The Challenges of relieving
cancer pain in 2014
Bernard J. Lapointe, MD
Eric M. Flanders Professor of Palliative
Medicine, McGill University, Montreal,
Canada
Potential conflict of interest
• During the last two years period:
– Consultant for NeoMed Institute.
– Co-lead investigator of Tectin for Cancer Pain
sponsored by Wex Pharmaceuticals.
– Consultant for Teva Pharmaceuticals Canada
© Bernard Lapointe
The relief of cancer pain remains a
true challenge in 2014
• According to a meta-analysis of literature, almost 50%
of cancer patients are under-treated. See Dandrea, Ann Onc,
2008
• WHO 1986 recommendations lead to an efficacious
pain management for about 80% of patients living with
cancer
• However this means that for 20% of our patients
existing approaches do not bring the expected benefit
• Prevalence on the rise (more than 2 millions North
Americans diagosed with cancer in 2013)
• One Canadian on four will develop cancer.
© Bernard Lapointe
PAIN MANAGEMENT GOALS:
• Improve quality of life
• Reduce pain intensity
• Improve functional
capacity.
– physical
– psychosocial
• Minimal side-effects
© Bernard Lapointe
Modify Pain Perception:
 ANTINOCICETIVE: decrease
intensity of ascending
nociception
 ANALGESIC: amplify the natural
inhibitory patways
Ascending
Pathways
Painful
Stimulus
Descending
Pathways
Treatment Modalities
•
•
•
•
•
Provide an explanation
Raise the pain threshold
Provide a psychological intervention
Modify lifestyle
Modify the pathological process
–
–
–
–
Usually good disease control equals good symptom control
Surgery
Chemotherapy, hormone therapy, immunotherapy
radiotherapy
• Modify pain perception
– Anti-nociception
– analgesia
• Interrupt pain pathway (nerve block)
© Bernard Lapointe
Psycho-behavioural interventions
• Provide an explanation and education
• Impact on the intensity of pain
• Higher satisfaction toward care received
• Less undesirable side-effects.
• Raise pain threshold
•
•
•
•
Sleep, anxiety, depression
Distraction, support
Intervention by psychologist often very helpful
Role of hypnosis
• High level of evidence for psychosocial
interventions documented in current systematic
review. See Sheinfeld-Gorin, Jclin Onc, 2012
Primary intent treatment
•
•
•
•
Chemotherapy
Surgery
Radiotherapy
In the case of concomitant infection,
antibiotherapy
Bone Related Cancer Pain new model
• Multiple sources of nociception
– Inflammatory reaction surrounding the tumor
– Secretions of the tumor ( NGF)
– Osteoclast activity in the case of tumor related
bone pain
– Damage to nervous system
• Peripheral
• central
Cancer pain model.
Antinociception.
Nerve growth factor
(NGF) induces sprouting
and neuroma formation
by sensory and
sympathetic nerve
fibers in a model of
skeletal pain. When
GFP+ tumor cells invade
the periosteum, they
induce ectopic
sprouting of CGRP+
sensory fibers (D,
arrow) and the
formation of neuromalike structures.
Tumor derived products
•
•
•
•
•
•
Prostaglandins
Endothelins
Tumor Necrosis Factor (TNF)
Interleukins IL-1 and IL-6
Epidermal growth factor
Nerve Growth Factor:
– Ability to directly activate sensory neurons expressing TrkA receptors
– Modulate also the expression of large number of molecules and
proteins ( substance P, cgrp, bradikinins)
– Appears to be involved in
• Upregulation
• Sensitization
• Disinhibition of multiple neurotransmitters, ion channels in afferent nerve
and DRG fibres
• 80% of C fiber innervating bone carry TrKa compared to 30% of C fibers
innervating skin
© Bernard Lapointe
Novel target: Trk receptor
(tropomyosin-receptor-kinase)
• Tanezumab
– is a monoclonal antibody
against nerve growth
factor
• Currently phase 3 trials
in bone related cancer
pain ( breast and
prostate)
• Other trials on chronic
pain syndromes
Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain
Juan Miguel Jimenez-Andradea,
Joseph R. Ghilardib, Gabriela Castañeda-Corrala, Michael A. Kuskowskic, Patrick W. Mantyha, b, d, Corresponding author contact information, E-mail
the corresponding author, Pain 2011
Cancer pain model.
