Methadone Dosing 2012
Dosing of patients considered
appropriate for Methadone
Therapy
.
Regina 08 Dec 2012
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
1
Methadone Dosing 2012.
• Credentials / Conflicts :
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Qualifications – mainly experience
Conflicts – talks for the College
Drug companies – fed and watered - rarely
Opioid companies – no involvement.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
2
Methadone Dosing 2012.
• Objectives :
• Intent - conversion or introduction to methadone
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1. Basic opioid agonist principles
2. Induction and stabilisation Phases dosing
3. Maintenance Phase dosing
4. Medically Supervised Withdrawal dosing
5. Special dosing issues (mainly P450).
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
3
Methadone Dosing 2012.
• 1. Opioid Agonist Principles :
• 1. Opioids are dosed to SUBJECTIVE EFFECT
• We do not have an objective test for it.
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Saskatoon, 08 Dec 2012
4
Methadone Dosing 2012.
• 1. Opioid Agonist Principles :
• 2. Methadone and opiates are chemically unrelated
• Opiates share common structures.
• Methadone is a totally different substance which simply
has some features typical of opiates.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 1. Opioid Agonist Principles :
• 3. Methadone and opiates have no dose equivalents
• Many attempts made to equate opiates and methadone,
including CPS and various methadone guidelines.
• All of them fail test #1 for methadone - safe induction.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
6
Methadone Dosing 2012.
• 1. Opioid Agonist Principles :
• 4. Methadone and opiate combinations work well.
• We are often told methadone blocks all other opiate
effects.
• This is incorrect. Many patients use opiates as well, and
clinicians in some fields have combined them for years.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
7
Methadone Dosing 2012.
• 1. Opioid Agonist Principles :
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1. Opioids are dosed to SUBJECTIVE EFFECT
2. Methadone and opiates are chemically unrelated
3. Methadone and opiates have no dose equivalents
4. Methadone and opiate combinations work well.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
8
Methadone Dosing 2012.
• 2. Elimination Half Lives :
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EHL = Elimination Half Life. For all drugs.
IE - time to eliminate half the blood level
Steady State = steady blood level.
Steady State assumes same dose repeated at EHL.
Steady State takes 5-6 EHL for all drugs.
During this time effects are cumulative.
So Methadone takes 5-6 days to steady state
And meth takes 5-6 days for dose changes to take effect.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 2. EHL and Steady State :
• Definition : The time it takes for half the
substance to be eliminated from the blood
stream.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 2. EHL and Steady State :
• Any substance at steady dose builds
rapidly for 3-4 half lives then levels off to
steady state.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 2. Example : 100 mg / day EHL = 24 hrs.
EHL
1
2
3
4
5
6
7
Total on board is combo of :
Total
50
25 + 50
12.5 + 25 + 50
6.25 + 12.5 + 25 + 50
3.12 + 6.25 + 12.5 + 25 + 50
1.5 + 3.12 + 6.25 + 12.5 + 25 + 50
0.75 + 1.5 + 3.12 + 6.25 + 12.5 + 25 + 50
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
50
75
87.5
93.75
96.87
98.37
99.12
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Methadone Dosing 2012.
• 2. EHL = Effective Half life ?
• Elimination Half Life = Effective Half Life .?
• Tempting to equate them however the real
desired effect of a substance may be weeks
beyond the EHL.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
14
Methadone Dosing 2012.
• 2. EHL Examples :
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Sbst
EHL
Full Effects
--------------------------------------------------------Diazepam
50-100
6-12 hours
Elavil
15
4-8 Weeks
Morphine
1
1-4 hours
Methadone
24
4-6 weeks
Ventolin
?
Immediate
Flovent
?
4-8 Weeks
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Saskatoon, 08 Dec 2012
15
Methadone Dosing 2012.
• 3. Tolerance :
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1. Thought mediated by NMDA receptor
2. Tolerance different for different effects, patients
3. Opioids have unlimited tolerance for use, pain.
4. But methadone is an NMDA antagonist.
5. Methadone -> stable dose without escalation.
6. Methadone can limit other opiate tolerance.
7. Methadone + Opiate -> no escalation of either dose.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 4. Induction dosing :
• Intent - safely introduce / convert opiate to methadone
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Initial doses over 35 mg can be fatal
Death from narcosis and respiratory depression
These take 7 - 10 days for tolerance regardless of dose.
So never exceed 30 mg first few days.
Zador and Sunjig, 2000, Australia.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
17
Methadone Dosing 2012.
• 4. Induction dosing :
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So never exceed 30 mg first few days.
For pain
30 mg may be OK at least as a test
For tolerance
10-30 clears narcosis and resp dep 10 days
For withdrawal
30 mg is subtherapeutic -> withdrawal
So patients use other opiates to deal with withdrawal.
Unless you prescribe the opiates yourself (DWI with methadone)
• This phase is critical. Retention is essential for best effect.
• Some patients will leave if you don’t treat the withdrawal.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 4. Induction typical scripts :
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1. Methadone starts at 20 - 30 mg / day three days
2. Methadone increases by 10 mg / day over time
3. Kadian starts at 100-200 mg / day with methadone
4. Kadian decreases as methadone increases, over about 4 weeks
• While on Kadian - all Daily Witnessed or no Kadian.
