PAIN MANAGEMENT IN CHILDREN WITH CANCER

1
PAIN MANAGEMENT IN CHILDREN WITH CANCER

• Dr. John J. Collins AM, MB BS, PhD, FFPMANZCA,
  FRACP
• Head of Department
• Pain Medicine Palliative Care
• The Childrens Hospital at Westmead
• Sydney, Australia

2
OBJECTIVES

• DISCUSS
• The symptoms of children with cancer
• Standards for cancer pain management
• Clinical and translational research
• Analgesic prescription at end of life
• Strategies for the management of intractable pain
  in children

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PREVALENCE AND CHARACTERISTICS OF SYMPTOMS IN
CHILDREN WITH CANCER AGED 10-18 (n159)

• Degree when symptom was present
• Overall
  Intensity Frequency
  Distress
• Symptom prevalence () Mod-V
  Sev () A lot-AA
  () QB-VM ()
• Lack of energy 49.7 61.6
  40.9 21.4
• Pain 49.1 80.8
  35.9 39.1
• Feeling drowsy 48.4 64.0
  34.6 18.6
• Nausea 44.7 65.9
  23.0 36.6
• Cough 40.9 47.7
  23.0 16.3
• Lack of appetite 39.6 66.3
  39.7 35.8
• Feeling sad 35.8 59.6
  17.5 39.5
• Feeling nervous 35.8 56.1
  28.1 23.7
• Worrying 35.4 66.1
  28.6 27.2
• Feeling irritable 34.6 63.6
  30.9 34.7
• Percentage moderate to very severe Percentage a
  lot to almost always Percentage quite a bit
  to very much.
• NE, not evaluated

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EXPECTED STANDARDS OF PAEDIATRIC CANCER PAIN
MANAGEMENT

• 1998 WHO monograph Establishing universal
  standards, irrespective of cancer treatment
  options
• 2011 WHO monograph
• The pharmacological management of children with
  persisting pain due to medical illness

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EXPECTED STANDARDS FOR ACUTE PAIN MANAGEMENT

• ASSOC. PAEDIATRIC ANAESTHETISTS GREAT BRITAIN
  IRELAND www.apagbi.org.uk/docs/APA_Guidelines_on_
  Pain_Management.pdf
• AMERICAN PAIN SOCIETY
• http//www.ampainsoc.org/advocacy/pediatric2.htm
• AUST. NZ COLLEGE OF ANAESTHETISTS NHMRC
• www.anzca.edu.au/resources/books_and_publications/
  acutepain_update.pdf

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EXPECTED INTERNATIONAL NATIONAL STANDARDS for
PROVIDING PALLIATIVE CARE
American Academy of Pediatrics Pediatrics 106
(2) 351-357, 2000 www.palliativecare.org.au
Eur J Pall Care, 2007 14 (3), 109-111
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CLINICAL RESEARCH PAEDIATRIC CANCER PAIN
MANAGEMENT
AUTHOR YEAR OUTCOME TYPE OF STUDY
Collins et al 1998 The epidemiology of intractable pediatric cancer pain Survey
Collins et al 1999 The management of intractable pediatric cancer pain Survey
Collins et al 2000 PCA morphine/hydromorphone for mucositis pain in children with cancer Randomised, 3 period cross-over
Collins et al 2000- 2002 The epidemiology of pain and other symptoms in children with cancer Validation study
Drake et al 2000 Opioid rotation in paediatrics Survey
Friedrichsdorf et al 2005 Breakthrough cancer pain in children Survey
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TRANSLATIONAL RESEARCH PAEDIATRIC CANCER PAIN
MANAGEMENT

• Basic sciences have shown cancer induced bone
  pain (CIBP) is distinct from other chronic pain
  states, such as inflammatory or neuropathic pain
• A. Delaney, S. M. Fleetwood-Walker, L. A.
  Colvin, M. Fallon. British Journal of Anaesthesia
  2008 101(1)87-94
• A translational medicine approach may allow
  improved understanding of the underlying
  mechanisms of CIBP to improve cancer pain
  management in children

