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

NarcoticsNarcoticsBernard J. LapointeBernard J. Lapointe

Chief, Palliative Care DivisionChief, Palliative Care DivisionAssociate Professor, Department of Oncology Associate Professor, Department of Oncology

& Department of Family Medicine, McGill & Department of Family Medicine, McGill UniversityUniversity

DisclosureDisclosure

Collaborated to clinical research sponsored by:Collaborated to clinical research sponsored by: Janssen-OrthoJanssen-Ortho Wex TechnologyWex Technology Lab PharmaLab Pharma PfizerPfizer

Clinical advisor:Clinical advisor: Janssen-OrthoJanssen-Ortho Purdue PharmaPurdue Pharma Wex TechnologyWex Technology PharmasciencePharmascience

Received in the past speaker fees from:Received in the past speaker fees from: Janssen-OrthoJanssen-Ortho Purdue PharmaPurdue Pharma

Cancer PainCancer Pain

Significantly affects the diagnosis, quality Significantly affects the diagnosis, quality of life and survival of patients with cancer.of life and survival of patients with cancer.Cancer Pain can arise:Cancer Pain can arise: Direct tumour infiltration/ involvementDirect tumour infiltration/ involvement Result of diagnostic / therapeutic surgeryResult of diagnostic / therapeutic surgery Side effect or toxicity of therapiesSide effect or toxicity of therapies Mechanism-Based Understanding of Cancer Mechanism-Based Understanding of Cancer

Induced Pain is helping us designing targetted Induced Pain is helping us designing targetted therapeutic approaches.therapeutic approaches.

Today’s agendaToday’s agenda

Genesis of the signal in the peripheryGenesis of the signal in the periphery

Pain secondary to bone metastasisPain secondary to bone metastasis

Neuropathic painNeuropathic pain

The interneuroneThe interneurone Normal painNormal pain Central sensitizationCentral sensitization

Central integration…’total pain’Central integration…’total pain’

Can we relieve cancer pain ?Can we relieve cancer pain ?

Pain relief is now possible in 90% of patients Pain relief is now possible in 90% of patients with relatively simple approaches.with relatively simple approaches.

Optimal relief is achieved in remaining 10% Optimal relief is achieved in remaining 10% using a slightly more complicated approach:using a slightly more complicated approach: multitherapymultitherapy anaesthetic approachesanaesthetic approaches

No single drug is likely to be completely effective No single drug is likely to be completely effective in managing persistent cancer induced pain.in managing persistent cancer induced pain.

Treatment Options for Chronic Treatment Options for Chronic Cancer PainCancer Pain

PHYSICALPHYSICAL PSYCHOLOGICPSYCHOLOGIC PHARMACOLOGICPHARMACOLOGIC INTERVENTIONALINTERVENTIONAL

Normal activitiesNormal activitiesSplinting / Taping Splinting / Taping AquafitnessAquafitnessPhysioPhysio

PassivePassive ActiveActive

StretchingStretchingConditioningConditioningWeight trainingWeight trainingMassageMassageTENSTENSTranscranial Transcranial Magnetic StimulationMagnetic StimulationChiropracticChiropracticAcupunctureAcupuncture

HypnosisHypnosisStress Stress ManagementManagementCognitive-Cognitive-BehaviouralBehaviouralFamily therapyFamily therapyPsychotherapyPsychotherapyMindfulness- Mindfulness- Based Stress Based Stress ReductionReduction

OTC medicationOTC medicationAlternative therapiesAlternative therapiesTopical medicationsTopical medicationsNSAIDs / COXIBsNSAIDs / COXIBsDMARDsDMARDsImmune modulatorsImmune modulatorsTricyclicsTricyclicsAnti-epileptic drugsAnti-epileptic drugsOpioidsOpioidsLocal anestheticLocal anestheticcongenerscongenersMuscle relaxantsMuscle relaxantsSympathetic agentsSympathetic agentsNMDA blockersNMDA blockersCGRP blockersCGRP blockers

I.A. steroidsI.A. steroidsI.A. hyaluronanI.A. hyaluronanTrigger pt. therapyTrigger pt. therapyIntraMuscular stim.IntraMuscular stim.ProlotherapyProlotherapyNerve blocks Nerve blocks BOTOXBOTOXEpiduralsEpiduralsOrthopedic surgeryOrthopedic surgeryRadio frequency Radio frequency facet neurotomyfacet neurotomyNeurectomyNeurectomyImplantable Implantable neurostimulatorsneurostimulatorsImplantable pain Implantable pain pumpspumps

