INITIATING METHADONE TREATMENT:INDUCTION AND STABILISATION

Nichole Riese, MD CCFP

June 11, 2010

DISCLOSURE OF CONFLICT OF INTEREST

Methadone: an introduction to clinical practice

Winnipeg Manitoba

June 11, 2010

No conflict of interest to declare

OBJECTIVES

Considerations in initiation of methadone dosing

Use & interpretation of methadone blood levels

Early, Late & Split dose inductions

METHADONE PHARMACOLOGY

Almost pure mu agonist Oral: 80-90% bioavailability Extended duration of action in suppressing

opioid withdrawal (T-1/2=24-36 hours) Analgesic properties of methadone differ

significantly from maintenance properties Accumulation with repeated use for pain can

result in sedation and respiratory depression in the non-tolerant patient

Source: Goodman & Gilman

TOLERANT/DEPENDENT DRUG STATES

“Loaded” “High”

Normal Range “Comfort Zone”

Subjective Withdrawal “Sick” Objective WithdrawalD

rug e

ffect

s sc

ale

“Abnormal Normality”

00 Time in Hours 24

“ANATOMY” OF A FIX

“Loaded”

“High”

“Comfort Zone”

“ Normal State”

“Subjective Withdrawal”

“Objective Withdrawal”

A

mount

“Abnormal Normality”

“Tolerance Threshold”

Time in hours

METHADONE VS OXYCONTIN

“Loaded”

“High”

“Comfort Zone”

“ Normal State”

“Subjective Withdrawal”

“Objective Withdrawal”

A

mount

“Abnormal Normality”

“Tolerance Threshold”

0 4 8 12 16 20 Time in hours

-- Methadone-- Oxycontin

METHADONE ABSORPTION

Detected in 30 min following oral dosing Peak plasma levels occur at 2 to 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 lipophilic, parental doses readily cross blood-brain barrier

Source: Goodman and Gilman, Kreek , and others.

METHADONE METABOLISM/EXCRETION

Extensive bio-transformation in liver N-demethylation and cyclization to form

principal metabolites:

PYRROLIDINES (EDDP) PYRROLINE (EMDP)

Metabolites are essentially inactive Metabolites and unchanged methadone are

excreted in bile and in urine

Source: Goodman and Gilman, Kreek, Bassett and others

BENEFITS OF PHARMACOTHERAPY FOR OPIOID DEPENDENCE

Increasing employment

Improved physical and mental health

Improved social function

Source: J Thomas Payte

ISSUES IN METHADONE TREATMENT

Dose

Duration

HOW LONG DOES MMT LAST?

PROFILE FOR POTENTIAL PSYCHOTHERAPEUTIC AGENT

Effective after oral administration

Long biological half-life (>24 hours)

Minimal side-effects during chronic administration

Safe – no true toxic or serious adverse effects

Efficacious for a substantial % of persons with the disorder

Source: MJ Kreek, Rational for Maintenance Pharmacotherapy of Opiate Dependence

STEADY-STATE SIMULATION – MAINTENANCE PHARMACOTHERAPYATTAINED AFTER 4-5 HALF-TIMES - 1 “DOSE” Q HALF-LIFE

0

100

200

300

400

500

600

700

800

900

0 1 2 3 4 5 6 7

ng/ml

Time (multiples of elimination half-time)Dose level remains constant

Source: Goodman and Gilman

INITIAL DOSE

Degree of Tolerance Dose Range

Non-Tolerant 10 mg +/- 5

Unknown Tolerance 20 mg +/- 5

Known Tolerance 20 – 40 mg

EARLY INDUCTION

Early dose adjustments to “approximate” established “Tolerance Threshold”

Remember STEADY-STATE PHARMACOLOGY! Today’s dose repeated tomorrow will have a greater effect and the next day, and the

next... until steady state is achieved

Provide full relief and prevention of withdrawal signs and symptoms and ensure reduction in drug hunger/craving

LATE 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 effects:

Prevention of withdrawal, drug hunger and relapse

DESIRED RESPONSE FROM METHADONE IN METHADONE MAINTENANCE TREATMENT

Prevention of onset of withdrawal syndrome for 24 hours or more

Reduction or elimination of drug hunger or craving

Blockade of euphoric effects of illicit narcotics

Source: Kreek 1987

INDIVIDUALIZED!

Adequate Dose

Based on clinical and laboratory data

HOW MUCH?

Enough!

HOW MUCH IS ENOUGH?

The amount required to produce the desired response for the

desired duration of time with an allowance for a margin of effectiveness and safety.

Source: Payte and Kun, 1992

RETENTION IN TREATMENT RELATIVE TO DOSE RELATIVE RISK OF LEAVING TREATMENT

80 + mg

60-79 mg

< 60 mg(Baseline)

Source: Caplehorn & Bell22

BLOOD LEVELS: WHEN AND WHY

Clinical picture – Dose incongruities

Suspected drug interactions Ensure adequacy of dose Documentation of “need” for dose level Determine need for and effectiveness of split-

dose practices

INTERPRETATION OF METHADONE BLOOD LEVELS

24-hour/trough level at 150-200 ng/ml or more

Peak/trough ration around 2.0 or less, 500/250 = 2.0 (values > 2 suggest rapid metabolism or elimination)

Rate of change – more important than absolute numbers or levels!

MY DOSE ISN’T HOLDING ME…

Environment? Stressors? Alcohol? Other drugs/medications? Vitamins? Urinary pH? Methadone blood levels?

“NOT HOLDING” STRATEGIES

Cognitive, behavioural interventions Increased contact, counselling, therapy Alter urinary pH? IV drugs? Faster metabolizers? Raise dose? Is patient fixing? Split dose?

SPLIT-DOSE INDUCTION

Day 1: 100% of dose observed 50% of dose taken in 12 hours

Day 2: 50% of dose every 12 hours

Note: Poor results from starting with half the ordinary dose on day 1

QUESTIONS?