Take the next step in pain management

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Methadone in the Management of Cancer Pain

• Dr. Deborah Robinson MD CCFP
• General Practitioner in Oncology and Palliative
  Medicine Physician
• 2007 CAGPO Annual Meeting

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Cancer Pain

• Epidemiology
• Pain is often the 1st sign (especially prostate,
  colon)
• 70 of all cancer patients experience mod. To
  severe pain (solid gtgthaematogenous)
• Only a fraction receive adequate pain management
• Etiology
• Cancer metastases
• Cancer treatment
• Complications 2 to mets/treatment
• Pain unrelated to cancer

Davis et al 2004
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Presentation Goals

• Avoid Post-Prandial Somnolence!
• Lay Down the Foundation
• Overview of pain including classification,
  treatment anatomy and neurochemistry
• Physiology of opioid analgesics
• Complex pain issues (peripheral/central
  sensitization)
• Methadone
• History, Indications (including clinical trial
  evidence), contraindications, advantages and
  disadvantages
• Neurochemistry and pharmacology
• Prescribing information and drug interactions

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And If we had more time

• Methadone
• Methadone for chronic pain vs. cancer pain
• Comparison of protocols for converting to
  methadone
• Rotating to and off of Methadone
• Stopping Methadone in chronic pain patients
• Initiation of Methadone in Opioid Naïve patients
• Patient Education and Risk Stratification
• Practical case based review of Methadone

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Classification of Pain
Non Cancer Pain
Canc e rPa i n

• Acute
• Symptom of danger
• Helps to heal/survive
• Meaningful
• It will end

• Chronic
• Not a symptom
• Meaningless
• Normal delay for healing is overdue
• Its a disease
• Lasts gt 3-6 months

• Nociceptive (Inflammatory)
• In response to tissue injury and the resulting
  inflammatory process
• Somatic constant or intermittent, aching,
  localized, superficial or deep
• Visceral constant, aching, squeezing,
  cramping, poorly localized and sometime
  referred

• Neuropathic
• In response to damage or dysfunction of either
  peripheral or central nervous system
• Dysesthetic Constant burning, paresthesias,
  tingling, occasionally radiates
• Neuralgic Lancinating, shooting

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The Analgesic Armamentarium
NON-OPIOIDS acetaminophen, NSAIDs, COX-2
OPIOIDS codeine, morphine,hydromorphone,fentanyl
, oxycodone,tramadol,methadone
ADJUVANT MEDICATION TCA, SSRI,
anticonvulsants, topical,corticosteroids,
cannabinoids, NMDAblockers, sodium channel
blockers,?2 agonists, GABA agonists,etc.
COMBINATION
Neuropathic Pain -Opioids, anticonvulsants,
TCAs -SNRIs, SSRIs, dexamethasone Canabinoids,
NMDA atagonists
Inflammatory Pain -NSAIDs, Acetaminophen -Opioids
, Corticosteroids Canabinoids
From Twycross R et al. RadcliffeMedical Press,
Oxford, 1998. p. 86.
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Anatomy and Physiology of Pain

• The Players in the Ascending Pathway
• Tissue/Nerve Damage and the subsequent release of
  inflammatory and pain perception mediators which
  stimulate nociceptors
• Primary sensory afferents which release glutamate
  and substance P (tissue to dorsal horn of the
  spinal cordFast A-delta fibres and Slow C
  fibres)
• Secondary sensory afferents (Spinothalamic tract)
• Dorsal Horn Interneurons
• A-? fibres (posterior column and Medial
  Lemniscus) in the gate control releasing GABA

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Anatomy and Physiology of Pain

• The Players in the Descending Pathway
• Descending controls from the limbic structures
• Descending inhibitory neurons from the
  supra-spinal level release endorphins,
  enkephalins, dynorphins which bind to opioid
  receptors (µ, k, ?)
• Dorsal Horn Interneurons
• Primary afferent nerve terminals and cell bodies
  of secondary afferents

