Assessing and Maintaining An Adequate Dose

Assessing and Maintaining An Adequate DoseSouthwest Behavioral Health TrainingTrusandra Taylor, MD, FASAM, MPHOctober 12, 2011Learning ObjectivesKnowledgeBest practice protocols and evidence-based guidelines for induction, stabilization and maintenance of opioid agonist medications.CompetenceAppropriately and adequately assess patients such that patients safely receive effective opioid agonist medications during induction, stabilization and maintenance PerformanceMonitor 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.

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

Importance of TopicSWBH InitiativeProgram Strategies to Facilitate RecoveryROM report, findings and objectivesMethadone-Associated DeathsMethadone ConundrumSAMHSA, ONDCP, NIDAFocus upon prescription drug abuse problemROM Phases of TreatmentStabilization: Phase IRehabilitation: Phase IISupportive-care:Phase IIIMedical MaintenancePhase IV

Adapted from TIP 43, Chapter 7Consensus PanelAcute, Rehabilitative, Supportive-care, Medical Maintenance, Tapering (optional), Continuing CareQUESTIONDo you utilize a phase of treatment model?Why?Rationale for Phased TreatmentComprehensive maintenance modelPatient treatment matchingIntensity of servicesNot one directionalDynamic continuum without fixed steps, specific timeframes and or boundariesTreatment outcomes based upon meeting patients needs, goals and expectationsPatient readiness for phase change

7QUESTIONHow many patients have you admitted for detoxification as opposed to maintenance treatment?CriteriaIf so , how many patients?Patient AssessmentIntakeScreeningAppropriatenessAlternative treatmentLevel of CareMedical History and Physical ExaminationBiopsychosocial EvaulationContinuous during treatmentAcute PhaseMethadone InductionGoalsEliminate illicit use, withdrawal symptomsMinimize sedation and undesirable side effectsAssess safety and adequacy of doseTitrate as rapidly as safely possibleAddress co-occurring disorders and problemsIdentify high-risk behaviors, develop strategiesMethadone Safety ProfileFavorable safety profile, >40 years> 1 Million worldwide Use based upon indicationFew serious adverse effectsNo cumulative organ damageMortality is 3 4 times greater for patients who discontinue treatment with methadone as opposed to those who continue

QUESTIONAre you familiar with the Dolophine package insert?Black Box WarningMethadone PharmacologyBasic principles, understandingPharmacokinetics Absorption, Distribution, MetabolismPharmacodynamicsAdverse drug effectIndividual variation among patientsMethadone PharmacologyDrug receptorsFull AgonistPartial Agonist (Mixed)Antagonist

Full Mu agonistBind to the receptor and activate the receptorIncreasing the amount or dose of the drug produces increasing receptor-specific effects with a maximum effectOften mimic action of a naturally occurring substance

-10-9-8-7-6-5-40102030405060708090100Intrinsic ActivityLog Dose of OpioidFull Agonist(Methadone)Partial Agonist(Buprenorphine)Antagonist (Naloxone)Mu Receptor Activity Dose Response CurveOpioid Maintenance Pharmacotherapy - A Course for Clinicians

No EffectDeathPharmacokineticsPharmacodynamicsPharmacokineticsAbsorption, 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 resultsReference: 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 Dependence1717MethadonePharmacokineticsMethadone is highly lipophilicRapidly distributed to tissues of the brain, gut, kidney, liver, muscle, lung, saliva, amniotic fluidPlasma concentrations are maintained by the tissue reservoirBinds 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 methadoneReference: 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

18Lipophilic = highly fat soluble18PharmacokineticsMethadoneBioavailability~80% (79 11.7%) Half-life ~30 hrs. (30.4 16.3) Morphine Bioavailability ~30% (26 13%) Half-life ~3 hrs. (2.7 1.2) 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

1919PharmacokineticsMethadonePeak 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

2020PharmacokineticsMethadone has a slow onset of action and gradual enhancement of its effect over timeImportant for both practitioners and patients to recognize and understand this important principleReference: 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

2121

Pharmacokinetics of MethadoneCharles E. Inturrisi, Ph.D. Department of Pharmacology, Weill Medical College of Cornell University and The Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer CenterClinical Pharmacology of Methadone

Long elimination phaseExtensive Distribution PhaseLarge Volume of Distribution22 Methadone has an extensive distribution phase indicative of a large volume distribution and a long elimination phase with a T1/2 that averages 24 hours.

The inter-individual variability is large (T1/2 can range from 5 to 130 hours). Clearance values vary 100 fold.

These PK data indicate that methadone will accumulate with repetitive dosing and that the rate and extent of accumulation will vary widely among individuals.

