Cancer Pain Management: Alternative Treatment Options to the Use of Narcotics

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Cancer Pain Management Alternative Treatment
Options to the Use of Narcotics

• Bernard J. Lapointe
• Chief, Palliative Care Division
• Associate Professor, Department of Oncology
  Department of Family Medicine, McGill University

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Disclosure

• Collaborated to clinical research sponsored by
• Janssen-Ortho
• Wex Technology
• Lab Pharma
• Pfizer
• Clinical advisor
• Janssen-Ortho
• Purdue Pharma
• Wex Technology
• Pharmascience
• Received in the past speaker fees from
• Janssen-Ortho
• Purdue Pharma

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Cancer Pain

• Significantly affects the diagnosis, quality of
  life and survival of patients with cancer.
• Cancer Pain can arise
• Direct tumour infiltration/ involvement
• Result of diagnostic / therapeutic surgery
• Side effect or toxicity of therapies
• Mechanism-Based Understanding of Cancer Induced
  Pain is helping us designing targetted
  therapeutic approaches.

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Todays agenda

• Genesis of the signal in the periphery
• Pain secondary to bone metastasis
• Neuropathic pain
• The interneurone
• Normal pain
• Central sensitization
• Central integrationtotal pain

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Can we relieve cancer pain ?

• Pain relief is now possible in 90 of patients
  with relatively simple approaches.
• Optimal relief is achieved in remaining 10 using
  a slightly more complicated approach
• multitherapy
• anaesthetic approaches
• No single drug is likely to be completely
  effective in managing persistent cancer induced
  pain.

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Treatment Options for Chronic Cancer Pain
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The Treatment Continuum
More available

Less available

Less expensive

More expensive

Fewer side effects

More side effects

Less invasive

More invasive

Physical

Psychological
















Pharmacological

Interventional

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Pharmacological management of cancer pain
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The Opioids
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Opioids for cancer induced pain

• Experience suggest that cancer pain can be
  relieved in more than 70 of patients using a
  simple opioid-based regimen.
• Despite all the fears of respiratory depression,
  addiction or diversion, opioids have never been
  shown to cause organ damage when taken
  therapeutically
• Some pain may impart a relatively lesser degree
  of opioid responsiveness

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Adjuvant analgesics

• Adjuvant any drug with a primary indication
  other than pain, but with analgesic properties in
  some painful conditions.
• Often administered as first-line drugs in the
  treatment of chronic non-malignant pain.
• Conventional practice has evolved to view opioids
  as first-line drugs, and adjuvant analgesics
  typically are considered after opioid therapy has
  been optimized.

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Transduction
S.P. c.g.r.p
Tumor
Prostaglandins Endothelins NGF
Damage Inflammation Plasma leakage
Bk
Immune cells
PGe2
cytokines.
Primary Nociceptor Afferent C Fiber
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Dealing with inflammation
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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

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• Long term corticosteroid is generally well
  tolerated
• may increase the risk of peptic ulcer disease (
  role for proton-pump inhibitor)
• the concurrent administration of an NSAID and a
  corticosteroid increases the risk of peptic ulcer
  substantially
• Corticosteroid drugs have several other
  indication (capsular distension, hollow viscus
  obstruction, headache sec brain mets, sudden
  nerve compression)

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NSAIDS including COX-2 inhibitors

• NSAIDS exert both
• Anti-inflammatory
• Analgesic
• By inhibiting PG synthesis via the COX enzyme
• Indiscriminate inhibition of COX activity leads
  to a range of undesirable side-effects (including
  gi ulceration-bleeding)

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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.

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NSAIDs in Chronic PainThe Risk of GI Toxicity

• 4 risk of P/U/B per year
• 12 risk of P/U/B per year with concomitant use
  of SSRI
• Taking an NSAID for two months or more
• 1 in 5 risk of endoscopic ulcer
• 1 in 70 risk of symptomatic ulcer
• 1 in 150 risk of bleeding ulcer
• 1 in 1200 risk of dying from a bleeding ulcer
• Risk factors
• Highly significant risks previous history of
  ulcer or bleed, age 50,
• Less significant risks females, prednisone,
  alcoholic liver disease, NSAIDs in combination,
  COPD and other chronic diseases

McQuay HJ, Moore RA. In Proceedings of the 10th
World Congress on Pain. Jonathon O. et al.
Progress in Pain Research and Management Volume
24, pp 499-510, IASP Press, Seattle.
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NSAIDs better than COXIBs ?