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Receptors involved in Pain

• Glutamate Receptors
• Found on the post-synaptic membranes in the
  dorsal horn (spinothalamic tract stimulation)
• AMPA (non-NMDA) receptors are rapidly
  desensitized and transmit rapid and short-lived
  excitatory effects
• NMDA receptor activation requires repeated
  stimulation of the post-synaptic membrane by AMPA
  receptors to be activated (slowly desensitized
  and transmit a more sustained excitatory effect)
• Opioid Receptors
• Mu receptors are found on the pre-synaptic
  membrane of the dorsal horn cells where their
  activation inhibits stimulation of the
  spinothalamic tract

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Opioid Receptors in Pain
?
?
µ
Dynorphin
Enkephalin
?-Endorphin
Endogenous opioid
Pentazocine, Oxycodone(?) Morhpine (?)
Methadone, Hydromorphone
Morphine, Codeine, Oxycodone, Hydromorphone,
Fentanyl, Methadone
Agonists
Protein G, Calcium channel closing
Protein G, Potassium channel opening
Protein G, Potassium channel opening
Mechanism of action
Spinal analgesia, aversion, sedation Diuresis,
respiratory depression
Same effects as µ but less pronounced (spinal
analgesia, respiratory depression)
Supsraspinal analgesia, euphoria, anxiolysis,
nausea, constipation, cough suppression,
sedation, respiratory depression, physical
dependance
Clinical effect
Sigma Opioid receptors dont play a role in
analgesia but may contribute to dysphoria,
delirium, hallucinations, tachycardia and
hypertension
Adapted from AH Dickinson, 1997.
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Classification of Opioids
Considering action on Receptors
Agonistµ
Ag-antag. µ
Partial ag. µ
Antagonistµ
Antag.NMDA
Origin
Naturally occuring
Codeine, Morphine
Semi-synthetic
Hydro-morphone, Oxycodone
Nubain
Bupre-norphine
Synthetic
Fentanyl, Methadone, Tramadol
Talwin
Naloxone, Naltrexone
Methadone
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Opioid Pharmacokinetics
Active Metabolites
Oral (transdermal) Bioavailabilty
Terminal Half-Life(hours)
Opioid
M6G, M3G
10 50
2 4
Morphine
Normeperidine
30 60
3 4
Meperidine
None known
60 90
6 150
Methadone
Norfentanyl
92 95
Fentanyl Transdermal
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Morphine
60 90
3 4
Codeine
Oxymorphone
40 80
2 6
Oxycodone
H3G?, H6G
35 80
2 4
Hydromorphone
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Peripheral Sensitization
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Descending Inhibitory controls
Second neuron
In Dorsal Horn (Gate Control)
Hyperpathia Hyperalgesia
NMDA works as a pain amplifier and pain
self-perpetuation
noradrénaline
prostaglandins
sérotonine
morphine
no
C fos
Wind-up
PKC
5ht
n.k.
µ
nmda
N-A
p
nmda
EAA
Fibre C
µ
G.A.B.A.
allodynia
Fibre A beta
Central Sensitization
Yvon Beauchamp M.D.
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Medications Used According to Their Site of Action
TCAs SSRIs SNRIs clonidine,
tizanidine opioids tramadol cannabinoids
Brain
Descending Inhibitor Pathways (NE/5HT, opioid
receptors)
Peripheral Sensitization
Central Sensitization
Spinalcord
Na carbamazepine TCA  topiramat  lidocai
ne
Ca gabapentin  pregabalin  lamotrigine NM
DA  ketamine  dextromethorphan  methadone
memantine  cannabinoids
Capsaicin (Substance P) NSAIDS (COX) Levodopa
Adapted from Beydoun A, et al. J Pain Symptom
Manage 2003 25(Suppl 5)S18-S30.
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Methadone
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MethadoneHistorical Context

• Invented in Germany during WWII
• Originally called Dolphine
• Commercially produced for the first time by
  Eli-Lilly in the U.S. in 1947
• Vancouver Physician was first to use/study the
  clinical use of the drug
• Became popular in the treatment of heroin
  addiction in the 1960s
• Lost favour in the 1970s
• Increased interest with better understanding of
  pharmacology in the 1980s