22PharmacokineticsMethadone undergoes biotransformation to inactive metabolites in the liverMethadone and metabolites are eliminated in the urine and fecesMetabolic clearance of methadone is generally not affected by liver disease requiring dose adjustmentExcept in ESRF it is not required to adjust the methadone dose because of renal insufficiencyReference: 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

23Methadone safe; liver transplantation23PharmacokineticsCytochrome P450 enzymesCYP3A4CYP2D6CYP1A2CYP2C9CYP2C19

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 Dependence24Methadone ClearanceRate of clearanceFat storesUrine phExpression of plasma proteinsExpression levels of metabolic enzymesCompetition for metabolic enzyme bindingCompetition for plasma protein bindingGenetic variation in metabolic enzymesVary across individualsVary 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 13:24-3025Inter-Individual VariationPharmacokinetic variability of CYP 450 enzymes, genetically and environmentally determinedMethadone has several mechanisms of actionPharmacodynamics genetic polymorphismOverall good relationship between dose and plasma concentrations within an individual

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 Dependence26polymorphism describes multiple possible states for a single property 26

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 CenterClinical Pharmacology of Methadone

27 The T1/2 of methadone can vary widely among individuals (5 to 130 hours) and this will be reflected in the rate of accumulation with repetitive dosing

Cancer patients receiving a fixed daily dose of methadone show different rates of accumulation

27Pharmacodynamic Effect of MethadoneAdverse Drug EffectsFDA WarningsPharmacodynamicsEffects of drugs on the body and the mechanism by which drugs produce their effectsOperationally viewed as what are the effects of a drugAlter cellular function; enzymes, cell membranes, receptorsReference: 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 Dependence2929Adverse Effects of MethadoneMost symptoms were present prior to beginning OMT and improved on methadoneAdverse effects rarely lead to discontinuation of medication

3030Most Common Adverse EffectsConstipation (Opioid Bowel Dysfunction)Excessive sweatingWeight gainDelayed ejaculation/sexual dysfunctionNumbness in hands and feetRash3131Possible Cardiac Adverse EffectsProlongation of QT interval - FDA black box warning- may be dose related- can lead to arrhythmia (torsade de pointes)3232Cardiac Adverse EffectsCase 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

3333Adverse Cardiac EffectsRisk factors (see AT Forum) - Family history - Patient historyIf risk factors present, do baseline and follow-up ECGs

3434From AT Forum Cardiac Considerations during MMT, Updated 2006

3535

3636QTc ProblemPatients 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

3838FDA Health AdvisoryNovember 27, 2006Revision of the package insertSharp rise in unintentional overdose deaths attributed to prescribed methadoneNCHS: > 2 million prescriptions in 2003 2,452 unintentional poisoning deaths with methadone listed as a cause; up from 623 in 1999USA Today, reported in Feb 2006, fatal methadone overdoses totaled 3,849, increased 390% from 1999NCHS report 13% of all overdose deaths in 2004 involved methadone, up from 4% in 199939FDA Health AdvisoryConcern focused upon increasing use of methadone for pain managementLabeling change with black box warnings apply to all methadone medications, including products used to treat opioid dependence, hence those used in OTPsFDA Public Health Advisory, November 27, 200640Recommendations for OTPsDear Colleague letter of December 15, 2006 from Dr. ClarkThree key points:Initial Dose

Black box warning (4)

Patient information sheetFDA Public Health Advisory, November 27, 200641MethadoneBlack Box WarningsDeathsRespiratory depressionCardiac complicationsUse as an analgesicFDA Public Health Advisory, November 27, 200642DeathsCardiac and respiratory, during initiation and conversion of pain patients to methadone from other opioidsDrug interactions, licit and illicit; too rapid titration without appreciation of accumulation of methadone; vigilance necessaryCaution patients against self-medicating with CNS depressantsFDA Public Health Advisory, November 27, 200643Respiratory DepressionChief hazard associated with methadone administrationMethadones 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 titrationFDA Public Health Advisory, November 27, 200644Cardiac ComplicationsQT 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, 200645Analgesic useMethadone for analgesic therapy in patients with acute or chronic pain should only be initiated if the analgesic and palliative care benefit outweighs the riskFDA Public Health Advisory, November 27, 200646Treatment of Adverse EffectsOpioid Bowel Dysfunction (OBD)Regular regimen of laxative and stool softener, e.g. senna and docusate and/or polyethylene glycolIncrease fluid intakeIncrease exerciseAvoid bulk laxativesOpioid antagonists (controversial)4747Treatment of Adverse EffectsExcessive SweatingHydroxyzine pamoateAnticholinergics (if not contradindicated)Weight GainDietary and exercise assessment and counselingEndocrine testing if indicated