The Treatment ContinuumThe Treatment Continuum

More available Less expensive Fewer side effects Less invasive

Less available More expensive More side effects More invasive

Physical

Psychological

Pharmacological

Interventional

Pharmacological Pharmacological management of cancer painmanagement of cancer pain

The OpioidsThe Opioids

Opioids for cancer induced pain Opioids for cancer induced pain

Experience suggest that cancer pain can be Experience suggest that cancer pain can be relieved in more than 70% of patients using a relieved in more than 70% of patients using a simple opioid-based regimen.simple opioid-based regimen.Despite all the fears of respiratory depression, Despite all the fears of respiratory depression, addiction or diversion, opioids have addiction or diversion, opioids have nevernever been been shown to cause organ damage when taken shown to cause organ damage when taken therapeuticallytherapeuticallySome pain may impart a relatively lesser degree Some pain may impart a relatively lesser degree of opioid responsivenessof opioid responsiveness

Adjuvant analgesicsAdjuvant analgesics

Adjuvant: any drug with a primary indication Adjuvant: any drug with a primary indication other than pain, but with analgesic properties in other than pain, but with analgesic properties in some painful conditions.some painful conditions.

Often administered as first-line drugs in the Often administered as first-line drugs in the treatment of chronic non-malignant pain.treatment of chronic non-malignant pain.

Conventional practice has evolved to view Conventional practice has evolved to view opioids as first-line drugs, and adjuvant opioids as first-line drugs, and adjuvant analgesics typically are considered after opioid analgesics typically are considered after opioid therapy has been optimized. therapy has been optimized.

TumorProstaglandinsEndothelins

NGF

PGe2

Bk

Primary Nociceptor AfferentC Fiber

Immune cells

cytokines.

Transduction

S.P.c.g.r.p

DamageInflammationPlasma leakage

Dealing with Dealing with inflammationinflammation

corticosteroidscorticosteroids

Very useful when there is a ‘pain crisis’Very useful when there is a ‘pain crisis’

‘‘cooling effect’cooling effect’

Relative risks and benefits of the various Relative risks and benefits of the various corticosteroids are unknowncorticosteroids are unknown Dexamethasone is often selected because of Dexamethasone is often selected because of

low mineralo-corticoidlow mineralo-corticoid MethylprednisoloneMethylprednisolone

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

NSAIDS including COX-2 inhibitorsNSAIDS including COX-2 inhibitors

NSAIDS exert both:NSAIDS exert both: Anti-inflammatory Anti-inflammatory AnalgesicAnalgesic

By inhibiting PG synthesis via the COX enzymeBy inhibiting PG synthesis via the COX enzyme

- Indiscriminate inhibition of COX activity Indiscriminate inhibition of COX activity leads to a range of undesirable side-leads to a range of undesirable side-effects (including gi ulceration-bleeding)effects (including gi ulceration-bleeding)

Non-steroidal anti-inflammatory Non-steroidal anti-inflammatory agents:agents:

Ceiling effectCeiling effect

start treatment at the lowest recommended dosestart treatment at the lowest recommended dose

wide inter-individual variabilitywide inter-individual variability

monitor closely patients ( acute renal monitor closely patients ( acute renal insufficiency)insufficiency)

Cytoprotection of gastric mucosa is indicatedCytoprotection of gastric mucosa is indicated

Clear evidence to support superior safety or Clear evidence to support superior safety or efficacy of one NSAID over another is lacking.efficacy of one NSAID over another is lacking.

NSAIDs in Chronic PainNSAIDs in Chronic PainThe Risk of GI ToxicityThe Risk of GI Toxicity

4% risk of P/U/B per year*4% risk of P/U/B per year*

12% risk of P/U/B per year with concomitant use 12% risk of P/U/B per year with concomitant use of SSRIof SSRI

Taking an NSAID for two months or more:Taking an NSAID for two months or more:

1 in 5 risk of endoscopic ulcer1 in 5 risk of endoscopic ulcer

1 in 70 risk of symptomatic ulcer1 in 70 risk of symptomatic ulcer

1 in 150 risk of bleeding ulcer1 in 150 risk of bleeding ulcer

1 in 1200 risk of dying from a bleeding ulcer1 in 1200 risk of dying from a bleeding ulcer Risk factors: Risk factors:

Highly significant risks: previous history of ulcer or bleed, age > 50, Highly significant risks: previous history of ulcer or bleed, age > 50,

Less significant risks: females, prednisone, alcoholic liver disease, Less significant risks: females, prednisone, alcoholic liver disease, NSAIDs in combination, COPD and other chronic diseasesNSAIDs 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.