• Optimal analgesia may require COX I and COX II1
• Increased risk of CV events with COXIBs2, 3,4
• COXIBs block prostacyclen but not thromboxane5
• COXIBs have no antiplatelet activity and do not
  substitute for ASA
• Delayed healing of fractures in animals6

1. McCormack, 2002 2. Mukheriee D. Jama 2001
3. Howard PA, Jam Coll Cardiol, 2004 4. Topol
E, NEJM 2004 5. Marcus A.J. NEJM 2002 6. Simon
AM. JBMR 2002
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however

• COX-2 inhibitors significantly decrease both
  ongoing and movement related pain (bone
  metastasis induced pain)
• Acute administration of COX-2 inhibitors reduces
  PG
• Chronic inhibition of COX-2
• Decreases osteoclastogenesis
• Decreases bone resorption
• Decreases tumour burden

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Mantyh Nature Reviews Neuroscience 7, 797809
(October 2006) doi10.1038/nrn1914
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Acidosis in bone cancer pain

• Osteoclasts contribute significantly to aetiology
  of bone cancer pain
• Osteoclasts maintain acidic micro-environment
• Both osteolytic and osteoblastic cancers are
  characterized by osteoclast proliferation and
  hypertrophy
• Role for biphosphonate
• Zoledronic acid, pamidronate, Alendronate,
• ibandronate
• Promising role for osteoprotegerin (OPG) which
  prevents activation and proliferation of
  osteoclasts.

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Other adjuvant analgesics for bone pain

• Calcitonin limited evidence does not support
  its use to control pain from bone mets.
• New targets in development
• Endothelin antagonists (prostate cancer)
• Nerve growth factor

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Pain afferent pathways
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Neuronal damage

• Direct invasion
• Compression
• changes in function of Na channels appear within
  24hrs of the injury
• lower threshold
• reduced recuperation time

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• All anticonvulsants
• 1. block voltage gated sodium channels
• 2. directly or indirectly enhance inhibitory
  GABA-ergic neurotransmission or
• 3. inhibit excitatory glutamatergic
  neurotransmission
• or some combination of the above

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Anticonvulsant drugs Gabapentin.

• Good evidence that the anticonvulsant drugs are
  useful in the management of neuropathic pain.
• Expanding role for the anticonvulsants began with
  the introduction of gabapentin. It is now widely
  used to treat cancer-related neuropathic pain.
  NNT 2,2
• Advantages - proven analgesic effect
• good tolerability
• rarity of drug-drug interactions
• first line agent
• initiated 100-300 up to 3,600
• adequate trial 1-2 weeks at the maximum tolerated
  dose.
• Somnolence can be a limiting factor.

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• Lamotrigine. Was reported to relieve
  non-malignant neuropathic in several randomized
  trials. However adverse effects ( somnolence,
  dizziness, ataxia) require slow titration.
  Potential for Stevens-Johnson syndrome.
• Pregabalin with a mechanism identical to that of
  gabapentin and strong evidence of analgesic
  efficacy. Multi-centre study for cancer induced
  bone pain. Lack significant drug-drug
  interactions.
• Among the older drugs, evidence of efficacy is
  best for carbamazepine , phenytoin, valproate.
• Frequent side-effects (sedation,
  dizziness,nausea, unsteadiness) and potential for
  drug-drug interactions, use has declined.

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• Voltage-gated ion channel modulators sodium
  channel blockers
• intravenous lidocaine
• oral mexiletine
• there are at least ten identified sodium channel
  subtypes

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Oral and parenteral local anesthetics

• Due to their potential for serious side effects,
  second line therapies reserved for crescendo
  neuropathic pain.
• Brief infusion of xylocaine. 1-5mg /kg over
  30min. ecg monitoring.
• If appears to be effective, oral local
  anesthetic, mexilitine.
• Role of Lidocaine 5 transdermal patch is
  unclear.

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Spinal cord the Pain Gate

• Sensory signals are carried to the dorsal horn
• Excitatory inter-neurones
• The spinal cord relays signal to the brain
• Dorsal horn is the site of a two-way network the
  gate
• either allows the signal to pass unadjusted,
  dampens the signal or boosts it.

