Download Initiating Methadone Treatment: Induction and stabilisation

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”
Drug effects scale
“High”
“Abnormal Normality”
Normal Range
“Comfort Zone”
Subjective Withdrawal
“Sick”
Objective Withdrawal
00
Time in Hours
24
“ANATOMY” OF A FIX
“Loaded”
“High”
Amount
“Comfort Zone”
“Abnormal Normality”
“ Normal State”
“Tolerance Threshold”
“Subjective Withdrawal”
“Objective
Withdrawal”
Time in hours
METHADONE VS OXYCONTIN
“Loaded”
-- Methadone
-- Oxycontin
“High”
Amount
“Comfort Zone”
“Abnormal Normality”
“ Normal State”
“Tolerance Threshold”
“Subjective Withdrawal”
“Objective
Withdrawal”
0
4
8
12
Time in hours
16
20
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 PHARMACOTHERAPY
ATTAINED AFTER 4-5 HALF-TIMES - 1 “DOSE” Q HALF-LIFE
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 & Bell
22
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?