NSAIDs better than COXIBs ?NSAIDs better than COXIBs ?

Optimal analgesia may require COX I and Optimal analgesia may require COX I and COX IICOX II11

Increased risk of CV events with COXIBsIncreased risk of CV events with COXIBs2, 3,42, 3,4

COXIBs block prostacyclen but not thromboxaneCOXIBs block prostacyclen but not thromboxane55

COXIBs have no antiplatelet activity and do not COXIBs have no antiplatelet activity and do not substitute for ASA substitute for ASA

Delayed healing of fractures in animalsDelayed healing of fractures in animals66

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

howeverhowever

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

Mantyh Nature Reviews Neuroscience 7, 797–809 (October 2006) | doi:10.1038/nrn1914

Acidosis in bone cancer painAcidosis in bone cancer pain

Osteoclasts contribute significantly to aetiology of Osteoclasts contribute significantly to aetiology of bone cancer painbone cancer painOsteoclasts maintain acidic micro-environmentOsteoclasts maintain acidic micro-environmentBoth osteolytic and osteoblastic cancers are Both osteolytic and osteoblastic cancers are characterized by osteoclast proliferation and characterized by osteoclast proliferation and hypertrophyhypertrophyRole for biphosphonateRole for biphosphonate Zoledronic acid, pamidronate, Alendronate,Zoledronic acid, pamidronate, Alendronate,ibandronateibandronate

Promising role for osteoprotegerin (OPG) which Promising role for osteoprotegerin (OPG) which prevents activation and proliferation of osteoclasts.prevents activation and proliferation of osteoclasts.

Other adjuvant analgesics for bone Other adjuvant analgesics for bone painpain

Calcitonin: limited evidence does not Calcitonin: limited evidence does not support it’s use to control pain from bone support it’s use to control pain from bone mets.mets.

New targets in development:New targets in development: Endothelin antagonists (prostate cancer)Endothelin antagonists (prostate cancer) Nerve growth factorNerve growth factor

Pain afferent pathways

Neuronal damageNeuronal damage

Direct invasionDirect invasion

CompressionCompression

changes in function of Na channels appear changes in function of Na channels appear within 24hrs of the injurywithin 24hrs of the injury lower thresholdlower threshold reduced recuperation timereduced recuperation time

All anticonvulsantsAll anticonvulsants::

1. block voltage gated sodium channels;1. block voltage gated sodium channels;2. directly or indirectly enhance inhibitory 2. directly or indirectly enhance inhibitory

GABA-ergic neurotransmission; orGABA-ergic neurotransmission; or3. inhibit excitatory glutamatergic 3. inhibit excitatory glutamatergic

neurotransmissionneurotransmissionor some combination of the aboveor some combination of the above

Anticonvulsant drugs: Gabapentin.Anticonvulsant drugs: Gabapentin.

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

Lamotrigine. Was reported to relieve non-malignant Lamotrigine. Was reported to relieve non-malignant neuropathic in several randomized trials. However neuropathic in several randomized trials. However adverse effects ( somnolence, dizziness, ataxia) require adverse effects ( somnolence, dizziness, ataxia) require slow titration. Potential for Stevens-Johnson syndrome.slow titration. Potential for Stevens-Johnson syndrome.

PregabalinPregabalin with a mechanism identical to that of with a mechanism identical to that of gabapentin and strong evidence of analgesic efficacy. gabapentin and strong evidence of analgesic efficacy. Multi-centre study for cancer induced bone pain. Lack Multi-centre study for cancer induced bone pain. Lack significant drug-drug interactions.significant drug-drug interactions.Among the older drugs, evidence of efficacy is best for Among the older drugs, evidence of efficacy is best for carbamazepine , phenytoin, valproate.carbamazepine , phenytoin, valproate.

Frequent side-effects (sedation, dizziness,nausea, Frequent side-effects (sedation, dizziness,nausea, unsteadiness) and potential for drug-drug interactions, use has unsteadiness) and potential for drug-drug interactions, use has declined.declined.