Antinociception.
Dealing with inflammation
Acidosis in bone cancer pain
• Acidosis triggers ASIC2 and TRPV1 receptors
• Inflammation lowers the pH
• Osteoclasts maintain acidic micro-environment
• Inflammation surrounding tumour as well
contributes to maintain an acidic micro-environment.
• The role of the vanilloid receptor TRPV1
© Bernard Lapointe
corticosteroids
• Very useful when there is a ‘pain crisis’
• ‘cooling effect’
• Relative risks and benefits of the various
corticosteroids are unknown
– Dexamethasone is often selected because of low
mineralo-corticoid
– Methylprednisolone
© Bernard Lapointe
Non-steroidal anti-inflammatory
agents:
•
•
•
•
•
•
Ceiling effect
start treatment at the lowest recommended dose
wide inter-individual variability
monitor closely patients ( acute renal insufficiency)
Cytoprotection of gastric mucosa is indicated
Clear evidence to support superior safety or efficacy
of one NSAID over another is lacking.
© Bernard Lapointe
Cancer related bone pain
• Dramatic proliferation of
osteoclasts at the tumor
bone interface
• Pain intensity correlates
with tumor growth and
progression of tumor
induced bone destruction
• Secretion of humoral and
paracrine factors by tumors
cells stimulates osteoclast
activity
A new target: OPG-RANK-RANKL
• In animal experiments, RANKL inhibition disrupted the
‘vicious circle’ of bone corrosion and growth of the
tumor.
• In 2012 two important publications:
– RCT denosumab vs zoledronic acid in 2046 patients effect on pain.
Statistically significant 4 month delay in progression to moderate/severe
pain observed with denosumab. Cleeland, Cancer 2012
– Combined analysis of 3 RCTs. Denosumab superior to zoledronic in
delaying time to skeletal complication. Lipton, Eur J Cancer, 2012
• OPG and OPG-ligands RANK ligands are a promising
future treatment options for the prevention and
treatment of cancer pain and skeletal complications
due to bone metastasis.
© Bernard Lapointe
Osteosarcome murin et OPG
Pharmacological targets (cancer related
pain)
•
•
•
•
Inflammation
Tumoral secretions (NGF, Cgrp, PGE2)
RANKL, RANK, OPG (bone metastasis)
Vanilloïd Receptors TRPV1
•
•
Voltage gated Na+
Voltage gated Ca++
•
•
•
•
•
Opioid receptors
Cannabinoid receptorsCB1
5ht3 receptors( sérotonergiques )
Alpha-2 adrenergic receptors (adrénaline)
Glutamate receptors (NMDA )
© Bernard Lapointe
Features of an Ideal Pain Medication?
• Highly effective
• Quick onset of action
• Long duration
• Good tolerability
• Low abuse potential
© Bernard Lapointe
The WHO analgesic ladder
3
1
mild to
moderate
2
severe
moderate
to severe
Opioid for
Nonopioid
(paracetamol / NSAIDS moderate pain
 nonopioid
COX2 inhibitor)
 adjuvant
 adjuvant
Opioid
for severe pain
 nonopioid
 adjuvant
Controversial aspects Second Step of
WHO analgesic ladder
• Lack of definite proof of efficacy of weak
opioids ( codeine, tramadol, dihydrocodeine)
for cancer pain. See ESMO, 2012
• Ceiling effect
• We need randomized studies
• Many authors have proposed the abolition of
the second step of the ladder in favour of the
early use of a step III opioid ( morphine,
oxycodone, hydromorphone ) at low dose.
© Bernard Lapointe
Strong Opioids for cancer pain
• Opioids produce analgesia through
interactions with three major opioid
receptors: µ, Ķ, ɖ
• Multiple distinct opioid receptor subtypes
have been described
© Bernard Lapointe
Inter-individual variability in the
response to Opioids
• Wide variability which has implications for our
practice (Pasternak, JCO, June 2014)
• Eg: redheads have mutated melanocortin
receptors
– Show increased pain tolerance
– Show also increased analgesic response to opioids.
