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Methadone Bernard J. Lapointe Associate Professor, department of Oncology and of Family Medicine Eric M. Flanders Chair in Palliative Medicine Potential conflict of interest • I have not received any support from the pharmaceutical industry in regard of the study or the clinical use of methadone. • I have received support from TEVA Canada for participating to advisory boards. • I have received support from Wex Technologies for participating to an advisory board. Introduction • Methadone is a synthetic opioid agonist developed by a German scientist during the second World War. • Methadone is actually a mixture of 2 enantiomers: – The R (Levro) methadone is the mu receptor agonist – The S (Dextro) methadone is stated to be the NMDA receptor antagonist Pharmacological properties • Methadone has unique opioid receptor interactions: • It is a mu-opioid receptor agonist and it also binds to the kappa and delta opioid receptors. • Additional mechanisms of action include: – inhibiting the re-uptake of serotonin and norepinephrine – works as an antagonist at the N-methyl-Daspartate (NMDA) receptor, thought to prevent central sensitization and reduce/ reverse opioid tolerance, Methadone in Canada • prescription of methadone for maintenance therapy or analgesia in Canada is restricted under the Controlled Substances and Regulations Act. • Formulations available: – – – – Flavoured liquid preparation (refrigeration) Tablets (1 mg, 5 mg, 10 mg and 25 mg) Custom made capsules or suppositories Injectable methadone (Synastone10 mg/ml) available through Health Canada Special Access Program (very often a lenghty process). • Additional methadone delivery modes include: – – – – – epidural, intra-thecal, rectal, subcutaneous, sublingual, rapid analgesic onset and avoidance of hepatic first-pass metabolism and provides relief for breakthrough cancer pain (Hagen et al., 2010) – topical administration. The oral dose q8h and prn (often reduced by 30%) may be compounded by an experienced pharmacist with Lipoderm . Concentration range was 2 mg/0.2 ml to 25 mg/0.2 ml (Love and Bourgeois, 2014) • Novel form of Methadone: Dextro-Methadone – d-Methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity at the expected therapeutic doses. – Phase Two to start in 2016. clinical target: neuropathic pain. methadone has unique properties that make it a little “trickier” – – – – Long and variable half-life Potential drug interactions with multiple medications Variability in equi-analgesic dose ratios Association with prolongation of QTc (predisposes patients to the ventricular arrhythmia torsades de pointes) – “Proportion of methadone-associated deaths related to arrhythmia is likely to be small relative to the proportion related to accidental overdose, though reliable estimates are not available” (Chou, APS) South of the border… • Methadone accounted for 1,7% of opioid prescriptions in 2009 and 9% in 2010. • Since 2000, the rate of deaths from drug overdoses has increased 137%, including a 200% increase in the rate of overdose deaths involving opioids (opioid pain relievers and heroin) MMWR 2016 Jan 1st • Methadone was associated with 31% of opioid related deaths and 40% of single drug deaths. – MMWR 2012, 61-493-7 • In Ontario, Canada, methadone had the highest relative percentage of deaths which were accidental (84%) when compared with other opioids (Madadi et al., 2013) Equi-analgesia conversion Initiating methadone (Chou, APS) • In opioid naïve patients or conversion from low dose of other opioids (EDDM 40-60) do not exceed methadone 2,5mg tid – Dose increase no more than 5mg /day every 5-7 days. Rotation to methadone • Methods of Rotation From Another Strong Opioid to Methadone for the Management of Cancer Pain: A Systematic Review of the Available Evidence – Sarah McLean, MB, MAO, BCh, Feargal Twomey, MB, MRCPI. Journal of Pain and Symptom Management, August 2015 – 3 days switch – Rapid conversion: Stop and Go – German model – Outpatient titration Recommendations AAHPM 2016 • EDDM – 40-60mg / 24hrs 2-7,5 mg in 2-3 divided doses – 60-200 mg /24hrs 10:1 (morphine: methadone) – Over 200mg/24hrs 20:1 – Do not adjust dose for 5-7 days (or per clinical judgement) Who could benefit from methadone ? • • • • Patients with true morphine allergy Patients with neuropathic pain Opioids adverse effects with another opioid Pain refractory to other opioids or uncontrolled pain • Significant renal impairment Methadone may not be an option: • Patients at the very end of their life (consider as adjuvant) • Needing drugs known to have an interaction with methadone • Drugs that prolong QTc interval • Patient living alone, poor cognitive functioning without a competent caregiver • Prior history or suspicion of chemical coping • Clinical instability/ liver failure Monitoring of Methadone Initiation and Titration: • Check for: – Excessive drowsiness/level of arousal – Slowed respiration or periods of apnea, more rapid respiration, shallow