at the end of life. Procedural guidelines are helpful to educate medical providers, set standards for best practice, promote optimal care, and convey the important message to staff, patients, and families that palliative care is an accepted, ethical practice when used in appropriate situations.
1. Craig F, Huijer HA-S, Benini F, et al. IMPaCCT: standards for paediatric palliative care
in Europe Eur J Pall Care.. 2007;14:109–114
2. Drake R, Frost J, Collins JJ. The symptoms of dying children J Pain Symptom Manage. 2003;26:594
3. Goldman A, Hewitt M, Collins GS, et al. Symptoms in children/young people with progressive malignant disease: United Kingdom Children's Cancer Study Group/Paediatric Oncology
Nurses Forum survey Pediatrics.. 2006;117:e1179
4. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer N Engl J Med. 2000;342:326
5. Hilden JM, Emanuel EJ, Fairclough DL, et al. Attitudes and practices among pediatric
oncologists regarding end-of-life care: results of the 1998 American Society of Clinical Oncology
survey J Clin Oncol. 2001;19:205
6. Ventafridda V, Tamburini M, Caraceni C, et al. A validation study of the WHO method for cancer pain relief Cancer.. 1987;59:850–856
7. McGrath PA. Development of the World Health Organization Guidelines on cancer pain relief and palliative care
in children J Pain Symptom Manage.. 1996;12:87
8. Mc Quay HJ, Tramer M, Nye BA, et al. A systemic review of antidepressants in neuropathic pain Pain. 1996;68:217–227
9. Greco C, Berde C. Pain management for the hospitalized pediatric
patient Pediatr Clin North Am. 2000;47:487
10. Dean M. Opioids in renal failure and dialysis patients J Pain Symptom Manage.. 2004;28:497
11. Doyle L, Colleti JE. Pediatric
procedural sedation and analgesia Pediatr Clin North Am.. 2006;53:279
12. Hunt AM, Goldman A, Devine T, et al. Transdermal fentanyl for pain relief in a pediatric palliative care
population Pall Med. 2001;15:405–412
13. Collins JJ, Grier HE, Kinney HC, et al. Control of severe pain inchildren with terminal malignancies J Pediatr. 1995;126:653–657
14. Postovsky S, Moaed B, Krivoy E, et al. Practice of palliative sedation in children with brain tumors and sarcomas at the end of life Pediatr Hematol Oncol. 2007;24:409–415
15. Hain RD. Pain in Children with Cancer. Psychosocial Aspects in Pediatric Oncology
. First edition. John Wiley and Sons, LTD; 2004:71–91.
16. Spinetta JJ. The dying child's awareness of death: a review Psychol Bull.. 1974;81:841–845
17. Spinetta J, Rigler D, Karon M. Anxiety in the dying child Pediatrics.. 1973;52:841–845
18. Hilden JM, Watterson J, Chrastek J. Tell the children J Clin Oncol. 2000;18:3193–3195
19. Attig T. Beyond the pain: the existential suffering of children J. Palliat Care.. 1996;12:20–23
20. Cassel EJ. The nature of suffering and the goals of medicine N Engl J Med. 1982;306:639–645
21. Sullivan MD. Finding pain between minds and bodies Clin J Pain.. 2001;17:146–156
22. Postovsky S, Weyl Ben Arush M. Care of a child dying of cancer. Psychosocial Aspects of Pediatric Oncology
. First edition. John Wiley and Sons; 2004:93–107.
23. Shvartzman P, Freud T, Singer Y, et al. Opioid use in an Israeli health maintenance organization: 2000-2006 Pain Med.. 2009;10:702–707