• Inter-individual variability in the response to one
single agent. Raises the question of combination
of opioids. See Davis, Expert Opinion, 2012.
© Bernard Lapointe
Opioids commercialized in Canada
PO(ir)
Morphine
X
Oxycodone
X
Oxycodone/naloxone
Hydromorphone X
Fentanyl
Tramadol
X
Codéine
X
Meperidine
Méthadone
X
Sufentanil
Tapentadol
Buprenorphine
IV
X
PR
X
X
X
X
X
X
X
X
LC
X
X
X
X
X
X
X
TD
TM
X
X
(X)
X
X
X
X
AP
X
X
PO : voie orale; IV : voie intraveineuse ou sous-cutanée; PR : voie rectale; LC : libération contrôlée;
TD : voie transdermique; TM : transmuqueuse; AP : action prolongée
First line opioid options for step III
• Morphine
• Concerns arising about poor and variable oral bioavailability and
the presence of pharmacologically active metabolites. See
McPherson, IASP, Pain2012
•
•
•
•
Hydromorphone
Oxycodone
Fentanyl
All have similar efficacy and side-effects for moderate
to severe cancer pain. However opioid selection is
based on consideration of:
– Patient-related variables
– Drug-related variables
© Bernard Lapointe
Opioid rotation (switching)
• Opioid rotation is considered when:
– Avoid tolerance
– Inadequate analgesia when despite dose increase
– Intolerable adverse effects develop
• Despite lack of solid evidence it is generally
accepted as clinical practice
• Most controversial drug for switching is
methadone and vast majority of studies with this
drug.
• Some guidelines published. See Fine, Portenoy, J Pain
Symptom Manage 2009
© Bernard Lapointe
Combination of step lll opioids
• Use of a single strong opioid in cancer pain
management has been common practice for
decades; however it is evident that opioid
prescribing practice is in a degree of
metamorphosis.
• Systematic review published EAPC. Weak
recommendation. See Fallon Pall Med 2010.
• Implications for patient
• Need for more studies (gulf between the bench and the
clinic)
© Bernard Lapointe
methadone
• 2013 more controversies
– Has a unique pharmacology
– Due to highly variable and prolonged half-life, methadone
has the highest risk of among opioids of accumulation and
overdosage
– Marketed in most of the world as a racemate mixture
• D-isomer being a relatively potent N-methyl-D-aspartate inhibitor
and not an opioid
• Can prolong QTc interval
– Analgesic role of methadone in treating cancer-related
pain remains to be supported by strong evidence.
Currently the data allows for a weak recommendation.
© Bernard Lapointe
• Combination of level III opioid with methadone
• Some data beginning to be published
– Letters to editor (10- 3 cases) Haughey McKenna J.
Pain Sym Man 2011, 2012.
– Retrospective analysis 16 cases. Wallace J Pallmed
2013
• Potential benefits:
– Practical and safe
– Avoid having to calculate an equi-analgesic dose
– Low doses of methadone at the start ( 1,5-6mg /
24hrs)
© Bernard Lapointe
Characteristics of Breakthrough Pain
1) Moderate to severe intensity
No relation to intensity of the background (chronic)
pain
2) Rapid Onset ( usually peak intensity 5-10
minutes)
3) Short Duration (generally less than 30 min.)
4) Occurs Frequently ( more than 3-4 episodes
day)
Portenoy RK and Hagen NA. Pain 1990;41:273–281.
© Bernard Lapointe
Pharmacological management of
breakthrough cancer pain
• Current approaches to the pharmacological management of
BTcP include the optimization of basal analgesia.
– titrating dose of long acting opioid to improve analgesia of
baseline pain ( particularly if numerous episodes)
• This might increase prevalence and severity of sedation at rest.
– addition of rescue analgesia:
- immediate-release opioids
– adjuvant therapies ( to prevent episodes eg.
Gabapentinoid in prevention of neuropathic pain flareups)
© Bernard Lapointe
The classical approach.
•Standard recommendation: 1/6 to 1/10 of 24hr dose
of ATC opioid. Usually q 1h prn.
•However, it is more and more evident that there is
very little relationship between the intensity of the ATC
pain and the paroxystic nature of certain episodes of
BTcP. Thus the need to individualized titration.