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Possible Uses for Methadone

• Level B evidence for use in cancer pain
  (moderate-severe)
• Evolving use in chronic non-cancer pain
• Patients with history of allergy to morphine
• May be suitable first-line choice in the
  following selected patient groups
• Patients with renal failure and/or on dialysis
• Patients with liver dysfunction
• Pregnant patients requiring chronic opioid
  therapy
• Patients with history of drug abuse (with
  appropriate monitoring)
• Patients with evolving opioid hyperalgesia
• Elderly, frail patients should use opioids
  without active metabolites (hydromorphone,
  fentanyl, methadone)

Toombs J. Am Fam Physician 2005
7(7)1353-8. Gallagher R. Can Fam Physician 2007
53426-7.
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Methadone vs. Morphine for Cancer Pain

• Subjects 18 cancer patients randomized to
  treatment with methadone or morphine for pain
  control
• Key results
• Long half-life of methadone was associated with
  prolonged pain relief
• Large variation in the half-life of methadone
  necessitated careful adjustment of the dosing
  interval in individual patients
• Significant variability in bioavailability for
  both agents

Gourlay GK, et al. Pain 1986 25(3)297-312.
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Methadone for Cancer Pain Retrospective Study

• Subjects 196 advanced cancer outpatients with
  moderate to severe pain (retrospective)
• Key results
• Mean dose of oral methadone ranged from 14 mg at
  day 7 to 23.65 mg at day 90
• Reduction in pain intensity with respect to
  baseline occurred at each analysis time
• In 55.1 of the patients the reduction during the
  follow-up period was 35 according to the
  Palliation Index
• A high percentage of patients reported an
  amelioration of insomnia

De Conno F, et al. J Clin Oncol 1996
14(10)2836-42.
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Methadone vs. Morphine for Advanced Cancer Pain

• Subjects 40 patients with advanced cancer
  requiring strong opioids for pain management
• Key results
• Methadone patients had opioid escalation indices
  significantly less than morphine patients
• 7 methadone patients maintained initial dosage
  until death 1 morphine patient did not require
  opioid dose escalation
• Symptom frequencies and intensities were similar
  in the two groups

Mercadante S, et al. J Clin Oncol 1998
16(11)3656-61.
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Switching from Morphine to Methadone to Improve
Analgesia in Cancer Pain

• Subjects 52 cancer patients receiving oral
  morphine with uncontrolled pain and/or moderate
  to severe opioid adverse effects
• Key results After switch to oral methadone q8h
• In those who switched to methadone because of
  uncontrolled pain (n10)
• A significant reduction in pain intensity (p lt
  0.005) was found after an average of 3.5 days
• Symptom distress score was significantly
  decreased (p lt 0.0005)
• In those switched because of uncontrolled pain
  and morphine-related adverse effects (n32)
• Significant improvement was found in pain
  intensity (p lt 0.0005), nausea and vomiting (p lt
  0.03), constipation (p lt 0.001), and drowsiness
  (p lt 0.01)

Mercadante S, et al. J Clin Oncol 2001
19(11)2898-904.
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Methadone for Refractory Neuropathic Pain

• Subjects 18 patients with a diverse range of
  chronic neuropathic pain syndromes
• All had responded poorly to traditional
  analgesics
• Key results
• Analgesia was seen after each dose of methadone
• Compared to placebo, methadone 10 mg bid
  significantly improved maximum pain intensity,
  average pain intensity and pain relief
• Analgesic effects extended over 48 hours
• Analgesic effects were not restricted to any
  particular type of neuropathic pain

Morley JS, et al. Palliat Med 2003 17(7)576-87.
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Methadone vs. Morphine First-line for Cancer Pain

• Subjects 103 cancer patients in palliative care
  clinics
• Interventions
• Methadone (7.5 mg orally q12h 5 mg q4h prn)
• Morphine (15 mg orally sustained release q12h 5
  mg q4h prn
• Key results
• gt 3/4 patients in each group reported a 20
  reduction in pain intensity by day 8
• Opioid escalation indices were similar in both
  groups
• Rates of patient-reported global benefit did not
  differ between the groups
• There were more opioid-related drop-outs in the
  methadone group