4848Treatment of Adverse EffectsSexual DysfunctionTestosterone, if indicated?Dopamine agonistsPossible decrease in methadone dose

4949Methadone-Associated DeathsMethadone Mortality A 2010 Reassessment July 29-30, 2010 in Washington, DCSAMHSADEAFDANIDAIHSQUESTIONDo you participate in SAMHSAs Mortality Reporting?How many patients were reported in 2010Concerns?Methadone-Associated DeathsSince late 2008 SAMHSAs voluntary initiative for collection of mortality data, the Mortality Report, now onlineReport of (406) patients reported in 2009, died while in an OTP27% of OD deaths occurred within first two weeks of treatment32% of overdose deaths had benzodiazepines mentioned in the report

Methadone-Associated Deaths67% maleAverage age: 49.8 years (18-88)Average length of stay: 4.5 years (0-38.6)Average number of THs: 5 (range:0-29)Average dose: 91.8 mg (range: 10-270 mg)Methadone-Associated Deaths61% mental disorder, 14% MDD, 9% Anxiety22% BZD prescription 15% anti-depressants, 12% SSRIs28% liver disease, 19%HCV, 17% COPD, 10% metabolic diagnosis, 9% musculoskeletal disorder, 9% HTN, 8% circulatory, 6% DM, 4% kidney disease, 4% trauma, 3% AsthmaMethadone-Associated DeathsTwo categories of deaths:Older patients with long treatment durations dying of illnesses of liver disease, CVD and or COPDYounger patients who died of trauma, Overdose, MVA, homicide and suicideNeed to monitor potential toxicities of methadone and benzodiazepinesNeed better data to understand suicide and overdose deaths of OTP patientsEducate families on overdose symptomsCase Scenario - RobertRobert is a 30 yo male who presents to your clinic for treatment. He used drugs such as Vicodin and Oxycontin since 17 yo starting out 1-2 times per month with friends on the weekends. During the past 5 years his use increased progressively, multiple times per day, up to a total of 240 mg or > per day. He switched to heroin about 2 yrs ago because his drug dealer was arrested, also because heroin is less expensive. He still prefers Oxycontin and injects it when he uses it. He starting out snorting a few bags of heroin a couple times per day, but soon starting injecting 3-4 bags of heroin a couple of times per day. He now admits daily injection use of a bundle heroin.Robert D/A HistoryHe also admits snorting cocaine since ~20 yo, and estimates use < one time per month; admits that he prefers downers like alcohol and benzos.He had previous treatment IP detox, age 25, 27 and last year at WDR followed by short term rehab for 21 days and 2 months IOP in 2009. He achieved ~ 6 months abstinence before relapsing in early 2010.Robert Med/Psych/Social HistoryHe denies psychiatric hospitalization or psych medications and admits Asthma and Hepatitis C as his only medical problems. He uses an inhaler as needed to control his Asthma. He is single, unemployed and has been unable to maintain steady employment because of his drug problem. His last job was 2 yrs ago, working in a warehouse. He was fired because of lateness and calling out sick. He is on probation for drug possession and old DUI charge.Robert Intake /Day 1Robert is very eager to start methadone. He stated he is unable to stay clean and his father is going to kick him out of the house and his probation officer plans to put him back in jail if he is arrested again for drug possession or violates probation. He appeared a little anxious but was observed to become quiet and nod off briefly during the intake. He admitted taking a benzo this morning because he didnt know how long it would take before he would receive his dose of methadone.

Robert Intake /Day 1He stated his last use of heroin was before midnight, 2 bags.Upon exam, his VS are T=98.8, HR = 68, BP = 105/75 and RR = 12 He had new and old track marks on his arms and mild cellulitis of his left calf, skin warm and dryHis pupils are approximately 3mm and reactiveHe had no rhinorrhea, yawning, nasal stuffiness, agitation, hyperactive bowel sounds or piloerection. His urine is positive for opioids, benzodiazepines, cocaine and THC

60QUESTIONWhat is your diagnostic impression?DiscussionOpioid dependence to be determined if active or in partial remission Cocaine abuse vs dependenceBenzodiazepine abuse vs dependenceCannabis abuse vs dependenceHepatitis C +Cellulitis

History, accuracy

QUESTIONHow would you proceed at this point?Should Robert be started on methadone on day 1? If so, on what dose?

