PAIN MANAGEMENT IN
CHILDREN WITH CANCER
Dr. John J. Collins AM, MB BS, PhD, FFPMANZCA, FRACP
Head of Department
Pain Medicine & Palliative Care
The Children’s Hospital at Westmead
Sydney, Australia
OBJECTIVES
DISCUSS:
1.The symptoms of children with cancer
2.Standards for cancer pain management
3.Clinical and translational research
4.Analgesic prescription at end of life
5.Strategies for the management of intractable
pain in children
PREVALENCE AND CHARACTERISTICS OF SYMPTOMS IN
CHILDREN WITH CANCER AGED 10-18 (n=159)
Degree when symptom was present
Overall
Symptom prevalence (%)
Intensity
Mod-V Sev (%)*
Frequency
A lot-AA (%)†
Distress
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
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”
EXPECTED STANDARDS FOR ACUTE
PAIN MANAGEMENT
ASSOC. PAEDIATRIC
ANAESTHETISTS GREAT
BRITAIN & IRELAND:
www.apagbi.org.uk/docs/APA_
Guidelines_on_Pain_Manage
ment.pdf
AMERICAN PAIN SOCIETY:
http://www.ampainsoc.org/advoca
cy/pediatric2.htm
AUST. NZ COLLEGE OF
ANAESTHETISTS & NHMRC:
www.anzca.edu.au/resources/boo
ks_and_publications/acutepain
_update.pdf
EXPECTED INTERNATIONAL & NATIONAL
STANDARDS for PROVIDING PALLIATIVE CARE
* Eur J Pall Care, 2007; 14 (3), 109-111
*American Academy of Pediatrics
Pediatrics 106 (2): 351-357, 2000
*www.palliativecare.org.au
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
20002002
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
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
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
TRANSLATIONAL RESEARCH: PAEDIATRIC
CANCER PAIN MANAGEMENT
MECHANISMS of CIBP:
2. CENTRAL EFFECTS
a. Changes in the endogenous opioid system: ↓
mu opioid receptors in DRG + higher doses of
opioid needed
b. Sensitisation of Wide Dynamic Range (WDR)
neurones in the spinal cord with
↑responsiveness to mechanical & thermal
stimuli
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 1:6-10; 2007
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; 65:63-69
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
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: 79102
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. 2007;34(2):209216.Journal of Pain and Symptom Management
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; 49:87-91
**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
OPIOID SWITCHING: PAEDIATRIC DATA
Review of opioid prescriptions in the Oncology Unit, Children’s
Hospital at Westmead*
14% children (n=11) 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
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; 58:347-354
**Persson J, Axelsson G, Hallin RG, et a. Beneficial effects of ketamine in a chronic pain state with allodynia. Pain 1995; 60:217-222
**Nelson KA, Park KM, Robinovitz E, et al. High dose dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia.
Neurology 1997; 48:1212-1218
**Eisenberg E, Pud D. Can patients with chronic neuropathic pain be cured by acute administration of the NMDA-receptor antagonist amantadine? Pain
1994; 74:37-39
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 doselimiting 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; 65:63-69
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