1. Methadone “ Methadone “Simply Rotate” Study Ahmed Elsayem, MD Associate professor Director of PCU Dept of PC & Rehabilitation Med.

2. Cancer Pain Most feared complication of cancer Most feared complication of cancer < 50% obtain optimal pain control < 50% obtain optimal pain control Uncontrolled pain leads to other symptoms, worsen QOL, and interferes with treatment. Uncontrolled pain leads to other symptoms, worsen QOL, and interferes with treatment. 2/3 related to tumor 2/3 related to tumor 1/3 related to treatment 1/3 related to treatment Opioids is cornerstone for pain control Opioids is cornerstone for pain control

3. Opioid Side effects Respiratory depression Respiratory depression Constipation Constipation Nausea Nausea Drowsiness & fatigue Drowsiness & fatigue Opioid induced neurotoxicity (accumulation of active metabolites (e.g. morphine-3-G): Opioid induced neurotoxicity (accumulation of active metabolites (e.g. morphine-3-G): - Hallucination/Delirium - Myoclonus/ seizures - Hyperalgesia

5. Opioid Rotation (“Switching”) Morphine initial strong opioid Others include oxycodoen, fentanyl, hydromorphone, methadone… Others include oxycodoen, fentanyl, hydromorphone, methadone… Switching to a different opioid improve pain control and/or reduce opioid-related side effects (Incomplete cross-tolerance) 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

6. 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.

7. Rationale for Methadone Most common rotation at MDACC palliative care clinic Most common rotation at MDACC palliative care clinic Use increased in the last decade Use increased in the last decade Better analgesia “more stable ” Better analgesia “more stable ” Less opioid escalation with methadone Less opioid escalation with methadone Receptor agonist μ and δ & NMDA receptor antagonist Receptor agonist μ and δ & NMDA receptor antagonist NMDA receptor implicated in neuropathic pain NMDA receptor implicated in neuropathic pain Less affinity on μ receptors compared to morphine → less side effect (e.g. constipation) Less affinity on μ receptors compared to morphine → less side effect (e.g. constipation) Mercadante et al. JCO 1998

8. Rationale for Methadone Potent opioid analgesic Potent opioid analgesic Slowly produces tolerance and can reverse tolerance from other opioids Slowly produces tolerance and can reverse tolerance from other opioids Effective for treating neuropathic pain (NMDA receptor antagonist). Effective for treating neuropathic pain (NMDA receptor antagonist). Lacks active metabolites Lacks active metabolites Available in a variety of dosage formulations (most common 5 & 10 mg tablets, and 1:1 elixir) Available in a variety of dosage formulations (most common 5 & 10 mg tablets, and 1:1 elixir) Inexpensive Inexpensive

9. Pharmacokinetics Absorption-Rapid due to liphophilic properties Absorption-Rapid due to liphophilic properties Oral bioavailability 80% (41-99%) - 3x morphine Oral bioavailability 80% (41-99%) - 3x morphine Less than 10% of drug is extracted during first pass Less than 10% of drug is extracted during first pass Accumulates in chronic use Accumulates in chronic use Hepatic metabolism (CYP 450) mainly 3A4 but also 2D6. Hepatic metabolism (CYP 450) mainly 3A4 but also 2D6.

10. Kinetics In renal failure eliminated by feces increases, hence safe in renal failure patients In renal failure eliminated by feces increases, hence safe in renal failure patients HD- Poorly removed HD- Poorly removed In chronic liver failure no need to change the dose In chronic liver failure no need to change the dose No relationship between plasma conc and analgesic effect No relationship between plasma conc and analgesic effect

11. Caveats with Methadone Interindividual variability Interindividual variability –Long and unpredictable half-life –Drug interactions Dosing challenges Dosing challenges –The dose of methadone varies (inversely) with the previous oral morphine equivalent dose –The precise opioid dose ratio for methadone is unknown

12. 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.

13. Disadvantages Long and variable elimination half-life Long and variable elimination half-life Stigmatization Stigmatization Variation in the pharmacokinetics Variation in the pharmacokinetics QTc prolongation with ?high doses (≥ 300 mg) QTc prolongation with ?high doses (≥ 300 mg) Drug interactions at CYP 450(3A4, 2D6): - Inhibitors ↑ methadone level = toxicity. Drug interactions at CYP 450(3A4, 2D6): - Inhibitors ↑ methadone level = toxicity. - Inducers ↑ clearance = pain

14. CYP Inhibitors… And…Inducers Macrolides (erythromycin) Imidazoles (ketoconazole) Quinolones (ciprofloxacin) SSRI (fluvoxamine) Benzodiazepines (diazepam) Antiviral drugs (ritonavir) Acute alcohol ingestion Anticonvulsants (phenobarbital, phenytoin) RifampicinCorticosteroids Chronic alcoholism

15. “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).

16. 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.

17. 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.

18. 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

19. 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).

20. Randomization and Stratification Assignment by CCOP database Assignment by CCOP database Stratification according to baseline opioid (morphine or oxycodone) Stratification according to baseline opioid (morphine or oxycodone) Randomization Methadone or another opioid (e.g. patient on morphine will receive either methadone 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 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. Rescue opioid for methadone will be a short acting drug other than the one patient was using.

21. Treatment and Follow up Baseline evaluation before starting drug Baseline 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 evaluated face to face +/-3 days 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. 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. Provide adjuvant drugs for constipation, N/V.

23. MEDD Morphine 1:1 Hydromorphone 1:5 Oxycodone 1:1.5 Combinations of oxycodone, use the oxycodone portion and ignore tylenol or NSAIDS.

24. Dosing Methadone: Overview 1. 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 2. 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

25. Dosing Methadone: Table Calculated Oral MEDD Dose Ratio * 40-99mg4 100-180mg6 181-240mg8 241-300mg10 * Divide the calculated oral MEDD by this number to get the initial methadone dose Administer this dose every 12 or 8 hours Administer this dose every 12 or 8 hours

26. Dosing Methadone: Calculator

27. 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?

28. Dosing Methadone: Table 1. 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) 2. Initial methadone dose –Dose ratio from table (180-240mg MEDD) = 8 –Initial methadone dose = 30mg/day (240mg ÷ 8) –Give methadone 10mg every 8 hours

29. Dosing Methadone: Overview cont’ 3. Stop the previous opioid and start methadone 4. Utilize immediate-release opioid for breakthrough pain –Switch to an opioid different than the one used previously –Do not use methadone for breakthrough pain

30. Dosing Methadone: Overview cont’ 5. Titrate the methadone dose –The methadone dose should not be titrated (25%- 50%) any sooner than every 3 days 6. 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

31. Efficacy Analgesia: 3 points reduction in pain as measured by MDASI Analgesia: 3 points reduction in pain as measured by MDASI Side effects: reduction by 30% Side effects: reduction by 30%

32. Questions CCOP Research Base at (713) 563-0276. After hours or on weekends: - Dr. Michael Fisch, - Dr. Ahmed Elsayem, - Dr. Nada Fadul through the M. D. Anderson page operator (713 792 7090)

33. Questions? Thank you.