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Acetaminophen

• Inhibitor of COX-3
• Used for mild-moderate nociceptive pain
• Evidence in post-op pain
• A single dose of 1000 mg had an NNT of 3.8
  (3.4-4.4) for at least 50 pain relief over 4-6
  hours in patients with moderate or severe pain (a
  single dose of 600-650 mg had an NNT of 4.6)
• May use in combination with opioids for more
  severe pain
• Dose ceiling with short-term use of 4gm / day
• (12 x 325mg)

Case, 2003 Zimmerman, 1995, 2000 Bromer, 2003
Perneger, 1994 Garcia Rodriguez, 2001 FDA
Sept. 2002 Health Canada Feb. 2003 Curhan 2002.
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Acetaminophen Chronic Pain

• No placebo-controlled evidence in chronic pain
  (usually compared to other study meds)
• Recent concerns re
• hepatic toxicity
• renal toxicity
• Long-term risk of renal impairment
• Medium to high risk if 1000 tablets and 2
  pills per day
• Restricting dosage to incidence of ESRD by 8-10

Case, 2003 Zimmerman, 1995, 2000 Bromer, 2003
Perneger, 1994 Garcia Rodriguez, 2001 FDA
Sept. 2002 Health Canada Feb. 2003 Curhan 2002.
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Acetaminophen- Suggested Dose Ceilings

• 4 gm/day short-term use in healthy patients
• 3.2 gm / day chronically in healthy patients
• 2.6 gm / day chronically in at risk patients
• Daily alcohol consumption, warfarin, fasting, a
  low protein diet, cardiac or renal disease
  increase the risk of hepatotoxicity

Latta, 2000 http//pain.mc.duke.edu/mild_pain.cfm
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Tramadol

• Synthetic analgesic developped by Grunenthal in
  1962.
• Used clinically since 1977 in Germanyl, 1995 in
  the US, 1997 in the UK, in Canada since 2005.
• Tramadol is a racemic mix of 2 enantiomers ()
  tramadol and (-) tramadol.
• Was for a long time considered as a weak opioid,
  we now know that it has at least 3 mechanisms of
  action, at the interneurone.

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Tramadol for neuropathic pain

• Recent meta-analysis (2005) from The Cochrane
  Collaboration
• NNT 3,5
• Significant impact on
• Paresthesia
• Allodynia
• Pain to touch
• Conclusion Tramadol is useful for the
  managment of neuropathic pain

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Tramacet in Canada

• Association of 2 analgesics
• Acétaminophen 325mg
• Tramadol 37,5mg
• Indication management of acute pain
• However extensive litterature on its use for
  cancer pain.
• Suggested dosage
• 1-2 tabs qid
• Maximum daily dosage 8/day
• In the elderly start slow go slow

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Tramadol/acétaminophen
Effets indésirables
(Rosenthal et al., JAGS 2004)
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Antidepressant drugs

• Tertiary amines ( amitriptyline, imipramine,
  doxepin, clomipramine) and the secondary amines
  (nortriptyline, desipramine) are analgesics.
• 10-25mg qhs as starting dose, usual effective
  dose 50-150 qhs.
• Tricyclic may be limited by occurrence of
  side-effects
• sedation, confusion
• orthostatic hypotension
• weight gain
• tachycardia, arrhythmia,
• anticholinergic effects ( dry mouth, blurred
  vision, urinary hesitancy)
• patients who have significant heart disease
  should not be treated with a tricyclic.

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• The secondary amine tricyclic (desipramine-nortrip
  tyline) are less anticholinergic and better
  tolerated.
• Beneficial analgesic effect is usually observed
  within a week after achieving an effective dose
  of tricyclic.
• Other antidepressants
• Some evidence from randomized controlled trials
  that several other antidepressants are
  analgesic.However this evidence is far less than
  that which supports the efficacy of tricyclic.
• Indication for patients with neuropathic pain
  whose response to opioids has been inadequate,
  also justified when pain is accompanied by
  depression.
• Sedating tricyclic insomnia
• Anxiolytic SSRIs anxious
• Bupropion sedated or fatigued patients.

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Alpha2-adrenergic agonists

• Alpha-2 adrenergic agonists. (clonidine)
• Supporting data is limited and the potential for
  side-effects ( somnolence and hypotension) is
  relatively great.
• Trials of these drugs are considered after others
  have proved ineffective.
• Intraspinal clonidine has been shown to reduce
  pain.
• Potential role for tizanidine (Zanaflex) an
  antispasticity agent.