Bruera E, et al. J Clin Oncol 2004 22(1)185-92.
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Methadone Disadvantages/Challenges

• Long and unpredictable half life
• Potential for accumulation and overdose during
  titration
• Unpredictable equianalgesic potency compared to
  other opioids
• Variable protein binding related to AAG levels
• Social stigma because of its association with
  addiction treatment
• Parenteral formulation not easily accessible

Peng et al. Can J Anesthesia 2005 52(5)513-523.
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Methadone Disadvantages/Challenges

• Subcutaneous route associated with localized
  adverse reactions
• High doses and iv formulation associated with QT
  prolongation
• Requires a license to prescribe
• Many physicians unfamiliar with the pharmacology
  and unwilling to obtain a license to even
  continue prescribing a stable dose
• Solution prone to errors (different
  concentrations available) and has a bitter taste

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Methadone Advantages

• High oral bioavailability
• Lack of significant active or toxic metabolites
• Does not accumulate in renal insufficiency
  effective in dialysis patients
• Dosing change not necessary in hepatic failure
• Does not cause euphoria
• Long half-life prevents acute withdrawal

Peng et al. Can J Anesthesia 2005 52(5)513-523.
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Methadone Advantages

• NMDA antagonist activity and prevention of
  reuptake of serotonin/norepinephrine may
  contribute to effectiveness in neuropathic pain,
  mitigation of opioid-induced tolerance/hyperalgesi
  a
• Solution allows for submucosal/sublingual dosing
  in patients in whom swallowing or consciousness
  is impaired

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Methadone Contraindications and Cautions

• Caution during dose titration due to dose
  accumulation and variable half life
• Significant sleep apnea,1 severe COPD, acute
  asthma or other clinically relevant states of
  respiratory depression
• Combining with alcohol or other sedating drugs,
  especially BZD
• Concurrent administration of any other drugs that
  might result in drug-drug interactions (e.g.,
  antiretrovirals)
• Patients unable to comply with use instructions
• Prolonged QT (gt 440 msec in males or 460 msec in
  females)

1. Wang D. Sleep Med Review 2007 Feb11 (1)
35-46.
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Methadone and Prolonged QT

• Risk factors
• low K or Mg (a side-effect of cisplatinum
  therapy), hx of CHF, bradycardia or baseline long
  QT, liver disease, drugs
• Rare in doses of lt 50 mg/day and more common in
  doses gt 80 mg/day (QTc in females normal up to
  460 msec and 440 msec in males)
• A change of 40-60 msec from baseline or absolute
  value greater than 500 is considered significant
• Symptoms include presyncopal/syncopal episodes
  and shortness of breath
• http//www.torsades.org/medical-pros/drug-lists/dr
  ug-lists.htm

Krantz M. Lancet 2007 369(9559)336-7.
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Methadone Chemical Composition

• Racemic Mixture
• R-methadone analgesia
• S-methadone antitussive

1. Davis AM, et al. J Pharmacol Exp Ther 1999
289(2)1048-53. 2. Inturrisi CE. Minerva
Anestesiol 2005 71(7-8)435-7. 3. Wheeler WL, et
al. Am J Hosp Palliat Care 2000 17(3)196-203.
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Methadone Neurochemical Activity

• mu and delta opioid receptor agonist
• Analgesia and typical opioid SE profile may have
  more diaphoresis and flushing
• NMDA receptor antagonist
• May help to prevent or reverse opioid tolerance
  and hyperalgesia
• Theoretical advantage for neuropathic pain
• Inhibits re-uptake of norepinephrine serotonin
• Evolving evidence for this mechanism-based
  analgesia via descending modulation in
  neuropathic pain

Lynch ME. Pain Res Manag 2005 10(3)133-44. Davis
MP.Support Cancer Care 2001 9773-83. Fishman
SM.Pain Med 2002 3339-48.
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Onset of Action