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TRANSLATIONAL RESEARCH PAEDIATRIC CANCER PAIN
MANAGEMENT

• MECHANISMS of CIBP
• Tumour type, site extent of bony destruction
  may influence the mechanisms of CIBP
• 1. PERIPHERAL FACTORS
• Direct effects -pressure/compression
  nerves -sensitization periosteal afferents
• -peripheral nerve sensitisation due to
  cytokines
• -osteoblast inflammatory response ?cytokines
  ? ?osteoclast activity
• ? nerve injury ? PAIN

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TRANSLATIONAL RESEARCH PAEDIATRIC CANCER PAIN
MANAGEMENT

• MECHANISMS of CIBP
• 2. CENTRAL EFFECTS
• Changes in the endogenous opioid system ? mu
  opioid receptors in DRG higher doses of opioid
  needed
• Sensitisation of Wide Dynamic Range (WDR)
  neurones in the spinal cord with ?responsiveness
  to mechanical thermal stimuli

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COMBINATION ANALGESIC THERAPY

• A combination analgesic therapeutic approach to
  cancer pain management, may be the most
  appropriate approach
• Gordon-Williams, R.M., Dickenson, A.H. Central
  neuronal mechanisms in cancer-induced bone pain.
• Curr Opin Support Palliat Care 16-10 2007

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ANALGESIC PRESCRIPTION AT THE END OF LIFE
IN CHILDREN WITH CANCER, 1996

• Conventional analgesic doses and routes is
  achievable for the majority of children with
  cancer
• Approx. 6 of these patients required massive
  doses of an opioid infusion
• Half required extraordinary analgesic
  measures, such as sedation or subarachnoid
  infusions
• Regional anaesthetic techniques are infrequent
  in treating pain at end-of-life for children with
  cancer
• Collins JJ, Grier HE, Kinney HC, Berde CB.
  Control of severe pain in terminal pediatric
  malignancy. Journal of Pediatrics 1995
  126(4)653-657
• Collins JJ, Grier HE, Sethna NF, Berde CB.
  Regional anesthesia for pain associated with
  terminal malignancy. Pain 1996 6563-69

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CHANGING MANAGEMENT OF INTRACTABLE PAIN IN
CHILDREN WITH CANCER

• Practice has become more sophisticated, greater
  understanding of
• 1. Management of the paediatric pain crisis
• 2. Calculation of opioid rescue dosing and
  dose escalation
• 3. Opioid switching
• 4. Management of opioid side-effects
• 5. NMDA antagonists as new therapeutic options
• 6. Combination analgesic chemotherapy
• 6. Invasive approaches to pain management in
  children
• Fewer children may need to be sedated to reduce
  conscious awareness of intractable symptoms

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THE PAEDIATRIC PAIN CRISIS

• Emergency
• Make a diagnosis
• Titrate incremental intravenous opioid doses
  every 10-15 minutes until analgesia effective
• Analgesic effect of opioids increase in a
  log-linear function, with incremental opioid
  dosing required until either analgesia is
  achieved or somnolence occurs
• Total amount of opioid administered is the
  opioid loading dose
• A continuous infusion of opioid may need to be
  commenced to maintain this level of analgesia
• Cherny NI, Foley KM. Nonopioid and opioid
  analgesic pharmacotherapy of cancer pain. In
  Cherny NI, Foley KM, editors. Hematol Oncol Clin
  North Amer. 1996 79-102

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BREAKTHROUGH CANCER PAIN IN CHILDREN

• Breakthough cancer pain in children is
• - severe
• - sudden in onset
• - short-lived
• Unclear what is the best breakthrough dose.
  This is probably better determined by the nature
  of the pain being treated.
• Role of oral opioids??
• Friedrichsdorf, S, Collins JJ. Breakthrough pain
  in children with cancer. 200734(2)209-216.Journa
  l of Pain and Symptom Management