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cannabinoids
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DISCOVERIES

• 1964 ?9-THC identified as main psychoactive
  ingredient of the Cannabis Sativa plant
• 1988 CB1 receptor identified (A. Howlett and W.
  Devane)
• 1990 CB1 is cloned and found located in the
  brain (L. Matsuda and M. Herkenham et al.)
• 1992 Anandamide is discovered_ a naturally
  occurring substance in the brain that acts on
  cannabinoid receptors (R. Mechoulam and W.
  Devane)
• CB2 receptor is identified (Kaminski)
• 1993 CB2 receptor is cloned (S. Munro)
• 1998 Endogenous ligands shown to be analgesic

Mack 2001
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ACTION ON SYSTEMS

• Pain pathway Cannabinoids
• Serotoninergic Stimulation suppresses GABA
• Norepinephrine Stimulation suppresses GABA
• Glutamate/NMDA Blocks NMDA in dorsal horn
• Inflammatory Response Blocks inflammatory
  action of
• 
  Prostaglandins and substance P
• Opiate System Act on opioid
  receptors kappa, delta and
  mu

Russo E. Pain management A practical guide for
clinicians. 31 - 2002. 357-375
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SYNERGY WITH OPIOID

• THC enhances the potency of opioids such as
  morphine.
• Studies have determined that the analgesic effect
  of THC is, at least in part, mediated through
  delta and kappa opioid receptors, indicating an
  intimate connection between cannabinoid and
  opioid signaling pathways in the modulation of
  pain perception.

Cichewick D., 2004
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PHARMACOKINETIC
Néron 2001, Product monographs 2005
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Other systemic drugs

• Baclofen (GABA agonist) 20mg-200mg/day
• Sedating
• Attention to withdrawal reaction
• Benzodiazepines conflicting evidence
• Psychostimulants
• Dextroamphetamine
• Methylphenidate 2,5-5mg am-pm po
• Caffeine
• Neuroleptics not recommended as adjuvant
  analgesics unless agitated delirium

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Central Sensitization

• Facilitate the transmission and conscious
  awarenes of both noxious and non-noxious sensory
  information
• Progresive neurochemical and cellular remodelling
  of both the peripheral and central nervous
  systems

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Chronic pain is not merely a temporal extension
of acute pain

• neuroplasticity
• synaptic potentiation
• wind up
• sensitization (hyperalgia / allodynia)
• additional nerve connections can develop in the
  spine in response to chronic pain, boosting the
  number of channels carrying the signal
• neurotransmitters can also increase in number. A
  more powerful pain signal manages to bridge the
  synapses between the nerves

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N-methyl-D-Aspartate Receptor blockers

• Antagonist at the nmda receptor may offer another
  novel approach to the treatment of neuropathic
  pain in cancer patients.
• Dextromethorphan
• Ketamine
• Amantadine
• Memantine
• Most of these drugs have been shown to have
  analgesic effects in non-malignant neuropathic
  pain.

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NMDA receptors antagonists

• Ketamine, iv or po is effective in relieving
  cancer pain and reducing opioid requirements.
• The side-effect profile of ketamine can be
  daunting.
• Starting dose 0,1-0,15mg/kg/hr by brief infusion
  or by sc infusion.
• Oral administration is easy, 11 ratio
• It is also recommended to lower the opioid dose
  when starting ketamine.
• Dextromethorphan 45-60mg /day up to 1g.
• Amantadine, limited data.
• Memantine. Controlled trials have been
  disappointing so far.

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New interest for methadone

• Acts clinically as an antagonist of the NMDA
  receptor.
• Indicated for troublesome neuropathic pain
  syndromes.

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Pain prevention ?

• Early detection
• Early intervention
• will prevent the development of plasticity and
  chronicity of the pain syndrome

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Superior cortex

• Cognitive factors
• e.g. past experience of pain / conditioning
• Psychological factors
• pain tresholds (sensation, perception,
  tolerance, tolerance with encouragement)
• personality
• meaning of pain
• anxiety / depression

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Total Pain

• Physical
• emotional / psychological
• social
• spiritual

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• To Cure Sometimes,
• To Relieve Often,
• To Comfort Always,
• Anonymous author, XVI century