Voltage-gated ion channel Voltage-gated ion channel modulators: sodium channel modulators: sodium channel blockersblockersintravenous lidocaineintravenous lidocaine

oral mexiletineoral mexiletine

there are at least ten identified sodium there are at least ten identified sodium channel subtypeschannel subtypes

Oral and parenteral local Oral and parenteral local anestheticsanesthetics

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

Spinal cord: the Pain GateSpinal cord: the Pain Gate

Sensory signals are carried to the dorsal Sensory signals are carried to the dorsal hornhornExcitatory inter-neuronesExcitatory inter-neuronesThe spinal cord relays signal to the brainThe spinal cord relays signal to the brainDorsal horn is the site of a two-way Dorsal horn is the site of a two-way network: the gatenetwork: the gate either allows the signal to pass unadjusted, either allows the signal to pass unadjusted,

dampens the signal or boosts it.dampens the signal or boosts it.

AcetaminophenAcetaminophen Inhibitor of COX-3Inhibitor of COX-3Used for mild-moderate nociceptive painUsed for mild-moderate nociceptive painEvidence in post-op painEvidence in post-op pain A single dose of 1000 mg had an NNT of 3.8 (3.4-4.4) 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 for at least 50% pain relief over 4-6 hours in patients with moderate or severe pain (a single dose of 600-with moderate or severe pain (a single dose of 600-650 mg had an NNT of 4.6)650 mg had an NNT of 4.6)

May use in combination with opioids for more severe May use in combination with opioids for more severe painpain

Dose ceiling with short-term use of 4gm / dayDose ceiling with short-term use of 4gm / day (12 x 325mg)(12 x 325mg)

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

Acetaminophen – Chronic PainAcetaminophen – Chronic PainNo placebo-controlled evidence in chronic No placebo-controlled evidence in chronic pain (usually compared to other study pain (usually compared to other study meds)meds)

Recent concerns re: Recent concerns re: hepatic toxicity hepatic toxicity renal toxicityrenal toxicity

Long-term risk of renal impairmentLong-term risk of renal impairment Medium to high risk if > 1000 tablets and > 2 pills per dayMedium to high risk if > 1000 tablets and > 2 pills per day Restricting dosage to < 1000 tablets could reduce Restricting dosage to < 1000 tablets could reduce

incidence of ESRD by 8-10%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.

Acetaminophen*- Acetaminophen*- Suggested Dose CeilingsSuggested Dose Ceilings

4 gm/day – short-term use in healthy 4 gm/day – short-term use in healthy patientspatients

3.2 gm / day chronically in healthy patients3.2 gm / day chronically in healthy patients

2.6 gm / day chronically in at risk patients2.6 gm / day chronically in at risk patients

*Daily alcohol consumption, warfarin, *Daily alcohol consumption, warfarin, fasting, a low protein diet, cardiac or renal fasting, a low protein diet, cardiac or renal disease increase the risk of hepatotoxicitydisease increase the risk of hepatotoxicity

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

TramadolTramadol

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

Tramadol for neuropathic painTramadol for neuropathic pain

Recent meta-analysis (2005) from ‘The Recent meta-analysis (2005) from ‘The Cochrane Collaboration’:Cochrane Collaboration’: NNT 3,5NNT 3,5 Significant impact onSignificant impact on

ParesthesiaParesthesiaAllodyniaAllodyniaPain to touchPain to touch

Conclusion : Tramadol is useful for the Conclusion : Tramadol is useful for the managment of neuropathic painmanagment of neuropathic pain

Tramacet in CanadaTramacet in Canada

Association of 2 analgesics: Association of 2 analgesics: Acétaminophen Acétaminophen 325mg325mg TramadolTramadol 37,5mg 37,5mg

Indication: management of acute painIndication: management of acute pain However extensive litterature on it’s use for cancer However extensive litterature on it’s use for cancer

pain.pain.

