1. Cancer Pain in Children 13 th Annual Palliative Care Seminar Hector Rodriguez-Cortes, MD Pediatric Hematologist and Oncologist Pediatric Palliative Care and Hospice

2. Objectives: Epidemiology of cancer pain Identify the three different pain categories Identify Treatment and Tumor-Related pain syndromes Review the Two-step strategy of the WHO guideline

3. Introduction Cancer: evokes immediate fear for patients and their families potentially fatal disease can be associated with pain Symptoms: may be interconnected treatment of one symptom may exacerbate another

4. FREQUENCY OF CANCER PAIN Multi-factorial: type of malignancies sites of involvement presence or absence of metastases Prevalence of moderate/severe pain increases during the late phases of malignancy

5. EPIDEMIOLOGY OF CANCER PAIN IN CHILDREN Cancer pain: tumor-related treatment-related pattern: surgery, medications Tumor-related pain: predominates at diagnosis/ early treatment phase May persisted for a median of 10 days after initiation of treatment. Examples of tumor-related pain: Brain tumors: headache/ abnormal neurologic signs Mets w spinal cord compression: back pain

6. EPIDEMIOLOGY OF CANCER PAIN IN CHILDREN Treatment-related pain: mucositis antineoplastic therapy postoperative pain procedure-related pain

7. Breakthrough pain in Children with Cancer Freidrichsdorf and Postier (2014) Breakthrough Pain Questionnaire for Children 57% of children experienced pain Pain: major tumor tumor surgery >> tumor/ drug-related Younger children (7-12 year of age) at higher risk than teenagers PCA

8. Reason for Breakthrough pain in Children with Cancer Freidrichsdorf and Postier (2014) disease progression infection at the tumor site development of tolerance drug interactions decreasing renal function somatization and psychological distress.

9. Pain Mechanisms

10. PAIN MECHANISMS: Experience of pain: Subjective can be modulated by developmental, familial, situational, emotional, and other factors. lack of correlation between the extent of tissue injury and the intensity of pain or suffering.

11. PAIN MECHANISMS: Terminology Nociception: sensation of tissue injury or inflammation alerts an individual to potential or ongoing injury prompts the avoidance or limitation of further injury can be activated by: chemical, thermal, or mechanical stimuli lack of it can lead to a variety of medical complications decubitus ulcers.

12. Nociception

13. Somatic pain: Pathophysiology 1. noxious stimuli mechanical, thermal, or chemical 2. Pain signals are carried to the dorsal horn of the spinal cord by: A-delta fibers: mechanical/thermal C fibers: all three stimulus types 3. The signals ascend in the contralateral spinothalamic and spinoreticular tracts 4. thalamus

14. Somatic pain

16. TYPES OF PAIN Pain can be divided into 3 categories: Somatic Visceral Neuropathic These categories are not mutually exclusive since a patient's pain may have multiple etiologies.

17. Somatic pain Triggered by potential or real injury to tissues cutaneous burn or an arthritic joint. Pain tender and localized. constant and sometimes throbbing or aching. it can be acute or chronic. Bone metastasis is the most common cause of somatic pain

18. Visceral pain Mechanism is not well characterized. Pain: Poorly localized less constant it can dull, colicky Often referred to a distant cutaneous site. diaphragmatic irritation: ipsilateral shoulder passage of a renal stone Associated: nausea and diaphoresis. Noxious stimuli that can trigger visceral pain: ischemia, inflammation, torsion, traction, distension, or impaction

19. Visceral pain

20. Neuropathic pain Causes: Peripheral or central in etiology infiltration of neural structures by tumor fibrosis: radiation injury: surgery Described as: prolonged, severe, burning, or squeezing It can paroxystic often associated with focal neurologic deficits relatively resistance to opioids Often associated with symptoms and signs of autonomic instability ( i.e.., tachycardia, sweating) Example: herniated intervertebral disc, phantom limb pain, degenerative neuropathies such as Guillain-Barre syndrome.

21. Neuropathic pain Clinical features: Dysesthesias: abnormal or unfamiliar unpleasant sensations Allodynia: an exaggerated response to otherwise non-noxious stimuli, such as light touch of the skin

22. Neuropathic Pain

23. Neuropathic pain

24. Pain Assessment

25. Measuring Pain Pain: often under-recognized in cancer patients should be assessed frequently and systematically Principal barrier to effective pain management: discrepancy between the patient's and physician's assessments of the pain Anxiety and depression: may exacerbate, rather than exaggerate, the pain.

