Methadone “Methadone “Simply Rotate” Study

Ahmed Elsayem, MDAhmed Elsayem, MD

Associate professorAssociate professor

Director of PCUDirector of PCU

Dept of PC & Rehabilitation Med.Dept of PC & Rehabilitation Med.

Cancer PainCancer Pain

Most feared complication of cancer Most feared complication of cancer < 50% obtain < 50% obtain optimaloptimal pain control pain control Uncontrolled pain leads to other symptoms, Uncontrolled pain leads to other symptoms,

worsen QOL, and interferes with treatment.worsen QOL, and interferes with treatment. 2/3 related to tumor2/3 related to tumor 1/3 related to treatment1/3 related to treatment Opioids is cornerstone for pain controlOpioids is cornerstone for pain control

Opioid Side effectsOpioid Side effects

Respiratory depression Respiratory depression ConstipationConstipation NauseaNausea Drowsiness & fatigueDrowsiness & fatigue Opioid induced neurotoxicity (accumulation Opioid induced neurotoxicity (accumulation

of active metabolites (e.g. morphine-3-G): of active metabolites (e.g. morphine-3-G): - Hallucination/Delirium- Hallucination/Delirium- Myoclonus/ seizures- Myoclonus/ seizures- Hyperalgesia- Hyperalgesia

Opioid Rotation (“Switching”)Opioid Rotation (“Switching”)

Morphine initial strong opioid Others include oxycodoen, fentanyl, Others include oxycodoen, fentanyl,

hydromorphone, methadone…hydromorphone, methadone… Switching to a different opioid improve pain Switching to a different opioid improve pain

control and/or reduce opioid-related side effects control and/or reduce opioid-related side effects (Incomplete cross-tolerance)(Incomplete cross-tolerance)

Methadone is commonly used in the switch

Evidence for RotationEvidence 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.

Rationale for MethadoneRationale for Methadone

Most common rotation at MDACC palliative care Most common rotation at MDACC palliative care clinic clinic

Use increased in the last decadeUse increased in the last decade Better analgesia “more stable” Better analgesia “more stable” Less opioid escalation with methadoneLess opioid escalation with methadone Receptor agonist Receptor agonist μμ and and δδ & NMDA receptor & NMDA receptor

antagonist antagonist NMDA receptor implicated in neuropathic painNMDA receptor implicated in neuropathic pain Less affinity on Less affinity on μμ receptors compared to morphine receptors compared to morphine

→ less side effect (e.g. constipation)→ less side effect (e.g. constipation)

Mercadante et al. JCO 1998

Rationale for MethadoneRationale for Methadone

Potent opioid analgesicPotent opioid analgesic Slowly produces tolerance and Slowly produces tolerance and can reverse can reverse

tolerance from other opioidstolerance from other opioids Effective for treating neuropathic pain (NMDA Effective for treating neuropathic pain (NMDA

receptor antagonist).receptor antagonist). Lacks active metabolitesLacks active metabolites Available in a variety of dosage formulationsAvailable in a variety of dosage formulations

(most common 5 & 10 mg tablets, and 1:1 elixir)(most common 5 & 10 mg tablets, and 1:1 elixir) InexpensiveInexpensive

PharmacokineticsPharmacokinetics

Absorption-Rapid due to liphophilic Absorption-Rapid due to liphophilic propertiesproperties

Oral bioavailability 80% (41-99%) - 3x Oral bioavailability 80% (41-99%) - 3x morphinemorphine

Less than 10% of drug is extracted during Less than 10% of drug is extracted during first passfirst pass

Accumulates in chronic use Accumulates in chronic use Hepatic metabolism (CYP 450) mainly 3A4 Hepatic metabolism (CYP 450) mainly 3A4

but also 2D6. but also 2D6.

