Managing Pain: A Focus on the Appropriate Use of Methadone

Managing Pain: A Focus on the Appropriate Use of Methadone Karla Anderson, PharmD Regional Client Liaison Anthony Contreras, RPh Regional Sales Associate Hospice Pharmacia, a division of excellerx, Inc. www.hospicepharmacia.com Office: 480.629-5132 Disclaimer The information and the materials included in this presentation are intended for educational use. Review or discussion of any agent does not alter in any way the conditions for use contractually agreed upon and outlined in the Hospice Pharmacia Medication Use Guidelines. This program will not be a focus on the Medication Use Guidelines and is intended for educational purposes. Presentation Objectives Describe the mechanism of action, pharmacokinetics, and other properties of methadone. Discuss how to recognize the need for opioid rotation and the practical application of this strategy in the hospice setting. Recognize various patient specific considerations that may influence methadone dosing recommendations. Calculate an equianalgesic dose given a patient case using current methadone dosing guidelines. www.ahpco.org 1

Presentation Overview Mechanism and uses Characteristics of methadone Opioid rotation Methadone dosing Drug interactions and dosing considerations Cases Methadone (Dolophine ) A synthetic opioid developed in Germany Potent and long acting opioid analgesic Chemically unrelated to morphine and semi-synthetic opioids Multiple mechanisms of action Commercially Available Dosage Forms of Methadone Tablets 5mg, 10mg oral tablets 40mg oral disintegrating or water soluble tablets Liquid 10mg/5ml, 10mg/ml Parenteral 10mg/ml for injection www.ahpco.org 2

Methadone Methadone Methadone is in a different chemical class than morphine and related opioids Oxycodone, hydromorphone, hydrocodone, etc. Can be used in patients with true opioid allergies Related to propoxyphene Use with caution in patients who cannot tolerate Darvocet, Darvon, etc. Receptor Effects of Opioid Analgesics Receptor: Mu Morphine High Methadone Low Kappa Morphine High Methadone Low/none Delta Morphine Low/none Methadone High Response: Analgesia, respiratory depression, miosis, euphoria, constipation Analgesia, dysphoria, hallucinations, miosis, respiratory depression Analgesia Oxford Textbook of Palliative Medicine; 2nd edition: 332 Methadone Mechanisms of Action mu and delta receptor agonist Treats cancer and other visceral pain Other opioids act at Mu and Kappa receptors NMDA receptor antagonist Counteracts opioid tolerance, physical dependence, and treats hyperalgesia and allodynia Increases visceral pain relief of opioids NE reuptake inhibitor Useful for neuropathic pain Similar mechanism to tricyclic anti-depressants Very weak Serotonin reuptake inhibitor Support Care Cancer 2001;9:73-83; Oncology 1999;13(9);1275-1281 www.ahpco.org 3

Methadone for Neuropathic Pain Possibly from combination of methadone s mechanisms Shown effective for PHN, post-stroke pain, diabetic neuropathy, and sciatica pain Pain described as dull, burning, stabbing, tingling, electric-like, etc. Pain in response to non-painful stimuli or nothing at all Hyperalgesia exaggerated response to painful stimulus Allodynia pain produced by normally non-painful stimulus Both are potential consequences of morphine tolerance Additional benefit of methadone Patients experiencing neuropathic pain along with visceral pain Methadone: Characteristics Absorption: Quick onset (30-60min) High bioavailability (approximately 80% of dose by mouth) Can be given PO, PR, IV 1:1 PO to PR conversion 1:2 IV to PO conversion Distribution: Two-Compartment Model Acute Dosing Alpha distribution phase= 2-3 hours Alpha elimination phase = 6-8 hours Chronic Dosing Beta distribution phase = 8-12 hours Betaelimination phase = 15-60 hours Support Care Cancer 2001;9:73-83 Methadone Variability What s the significance of this variability? We must use caution when dosing methadone An adequate dose for one may be too high for another Methadone can be especially dangerous because of its long half life Rule of thumb with dosing: start low, go slow www.ahpco.org 4

