Understanding the Medical Issues of Methadone Patients Karen Miotto , M.D. Semel Institute for Neuroscience and Human

1. Understanding the Medical Issues of Methadone Patients Karen Miotto, M.D. Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles kmiotto@mednet.ucla.edu 310 206-2782

2. Areas of Discussion Increase in methadone use for pain Pain patients on methadone may be treated by doctors with less than optimal training in pain/addiction Nature of medical concerns associated with methadone Safety concerns Induction Drug interaction Cardiac concerns Increase in methadone death increase stigma

3. Methadone Synthetic opioid, structure very different from other opioid methadone codeine morphine Philip Peng MBBS FRCPC Director, Anesthesia Chronic Pain Program, University Health Network, Wasser Pain Management Center, Mount Sinai Hospital

4. Methadone Distribution*2000 – 2007** GRAMS PER 100K POPULATION ** 01/01/2007 – 03/31/2007 * Includes NTPs Source: ARCOS Date Prepared: 07/19/2007 Drug Enforcement Administration, Office of Enforcement Operations, Pharmaceutical Investigations Section, Targeting and Analysis Unit

5. Sales data: Total extended units of methadone sold to retail and non-retail channels of distribution, Years 2002 – 2006, IMS Health, IMS National Sales PerspectivesTM • Overall sales of methadone have increased by 89% between year 2002 and 2006 • Sales in retail channels have doubled since 2002, whereas only 59% increase in the non-retail sector IMS Health, IMS National Sales Perspectives™, Years 2002 - 2006, Extracted July 2007.

6. Total PrescriptionsSelected Narcotic AnalgesicsSource: IMS Health Prescription Audit Millions of Prescriptions Note: In 2006, there were about 35-fold more hydrocodone prescriptions and 10-fold more oxycodone prescriptions compared to methadone prescriptions.

8. Trends In Emergency Department Mentions2004-2005

9. Methadone deaths by underlying mechanism and intent: 1999-2004 Lois Fingerhut Source: NCHS, data from the National Vital Statistics System

10. Relative Abuse Potential? • 3-year retrospective • Free-standing pain clinic • Patients discharged for opioid misuse vs. 200 random patients receiving opioid therapy • Multisourcing • toxicology discrepancies • repeated escalation , etc. • “Relative misuse potential” • Drug frequency in the discharged patients/frequency in active patients • Problem • True misuse potential would require prospective study with random assignment

11. Methadone Death Overdose, overmedication or drug-drug interaction?

14. Methadone And Pain

15. Chronic Pain Patients in Methadone Clinics: Types of Pain Low back pain (42.8%) Lower extremity pain (23.7%) Total body pain (13.2%) Headaches (9.2%) Upper extremity pain (5.3%) Chest & abdominal pain (3.9%) Neck pain (2.6%) * 65% have a second pain site

16. Methadone-maintenance Patients with Pain vs Those Without Pain • More medical illness • More psychiatric illness • More prescribed medications • More non-prescribed medications *Average pain duration more than 10 years • Average intensity > 5 on a 1-10 scale

17. Methadone-maintained Patients vs Other Pain Patients: Mysteries Methadone-maintained patients are hypersensitive to pain, especially to cold pressor pain. Methadone-maintained patients are very tolerant to methadone & morphine analgesia

18. Why is methadone a good pain medicine? • Efficacy • Long half life  Long duration effect • Useful in managing chronic pain • Convenient dosing schedule • Good oral bioavailability • Methadone a common choice of drug for pain that does not respond to weaker agonists • Low cost • Methadone is synthetic and easily manufactured; it is also 1/10 the cost of other opioids. It is particularly cost-saving for cancer patients who require high-dose opioids.

19. Pharmacology • Methadone is: • Mu receptor agonist • NMDA-antagonist (n-Methyl-d-Aspartate) • glutamate and aspartate are released in response to pain • bind to NMDA receptor and cause changes in CNS • may underlie chronic pain and neuropathic pain • hyperalgesia: exagerated pain response • wind-up: increase of nerve firing to point where it fires spontaneously Joel S. Policzer, M.D. Methadone:Pharmacology and Usage Guidelines National Medical Director Vitas Healthcare

20. Dosing Methadone • Some methadone conversion tables are: • at least problematic; • some are incorrect (recommending too high initial methadone doses) This contributes to confusion and dosing error! Pain treatment providers should call Pain Resource for dosing guidelines -Dolophine Solution IV methadone Tablets

21. Ripamonti Method Determine 24-hour oral morphine equivalent dose For 24-hour morphine dose of: 0-90 mg Use 4:1 morphine:methadone 90-300 mg Use 8:1 morphine:methadone 300+ mg Use 12:1 morphine:methadone Generally use another opioid for breakthrough pain Ripamonti, et al., 1998

22. Ayonrinde Method For 24-hour morphine dose of: <100mg Use 3:1 morphine:methadone 101-300 mg Use 5:1 morphine:methadone 301-600 mg Use 10:1 morphine:methadone 601-800 mg Use 12:1 morphine:methadone 801-1000 mg Use 15:1 morphine:methadone >1000 mg Use 20:1 morphine:methadone Gazelle, G and Fine, P. Methadone for pain: #75, Journal of Palliative Medicine, vol.7(2), 2004

24. Absorption - Methadone Source: Goodman & Gilman, Kreek, and others Detected at 30 min. following oral dosing Peak plasma levels occur at 2-4 hours Large amounts stored in liver and other tissues for later release into circulation to maintain steady-state (Reservoir Effect) Protein binding extensive, up to 90% of therapeutic dose Highly lipophillic, parenteral doses readily cross blood-brain barrier Opioid Agonist Treatment of Addiction - Payte - 1998