KineticsKinetics

In renal failure eliminated by feces In renal failure eliminated by feces increases, hence safe in renal failure increases, hence safe in renal failure patientspatients

HD- Poorly removedHD- Poorly removed In chronic liver failure no need to change In chronic liver failure no need to change

the dosethe dose No relationship between plasma conc and No relationship between plasma conc and

analgesic effectanalgesic effect

Caveats with MethadoneCaveats with Methadone

Interindividual variabilityInterindividual variability

– Long and unpredictable half-lifeLong and unpredictable half-life

– Drug interactionsDrug interactions Dosing challengesDosing challenges

– The dose of methadone varies (inversely) The dose of methadone varies (inversely) with the previous oral morphine with the previous oral morphine equivalent doseequivalent dose

– The precise opioid dose ratio for The precise opioid dose ratio for methadone is unknownmethadone is unknown

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 Disadvantages

Long and variable elimination half-lifeLong and variable elimination half-life StigmatizationStigmatization Variation in the pharmacokineticsVariation in the pharmacokinetics QTc prolongation with ?high doses (≥ 300 mg) QTc prolongation with ?high doses (≥ 300 mg) Drug interactions at CYP 450(3A4, 2D6): Drug interactions at CYP 450(3A4, 2D6):

- Inhibitors ↑ methadone level = toxicity. - Inhibitors ↑ methadone level = toxicity.- Inducers ↑ clearance = pain- Inducers ↑ clearance = pain

CYP CYP InhibitorsInhibitors…… AndAnd……InducersInducers

Macrolides (erythromycin)Macrolides (erythromycin)

Imidazoles (ketoconazole)Imidazoles (ketoconazole)

Quinolones (ciprofloxacin)Quinolones (ciprofloxacin)

SSRI (fluvoxamine)SSRI (fluvoxamine)

Benzodiazepines Benzodiazepines (diazepam)(diazepam)

Antiviral drugs (ritonavir)Antiviral drugs (ritonavir)

Acute alcohol ingestionAcute alcohol ingestion

Anticonvulsants Anticonvulsants (phenobarbital, (phenobarbital, phenytoin)phenytoin)RifampicinRifampicinCorticosteroidsCorticosteroidsChronic alcoholismChronic 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).

Hypotheses

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.

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.

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

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).

Randomization and StratificationRandomization and Stratification

Assignment by CCOP databaseAssignment by CCOP database Stratification according to baseline opioid Stratification according to baseline opioid

(morphine or oxycodone)(morphine or oxycodone) Randomization Methadone or another opioid (e.g. Randomization Methadone or another opioid (e.g.

patient on morphine will receive either methadone patient on morphine will receive either methadone or oxycodone).or oxycodone).

Rescue opioid for patients on oxycodone or Rescue opioid for patients on oxycodone or morphine will be short acting similar drug.morphine will be short acting similar drug.

Rescue opioid for methadone will be a short acting Rescue opioid for methadone will be a short acting drug other than the one patient was using. drug other than the one patient was using.

Treatment and Follow upTreatment and Follow up

Baseline evaluation before starting drugBaseline evaluation before starting drug Calculate the scheduled and rescue dose(5-15%)Calculate the scheduled and rescue dose(5-15%) Study duration 28 days. Patients should be Study duration 28 days. Patients should be

evaluated face to face +/-3 daysevaluated face to face +/-3 days Follow up on days 8, 15, 22 and 28. One of the Follow up on days 8, 15, 22 and 28. One of the

first 2 visits face to face, and the rest by phone. first 2 visits face to face, and the rest by phone. Provide adjuvant drugs for constipation, N/V. Provide adjuvant drugs for constipation, N/V.

MEDDMEDD

Morphine 1:1 Hydromorphone 1:5 Oxycodone 1:1.5 Combinations of oxycodone, use the

oxycodone portion and ignore tylenol or NSAIDS.