• Administration tid or (sometimes in chronic
  dosing) bid for analgesia
• Onset of action
• Parenteral 10 to 20 minutes with a peak
  concentration in brain within 1 to 2 hours
  suggested iv dose is half of the oral
• Oral 30 to 60 minutes
• Rectal complete absorption 30 minutes
  suggested rectal to oral ratio is 11
• Oral transmucosal (between gum and cheek) very
  rapid onset
• Has been used in solution of up to 50 mg/ml, up
  to 2 ml at a time to administer methadone in
  unresponsive patients (end of life) as
  alternative to IV or SC routes. The dose is 11
  transmucosal to oral. Very large doses may be
  divided and given q 2-4 h. Lower concentrations
  may be less irritating to the mucosal membranes
  (20 mg/ml).
• Time to peak concentration
• Parenteral 1-2 hours
• Oral 2.5-4 hours
• Steady state 2-10 days (generally 3-4 days)

Davis M. Support Care Cancer 2001 973-83.
Peng P. Can J Anesth 2005 52513-523.Toombs J.
Amer Fam Phys 2005 7(7)1353-1358.
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Absorption and Distribution

• Absorption
• Oral - 80 bioavailability (range of 41-99)
• detected in plasma in 30 minutes
• T-max varies from 1-6 hours (avg 2.5-4.4h)
• Very lipophilic so absorbed easily across mucous
  membranes (mouth/rectum)
• Distribution
• Rapid extensive initial distribution within 1-2
  hours
• 98 transferred to tissues (liver, kidney, lungs)
• 2 remains in blood of which 60 - 90 is bound in
  plasma to AAG (alpha 1-acid glycoprotein an
  acute phase reactant) only unbound methadone is
  active

Davis M. Support Care Cancer 2001 973-83. Peng
P. Can J Anesth 2005 52513-523. Toombs J. Amer
Fam Phys 2005 7(7)1353-1358. Ferrari A.
Pharmacological Research 2004 50551-559.
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Methadone Pharmacology During Initial Dosing
Period (0 to 1 day)
A
Free fractionin plasma
Drugelimination
B
Analgesia
A Majority of drug initially sequestered to
tissue binding sites B Small quantity of
methadone available
Gannon C. Eur J Palliative Care 1997 4152-8.
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Methadone PharmacologyAt Steady State (3 5
days )
C
E
D
Analgesia
C Once the reservoir is full, subsequent doses
available to plasma (leading to reduced
requirement) D Increased dose fraction for
analgesia E In steady state equilibrium is
maintained in effect a slow-release reservoir
Gannon C. Eur J Palliative Care 1997 4152-8.
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Metabolism and Elimination

• Methadone is predominantly biotransformed (rather
  than conjugated) in the liver ( 90) by P450
  enzymes
• Inter-individual variation major reason for
  variations in bioavailability
• Methadone dosing does not need to be changed for
  hepatic failure
• Metabolites appear to be inactive
• Eliminated in the urine and feces
• Renal (15-60) Filtered through glomerulus and
  reabsorbed depending on pH
• If urine route not effective, fecal route will
  dominate and urine drug tests may show less or
  even no methadone
• Methadone does not accumulate in renal failure
• Methadone is poorly removed by hemodialysis
• At doses lt 55mg/day majority of metabolites
  cleared fecally

Ferrari A. Pharmacological Research 2004
50551-559. Davis M. Support Care Cancer 2001
973-83. Peng P. Can J Anesth 2005 52513-523.
Toombs J. Amer Fam Phys 2005 7(7)1353-1358.
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Prescribing Methadone for Pain

• Take a careful history!
• Administer BID or TID (po, pr, sc, iv)
• Titrate slowly to analgesic effect
• reduces risk of toxicity/sedation/respiratory
  arrest
• Avoid drug interactions via careful history
• Monitor closely for adverse effects and drug
  interactions
• ask about/investigate drug interactions at every
  visit
• Educate and recruit patients as part of the
  care team
• include importance of compliance, being attentive
  to/reporting adverse effects and informing about
  other drugs being taken

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Methadone Dosing for Pain

• No reliable conversion factors for other opioids
• Any new side effects related to sedation or
  respiratory depression are more likely due to
  methadone and NOT to the previous opioid
• Methadone blood levels continue to rise for
  approximately 5 days after starting treatment