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OPIOID SWITCHING

• Indication is dose-limiting opioid side-effects
  preventing opioid dose escalation
• Changing opioids is often accompanied by change
  in ratio between analgesia and side-effects,
• Following a prolonged period of regular dosing
  with one opioid, equivalent analgesia may be
  attained with a dose of a second opioid that is
  smaller than that calculated from an
  equianalgesic table
• Galer BS, Coyle N, Pasternak GW, et al.
  Individual variability in the response to
  different opioids report of five cases. Pain
  1992 4987-91
• Portenoy RK. Opioid tolerance and
  responsiveness research findings and clinical
  observations. In Gebhart GF, Hammond DI, Jensen
  TS, editors. Progress in Pain Research and
  Management. Seattle IASP Press, 1994 615-619

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OPIOID SWITCHING PAEDIATRIC DATA

• Review of opioid prescriptions in the Oncology
  Unit, Childrens Hospital at Westmead
• 14 children (n11) had 30 opioid rotations
• Indications
• - opioid side-effects with adequate analgesia
• opioid side-effects with inadequate analgesia
• Outcome Opioid side-effects resolved in 90
  cases
• Drake R, Longworth J, Collins JJ. Opioid
  rotation in children with cancer. Journal of
  Palliative Medicine 2004 7(3)419-42

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NMDA RECEPTOR ANTAGONISTS

• NMDA- receptor antagonists depress central
  sensitisation
• Dextromethorphan, dextrorphan, ketamine,
  memantine and amantadine have been shown to have
  NMDA-receptor antagonist activities
• Clinical usefulness is compromised by an adverse
  effect to side effect ratio
• No data of their utility in paediatrics, other
  than procedural pain management
• Clinical usage is increasing, particularly in the
  setting of severe neuropathic pain and rapid
  opioid dose escalation and perceived tolerance
• Eide PK, Jorum E, Stubhaug A, et a. Relief of
  post-herpetic neuralgia with the
  N-methyl-D-aspartic acid receptor antagonist
  ketamine a double-blind cross-over comparison
  with morphine and placebo. Pain 1994 58347-354
• Persson J, Axelsson G, Hallin RG, et a.
  Beneficial effects of ketamine in a chronic pain
  state with allodynia. Pain 1995 60217-222
• Nelson KA, Park KM, Robinovitz E, et al. High
  dose dextromethorphan versus placebo in painful
  diabetic neuropathy and postherpetic neuralgia.
  Neurology 1997 481212-1218
• Eisenberg E, Pud D. Can patients with chronic
  neuropathic pain be cured by acute administration
  of the NMDA-receptor antagonist amantadine? Pain
  1994 7437-39

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INVASIVE APPROACHES TO INTRACTABLE PAEDIATRIC
CANCER PAIN

• Anaesthetic approaches
• Experience of regional anaesthesia for children
  with intractable pain is limited
• Regional anaesthesia may be appropriate in a
  highly select subset of children
• The indications for regional anaesthesia related
  to either dose-limiting side-effects of opioids
  or opioid unresponsiveness in patients where pain
  was confined to one region of the body
• Rapid intravenous opioid dose reduction was
  required in some cases
• Collins JJ, Grier HE, Sethna NF, Berde CB.
  Regional anesthesia for pain associated with
  terminal malignancy. Pain 1996 6563-69

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SEDATION AS A THERAPEUTIC MODALITY FOR
REFRACTORY PAIN

• Sedation assumes therapies beyond the
  conventional have been utilised and there is no
  acceptable means of providing analgesia without
  compromising consciousness
• Trade-off between sedation and inadequate pain
  relief requires the consideration of the wishes
  of the child and his or her family
• Ethical issues include the principle of double
  effect
• Continuation of high-dose opioid infusions in
  these circumstances is recommended
• A variety of drugs have been used in this
  setting, including barbiturates, benzodiazepines,
  and phenothiazines