Suggested dosage:Suggested dosage: 1-2 tabs qid1-2 tabs qid Maximum daily dosage 8/dayMaximum daily dosage 8/day In the elderly start slow go slow…In the elderly start slow go slow…

Effets indésirables

< 65 ans< 65 ans > 65 ans> 65 ans

Tr/APAPTr/APAP PlaceboPlacebo Tr/APAPTr/APAP PlaceboPlacebo

NauséeNausée 16,416,4 33 18,818,8 4,54,5

ÉtourdissementÉtourdissement 11,711,7 33 11,611,6 6,86,8

VomissementVomissement 77 00 1313 4,54,5

SomnolenceSomnolence 9,49,4 1,51,5 2,92,9 2,32,3

PruritPrurit 7,87,8 00 2,92,9 2,32,3

ConstipationConstipation 4,74,7 4,54,5 4,34,3 2,32,3

DiarrhéeDiarrhée 3,93,9 1,51,5 1,41,4 9,19,1

CéphaléeCéphalée 2,32,3 99 2,92,9 6,86,8

DyspepsieDyspepsie 3,13,1 33 4,34,3 2,32,3

Tramadol/acétaminophenTramadol/acétaminophen

(Rosenthal et al., JAGS 2004)

Antidepressant drugsAntidepressant drugs

Tertiary amines ( amitriptyline, imipramine, doxepin, clomipramine) Tertiary amines ( amitriptyline, imipramine, doxepin, clomipramine) and the secondary amines (nortriptyline, desipramine) are and the secondary amines (nortriptyline, desipramine) are analgesics.analgesics.10-25mg qhs as starting dose, usual effective dose 50-150 qhs.10-25mg qhs as starting dose, usual effective dose 50-150 qhs.Tricyclic may be limited by occurrence of side-effectsTricyclic may be limited by occurrence of side-effects

sedation, confusionsedation, confusion orthostatic hypotensionorthostatic hypotension weight gainweight gain tachycardia, arrhythmia, tachycardia, arrhythmia, anticholinergic effects ( dry mouth, blurred vision, urinary anticholinergic effects ( dry mouth, blurred vision, urinary

hesitancy)hesitancy)patients who have significant heart disease should not be treated patients who have significant heart disease should not be treated with a tricyclic.with a tricyclic.

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

Sedating tricyclicSedating tricyclic insomniainsomnia Anxiolytic SSRIs Anxiolytic SSRIs anxiousanxious BupropionBupropion sedated or fatigued patients.sedated or fatigued patients.

Alpha2-adrenergic agonistsAlpha2-adrenergic agonists

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

cannabinoidscannabinoids

19641964 Δ9-THC identifiedΔ9-THC identified as main psychoactive ingredient of as main psychoactive ingredient of the the Cannabis SativaCannabis Sativa plant plant

1988 1988 CBCB11 receptor identified receptor identified (A. Howlett and W. Devane)(A. Howlett and W. Devane)

1990 1990 CBCB11 is cloned and found located in the brain is cloned and found located in the brain (L. Matsuda and (L. Matsuda and

M. M. Herkenham et al.) Herkenham et al.)

1992 1992 Anandamide is discoveredAnandamide is discovered_ a naturally occurring _ a naturally occurring substance in the brain that acts on cannabinoid receptorssubstance in the brain that acts on cannabinoid receptors (R. (R.

Mechoulam and W. Devane)Mechoulam and W. Devane)

CBCB22 receptor is identified receptor is identified (Kaminski)(Kaminski)

1993 1993 CBCB22 receptor is cloned receptor is cloned (S. Munro)(S. Munro)

1998 1998 Endogenous ligands shown to be analgesicEndogenous ligands shown to be analgesic

DISCOVERIESDISCOVERIES

Mack 2001

Pain pathwayPain pathway Cannabinoids CannabinoidsSerotoninergicSerotoninergic Stimulation suppresses GABA Stimulation suppresses GABA

NorepinephrineNorepinephrine Stimulation suppresses GABA Stimulation suppresses GABA

Glutamate/NMDAGlutamate/NMDA Blocks NMDA in dorsal horn Blocks NMDA in dorsal horn

Inflammatory ResponseInflammatory Response Blocks inflammatory action of Blocks inflammatory action of Prostaglandins and substance PProstaglandins and substance P

Opiate System Act on opioid receptors: Opiate System Act on opioid receptors: kappa, kappa, delta and mu delta and mu

Russo E. Pain management: A practical guide for clinicians. 31 - 2002. 357-375

ACTION ON SYSTEMSACTION ON SYSTEMS

THC THC enhances the potency of opioidsenhances the potency of opioids such such as morphine. as morphine.

