Cancer Pain in Children

13th Annual Palliative Care SeminarHector Rodriguez-Cortes, MD

Pediatric Hematologist and OncologistPediatric Palliative Care and Hospice

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

Introduction Cancer:

evokes immediate fear for patients and their families

potentially fatal diseasecan be associated with pain

Symptoms:may be interconnectedtreatment of one symptom may exacerbate

another

FREQUENCY OF CANCER PAIN 

Multi-factorial:type of malignanciessites of involvementpresence or absence of metastases

Prevalence of moderate/severe painincreases during the late phases of

malignancy

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

EPIDEMIOLOGY OF CANCER PAIN IN CHILDREN

Treatment-related pain: mucositisantineoplastic therapypostoperative painprocedure-related pain

Breakthrough pain in Children with Cancer

Freidrichsdorf and Postier (2014)Breakthrough Pain Questionnaire for Children

57% of children experienced painPain: major tumor tumor surgery >> tumor/ drug-

relatedYounger children (7-12 year of age) at higher risk

than teenagersPCA

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.

Pain Mechanisms

PAIN MECHANISMS:Experience of pain:

Subjectivecan 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.

PAIN MECHANISMS: Terminology

Nociception:sensation of tissue injury or inflammationalerts an individual to potential or ongoing injuryprompts the avoidance or limitation of further injurycan be activated by:

chemical, thermal, or mechanical stimuli lack of it can lead to a variety of medical complications

decubitus ulcers.

Nociception

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 types3. The signals ascend in

the contralateral spinothalamic and spinoreticular tracts

4. thalamus

Somatic pain

TYPES OF PAINPain can be divided into 3 categories:

SomaticVisceralNeuropathic

These categories are not mutually exclusive since a patient's pain may have multiple etiologies.

Somatic painTriggered 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

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

Visceral pain

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.

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

Neuropathic Pain

Neuropathic pain 

Pain Assessment

Measuring PainPain:

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.

Pain measurement toolsVerbal 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

Pain measurement toolsNon-communicate pain:

intensity must be evaluated by other means.nonverbal signs of pain

These include:hypertension, tachycardia, and diaphoresis Agitation or confusionApathy, inactivity, or irritability in patients with

cognitive impairment

Pain measurement tools

Pain Management

Principles for the pharmacological management of pain.

WHO: 1986dosing at regular intervalsusing the appropriate route of administration adapting treatment to the individual child

WHO: 2012using a two-step strategy

Principles for the pharmacological management of pain.

WHO: 1986dosing at regular intervals

steady blood level: reducing peaks and troughsusing the appropriate route of administration

Least invasive route (often chosen by the child)Transdermal patches: long onset time

adapting treatment to the individual childFrequently assessment, reassessment and

modification

Principles for the pharmacological management of pain.

WHO: 1986

WHO: 2012: two-step strategychoice depends on the child’s level of pain.

MildModerate to severe pain

Three-step vs. Two-step approach

Difference: three-step analgesic ladder:

use of codeine as a weak opioidtreatment of moderate pain

two-step approach: low doses of strong opioid

Two-step: more effective strategy for persisting pain.

The First Step: mild painRecommendations:

Paracetamol and ibuprofenchoice for first step (mild pain) widely available in child-appropriate dosage forms

oral liquidsrelatively inexpensive

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

WHO PAIN 2012 guidelines

The Second Step: Moderate to Severe pain

Recommendations:

Morphinedrug of choiceother strong opioids

intolerable side-effects.

Administer opioid analgesics in the first step:clinical judgementcareful considerations of the disability caused

by pain

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

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 IV50-100 times more potent than morphinevery rapid onset: high lipid solubility shorter duration of action after IV

administration: used in patients with dose-limiting side

effects: pruritus

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

WHO PAIN 2012 guidelines

TramadolCentrally 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

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 problemsgenetic variability in biotransformation.

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

Excluded medicine for pain relief:

Codeine Poor metabolizers:

vary in ethnic groups from 1% to 30% ineffectiveness

Rapid metabolizer: metabolize codeine quickly and extensivelyrisk of severe opioid toxicity,

high and uncontrolled conversion into morphine.

SYNDROMES OF PEDIATRIC CANCER PAIN

Treatment-Related Syndromes

Tumor-Related Syndromes

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.

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

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

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

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.

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.

Lumbar PunctureBone 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

Tumor-Related SyndromesTumor 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

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

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

Bone PainDiagnosis

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

Bone Pain: lesion

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

BACK PAINDiagnostic 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.

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

References Overview of cancer pain, Z.H Bajwa, C. A. Warfield,UpToDate: July

17, 2007

Cancer pain syndromes, Z.H Bajwa, C. A. Warfield,UpToDate: July 17, 2007

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 , 4th 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