Davis, Mellor P. et al. Lancet Oncology. 2005
© Bernard Lapointe
The classical approach fails many patients
• Breakthrough pain can be sudden in onset, severe, and of brief duration
leading to a clinical challenge
– Average time to meaningful pain relief is 30-45 min for po opioids
(whereas the average duration of breakthrough pain in these patients
is 35 min)
• For example oral morphine immediate release:
– Time to onset of analgesia of approx 30 minutes
– Takes 1,1 hour to achieve maximal plasma conc. (Cmax)
– Extensive first pass metabolism and poor bioavailability
• A range of other routes, drugs and drug delivery systems have been
evaluated
– Faster relief of pain
– Hopefully shorter half-life
© Bernard Lapointe
Methods of Administration
• Oral transmucosal opioids
– Rapid absorption, convenient (some formulations more than others)
• Inhaled
– Lungs present large surface for drug absorption
– Inhalation may be difficult for certain patients
• Intranasal
– Rapid onset of action
– The nose is able to accommodate a relatively small volume of drug
• Sublingual
– Rapid absorption, convenient
– Sublingual absorption must be rapid, limited space therefore relatively
small volume of drug
40
© Bernard Lapointe
Characteristics of opioids used for
breakthrough pain
Opiod
Analgesic onset Availabilty (%)
(min)
Oral morphine
30-45
30
Oral oxycodone
30-45
40-50
OTFC
15
50
FBT (buccal tablet)
15
65
SLF (sublingual)
15
70
INFS (intranasal)
5-10
70-90
FPNS (f pectin nasal)
5-10
70-90
Which formulation to select.
• Although the efficacy of all of the available
agents for BTP has been demonstrated by
RCTs, a lack of head-to-head evaluations
makes it challenging for physicians to select
based on efficacy alone.
• Meta-analysis have been attempted byt
differences between populations studied and
design prevent comparison.
© Bernard Lapointe
Safety / tolerability
• It must be emphasized that fentanyl is a highly
potent opioid, the use of which leads to peak
concentrations similar to those of intravenous
administration, and thus needs to be handled
responsibly by both doctors and patients.
• There are case reports of misuse. NunezOlarte.jpainsymman,2011
© Bernard Lapointe
Evidence based recommendations:
• The data permit a strong recommendation that pain
exacerbations resulting from uncontrolled background pain
should be treated with additional doses of immediaterelease oral opioids, and that an appropriate titration of
around the clock opioid therapy should always precede the
recourse to potent rescue opioid analgesics.
• Breakthrough pain can be effectively managed with oral
immediate-release opioids or with buccal or intranasal
fentanyl preparations.
• In some cases the buccal or intranasal fentanyl
preparations are preferable to immediate-release oral
opioids because of more-rapid onset of action and shorter
duration of effect.
Use of opioid analgesics in the treatment of cancer pain: evidence-based
recommendations from the EAPC, 2012.
Evidence based recommendations:
• Recommendations:
• Immediate release formulation of opioids must be used to
treat
• exacerbations of controlled background pain [I, A].
• Immediate release oral morphine is appropriate to treat
predictable episodes of BTP (i.e. pain on moving, on
swallowing, etc.) when administered at least 20 min
beforesuch potential pain triggers [II, A].
• Intravenous opioids; buccal, sublingual and intranasal fentanyl
drug delivery have a shorter onset of analgesic activity in
treating BTP episodes in respect to oral morphine [I, A]
– ESMO Cancer Pain, Annals Oncology, 2012
© Bernard Lapointe
Evidence based recommendations:
• Key results available data suggest that both oral and nasal
transmucosal fentanyl citrate are safe and effective
(compared with both placebo and morphine) in relieving
breakthrough pain.
• The side effect profiles of oral and nasal transmucosal
fentanyl citrate were similar to other opioids.
• Recommendations are made about future clinical trials.
Quality of the evidence We could wish for more consistency in
study design and more studies comparing the oral and nasal
transmucosal fentanyl citrate formulations to one another.