Methadone: Characteristics Metabolism: By CYP3A4 iso-enzyme in the liver CYP1A2 and CYP2D6 to a lesser extent No active metabolites No accumulation in renal insufficiency Elimination: Fecal and urinary excretion Acidifying urine enhances elimination of methadone Methadone: Characteristics Side Effects Nausea, vomiting, euphoria, and respiratory depression Less sedation, constipation, and hallucinations Possible Torsades de Pointes at high doses (>200mg/day) Drug Interactions Inducers and inhibitors of CYP3A4, 2D6, 1A2 Drugs that increase arrhythmia risk Methadone Dosing Considerations Enzyme inhibitors Drug Interactions fluconazole (Diflucan ) ketoconazole erythromycin clarithromycin (Biaxin ) cimetidine (Tagamet ) paroxetine (Paxil ) amiodarone Others Increase methadone levels Enzyme inducers phenobarbital carbamazepine phenytoin (Dilantin ) St. Johns Wort Rifampin Steroids Others Decrease methadone levels www.ahpco.org 5

Drug Interactions Cont. Some medications increase risk for lifethreatening arrhythmias Some examples Amiodarone Chlorpromazine (Thorazine ) Clarithromycin (Biaxin ) Fluoxetine (Prozac ) Haloperidol (Haldol ) Paroxetine (Paxil ) Quinidine Risperidone (Risperdal ) Use cautiously with methadone and with patients at risk for arrhythmias Drug Interactions Cont. Acidifying the urine can increase clearance Acidic medications like Vitamin C Citric foods and juices Half-life and duration of action of methadone can be drastically reduced May see treatment failures requiring higher doses of methadone Patient Specific Factors Severe renal impairment Reduce methadone interval No more often than every 12 hours Hepatic impairment No dose reduction needed for stable chronic liver disease Use with caution in patients with acute liver failure Genetics Some patients are genetically predisposed to metabolize methadone faster or slower than others www.ahpco.org 6

Case #1 68 yo woman notes worsening chest and rib pain caused by non-small cell lung cancer Controlled on long-acting morphine 200mg q12h and 40mg q4h prn for 4 months Added Ibuprofen 800mg TID for bone pain and gradually titrated to Morphine 400mg q12h and 80mg q4h prn Despite the increase in dose and the addition of an NSAID, her pain continues to be uncontrolled, and she is experiencing intolerable hallucinations, thought to be opioid-related What is the Goal? To achieve a better balance between pain relief and side effects In this case, our patient s pain management is not in balance What are Our Therapy Options? Reduction in dose of systemic opioid Aggressive management of the adverse effect Changing route of administration Co-administration of non-opioid or adjuvant Non-pharmacologic interventions Opioid rotation www.ahpco.org 7

What is Opioid Rotation? Simply put, it is switching from one opioid to another Why switch? To achieve better balance Better pain relief Reduction of side effects Current Opinions in Oncol 2000;12:308-313 When to Consider Switching Intolerable side effects Development of tolerance Can be rapid Difficult pain syndromes Refractory pain Uncontrolled pain Current Opinions in Oncol 2000;12:308-313 Opioid Use in Cancer Pain 80% of cancer patients experience moderate to severe pain Strong opioids usually agents of choice 20% of patients respond poorly to opioids Others have dose limiting toxicities Support Care Cancer 2001:9:73-83 www.ahpco.org 8

Adverse Effects of Morphine Morphine is broken down into several metabolites that can Drowsiness cause mild to severe side effects: Hallucinations Nausea and vomiting Euphoria Respiratory depression Myoclonic spasms Sweating Tonic-clonic seizures Morphine metabolites can accumulate with: -High doses -Repeated morphine dosing -Dehydration -Impaired renal function Current Opinions in Oncol 2000;12:308-313 Adverse Effects of Morphine Repeated high doses, dehydration, and renal impairment can all be seen in hospice patients Therefore, these patients are at risk for morphine side effects Methadone does not have active metabolites A viable option for patients experiencing intolerable side effects caused by morphine Methadone Dosing Methadone dosing can be difficult Dosing regimens are numerous and their use controversial High variability between patients Methadone seems to be more potent in patients tolerant to other opioids J of Clinical Oncology 1998;16(10)3216-3221 www.ahpco.org 9

Age of the patient Methadone Dosing Considerations Previous opioid dose Drug interactions Previous cardiac history with arrhythmia risk Structural cardiac disease Atrial fibrillation Electrolyte abnormalities Hypomagnesemia, hyper- and hypokalemia Common Themes of Methadone Dosing Every 8-12 hour dosing Using methadone for breakthrough pain Onset of action remains consistent Get patient to steady state faster Methadone builds up in system to last longer Using for breakthrough cuts time to steady state Ok to use other medications for breakthrough If previous med works well, ok to keep on board Go with methadone if possible Methadone is compared to morphine Convert all previous pain medications to a morphine equivalent Methadone Dosing Three different guidelines presented here Ripamonti, et al. 1998 Mercadante et al. 2001 Hospice Pharmacia www.ahpco.org 10

