Download Patient Characteristics

Methadone “Simply Rotate” Study
Ahmed Elsayem, MD
Associate professor
Director of PCU
Dept of PC & Rehabilitation Med.
Cancer Pain
Most feared complication of cancer
 < 50% obtain optimal pain control
 Uncontrolled pain leads to other symptoms,
worsen QOL, and interferes with treatment.
 2/3 related to tumor
 1/3 related to treatment
 Opioids is cornerstone for pain control
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Opioid Side effects
Respiratory depression
 Constipation
 Nausea
 Drowsiness & fatigue
 Opioid induced neurotoxicity (accumulation
of active metabolites (e.g. morphine-3-G):
- Hallucination/Delirium
- Myoclonus/ seizures
- Hyperalgesia
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Opioid Rotation (“Switching”)
Morphine initial strong opioid
 Others include oxycodoen, fentanyl,
hydromorphone, methadone…
 Switching to a different opioid improve pain
control and/or reduce opioid-related side effects
(Incomplete cross-tolerance)
 Methadone is commonly used in the switch
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Evidence for Rotation
Cochrane Database systematic review
 52 reports
 morphine was first-line opioid
 All (but one) concluded improved pain
control and/or reduced side effects
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Quigley C. Opioid switching. Cochrane Database Syst Rev 2004.
Rationale for Methadone
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Most common rotation at MDACC palliative care
clinic
Use increased in the last decade
Better analgesia “more stable”
Less opioid escalation with methadone
Receptor agonist μ and δ & NMDA receptor
antagonist
NMDA receptor implicated in neuropathic pain
Less affinity on μ receptors compared to morphine
→ less side effect (e.g. constipation)
Mercadante et al. JCO 1998
Rationale for Methadone
Potent opioid analgesic
 Slowly produces tolerance and can reverse
tolerance from other opioids
 Effective for treating neuropathic pain (NMDA
receptor antagonist).
 Lacks active metabolites
 Available in a variety of dosage formulations
(most common 5 & 10 mg tablets, and 1:1 elixir)
 Inexpensive
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Pharmacokinetics
Absorption-Rapid due to liphophilic
properties
 Oral bioavailability 80% (41-99%) - 3x
morphine
 Less than 10% of drug is extracted during
first pass
 Accumulates in chronic use
 Hepatic metabolism (CYP 450) mainly 3A4
but also 2D6.
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Kinetics
In renal failure eliminated by feces
increases, hence safe in renal failure
patients
 HD- Poorly removed
 In chronic liver failure no need to change
the dose
 No relationship between plasma conc and
analgesic effect
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Caveats with Methadone
Interindividual variability
– Long and unpredictable half-life
– Drug interactions
 Dosing challenges
– The dose of methadone varies (inversely)
with the previous oral morphine
equivalent dose
– The precise opioid dose ratio for
methadone is unknown
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Equianalgesic Ratio
Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A, De Conno F.
Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio?
Journal of Clinical Oncology. 1998;16(10):3216-21.
Disadvantages
Long and variable elimination half-life
 Stigmatization
 Variation in the pharmacokinetics
 QTc prolongation with ?high doses (≥ 300 mg)
 Drug interactions at CYP 450(3A4, 2D6):
- Inhibitors ↑ methadone level = toxicity.
- Inducers ↑ clearance = pain
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CYP
Inhibitors… And…Inducers
Macrolides (erythromycin)
Imidazoles (ketoconazole)
Quinolones (ciprofloxacin)
SSRI (fluvoxamine)
Benzodiazepines
(diazepam)
Antiviral drugs (ritonavir)
Acute alcohol ingestion
Anticonvulsants
(phenobarbital,
phenytoin)
Rifampicin
Corticosteroids
Chronic alcoholism
“Simply Rotate” Study
NCI Protocol #: MDA 05-08-04
 PI Dr. Fisch
 Primary Objective:
To compare the effectiveness (i.e. nalgesia)
of an opioid rotation to oral methadone vs
opioid rotation to another long-acting strong
opioid (sustained-release morphine
or oxycodone).
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Hypotheses
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60% of patients will achieve a ≥ 30%
reduction in pain and/or opioid side effects
with opioid rotation to oral methadone.
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In contrast, 40% of patients will achieve
this kind of response with opioid switching
to either sustained-release morphine or
oxycodone.
Inclusion Criteria
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18 years of age
Care in the outpatient medical oncology
Morphine or oxycodone SR..
Oral MEDD 40 mg/day to < 300 mg/day.
Worst pain ≥ 5 of for at least one week’s
AND/OR One or more persistently bothersome
symptoms attributed to an opioid side effect.