DiscussionNo. We cannot document physiological dependence and that must be present in order to start methadone. His pupils were approximately 3mm and reactiveHe had no rhinorrhea, yawning, nasal stuffiness, agitation, hyperactive bowel sounds or piloerection or diaphoresis. His urine is positive for opioids, benzodiazepines, cocaine and THC

QUESTIONHow many use an objective instrument to grade the presence of withdrawal?If so, what?Clinical Opiate Withdrawal Scale COWS

Last use (OPIOIDS) :Type, Date, Time _________________________________________________________

Resting Pulse Rate: _________beats/minute Measured after patient is sitting or lying for one minute 0 pulse rate 80 or below 1 pulse rate 81-100 2 pulse rate 101-120 4 pulse rate greater than 120 GI Upset: over last hour 0 no GI symptoms 1 stomach cramps 2 nausea or loose stool 3 vomiting or diarrhea 5 Multiple episodes of diarrhea or vomiting Sweating: over past hour not accounted for by room temperature or patient activity. 0 no report of chills or flushing 1 subjective report of chills or flushing 2 flushed or observable moistness on face 3 beads of sweat on brow or face 4 sweat streaming off face Tremor observation of outstretched hands0 No tremor 1 tremor can be felt, but not observed 2 slight tremor observable 4 gross tremor or muscle twitching Restlessness Observation during assessment 0 able to sit still 1 reports difficulty sitting still, but is able to do so 3 frequent shifting or extraneous movements of legs/arms 5 Unable to sit still for more than a few seconds Yawning Observation during assessment0 no yawning 1 yawning once or twice during assessment 2 yawning three or more times during assessment 4 yawning several times/minute Pupil size0 pupils pinned or normal size for room light 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 5 pupils so dilated that only the rim of the iris is visible Anxiety or Irritability 0 none 1 patient reports increasing irritability or anxiousness 2 patient obviously irritable anxious 4 patient so irritable or anxious that participation in the assessment is difficult Bone or Joint aches If patient was having pain previously, only the additional component attributed to opiates withdrawal is scored0 not present 1 mild diffuse discomfort 2 patient reports severe diffuse aching of joints/ muscles 4 patient is rubbing joints or muscles and is unable to sit still because of discomfort Gooseflesh skin0 skin is smooth 3 piloerrection of skin can be felt or hairs standing up on arms 5 prominent piloerrection Runny nose or tearing Not accounted for by cold symptoms or allergies0 not present 1 nasal stuffiness or unusually moist eyes 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks Total Score ________ The total score is the sum of all 11 items Initials of person completing Assessment: ______________ Score: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal

6666Robert Day 2Robert returns to the clinic as advised, agitated, asking Why do I have to be sick in withdrawal?VS: Temp = 99.0, HR = 80, BP = 120/80 and RR = 18; pupils (6mm) bilaterally and reactive Eyes are watery, he sniffs constantly and yawns frequently; he is anxious and restlessness and excuses himself once to use the bathroom, c/o diarrheaDiscussionImpression?Q & ABreakSAFE INDUCTION TECHNIQUES71Robert Meets CriteriaDemonstration and documentation of withdrawal and physiological dependence upon opioidsObjective assessmentRequired Physicians Documentation of AddictionPHYSICIANS DOCUMENTATION OF ADDICTION_______________________________________________________________Patient Name

1. The following will identify current physiologic addiction to heroin or other opioid drugs for this patient: Early signs of withdrawal (dilated pupils, lacrimation, rhinorrhea, piloerection, sweats) Nausea, vomiting, stomach cramps, diarrhea, leg cramps, (elevated: temperature, pulse, blood pressure, respiratory rate), cravings Documented enrollment in an OTP Positive drug screen test for opiate / opioid derivative metabolites Other signs noted (i,e., sedation, constricted pupils, nasal problems, fresh track marks, skin abscesses) 2. The following are indicative that this patient has been addicted to heroin or other Opioid drugs for a period of at least one year prior to the date of intake: Patient statement to physician Physician statement regarding patient Documented history of one year addiction on file Previous treatment history on file, enrollment in an OTP Drug related criminal history on file Verifiable history from family and friends Other history noted (i.e., old track marks, scars)3. It is my best judgment as a physician and verified below by my signature, that this patient demonstrates evidence of current physiologic addiction to heroin or other opioid drugs, and has a history of at least one-year addiction as documented in the medical history and physical examination and as above. ______________________________________________ ______________________Signature Date 73Robert - InductionWhat is the starting dose and the titration schedule?How do you write orders in your clinic?Electronic medical record software?Robert - InductionHe receives a dose of 30mg of methadone and leaves the clinic 1 hour later. How many observe patients after their first dose and for how long?Robert Induction Day 2Robert returns to the clinic the next day and states that the stuff didnt hold me. He states that he was fairly comfortable for about 8 hours, then started feeling really sick. He asks for an increase in his dose.