Ripamonti, et al. 1998 Dosing guidelines: developed by clinical experience Day 1: Reduce morphine total daily dose by 30% and started oral methadone on a q8h schedule at a ratio of: if morphine TDD is 30-90mg, use a dosing ratio of 4:1 (M:ME) if morphine TDD is 90-300mg, use ratio of 6:1 (M:ME) if morphine TDD is >300mg, use ratio of 8:1 (M:ME) Day 2: Reduce morphine by 30%. Increase methadone only if patient is in severe pain. Day 3: Discontinue morphine and continue M=Morphine. ME=Methadone methadone q8h ATC with 10% of dose for BTP Ripamonti, et al. 1998 Pros Prospective, published study Slow titration off morphine and increase of methadone Clearly defined ratios based on previous morphine dose Accounts for high initial morphine dose Cons Many steps and variables 3 day titration 3-tiered conversion ratio Does not account for drug interactions Does not account for patient specific factors Mercadante et al. 2001 Dosing guidelines: Stop morphine Immediately substitute methadone at a ratio of: if morphine dose is <90mg, use a ratio of 4:1 (M:ME) if morphine dose is 90-300mg, use a ratio of 8:1 (M:ME) if morphine dose is >300mg, use a ratio of 12:1(M:ME) Methadone was given q8h and a breakthrough dose of 1/6 the total daily dose was available Titration was based on breakthrough dosage use M=Morphine. ME=Methadone www.ahpco.org 11

Mercadante et al. 2001 Pros Simple, 1 step titration Clearly defined ratios based on previous morphine dose Prospective, published study Accounts for higher initial dose of morphine Cons 3-tiered conversion ratio Does not account for drug interactions Does not account for patient specific factors Hospice Pharmacia Either a 10:1 or a 20:1 ratio with morphine:methadone. Based on patient age, total daily morphine equivalent intake, drug interactions, and arrhythmia risk Example: Pt > 65 years old: 20:1 (M:ME) Taking > 1000mg morphine/day: 20:1 (M:ME) Dose reduction of 25% for certain drug interactions Arrhythmia risk with high dose of methadone (>200mg/day): avoid use M=Morphine. ME=Methadone Hospice Pharmacia Dose methadone at q8h scheduled Dose methadone at 1/3 total daily dose q3h prn breakthrough pain (max 30mg/dose) Readjust breakthrough after 7 days to 10% total daily dose if necessary www.ahpco.org 12

Hospice Pharmacia Pros Conservative ratio geared towards hospice patients Takes into account patient specific factors Age Previous morphine dose Drug interactions Arrhythmia risk Evidence taken from many studies Cons Not published in peer reviewed journal Complex dosing conversion Heavily reliance on breakthrough dosing early in treatment Case #1 Revisited 68 y/o woman titrated to Morphine 400mg q12h and 80mg q4h prn 800mg + 480mg = 1280mg morphine/day Severe hallucinations + uncontrolled pain Side effect of morphine and apparent tolerance Let s convert the patient to methadone using the Mercadante method vs. the HP method for comparison Case #1 Mercadante conversion Patient is taking 1280mg morphine/day Stop Dosing morphine protocol immediately 1280mg 12 Dosing calculations = 106mg if morphine dose is <90mg, methadone per day use a ratio of 4:1 (M:ME) 106mg 3 = 35mg q8h if morphine dose is 90-300mg, use a ratio of 8:1 (M:ME) scheduled if morphine dose is >300mg, use 1/6 total methadone dose use a ratio of 12:1 (M:ME) as breakthrough q3h prn Methadone given q8h and a 106mg 6 ~ 15mg q3h prn breakthrough dose of 1/6 the breakthrough pain total daily dose was available Final prescription: Methadone 35mg q8h scheduled and 15mg q3h as needed for breakthrough pain www.ahpco.org 13