Systemic anticancer therapy of any kind or
bisphosphonates at least 4 weeks prior to study entry.
Adjuvants ( tricyclic antidepressants, NSAIDs,
anticonvulsants) at least 2 weeks prior to study entry.
Exclusion Criteria
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Use of the same long acting opioid you are switching
to within 60 days of study enrollment.
Prior methadone therapy within 12 weeks of study
entry, or Methadone maintenance
Current use of transdermal fentanyl, oxymorphone, or
buprenorphine
Current use of intrathecal infusion of analgesics.
Radiation or surgery planned within 4 weeks
Suspected cognitive impairment
Conditions that predispose to prolonged QT interval
(Cocaine abuse Serum potassium <3.0, Concurrent
use of antiarrhthmic medications
Advanced heart failure. Family hx of sudden death.
Pregnancy
Study Entry Evaluations
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Informed Consent
Vital signs, height, weight, ECOG, H & P
M.D. Anderson Symptom Inventory (MDASI)
Composite Drug Toxicity Score (15 specific
items) of the Common Terminology Criteria for
Adverse Events
Revised Edmonton Staging System (rESS) for
cancer pain.
A completed brief treatment questionnaire (current
status of the cancer, current treatment approach,
major co-morbidities, and current medications).
Randomization and Stratification
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Assignment by CCOP database
Stratification according to baseline opioid
(morphine or oxycodone)
Randomization Methadone or another opioid (e.g.
patient on morphine will receive either methadone
or oxycodone).
Rescue opioid for patients on oxycodone or
morphine will be short acting similar drug.
Rescue opioid for methadone will be a short acting
drug other than the one patient was using.
Treatment and Follow up
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Baseline evaluation before starting drug
Calculate the scheduled and rescue dose(5-15%)
Study duration 28 days. Patients should be
evaluated face to face +/-3 days
Follow up on days 8, 15, 22 and 28. One of the
first 2 visits face to face, and the rest by phone.
Provide adjuvant drugs for constipation, N/V.
MEDD
Morphine 1:1
 Hydromorphone 1:5
 Oxycodone 1:1.5
 Combinations of oxycodone, use the
oxycodone portion and ignore tylenol or
NSAIDS.
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Dosing Methadone: Overview
1.
Determine the oral morphine equivalent daily
dose (MEDD)
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2.
Calculate manually using equianalgesic dosing
tables and/or
Use the Methadone Conversion Calculator on the
web site
Select the initial methadone dose based on
the oral MEDD
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Use the Table in the protocol and/or
Use the Methadone Conversion Calculator on the
web site
Dosing Methadone: Table
*Divide
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Calculated Oral MEDD
40-99mg
100-180mg
Dose Ratio*
4
6
181-240mg
241-300mg
8
10
the calculated oral MEDD by this number to get the initial methadone dose
Administer this dose every 12 or 8 hours
Dosing Methadone: Calculator
Dosing Methadone: Example
Patient is prescribed sustained-release morphine 60mg
every 12 hours and immediate-release morphine 15
mg every 3 hours as needed for breakthrough pain.
Patient is reportedly taking 8 doses of immediaterelease morphine per day with little relief (pain is
rated as a 9/10).
What is the starting methadone dose?
Dosing Methadone: Table
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Oral MEDD
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Sustained-release morphine = 120mg/day (60mg x
2)
Immediate-release morphine = 120mg/day (15mg x
8)
Total oral MEDD = 240mg/day (120mg + 120mg)
Initial methadone dose
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Dose ratio from table (180-240mg MEDD) = 8
Initial methadone dose = 30mg/day (240mg ÷ 8)
Give methadone 10mg every 8 hours
Dosing Methadone: Overview cont’
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Stop the previous opioid and start methadone
Utilize immediate-release opioid for
breakthrough pain
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Switch to an opioid different than the one used
previously
Do not use methadone for breakthrough pain
Dosing Methadone: Overview cont’
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Titrate the methadone dose
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The methadone dose should not be titrated (25%50%) any sooner than every 3 days
Provide supportive care
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Prevention of constipation (schedule laxatives) &
nausea (metoclopramide).
May titrate or initiate non-opioid analgesics after
the day 8 assessment
Drowsiness and pain: add methylphenidate
Efficacy
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Analgesia: 3 points reduction in pain as
measured by MDASI
Side effects: reduction by 30%
Questions
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CCOP Research Base at (713) 563-0276.
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After hours or on weekends:
- Dr. Michael Fisch,
- Dr. Ahmed Elsayem,
- Dr. Nada Fadul
through the M. D. Anderson page operator
(713 792 7090)
Questions?
Thank
you.