Robert Induction ScheduleDay 1Day 2Day 3Day 4Day 5Day 6Schedule A30 mg30 mg30 mg30 mg30 mg 30 mgSchedule B30 mg30 mg40 mg40 mg 40 mg40 mgSchedule C30 mg 40 mg 50 mg 60 mg60 mg60 mgSchedule D30 mg50 mg70 mg70 mg70 mg70 mgSchedule L30 mg40 mg50 mg60 mg70 mg 80 mgCSAT GuidanceStanding OrdersDear Colleague Letter September 9, 2007Risks associated with initial methadone dosing and the first two-weeks during induction processOTP InspectionsPublished literature review (Maxwell, 2005)OTP physician responsibility Knowledge of methadone pharmacokinetic and pharmacodynamic propertiesIndividualized initial methadone dosing7878Robert Day 8Robert is now on a dose of 50mg/day and has been on that dose for 2 days. He continues to complain the dose just doesnt hold me! He again asks for an increase in his dose and states that some of his new friends in the clinic have told him that methadone is most effective at about 150mg/day QUESTIONDo you increase Roberts dose today?

DiscussionAt 50-60mg, it is probably wise to let the pharmacokinetics stabilize before increasing the dose again. You should explore the 24-hour cycle with Robert to see how the dose feels at different points in that cycle, including whether he becomes sick or just does not feel the methadone anymore. It would be good time to (?again) discuss Roberts expectation of methadone and why it is important for him to allow the dose to stabilize and for him to abstain from supplementing with other opioids.

Robert Late InductionWhat do you tell Robert about methadone dosing, in general?

DiscussionThis is a good time to discuss the individuality of methadone doses as well as the concept of blocking doses and abnormal normality. Further emphasize that each patient is unique and the clinician is only discussing Roberts issues with Robert and not other patients.

Comparison- Methadone Dosing Schedules

Opioid Maintenance Pharmacotherapy - A Course for CliniciansCumulativeAmount remaining in body prior to next day dosingNumbers represent dose in milligramsInduction Days 8484Build-up To Steady-StateDays/Half-Lives (T-1/2=15-55 hrs.(Baselt)) Dose constant at 30 mg to steady-statePeak levels increase daily for 5-6 days with NO increase in dose!

Opioid Maintenance Pharmacotherapy - A Course for Clinicians 85Early InductionEarly dose adjustments to reach the Therapeutic Window as determined by established opioid tolerance. -- The Comfort Zone Increase dose daily until pt. comfortable during methadone peak levels (3-6 hours after dose) then;Hold dose for 3-5 days to reach steady-state before further dose adjustments.

REMEMBER STEADY-STATE PHARMACOLOGY!

PayteOpioid Maintenance Pharmacotherapy - A Course for Clinicians 86Early Induction- 2 - Effect of a dose IS NOT determined by clinical presentation at 24 hours..

- Initial doses WILL NOT hold for 24 hours - Effect of a given dose is based on status at 3-6 hrs. The patient doing well at 3-6 hours does not need adose increase, even if showing s/s withdrawal at 24 h.

If patient thinks an increase is needed, repeat dosefrom previous day and ask patient to return in 3-4hours for further assessment.

PayteOpioid Maintenance Pharmacotherapy - A Course for Clinicians 87Early Induction- 3- ANY SIGN OR SYMPTOM OF OVER-MEDICATION DURING EARLY INDUCTION REQUIRES A DOSE REDUCTION!

Beware the subtle s/s of overmedication; feeling good, extra energy, staying awake to work, etc. (AbnormalNormality)Initial dose honeymoon is usually an indication of over-medication. [yesterdays honeymoon dose may be tomorrows OD!]

Patients may need more time, not more meds!

