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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

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Methadone “Simply Rotate” Study

Ahmed Elsayem, MD

Associate professor

Director of PCU

Dept of PC & Rehabilitation Med.

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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

Quigley C. Opioid switching. Cochrane Database Syst Rev 2004.

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Rationale for Methadone

  • 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

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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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  • 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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  • 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.

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  • 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)



Chronic alcoholism

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“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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  • 60% of patients will achieve a ≥ 30% reduction in pain and/or opioid side effects with opioid rotation to oral methadone.

  • In contrast, 40% of patients will achieve this kind of response with opioid switching to either sustained-release morphine or oxycodone.

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Inclusion Criteria

  • 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.

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Exclusion Criteria

  • 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

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Study Entry Evaluations

  • 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).

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Randomization and Stratification

  • 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.

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Treatment and Follow up

  • 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.

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  • 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

  • Determine the oral morphine equivalent daily dose (MEDD)

    • 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

    • Use the Table in the protocol and/or

    • Use the Methadone Conversion Calculator on the web site

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Dosing Methadone: Table

*Divide the calculated oral MEDD by this number to get the initial methadone dose

  • Administer this dose every 12 or 8 hours

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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 immediate-release morphine per day with little relief (pain is rated as a 9/10).

What is the starting methadone dose?

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Dosing Methadone: Table

  • Oral MEDD

    • 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

    • Dose ratio from table (180-240mg MEDD) = 8

    • Initial methadone dose = 30mg/day (240mg ÷ 8)

    • Give methadone 10mg every 8 hours

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Dosing Methadone: Overview cont’

  • Stop the previous opioid and start methadone

  • Utilize immediate-release opioid for breakthrough pain

    • Switch to an opioid different than the one used previously

    • Do not use methadone for breakthrough pain

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Dosing Methadone: Overview cont’

  • Titrate the methadone dose

    • The methadone dose should not be titrated (25%-50%) any sooner than every 3 days

  • Provide supportive care

    • Prevention of constipation (schedule laxatives) & nausea (metoclopramide).

    • May titrate or initiate non-opioid analgesics after the day 8 assessment

    • Drowsiness and pain: add methylphenidate

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  • Analgesia: 3 points reduction in pain as measured by MDASI

  • Side effects: reduction by 30%

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  • CCOP Research Base at (713) 563-0276.

  • After hours or on weekends:

    - Dr. Michael Fisch, - Dr. Ahmed Elsayem, - Dr. Nada Fadulthrough the M. D. Anderson page operator (713 792 7090)

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