Dosing Methadone: OverviewDosing Methadone: Overview

1.1. Determine the oral morphine equivalent Determine the oral morphine equivalent daily dose (MEDD)daily dose (MEDD)

– Calculate manually using equianalgesic dosing Calculate manually using equianalgesic dosing tables and/ortables and/or

– Use the Methadone Conversion Calculator on the Use the Methadone Conversion Calculator on the web siteweb site

2.2. Select the initial methadone dose based on Select the initial methadone dose based on the oral MEDDthe oral MEDD

– Use the Table in the protocol and/orUse the Table in the protocol and/or– Use the Methadone Conversion Calculator on the Use the Methadone Conversion Calculator on the

web siteweb site

Dosing Methadone: TableDosing Methadone: Table

Calculated Oral MEDDCalculated Oral MEDD Dose RatioDose Ratio**

40-99mg40-99mg 44

100-180mg100-180mg 66

181-240mg181-240mg 88

241-300mg241-300mg 1010*Divide the calculated oral MEDD by this number to get the initial methadone dose

Administer this dose every 12 or 8 hoursAdminister this dose every 12 or 8 hours

Dosing Methadone: CalculatorDosing Methadone: Calculator

Dosing Methadone: ExampleDosing Methadone: Example

Patient is prescribed sustained-release morphine 60mg Patient is prescribed sustained-release morphine 60mg every 12 hours and immediate-release morphine 15 every 12 hours and immediate-release morphine 15 mg every 3 hours as needed for breakthrough pain. mg every 3 hours as needed for breakthrough pain.

Patient is reportedly taking 8 doses of immediate-Patient is reportedly taking 8 doses of immediate-release morphine per day with little relief (pain is release morphine per day with little relief (pain is rated as a 9/10). rated as a 9/10).

What is the starting methadone dose?What is the starting methadone dose?

Dosing Methadone: TableDosing Methadone: Table

1.1. Oral MEDDOral MEDD– Sustained-release morphine = 120mg/day (60mg x Sustained-release morphine = 120mg/day (60mg x

2)2)– Immediate-release morphine = 120mg/day (15mg x Immediate-release morphine = 120mg/day (15mg x

8)8)– Total oral MEDD = 240mg/day (120mg + 120mg)Total oral MEDD = 240mg/day (120mg + 120mg)

2.2. Initial methadone doseInitial methadone dose– Dose ratio from table (180-240mg MEDD) = 8Dose ratio from table (180-240mg MEDD) = 8– Initial methadone dose = 30mg/day (240mg Initial methadone dose = 30mg/day (240mg ÷ 8)÷ 8)– Give methadone 10mg every 8 hoursGive methadone 10mg every 8 hours

Dosing Methadone: Overview cont’Dosing Methadone: Overview cont’

3.3. Stop the previous opioid and start methadoneStop the previous opioid and start methadone

4.4. Utilize immediate-release opioid for Utilize immediate-release opioid for breakthrough painbreakthrough pain

– Switch to an opioid different than the one used Switch to an opioid different than the one used previouslypreviously

– Do Do notnot use methadone for breakthrough pain use methadone for breakthrough pain

Dosing Methadone: Overview cont’Dosing Methadone: Overview cont’

5.5. Titrate the methadone doseTitrate the methadone dose– The methadone dose should not be titrated (25%-The methadone dose should not be titrated (25%-

50%) any sooner than 50%) any sooner than every 3 daysevery 3 days

6.6. Provide supportive careProvide supportive care– Prevention of constipation (schedule laxatives) & Prevention of constipation (schedule laxatives) &

nausea (metoclopramide). nausea (metoclopramide). – May titrate or initiate non-opioid analgesics after May titrate or initiate non-opioid analgesics after

the day 8 assessmentthe day 8 assessment– Drowsiness and pain: add methylphenidateDrowsiness and pain: add methylphenidate

EfficacyEfficacy

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

Side effects: reduction by 30%Side effects: reduction by 30%

QuestionsQuestions

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)

Questions?

Thank

you.