26. Pain measurement tools Verbal numerical scale rating pain from zero for "no pain," to 10 for "the worst imaginable pain" easily implemented and recorded 10 cm visual analog scale: used, with or without intensity descriptors do not reflect the complexity of the pain experience

27. Pain measurement tools Non-communicate pain: intensity must be evaluated by other means. nonverbal signs of pain These include: hypertension, tachycardia, and diaphoresis Agitation or confusion Apathy, inactivity, or irritability in patients with cognitive impairment

28. Pain measurement tools

29. Pain Management

30. Principles for the pharmacological management of pain. WHO: 1986 dosing at regular intervals using the appropriate route of administration adapting treatment to the individual child WHO: 2012 using a two-step strategy

31. Principles for the pharmacological management of pain. WHO: 1986 dosing at regular intervals steady blood level: reducing peaks and troughs using the appropriate route of administration Least invasive route (often chosen by the child) Transdermal patches: long onset time adapting treatment to the individual child Frequently assessment, reassessment and modification

32. Principles for the pharmacological management of pain. WHO: 1986 WHO: 2012: two-step strategy choice depends on the child’s level of pain. Mild Moderate to severe pain

33. Three-step vs. Two-step approach Difference: three-step analgesic ladder: use of codeine as a weak opioid treatment of moderate pain two-step approach: low doses of strong opioid Two-step: more effective strategy for persisting pain.

34. The First Step: mild pain Recommendations: Paracetamol and ibuprofen choice for first step (mild pain) widely available in child-appropriate dosage forms oral liquids relatively inexpensive

35. ANALGESIC MEDICATIONS: Non-opioids Acetaminophen: inhibits prostaglandin synthesis lacks the sedative effects minimal anti-inflammatory effect no side effects such as gastritis and inhibition of platelet Aspirin and NSAIDs in cancer patients: risk for bleeding Aspirin: irreversible inhibition of platelet

36. WHO PAIN 2012 guidelines

37. The Second Step: Moderate to Severe pain Recommendations: Morphine drug of choice other strong opioids intolerable side-effects. Administer opioid analgesics in the first step: clinical judgement careful considerations of the disability caused by pain

38. Strong Opioids Morphine: first choice metabolize in the liver widely used It can be administered: oral, rectal, IV, SQ, epidural, intrathecal, or intraventricular Starting dose for immediate-release oral morphine 0.1 mg/kg q4 hours. Very young infants should receive a reduced dose due delayed clearance

39. Strong Opioids: Hydromorphone: oral, IV, SQ, epidural, and intrathecal used if there are dose-limiting side effects from morphine. 5-8 times as potent as morphine. Fentanyl: transdermal, oral transmucosal, and IV 50-100 times more potent than morphine very rapid onset: high lipid solubility shorter duration of action after IV administration: used in patients with dose-limiting side effects: pruritus

40. Strong Opioids: Meperidine no advantages over morphine major drawback: can cause dysphoria, excitation, and convulsions, particularly in patients with impaired renal clearance Methadone synthetic opioid that has a prolonged duration of action its potency is similar to morphine. convenient as a long-acting medication in patients who are unable to swallow slow-release morphine tablets

41. WHO PAIN 2012 guidelines

43. Tramadol Centrally acting analgesic with opioid effects Control of moderate to moderately severe pain Food does not affect its rate of absorption Dosing: 17 years of age and over: Starting dose: 25 mg/day q AM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). How supplied: 50 mg tab

44. Codeine Excluded for pain relief from the two-steps Codeine “weak” opioid widely available previously recommended to control moderate pain. well-known safety but efficacy problems genetic variability in biotransformation.

45. Codeine: prodrug enzyme CYP2D6: converted into its active metabolite morphine. efficacy depends on the amount of active metabolite. variable expressions of the enzymes inter-individual and inter-ethnic differences Fetus: absent or less than 1% Children less < 5 year: 25% of the adult values

46. Excluded medicine for pain relief: Codeine Poor metabolizers: vary in ethnic groups from 1% to 30% ineffectiveness Rapid metabolizer: metabolize codeine quickly and extensively risk of severe opioid toxicity, high and uncontrolled conversion into morphine.

47. SYNDROMES OF PEDIATRIC CANCER PAIN Treatment-Related Syndromes Tumor-Related Syndromes

48. Treatment-Related Syndromes: Mucositis Optimal management is not well established. S/P BMT: more intense and prolonged that chemotherapy-related. Therapy: topical therapies: sodium bicarbonate, hydrogen peroxide, nystatin, viscous lidocaine, dyclonine, systemic therapies: opioids and systemic antifungal agents.