25. “All substances are poison. The right dose differentiates a poison and a remedy” Paracelsus, 1493-1541 AD

26. Edwin Salsitz, M.D.

27. Methadone Single Dose Kinetics INTOXICATON T½ 5-6 hrs ANALGESIA T½ 20-40 hrs PAIN 5 10 15 20 Nilsson MI, et al. Acta anaesth. scand 1982, Suppl 74

28. Steady State: The point at which during each interdose interval the rise and fall of drug concentration for the interdose interval is identical for each dose Days/Half-Lives – Methadone half-life= 24-36 hoursDose constant at 30 mg daily. Interdose interval = 24 hrs (trough to trough)Peak levels increase daily for 5-6 days with NO increase in dose! 28 Colonial Management Group, LP -- J. Thomas Payte, MD

29. The 3 most important questions for methadone titration are: DL Gourlay MD, FRCP, FASAM 29 • What are you like before your first dose in the AM? (Trough Level) - Is there an “opioid debt”? • What are you like 1/2hr after the first dose? (Onset) – Symptom improvement with first dose is most likely withdrawal mediated, i.e., inadequate 24hr total dose 3. What are you like 2-4 hours after the first dose of the morning? (Peak) - Symptoms that are gone by 3 or 4 hrs are almost certainly withdrawal mediated

30. CYP in Methadone Metabolism The most important enzymes in methadone metabolism are CYP3A4 and CYP2B6. Secondarily CYP2D6 appears to have a role, and CYP1A2 may possibly be involved.

31. Potential Inhibitors of CYP3A4-Mediated Metabolism — may ↑methadone level • Selective Serotonin Reuptake Inhibitors (SSRI) • Sertraline(zoloft®), fluoxetine(prozac®), paroxetine(seroxate®) • Serotonin Norepinephrine Reuptake Inhibitors(SNRI) • venlafaxine, nefazodone • Broad-spectrum antifungals and antibacterials • clotrimazole, fluconazole, fluoroquinolone, macrolides, etc. • HIV drugs : ritonavir • NNRTI : zidovudine will decreased by methadone • Hormones (progesterone, ethinylestradiol, dexamethasone) • Calcium channel antagonists (nifedipine, verapamil, diltiazem) • Miscellaneous (quinidine, midazolam, cyclosporin, vinblastine, bromocriptine, cimetidine, omeprazole, allopurinol, etc.)

32. Potential Inducers of CYP3A4-Mediated Metabolism — may↓methadone level • Some antiepileptics • phenobarbital, phenytoin, primidone, carbemazepine, but not valproate or benzodiazepines • Glucocorticoids • Antituberculosis drugs : rifampin, rifabutin • HIV drugs : • NNRTI (efavirenz, nevirapine) • PI (kaletra, nelfinavir)

33. Methadone Interactions • http://atforum.com/SiteRoot/pages/addiction_resources/ P450%20Drug%20Interactions.PDF Potential serotonin syndrome with SSRIs, tramadol Grapefruit inhibits methadone metabolism Smoking induces CYP1A2, and ↓ methadone levels

34. Urinary pH Disposition of Methadone Source: Nilsson et al., 1982 Opioid Agonist Treatment of Addiction - Payte - 1998

35. Other Mechanisms of Drug Interaction benzodiazepine Excitatory: NMDA Inhibitory : GABA Respiration rhythm methadone Philip Peng MBBS FRCPC Director, Anesthesia Chronic Pain Program, University Health Network, Wasser Pain Management Center, Mount Sinai Hospital • 1-acid glycoprotein • Circulating level  with stress, addiction, cancer and drugs such as amitriptylline • Pharmacodynamics interaction

37. Methadone Deaths: 3 Ways Finding of the 2003 National Assessment: • Accumulation during induction for pain or addiction • Clinicians overestimate tolerance, or • Patient combines other CNS depressants with methadone • Misuse / Abuse / Bingeing on diverted methadone • High doses or non-tolerant • Synergistic effects with other depressants • “Poison cocktail” resulting from the intake of multiple psychotropic drugs • Alcohol, benzodiazepines, other opioids. • Methadone seldom is the sole cause of death

38. MEDICATION/PSYCHOSOCIAL

39. Methadone Side Effects • Minimal sedation once tolerance achieved • Constipation • Increased Appetite/Weight Gain • Lowered Libido; May decrease gonadal hormone levels • Exhaustively studied in all organ systems with no evidence of chronic harm

40. QTc Prolongation Methadone Warnings In November 2006, the US Food and Drug Administration (FDA) issued a Public Health Advisory: "Methadone use for pain control may result in death and life-threatening changes in breathing and heartbeat.“

41. To EKG or not to EKG? Risk Factors for Prolonged QTc advanced age female gender electrolyte abnormalities e.g. hypokalaemia or severe hypomagnesaemia bradycardia heart disease (e.g. heart failure or ischaemia) congenital long QT syndrome or pre-existing QT prolongation concomitant use of other QT prolonging medicines (e.g. tricyclic antidepressants, some antipsychotics and antibiotics- see www.torsades.org/medical-pros/drug-lists/drug-lists.htm for a more comprehensive listing) concomitant use of medicines that inhibit the metabolism of methadone (e.g. fluconazole and some SSRI antidepressants).

42. HARMDHelping America Reduce Methadone Deaths “Helping America Reduce Methadone Deaths” http://www.harmd.org/

43. Edwin Salsitz, M.D.