PayteOpioid Maintenance Pharmacotherapy - A Course for Clinicians 88Clinical Pearls Very severe withdrawal s/s does not mean very high tolerance or the need for higher doses of methadone. Document s/s withdrawal with at least 2 objective signs. Document daily assessment during induction including basis for decisions to increase dose. Opioid Maintenance Pharmacotherapy - A Course for Clinicians 89Late Induction Gradual continued dose adjustment beyond initial relief in order to: Establish adequate level of cross-tolerance or Blockade Provide a dose adequate to achieve the desired/optimal effects: Prevention of withdrawal, craving and relapse Opioid Maintenance Pharmacotherapy - A Course for Clinicians 90Steady-State Fluctuations Determined by of Dose IntervalTime in DaysMean Plasma Level 100 mg qd 50 mg q 12 h 25 mg q 6 h InfusionOver-MedicationTherapeutic WindowUnder-MedicationWHO Guide to Good Prescribing: Essentials of Pharmacology in Daily Practice. Annex 1. http://www.docnet.org.uk/who/ggp/homepage.htmP/T =5P/T =2P/T =1.4Methadone StabilizationMAINTENANCE:PRINCIPLES OF ADEQUATE DOSING 93Issues in Maintenance:HOW MUCH?&HOW LONG?Opioid Agonist Treatment of Addiction - Payte - 199894QUESTIONWhat is the effective dose range for patients maintained on methadone?Effective Methadone Dose Range(80-120/150 mg)Multiple studies since late 1960sDosing IssuesOvermedication

Nodding or falling asleep at inappropriate times, feeling loadedNausea, particularly in newer patientsScratching face, nose continuouslySedation may be unapparent in some, feeling mildly stimulatedPhysical reminder of intoxication, discouraging, frightening, relapse triggeringClinical Pharmacology, Chapter 5, (TIP) Treatment Improvement Protocol #43

1 2 Missed DosesLess than 3 consecutive days absent, the dosage can remain unchanged3 5 Missed Doses> 3 consecutive days absent, dosage reduction or re-induction is advised, tolerance may be altered due to absence, may require reinductionIncreases 5 10 mg per dose up to the previous levelRecurrent pattern of irregular attendanceCase consultation to address non-adherence is recommended

Missed DosesClinical Pharmacology, Chapter 5, (TIP) Treatment Improvement Protocol #43

Split doses Patients receive divided daily dose, generally 2-3 times per dayGoal is to achieve the peak-to-trough ratio in blood level concentrations to avoid withdrawal symptomsConsideration for clinical stability and responsibility to handle take-homes, risk/benefitOpioid Maintenance Pharmacotherapy - A Course for Clinicians

Serum Methadone Levels: Do NOT indicate adequacy of dose Do not predict methadone toxicity Define Peak to Trough ratio, the rate of decline or metabolism Define the optimum dosing interval to maximize benefits of OMT Clinical Picture / Dose Incongruities Suspected Drug Interactions Justification of unusual dose levels/schedules Monitor effectiveness of divided dose schedulesOpioid Maintenance Pharmacotherapy - A Course for CliniciansInterpretation of Serum Methadone LevelsPeak or trough Levels alone are of negligible clinical utility in determining adequacy or toxicity of a given dose.

Dose adequacy is determined clinically! Optimum levels for cross-tolerance (Blockade) are not clear, thought to be >400 ng/ml but or more but does occur at lower levels, such as 200 ng/ml.Peak/Trough Ratio ideally less than 2, 700/400=1.75,values > 2 suggest rapid metabolism, 800/200=4 Rate of change !Opioid Maintenance Pharmacotherapy - A Course for Clinicians

Medical ComorbidityCertain medical disorders are more common in patients with Heroin / IDUChronic diseases are common in the general population and therefore also found in patients with Heroin / IDUAging population of patients in methadone maintenance treatmentMedical care is often suboptimal for many patients in methadone maintenance treatment

103103Pregnancy2nd 3rd TrimesterIncreased total body clearanceDecreased terminal half-lifeDosage adjustmentsSplit dose regimensMethadone and Drug Interactions105Interactions with MethadoneDrug Interactions:Methadone metabolized by 3A4, 2B6, 2D6May interact with these enzymesMedications that alter function of these enzymes may increase/decrease methadone effectivenessCYP-450 inducers: decrease (SML) opiate withdrawal?CYP-450 inhibitors: increase (SML) opiate toxicityInteractions with MethadoneWhats been studied? Whats hypothesized?ARVs (NRTIs, NNRTIs, PIs): nevirapine, efavirenz, lopinavir/ritonavir, delavirdine, zidovduine, ddI, d4T: TB medications (rifampin)Hep C medications (IFN)Antifungals (voriconazole, fluconazole)Antibiotics (ciprofloxacin, biaxin) inhibition of 3A4, possible sedation/cognitive impairment

Interactions with MethadoneAnxiolytics (diazepam) (increased physiologic/subjective effects) alprazolam (deaths with low methadone concentrations)

Antidepressants fluoxetine-no effect, fluvoxamine increased methadone (inhibits 3A4, 2D6), paroxetine increases methadone (inhibits 2D6), desipramine may induce methadone metabolism