Case #1 HP Conversion Total daily morphine 1280mg/day Pt > 65 years old. Use 20:1 ratio, every 8 hours No drug interactions or cardiac risk 1280mg 20 = 64mg methadone/day 64mg 3 ~ 20mg q8h scheduled Use 1/3 total methadone dose as breakthrough (max 30mg per dose) 64mg 3 ~ 20mg q3-4h prn breakthrough pain Readjust after 1 week No drug interactions or cardiac risk No further adjustment needed Final prescription: Methadone 20mg q8h scheduled and 20mg q3-4h prn breakthrough pain Case #1 Results Mercadante method results in higher dose than HP 35mg q8h > 20mg q8h Does not make one conversion superior to another Methadone dosing should be individualized for the patient Base on clinical experience Case #2 MP is a 45 y/o male receiving morphine treatment for severe pain secondary to pancreatic cancer PHM significant for CRF and Type I diabetes He describes his pain as a deep stabbing pain with an electric-like shock around and down his back He is receiving morphine LA at 60mg q8h with little to no relief He now reports frequent muscle jerks and spasms in his arms and legs www.ahpco.org 14

Case #2 Is methadone a good choice? Uncontrolled pain Neuropathic pain a component (electric-like) Renal failure with morphine resulting in mycoclonic jerks What dose to recommend Let s use the Ripamonti method Case #2: Ripamonti Dosing protocol Day 1: Reduce morphine total daily dose by 30% and started oral methadone on a q8h schedule at a ratio of: if morphine TDD is 30-90mg, use a dosing ratio of 4:1 (M:ME) if morphine TDD is 90-300mg, use ratio of 6:1 if morphine TDD is >300mg, use ratio of 8:1 Day 2: Reduce morphine by 30%. Increase methadone only if patient is in severe pain. Day 3: Discontinue morphine and continue methadone q8h ATC with 10% of daily dose for BTP TDD = Total Daily Dose Patient is taking 180mg morphine/day Dosing calculations Day 1: 180mg morphine/day 30% ~ 135mg morphine/day -> 45mg q8h 180mg morphine/day 6 = 30mg/methadone/day > 10mg q8h Day 2: 135mg morphine/day 30% ~ 90mg morphine/day -> 30mg morph q8h Assess pt s pain for methadone increase Day 3: Stop morphine Assuming pain controlled: methadone 10mg q8h with 5mg q3h prn breakthrough pain Case #2 Results After 3 days, morphine is stopped and methadone is started at 10mg q8h Breakthrough dose is 5mg q3h prn Final prescription: Methadone 10mg po q8h routine and 5mg q3h prn breakthrough pain Methadone is titrated based on patient need www.ahpco.org 15

Conclusion Methadone has several uses and benefits Dosing can be difficult Many patient specific considerations must be taken into account Monitoring for pain relief and side effects are a must Clinical experience plays a large role in dosing methadone References 1. Fishman S, Wilsey B, Mahajan M, Molina O. Methadone reincarnated: Novel Clinical Applications with Related Concerns. Pain Medicine 2002;4:1-10 2. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions, and protocols of administration. Support Care Cancer 2001;9:73-83. 3. Morley J, Bridson J, Nash T, Miles J, White S, Makin M. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliative Medicine 2003;17:576-587 4. Hansen S. Pathophysiology. Foundations of Disease and Clinical Intervention. 1998, pg. 658 5. Price D, Mayer D, Mao J, Caruso F. NMDA-Receptor Antagonists and Opioid Receptor Interactions as Related to Analgesia and Tolerance 6. Mancini I, Lossignol DA, Body JJ. Opioid switch to oral methadone in cancer pain. Current Opinion in Oncology 2000;12:308-313 7. Gillman P K. Monoamine oxidase inhibitors, opioid analgesics, and serotonin toxicity. British Journal Anesthesiology 2005;95:434-41 www.ahpco.org 16

References 8. Lugo R, Satterfield K, Kern S. Pharmacokinetics of Methadone. Journal of Pain and Palliative Care Pharmacotherapy 2005;19(4):13-24 9. Ripamonti C, Groff L, Brunelli C, Polastri D, Stavraski S, De Conno F. Switching from Morphine to Oral Methadone in Treating Cancer Pain: What isthe Equianalgesic Ratio? Journal of Clinical Oncology 1998;16:3216-3221 10. Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from Morphine to Methadone to improve Analgesia and Tolerability in Cancer Patients: A Prospective Study. Journal of Clinical Oncology 2001;19:2898-2904 11. Allen W L, et. al. Pharmacogenomics. 2004, pg. 291 www.ahpco.org 17