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Assessing and Maintaining An Adequate Dose. Southwest Behavioral Health Training Trusandra Taylor, MD, FASAM, MPH October 12, 2011. Learning Objectives. Knowledge

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    1. Assessing and Maintaining An Adequate Dose Southwest Behavioral Health Training Trusandra Taylor, MD, FASAM, MPH October 12, 2011

    2. Learning Objectives • Knowledge • Best practice protocols and evidence-based guidelines for induction, stabilization and maintenance of opioid agonist medications. • Competence • Appropriately and adequately assess patients such that patients safely receive effective opioid agonist medications during induction, stabilization and maintenance • Performance • Monitor adherence with best practice protocols and evidenced-based guidelines for the safe and effective use of opioid agonist medications and to measure patient outcomes of treatment for opioid addiction.

    3. Agenda • Part 1 • ROM phases, Patient Assessment, Pharmacology Mechanism of Action, Safety Profile, Methadone Induction, Methadone-associated Deaths, Case scenario, Q&A • Break • Part 2 • Methadone Stabilization, Medical Comorbidity, Drug-Drug Interactions, Overdose, Case Scenario, Risk Management, Staff training, Patient and Family Education, Q&A, Evaluation

    4. Importance of Topic • SWBH Initiative • Program Strategies to Facilitate Recovery • ROM report, findings and objectives • Methadone-Associated Deaths • Methadone Conundrum • SAMHSA, ONDCP, NIDA • Focus upon prescription drug abuse problem

    5. ROM Phases of Treatment • Stabilization: Phase I • Rehabilitation: Phase II • Supportive-care: Phase III • Medical Maintenance Phase IV • Adapted from TIP 43, Chapter 7 • Consensus Panel • Acute, Rehabilitative, Supportive-care, Medical Maintenance, Tapering (optional), Continuing Care

    6. QUESTION • Do you utilize a “phase of treatment” model? • Why?

    7. Rationale for Phased Treatment • Comprehensive maintenance model • Patient treatment matching • Intensity of services • Not one directional • Dynamic continuum without fixed steps, specific timeframes and or boundaries • Treatment outcomes based upon meeting patients needs, goals and expectations • Patient readiness for phase change

    8. QUESTION • How many patients have you admitted for “detoxification” as opposed to maintenance treatment? • Criteria • If so , how many patients?

    9. Patient Assessment • Intake • Screening • Appropriateness • Alternative treatment • Level of Care • Medical History and Physical Examination • BiopsychosocialEvaulation • Continuous during treatment

    10. Acute Phase • Methadone Induction • Goals • Eliminate illicit use, withdrawal symptoms • Minimize sedation and undesirable side effects • Assess safety and adequacy of dose • Titrate as rapidly as safely possible • Address co-occurring disorders and problems • Identify high-risk behaviors, develop strategies

    11. Methadone Safety Profile • Favorable safety profile, >40 years • > 1 Million worldwide • Use based upon indication • Few serious adverse effects • No cumulative organ damage • Mortality is 3 – 4 times greater for patients who discontinue treatment with methadone as opposed to those who continue

    12. QUESTION • Are you familiar with the Dolophine package insert? • Black Box Warning

    13. Methadone Pharmacology • Basic principles, understanding • Pharmacokinetics • Absorption, Distribution, Metabolism • Pharmacodynamics • Adverse drug effect • Individual variation among patients

    14. Methadone Pharmacology • Drug receptors • Full Agonist • Partial Agonist (Mixed) • Antagonist • Full Mu agonist • Bind to the receptor and activate the receptor • Increasing the amount or dose of the drug produces increasing receptor-specific effects with a maximum effect • Often mimic action of a naturally occurring substance

    15. Mu Receptor Activity Dose Response Curve 100 Death 90 Full Agonist (Methadone) 80 70 Intrinsic Activity 60 Partial Agonist 50 (Buprenorphine) 40 30 20 10 No Effect Antagonist (Naloxone) 0 -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid Opioid Maintenance Pharmacotherapy - A Course for Clinicians

    16. PharmacokineticsPharmacodynamics

    17. Pharmacokinetics Absorption, distribution, binding in tissue, biotransformation and excretion of drugs Operationally viewed as how the body handles a drug Clinically important to understanding variation in patient responses in addiction medicine related to medications used for treatment, drug-drug interactions, interpretation of drug screening results Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    18. MethadonePharmacokinetics Methadone is highlylipophilic Rapidly distributed to tissues of the brain, gut, kidney, liver, muscle, lung, saliva, amniotic fluid Plasma concentrations are maintained by the tissue reservoir Binds readily to plasma proteins, unbound fraction, pharmacologically active portion averages ~12%, which is variable and may account for some of the differences in patient response to methadone Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    19. Pharmacokinetics Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    20. Pharmacokinetics Methadone Peak plasma concentration occurs ~(1-7.5) hrs following ingestion Half-life may be 30 hrs or >, and duration of relief of withdrawal symptoms, the duration of analgesia is much shorter (mismatch) Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    21. Pharmacokinetics Methadone has a slow onset of action and gradual enhancement of its effect over time Important for both practitioners and patients to recognize and understand this important principle Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    22. Pharmacokinetics of Methadone Extensive Distribution Phase Large Volume of Distribution Long elimination phase Charles E. Inturrisi, Ph.D. Department of Pharmacology, Weill Medical College of Cornell University and The Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center Clinical Pharmacology of Methadone