breathing – Slurring of speech – Loud snoring – Pinpoint pupil size • Since patients are not taking one large dose (as in an overdose situation), it is important to monitor for these signs and symptoms of toxicity over a 5–7 day period after initiation of methadone therapy or a dosage change. – McPHerson • Monitor for sleep apnea. Pharmaco-dynamic drug interactions • Methadone and other opioids • Increased analgesia • Additive toxicities • Methadone and cns depressants ( alcohol, neuroleptics, benzos…) • Methadone and other medications that prolong QT interval. (antiarrhytmics, antidepressants) – Proportion of death due to prolongation of QT in patients receiving methadone is likely to be very low, but unknown. Drug-drug Interactions with Methadone Enzyme Inducers • The enzyme inducing medication will increase the metabolism of methadone, resulting in a decreased methadone serum level. • The dose of methadone may be insufficient and the patient can experience increased pain. • Some of the Enzyme Inducers important to know when using Methadone: – Rifampicin/rifampin/rifabutin – Phenytoin – Spironolactone – Nevirapine – Amprenavir, Nelfinavir, Ritonavir – Carbamazepine – St. John’s Wort Enzyme Inhibitors • The enzyme inhibiting medication will slow the metabolism of methadone, resulting in an increased methadone serum level. The patient may become toxic from a methadone overdose. • Some of the Inhibitors important to know when using Methadone: – – – – – – – – – – – Fluoxetine, Paroxetine Sertraline Ciprofloxacin Fluvoxamine Amitriptyline Ketoconazole, Fluconazole Erythromycin Citalopram Desipramine Clarithromycin Itraconazole Methadone Safety Guidelines • Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society – Roger Chou,* 2014, Pain Should we monitor with ECG ? • L-methadone blocks hERG potassium channel which results in QTC prolongation, increasing risk of torsade de pointes. • The American Pain Society recommends that clinicians obtain an ECG prior to initiation of methadone in patients: – – – – with risk factors for QTc interval prolongation, any prior ECG demonstrating a QTc > 450 ms, or a history suggestive of prior ventricular arrhythmia; An ECG within the past three months with a QTc < 450 ms in patients without new risk factors for QTc interval prolongation can be used for the baseline study • An ECG higher than 500ms: no methadone • 450-500 ms: are there other alternatives, can we change some of the drugs contributing to QTC prolongation Follow-up ECG recommendations • In patients identified as a risk a follow-up ECG should be obtained 2-4 weeks after initiation or after significant dose increase • Patients reaching 30-40 mg • Patients reaching doses over 100 mg • Signs or symptoms suggestive of arrythmia Methadone Prescribing Rights: • Authorized prescribers may write and sign prescriptions for methadone. • If a physician does not have the license to prescribe methadone, he/she must apply for a temporary exemption to prescribe methadone for a patient during hospital admission • Only a staff physician is allowed to request for a temporary exemption to prescribe methadone • Methadone can be started for a patient while waiting for Health Canada response • Please note that a temporary exemption can be obtained ONLY for a patient on methadone PRIOR to hospital admission. A temporary exemption does not allow the physician to initiate treatment but allows for dosage modifications. Co-administration of methadone • Addition of a second opioid may improve opioid response in cancer pain: preliminary data. Mercadante S et al. Support Care Cancer 2004:12;762-6__ (14 cases, Palermo) • Use of Methadone as Coanalgesic. McKenna M. J Pain Symptom Manage 2011; 46(6)e5__(10 cases, UK) • Addition of Methadone to Another Opioid in the Management of Moderate to Severe Cancer Pain: A Case Series. Wallace E. et al. J Pall Med 2013;16(3):305-9__(20 cases, Toronto) • Use of Very low dose methadone for palliative pain control at the prevention of opioid hyperalgesia. Salpeter S. et al. J Pall 2013; 16(6):616-622__ (96 cases, California) • La methadone. Société québécoise des médecins en soins palliatifs. Médecine Palliative. Elsevier, In press. Co-administration of methadone Conclusion: The use of very-low-dose of methadone in conjunction with adjuvant haloperidol Resulted in excellent pain control without dose escalation or opioid-induced Hyperalgia, for both cancer and noncancer diseases. We conclude that low-dose Methadone should be part of first-line treatment in palliative pain management. Take home messages: • Assess risk for abuse or diversion • Pay attention when attempting conversion • Avoid benzodiazepines HS (potentiates sleep disordered breathing) • Use methadone as a 2nd or 3rd line agent or use as adjuvant • If respiratory tract infection monitor and consider reducing daily dose by 30% (McPHerson 2016) Methadone for Analgesia KT Tools Project Litterature Search and Review for Online Training Tool Methadone for Analgesia By: Jane Kondejewski PhD