Interactions with MethadoneAntipsychotics quetiapine (inhibits 2D6) increased methadoneAnticonvulsants (carbamazepine, barbiturates)SA medications (disulfiram/3A4)Antihistamines (Phenergan: inhibits 2D6/sedation)Omeprazole: increased methadone with respiratory depression; may inhibit 3A4Interactions with MethadoneAlcohol increased peak methadone (acute), decreased methadone levels chronically; combination more reinforcingNicotine greater methadone consumptionOTCs (St. Johns Wort): 3A4 induction decrease (SML)Foods Grapefruit juice (inhibition of intestinal 3A4) increase in (SML)BenzodiazepinesFrequently taken with methadone/buprenorphineSynergism with methadoneDeaths have been reported with injection of BZD and buprenorphine, methadone/BZDDrugs Contraindicated with MethadonePartial/mixed opioid agonistsbuprenorphine, butorphanol, nalbuphine, pentazocineOpioid antagonistsnaltrexone, naloxone, nalmefeneTramadolCarisoprodol (Soma)112Consequences of Undetected Drug InteractionsWithdrawalOverdose/toxicitiesLack of efficacyIllicit drug use

Drug-Drug InteractionsResource / Web-based information http://drug-interactions.com (Flockhart)http://www.atforum.com

Overdose ComplicationsPatients are 6.7 times more likely to die during induction than untreated heroin addicts (Caplehorn & Drummer, 1999). 42% of drug-related deaths occurred during the first week of OMT (Zador & Sunjic, 2000). 10 OMT deaths are reported All 10 had been in treatment less than 7 days (Drummer, Opeskin, Syrjanen & Cordner, 1992). 116Case ScenariosBarbara B26 yo, opioid addiction 3-4 yrs, heroin, prescription opioidsIntake reported IDU with heroin, 3 bags, (2) Percocet tabs in the early amExam demonstrated physiological withdrawal: signs and symptoms, COWS 21, + UDS for opiates+HCV, HBV, MDD, PSTDBarbara BDay 1Day 2Day 3Day 4Day 5Day 6Day 78/7/078/8/078/9/078/10/078/11/078/12/078/13/07Dose Schedule305050707040ObservationCOWS = 2118hrs, restless sleep, nausea, sweats, dilated pupils 22hrs,visibly ill, clammy, pupils dilatedClinic ~10 am, home, asleep onSofa ~11 am, found unresponsiveby family, 911 callICUNarcanD/Ced to home, RTCGeorge B37 yo, opioid dependence, heroin, age first use 27; cocaine, age first use 21; ETOH age first use 12Intake, reported daily heroin, for past 3yrs, varying amounts, based upon how much money available; denied cocaineUDS + opiates+HCV, HBVGeorge BDay 1Day 2Day 3Day 4Day 5Day 6Day 71/12/071/13/071/14/071/15/071/16/071/17/071/22/07Dose Schedule304050607080 COWS not availablePhysiological dependenceNo Follow up XFather called clinic, advised of patientsdemise on 1/17/07; funeral was at 1:00 pmMary T28 yo female, IV opiates x 5yrs, Oxycontin drug of choice, heroin past yr, last use opiates ? 4-5 days prior to intake, c/o severe withdrawal, sweats, diarrhea, N/V, insomniaSeveral previous admissions for IP treatment, detox, rehab since age 19Past Psychiatric history of MDD, non-adherent with medicationsExam by the NP revealed normal VS, scattered old and new track marks, pupils slightly dilatedUDS was negative for opiates, cocaine, methadone; positive for BZDs and THCMary TDay 1Day 2Day 3Day 4Day 5Day 6ThurFriSatSun (TH)MonTue30 mg40 mg 50 mg 60 mg 65 mgNo ShowFound by her landlordthat morning, sheappeared to have fallenasleep on the couch. Shewas not breathing andher lips were blue.

An ambulance was calledand she was pronounceddead at the HospitalEmergency room

Mary T - Methadone Dose Equivalent EffectDay 1ThurMethadone dose 30mg30mgDay 2FriMethadone dose 40mg55mgDay 3SatMethadone dose 50mg77.5mgDay 4Sun (TH)Methadone dose 60mg98.75mgDay 5MonMethadone dose 65mg114.375mgDay 6TueNo ShowMethadone dose equivalent effect due to accumulative effect of tissue buildup

124124Risk ManagementRisk ManagementOTP Risk Management ProgramsLegal and liability concernsPatient deaths related to overdoseDosing and monitoring issuesInductionMaintenance, complex needs, co-occurring disorders, polydrug useTake-home bottles Liability for patients actions / behaviorImpaired driving concernsRisk ManagementStaff trainingKnowledge and competency Policy and ProcedureGuidelines / StandardsStandard of care that will be used to measure OTPs in assessing whether they meet their duty of care Patient informed consent / educationMinimize riskPatient and Family EducationStarting MethadonePatient Education - OrientationStarting MethadoneThe clinic doctor determines your first dose based upon your specific information.