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Conversion NomogramEstimated Dose
60 50 40 30 20 10 0
Estimated methadone dose (mg/day)
0 200
400 600
800
1000 Morphine equivalent (mg/day)
Toombs JD. February 2006. Available at
www.pain-topics.com.
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Making The Conversion
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The Edmonton Protocol A Popular Conservative
Approach
Decrease the original opioid daily dose by 30
and replace it with oral methadone every 8 hours
using a 101 ratio
Day 1
If pain control is good, decrease the original
dose of morphine by another 30 and increase the
methadone dose only if the patient experiences
moderate to severe pain. Treat transient pain
with rescue dose of short-acting opioid.
Day 2
Discontinue last 30 of the original morphine
dose and maintain the patient on regular
methadone administered every 8 hours. Use
methadone as breakthrough (10 of daily dose)
Day 3
Bruera E, et al. Cancer 1996 78 (4) 852-857.
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Methadone Drug Interactions

• There are 2 ways to cause an effect
• By starting a medication which will alter the
  metabolism
• By stopping a medication which will alter the
  metabolism
• Drug interactions may result in
• Rapid (lt24 hours) or delayed (gt24 hours)
  appearance of clinical effects

Ferrari A. Pharmacological Research 2004
50551-559.
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Starting Drugs That Will Increase Plasma
Methadone Levels by a Moderate Amount

• Rapidly fluoxetine, fluvoxamine, moclobemide,
  grapefruit juice
• Delayed diazepam, midazolam, erythromycin,
  zidovudine
• Other common drugs that inhibit 2D6 with variable
  (none to minor) but possible ability to increase
  methadone levels
• Ciprofloxacin, clarithromycin, norfloxacin,
  ketoconazole, holoperidol, sertraline,
  paroxetine, venlafaxine, thioridazine,
  cimetidine, diltiazem, quinidine

Ferrari A. Pharmacological Research 2004
50551-559.
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Starting Drugs That Will Decrease Plasma
Methadone Levels by a Moderate Amount

• Rapidly none
• Delayed rifampin, carbamazepine, dilantin,
  respiradone, rifabutine, efavirenz (8-10 days),
  nelfinavir, nevirapine (4-8 days), ritonavir,
  zidovudine
• Other common drugs that induce 3A4 with variable
  (none to minor) but possible ability to decrease
  methadone levels
• Barbituates, dexamethasone, St. Johns Wort,
  oxcarbazepine, phenytoin, topiramate

Ferrari A. Pharmacological Research 2004
50551-559.
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Actual and Potential Interactions with Methadone
From Théberge A and Néron A.
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Prescribing Methadone CDSA Exemption

• Temporary exemption (hospital/institutional
  per-patient use)
• Physicians wishing to prescribe methadone for
  analgesic use in their patients must obtain a
  Federal Ministerial exemption per section 56 of
  the Controlled Drugs and Substances Act (call
  Office of Controlled Substances 1-866-358-0453)
• General exemption (per practitioner)
• Conditions/process vary provincially inquire at
  provincial College or federal methadone program

exemption_at_hc-sc.gc.ca
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Take Home Messages

• NMDA receptors play and important role in complex
  pain issues such as Wind Up, Hyperalgesia,
  Tolerance, and Allodynia
• NMDA receptors/5HT/Norepi play and important
  role in neuropathic pain
• Methadone acts as an opioid receptor agonist, an
  NMDA receptor antagonist, and and 5HT/Norepi
  reuptake inhibitor
• Methadone has a demonstrated efficacy and role in
  the treatment of certain Cancer pain situations

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Take Home Messages

• Methadone has a complex pharmacology and
  drug-drug interaction profile making it a
  challenging drug to learn how to use safely and
  effectively
• There is a Mainpro C accredited program that can
  be held anywhere in Canada for groups of
  physicians who are interested in revisiting this
  material and learning more about prescribing and
  patient education.
• Send me an email for more information
  drobinson_at_gghorg.ca
• Methadone for Pain Guidelines are available on
  the College of Physicians and Surgeons of Ontario
  Website
• cpso.on.ca

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