– Cochrane Review, Opioids for the management of breakthrough pain
in cancer patients -2013
© Bernard Lapointe
Take Home messages
 Choice of formulation remains aleatory. No head-tohead comparisons
 No correlation between background pain and intensity
of the BTcP
 Always titrate to relief of episode
 Never use in an opioid naïve patient
© Bernard Lapointe
Take home messages:
• ALWAYS evaluate the risk for substance abuse in every
patient.
• Despite recent publication of a study concluding that
SLF given in doses proportional to the basal opioid
regimen for the management of BTP is safe and
effective ( see Mercadante,CMRO,2013): Titration strategies
should always be established following
recommendations of the manufacturer.
• Again most studies have shown no meaningful
relationship between the effective dose of
transmucosal opioid and the around-the-clock
scheduled medication.
© Bernard Lapointe
49
Symptomatic Management of
Breakthrough Pain
• Prevalence is reported with a wide range ; 1995%
• Breakthrough pain can be sudden in onset,
severe, and of brief duration leading to a clinical
challenge
– Average time to meaningful pain relief is 30 min for po
opioids (whereas the average duration of
breakthrough pain in these patients is 35 min)
• A range of other routes, drugs and drug delivery
systems have been evaluated
– Faster relief of pain
Davis, MP et al. Lancet Oncol. 2005;6:696-704
© Bernard Lapointe
A word of Caution:
• The various new formulations of
transmucosal Fentanyl for BTcP are
not equianalgesic and are not
therefore interchangeable.
© Bernard Lapointe
Should our prescriptions change when
offering Supportive care ?
• Long term effects of the prescription of strong
opioids never questioned in the past when we
only treated terminally ill patients
• Today:
– Patients undergoing active treatment
– Patients in remission
• Prevalence of opioid misuse is unknown in
cancer patients. Is it that different from that
of chronic non-malignant pain ?
© Bernard Lapointe
Non-Neuronal Effects of Morphine
• Morphine has been demonstrated to up-regulate release of
growth factors and other agents within the CNS and periphery
known to:
– Mediate enhanced pain sensitivity
– Modulate bone remodelling
– Modulate tumour growth
• King, T, University of Arizona. IASP, Chicago June 3-4,
2009
© Bernard Lapointe
Numbers needed to treat in peripheral and central neuropathic
pain
Adjuvant analgesics used for
neuropathic pain
• Adjuvant analgesics improve pain control within 4-8 days
when added to opioids to manage cancer pain. See Bennett
Pall Med 2010
• Tricyclic antidepressants.
• Efficacy is independent of their antidepressant effect.
• Action on descending modulatory inhibitory controls
• Most common side effects are anticholinergic and can also cause
cognitive disorders of confusion in elderly. Nortriptyline preferable.
• Starting dose 10-25 mg qHs
• SNRIs
• Duloxetine, venlafaxine
• Discontinuation rate 15-20%
• Duloxetine starting dose 30mg, to60-120mg die, venlafaxine high dose
150-225mg/d useful. see Attal, Cont Lifelong Learning Neurology 2012.
© Bernard Lapointe
Adjuvant analgesics used for
neuropathic pain
• Alpha-2-delta ligand agonists.
• Gabapentin and Pregabalin.
• Action on calcium channels
• Side-effects include dizziness, somnolence, peripheral
edema, weight gain, dry mouth
• Reduced dosage in renal insufficiency
• Older anticonvulsants
– Valproic acid.
© Bernard Lapointe
• Chronic gabapentin
administration
attenuates ongoing and
movement-evoked pain
behaviors and improves
ambulatory scores in
mice with bone cancer
C.M. Peters, Experimental neurology 2005
Emerging treatment for neuropathic
pain
• Cannabinoids.
• Therapeutic potential extensively investigated in chronic pain.
• In Canada oro-mucosal formulation of nabiximols ( THCcannabidiol) and oral nabilone
• Adverse effects: dizziness, dry mouth, sedation, fatigue, gi effects.
• Botulinum Toxin Type A.
• May have analgesic effect independent of its action on muscle
tone, possibly by acting on neurogenic inflammation.
• Three single-center RCTs reported long-term (3 months) efficacy of
a series of subcutaneous injections (from 100-200u). See Xiao, Pain
Med 2010.
© Bernard Lapointe