    23. Pharmacokinetics Methadone undergoes biotransformation to inactive metabolites in the liver Methadone and metabolites are eliminated in the urine and feces Metabolic clearance of methadone is generally not affected by liver disease requiring dose adjustment Except in ESRF it is not required to adjust the methadone dose because of renal insufficiency Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    24. Pharmacokinetics • Cytochrome P450 enzymes • CYP3A4 • CYP2D6 • CYP1A2 • CYP2C9 • CYP2C19 Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    25. Methadone Clearance • Rate of clearance • Fat stores • Urine ph • Expression of plasma proteins • Expression levels of metabolic enzymes • Competition for metabolic enzyme binding • Competition for plasma protein binding • Genetic variation in metabolic enzymes • Vary across individuals • Vary within an individual over time Reference: Tafton JA, Abhinav R, Methadone: A New Old Drug With Promises and Pitfalls, Current Pain and Headache Reports 2009 13:24-30

    26. Inter-Individual Variation Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence Pharmacokinetic variability of CYP 450 enzymes, genetically and environmentally determined Methadone has several mechanisms of action Pharmacodynamics – genetic polymorphism Overall good relationship between dose and plasma concentrations within an individual

    27. Charles E. Inturrisi, Ph.D. Department of Pharmacology, Weill Medical College of Cornell University and The Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer Center Clinical Pharmacology of Methadone

    28. Pharmacodynamic Effect of Methadone Adverse Drug Effects FDA Warnings

    29. Pharmacodynamics Effects of drugs on the body and the mechanism by which drugs produce their effects Operationally viewed as what are the effects of a drug Alter cellular function; enzymes, cell membranes, receptors Reference: Chin B. Eap,1 Thierry Buclin2 and Pierre Baumann1 Clin Pharmacokinet 2002; 41 (14): 1153-1193 Interindividual Variability of the Clinical Pharmacokinetics of Methadone: Implications for the Treatment of Opioid Dependence

    30. Adverse Effects of Methadone Most symptoms were present prior to beginning OMT and improved on methadone Adverse effects rarely lead to discontinuation of medication

    31. Most Common Adverse Effects Constipation (Opioid Bowel Dysfunction) Excessive sweating Weight gain Delayed ejaculation/sexual dysfunction Numbness in hands and feet Rash

    32. Possible Cardiac Adverse Effects Prolongation of QT interval - FDA black box warning - may be dose related - can lead to arrhythmia (torsade de pointes)

    33. Cardiac Adverse Effects Case Reports - High dose methadone linked to QTc prolongation and TdP (form of V Tach) - One prospective study demonstrating modest increase in QTc - Arrhythmia risk related to magnitude of QTc change from baseline - Need to assess individual risk

    34. Adverse Cardiac Effects Risk factors (see AT Forum) - Family history - Patient history If risk factors present, do baseline and follow-up ECG’s

    35. From AT Forum “Cardiac Considerations during MMT”, Updated 2006

    36. QTc Problem Patients may be receiving other medications that also prolong the QTc. May need to adjust doses of methadone and of concomitant medications; should be done in conjunction with any other treating physicians.

    37. FDA Health Advisory November 27, 2006 Revision of the package insert Sharp rise in unintentional overdose deaths attributed to prescribed methadone NCHS: > 2 million prescriptions in 2003 2,452 unintentional poisoning deaths with methadone listed as a cause; up from 623 in 1999 USA Today, reported in Feb 2006, fatal methadone overdoses totaled 3,849, increased 390% from 1999 NCHS report 13% of all overdose deaths in 2004 involved methadone, up from 4% in 1999

    38. FDA Health Advisory Concern focused upon increasing use of methadone for pain management Labeling change with “black box” warnings apply to all methadone medications, including products used to treat opioid dependence, hence those used in OTPs FDA Public Health Advisory, November 27, 2006

    39. Recommendations for OTPs “Dear Colleague” letter of December 15, 2006 from Dr. Clark Three key points: Initial Dose Black box warning (4) Patient information sheet FDA Public Health Advisory, November 27, 2006

    40. MethadoneBlack Box Warnings Deaths Respiratory depression Cardiac complications Use as an analgesic FDA Public Health Advisory, November 27, 2006

    41. Deaths Cardiac and respiratory, during initiation and conversion of pain patients to methadone from other opioids Drug interactions, licit and illicit; too rapid titration without appreciation of accumulation of methadone; vigilance necessary Caution patients against self-medicating with CNS depressants FDA Public Health Advisory, November 27, 2006

    42. Respiratory Depression Chief hazard associated with methadone administration Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak effects, particularly during induction. Can precipitate iatrogenic overdose, particularly during induction and dose titration FDA Public Health Advisory, November 27, 2006

    43. Cardiac Complications QT prolongation and serious arrhythmias (torsade de pointes) have been observed during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. FDA Public Health Advisory, November 27, 2006

    44. Analgesic use Methadone for analgesic therapy in patients with acute or chronic pain should only be initiated if the analgesic and palliative care benefit outweighs the risk FDA Public Health Advisory, November 27, 2006

    45. Treatment of Adverse Effects Opioid Bowel Dysfunction (OBD) Regular regimen of laxative and stool softener, e.g. senna and docusate and/or polyethylene glycol Increase fluid intake Increase exercise Avoid bulk laxatives Opioid antagonists (controversial)

    46. Treatment of Adverse Effects Excessive Sweating Hydroxyzine pamoate Anticholinergics (if not contradindicated) Weight Gain Dietary and exercise assessment and counseling Endocrine testing if indicated

    47. Treatment of Adverse Effects Sexual Dysfunction Testosterone, if indicated ?Dopamine agonists Possible decrease in methadone dose

    48. Methadone-Associated Deaths • Methadone Mortality – A 2010 Reassessment • July 29-30, 2010 in Washington, DC • SAMHSA • DEA • FDA • NIDA • IHS