Every patient is different.

Your body will become adjusted to methadone after several days.Starting MethadoneMethadone builds up in your body after several days.

For safety the clinic doctor will start your first dose Low and go Slow for dose increases.

The clinic doctor may increase your dose after you have had a dose for 3 to 5 days.MethadoneBlood LevelDays on MethadoneMethadone Build-upStarting MethadoneYou must come to the clinic every day for your dose of methadone.

It is not okay to miss a dose of methadone.

If you stop taking methadone for a few days, the doctor will have to restart your first dose.Starting MethadoneDuring the first few weeks after starting methadone, you may die from an overdose if you do not follow the instructions given to you by the clinic doctor and the clinic staff.Becoming StableIt may take your body a few weeks to fully adjust to methadone.

Each day you become more stable.

If you have withdrawal symptoms, do not take outside methadone tablets, Suboxone or other drugs.Becoming StableIf you have withdrawal symptoms and do not have an appointment with the clinic doctor, talk with the dispensing nurse.

The dispensing nurse will arrange an appointment with the clinic doctor and will advise your counselor.Loaded HighNormal RangeComfort ZoneSickWithdrawalOvermedicatedRisk for Over doseHeroinMethadone0 hrs.Time24 hrs.Dose ResponseMethadone versus HeroinOther DrugsAlcohol, cocaine and marijuana will block the affect of your methadone dose.

Your methadone dose will not hold you if you use alcohol, cocaine and marijuana.

BenzosIt is not safe to take benzos with methadone.

If you have a prescription for benzos, the clinic doctor must review it and will instruct you to bring in your medication for review.Pain PillsTaking pain pills such as Percocet, Oxycodone, Vicodin, Tylenol with codeine, morphine sulfate with methadone is dangerous.

Taking muscle relaxants such as Soma and Flexeril with methadone is very dangerous.Chronic PainIf your suffer from chronic pain related to a medical problem and take pain pills, the clinic doctor must work with your primary doctor or specialist to discuss your treatment for your safety.Sleep ProblemsSleep problems are very common until your body becomes adjusted to methadone.

Do not take sleeping pills such as Ambien, Restoril or benzos such as Xanax, Klonopin, Ativan or ValiumSleep ProblemsAs your body becomes adjusted to methadone, your sleep problems will improve.

If necessary, the clinic doctor may prescribe a medication for sleep that is safe to take with methadone.OverdoseIf you take pain pills, sleeping pills, or muscle relaxants with methadone you may have an overdose.Outside DoctorsYou should tell all doctors that you are taking methadone.

Outside doctors include your primary care doctor, all hospital doctors, emergency room doctors, psychiatrists and dentists.Outside DoctorsFor your safety the clinic doctor may ask to talk with outside doctors about your methadone dose and other medications.

The clinic doctor may ask you to sign a release of information in order to talk with your outside doctors.DrivingYou should not drive a car until your body has adjusted to methadone.

After your body becomes tolerant to methadone, it is safe for you to drive a car.Staying on MethadoneMethadone is safe and will not harm your liver, weaken your bones or rot your teeth.

Using methadone for many years will not harm your body and millions of patients have restored their life with methadone.Thank You!Trusandra@aol.comQ & AEvaluationSheet1Day 1Day 2Day 3Day 4Day 5Day 6Dose Schedule A303030303050%1522.52628Effect4552.55658Dose Schedule B303040404050%1522.53135Effect4562.57175Dose Schedule C304050606050%1527.538.7549.375Effect5577.598.75109.375Dose Schedule D305070707050%15325160.5Effect65102121130.5Dose Schedule LDay 1Day 2Day 3Day 4Day 5Day 63040506070801527.538.7549.37559.68755577.598.75119.375139.6875Day 1Day 2Day 3Day 4Day 5Day 6Dose Schedule A30303030303050%1522.526.2528.12529.0625Effect of dose4552.556.2558.12559.0625Dose Schedule B30304040404050%1522.531.2535.62537.8125Effect of dose4562.571.2575.62577.8125Dose Schedule C30405060606050%1527.538.7549.37554.6875Effect of dose5577.598.75109.375114.6875Dose Schedule D30507070707050%15325160.565.25Effect of dose65102121130.5135.25Dose Schedule LDay 1Day 2Day 3Day 4Day 5Day 630405060708050%1527.538.7549.37559.6875Effect of dose5577.598.75119.375139.6875

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