49. Treatment-Related Syndromes: Graft-Versus-Host Disease May be associated with severe abdominal pain. GVHD is the next most common cause of pain after an allogeneic BMT Pain due to GVHD frequently requires the administration of opioids

50. Treatment-Related Syndromes: Phantom Limb Pain Common among children after amputation of an extremity Incidence/severity decrease with time after amputation Prior treatment with chemo increased the risk after subsequent amputation. Therapy: tricyclic anti-depressants opioids seen to be ineffective early and frequent use of a limb prosthesis may reduce the duration and severity

51. Treatment-Related Syndromes Infection Usually associated with an acute illness. Common causes: perioral perirectal skin infection (particularly at sites of intravenous access). Acute herpes zoster is associated with post-herpetic neuralgia severe burning and skin hypersensitivity that persists years Treatment: antiviral agents tricyclic antidepressants anticonvulsants

52. Treatment-Related Syndromes Antineoplastic Therapy—Related Pain Peripheral venous injection: thrombophlebitis associated with local pain leucovorin, thiotepa Intrathecal chemotherapy: arachnoiditis and meningeal irritation syndrome (i.e., headache, nuchal rigidity; fever, nausea, and vomiting). Chemotherapy: Vesicants: local necrosis Irritants: burning or inflammation without necrosis. painful vincristine neuropathy.

53. Treatment-Related Syndromes Procedure—Related Pain Needle Puncture: major source of distress must be adequately prepared before their first needle puncture to minimize their fear and anxiety. Topical treatments: local anesthetics: EMLA skin cooling and EMLA can produce vasoconstriction, which may occasionally make venous cannulation more difficult.

54. Lumbar Puncture Bone Marrow Aspiration Lumbar puncture: puncture of the skin by the spinal needle or by contact with bone Spinal headache: cerebrospinal fluid leak. (epidural blood patch) BMA/Bx: needle through the periosteum suctioning of the marrow Treatment: EMLA or other topical conscious sedation: Propofol

55. Tumor-Related Syndromes Tumor commonly causes pain from involvement: Bone: Somatic pain Viscera: Visceral pain Nerves: Neuropathic pain Bone metastases: cause pain by stimulation of nerve endings in the endosteum by the destroyed bone tissue periosteum is more sensitive than bone marrow and cortex

56. BONE PAIN Tumor involvement of bone is the most common cause of cancer pain Type of tumors: Neuroblastoma, ostesarcoma, Ewing sarcoma: Breast, lung, prostate, and multiple myeloma: high incident of bone metastatic cancer Common sites: Vertebral, skull, humerus, ribs, pelvis, and femur. Pain due to bone metastases has an important negative impact on quality of life

57. Bone Pain: Pathophysiology Caused by imbalance between bone formation (mediated by osteoblasts) and resorption, which is mediated by osteoclasts. Purely somatic unless a pathologic fracture or tumor extension disrupts a nerve. Avascular necrosis steroid treatment Osteoradionecrosis may develop months or years after irradiation. Pseudorheumatism may result from the rapid withdrawal of corticosteroids reinstitution of steroid treatment followed by slow withdrawal confirms the diagnosis by relieving the arthralgias and myalgias

58. Bone Pain Diagnosis Plain x-rays may show lytic or blastic lesions. CT scan may further define the morphology Bone scans: more sensitive than plain x-ray, but may be negative with purely osteolytic lesions MRI: less sensitive than x-ray or CT for cortical bone destruction may show marrow edema and soft tissue extension

59. Bone Pain: lesion

60. BACK PAIN Cancer: <1 percent of back pain But 98% of known cancer patients who present with back pain will have evidences of metastases. Thoracic spine, is the most common site of bony metastasis Symptoms: High cervical spine: posterior headache (? tension headache) C7 to T1 refer to the interscapular region T12 or L1: refer pain to the flank, iliac crest, or sacroiliac joint Sacral destruction: saddle distribution Loss of motor function, hyperreflexia or hyporeflexia, or bowel or bladder dysfunction are suggestive of myelopathy. prompt immediate intervention

61. BACK PAIN Diagnostic evaluation: Plain radiographs will detect appx.70 % MRI or CT/myelography should be added if plain films are normal and there is a high suspicion of tumor. Bone scan: appropriate when suspicion of tumor is low and the X-ray is normal sensitivity of bone scan is high, especially for osteoblastic lesions and fracture.

62. Freidrichsdorf and Postier (2014) Journal of Pain Research 2014:7

63. References Overview of cancer pain, Z.H Bajwa, C. A. Warfield,UpToDate: July 17, 2007Z.H BajwaA. Warfield Cancer pain syndromes, Z.H Bajwa, C. A. Warfield,UpToDate: July 17, 2007Z.H BajwaA. Warfield Pain Assessment and Management in Infants With Cancer, Bonnie Stevens, PhD* Pediatr Blood Cancer 2007;49:1097—1101 Symptom Management in Supportive Care; P.A. Pizzo, D. Poplack, Principles and Practice of Pediatric Oncology, 4 th edition WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses 2012. Freidrichsdorf and Postier (2014), Management of breakthrough pain in children with cancer, Journal of Pain Research 2014:7 117-123