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

SYNERGY WITH OPIOIDSYNERGY WITH OPIOID

Cichewick D., 2004

PHARMACOKINETICPHARMACOKINETIC

Nabilone Dronabinol THC:CBD

SourceSynthetic cannabinoid

(THC analog)Synthetic cannabinoid

(THC)THC: CBD

Number of metabolites 2 >21 > 21

Distribution volumeLiposoluble (very large)

Liposoluble (very large)

Liposoluble (very large)

Onset of Action 60-90 minutes 30-60 minutes 30-150 minutes

Tmax 2 hours 1-4 hours 1-4 hours

Duration of Action 8-12 hours 4-6 hours Very variable

Half-life:Initial 2 hours 19-56 hours 2 hoursTerminal 35 hours 49-53 hours 24-36 hours and +

Néron 2001, Product monographs 2005

Other systemic drugsOther systemic drugs

Baclofen (GABA agonist) 20mg-200mg/dayBaclofen (GABA agonist) 20mg-200mg/day SedatingSedating Attention to withdrawal reactionAttention to withdrawal reaction

Benzodiazepines: conflicting evidenceBenzodiazepines: conflicting evidencePsychostimulants: Psychostimulants: DextroamphetamineDextroamphetamine Methylphenidate 2,5-5mg am-pm poMethylphenidate 2,5-5mg am-pm po CaffeineCaffeine

Neuroleptics; not recommended as adjuvant Neuroleptics; not recommended as adjuvant analgesics unless agitated deliriumanalgesics unless agitated delirium

Central SensitizationCentral Sensitization

Facilitate the transmission and conscious Facilitate the transmission and conscious awarenes of both noxious and non-awarenes of both noxious and non-noxious sensory informationnoxious sensory information

Progresive neurochemical and cellular Progresive neurochemical and cellular remodelling of both the peripheral and remodelling of both the peripheral and central nervous systems central nervous systems

Chronic pain is not merely a Chronic pain is not merely a temporal extension of acute paintemporal extension of acute pain

neuroplasticity:neuroplasticity:synaptic potentiationsynaptic potentiationwind upwind upsensitization (hyperalgia / allodynia)sensitization (hyperalgia / allodynia)

additional nerve connections can develop in the additional nerve connections can develop in the spine in response to chronic pain, boosting the spine in response to chronic pain, boosting the number of channels carrying the signalnumber of channels carrying the signalneurotransmitters can also increase in number. neurotransmitters can also increase in number. A more powerful pain signal manages to bridge A more powerful pain signal manages to bridge the synapses between the nervesthe synapses between the nerves

N-methyl-D-Aspartate Receptor N-methyl-D-Aspartate Receptor blockersblockers

Antagonist at the nmda receptor may offer Antagonist at the nmda receptor may offer another novel approach to the treatment of another novel approach to the treatment of neuropathic pain in cancer patients.neuropathic pain in cancer patients. DextromethorphanDextromethorphan Ketamine Ketamine AmantadineAmantadine MemantineMemantine

Most of these drugs have been shown to have Most of these drugs have been shown to have analgesic effects in non-malignant neuropathic analgesic effects in non-malignant neuropathic pain.pain.

NMDA receptors antagonists:NMDA receptors antagonists:

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

New interest for methadoneNew interest for methadone

Acts clinically as an antagonist of the Acts clinically as an antagonist of the NMDA receptor.NMDA receptor.

Indicated for troublesome neuropathic pain Indicated for troublesome neuropathic pain syndromes.syndromes.

Pain prevention ?Pain prevention ?Early detectionEarly detection

Early interventionEarly intervention

will prevent the development of plasticity will prevent the development of plasticity and chronicity of the pain syndromeand chronicity of the pain syndrome

Superior cortexSuperior cortexCognitive factors Cognitive factors e.g. past experience of pain / conditioninge.g. past experience of pain / conditioning

Psychological factorsPsychological factors pain tresholds pain tresholds (sensation, perception, tolerance, (sensation, perception, tolerance,

tolerance with encouragement)tolerance with encouragement) personalitypersonality meaning of painmeaning of pain anxiety / depressionanxiety / depression

Total PainTotal PainPhysicalPhysical

emotional / psychologicalemotional / psychological

socialsocial

spiritualspiritual

To Cure Sometimes,To Cure Sometimes,

To Relieve Often,To Relieve Often,

To Comfort Always,To Comfort Always,Anonymous author, XVI centuryAnonymous author, XVI century