• Patient can thus avoid illegal use of drugs.
• Typical samples of these scripts at www.syscon.sk.ca
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
19
Methadone Dosing 2012.
• 4. Induction Process is the same for :
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1. Palliative care
2. Chronic Pain
3. Opioid Dependency
4. Chronic Pain and Opioid Dependency
• All patients start at < 35 mg per day.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
20
Methadone Dosing 2012.
• 5. Maintenance (fixed dose) dosing :
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1. Increase / decrease for effect.
2. Not lasting - likely needs more
3. Too drowsy - likely need less
4. Allow 1-2 weeks to assess effect.
5. Max change 10 % of prior dose
6. Beware ‘can’t feel it’ or “immune’
7. P450 interactions not uncommon
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
21
Methadone Dosing 2012.
• 6. MSW dosing :
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1. Only when patient insists or other factors OK
2. Reduce by no more than 10% current dose
3. Stay at that dose 2 - 4 weeks (or more)
4. At about 50 mg reduce by 5 mg
5. At about 30 mg reduce by 2.5 mg.
6. Continue all the way down by 2.5 per month.
7. Patient will tell you if not ok and wants back up.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
22
Methadone Dosing 2012.
• 5. Drug Interactions :
• 1. Pharmaco-Dynamic - Drug effects on the body.
• 2. Pharmaco-Kinetic - Body effects on the drug.
– Altered drug absorption - not common.
– Altered drug distribution - not common.
– Altered drug elimination - quite common.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
23
Methadone Dosing 2012.
• 5. Altered Drug Elimination :
• 1. Increase elimination - Drug effects reduced.
• 2. Decrease elimination - Drug effects increased.
• For many substances, including Methadone : the
Cytochrome P450 enzymes increase / decrease
elimination. Effects are quite variable.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Cytochrome P450 (CYP450) Enzymes :
• Discovered about 1985.
• A large class of proteins widely distributed in bacteria,
fungi, plants, animals, and therefore of ancient origin.
• Many are oxidases, classified either by source type
(Bacterial or Microsomal) or by the number of protein
components.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Cytochrome P450 (CYP450) Enzymes :
• Their names are impossible.
• For simplicity they are numbered / lettered / numbered
• Five are important in opioid drug interactions :
• 1A2, 2C9, 2C19, 2D6, 3A4.
• For methadone 3A4 may matter most.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Cytochrome P450 (CYP450) Enzymes :
• Every drug (substrate) metabolised by the P450 system
can be affected by changes to the availability of these
enzymes. For reasons not understood :
• Availability of all 5 enzymes can be (unpredictably) :
– a. Unaffected by a given drug
– b. Increased (=“induced”)
– c. Decreased (=“inhibited”)
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Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Enzyme Processes :
• 1. Substances acted on by enzymes are “Substrates”.
– a. Phase I oxidises substrates ->more soluble in water.
– b. Phase II glucuronidates -> yet more soluble.
• 2. In general this applies equally to :
– a. Hepatic / Renal processes.
– b. Cytochrome - P450 processes.
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Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Liver / Kidney vs Cytochrome P450 :
• 1. Substrates are metabolised by one or the other system.
• 2. Liver / kidney - rarely drug interactions.
• 3. Cytochrome P450 fairly common drug interactions.
• About 160 drugs and many foods metabolised by CYT P450.
• This includes most of the opioids.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Liver / Kidney vs Cytochrome P450 :
• Examples :
• 1. Non-P450 - Pravastatin, Avelox, many others.
• 2. P450, three possibilities (especially for 3A4 enzyme) :
– No effect on enzymes : Quite common
– Increase the enzymes : Rifampin, Tegretol, Barbiturates.
– Decrease the enzymes : Erythromycin, hormones, antifungals.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
30
Methadone Dosing 2012.
• 5. Cytochrome P450 (CYP450) Enzymes :
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Inducing (increasing) an enzyme increases its effect.
Sensitive substrates are metabolised faster.
They have less effect, shorter half lives
They are eliminated faster, may need increase dose.
• Inhibiting (decreasing) has reverse effect.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. Methadone and P450 :
• 1. Methadone is mainly metabolised by 3A4.
• 2. About 15 other drugs can INCREASE 3A4.
• 3. These drugs can REDUCE the effects of Methadone.
• 4. About 40 drugs can DECREASE 3A4.
• 5. They can all INCREASE the effect of Methadone.
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Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. 3A4 Increase -> can reduce Meth
effect :
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Aminoglutethimide
Barbiturates
Carbamazepine
Dexamethasone
Efavirenz
Ethanol (chr)
Glutethimide
Griseofulvin
Nafcillin
Nalfinavir
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Saskatoon, 08 Dec 2012
Nevirapine
Phenytoin
Primidone
Rifabutin
Rifampin
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Methadone Dosing 2012.
• 5. 3A4 Decrease -> can increase Meth
effect :
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Cimetidine
Fluoxetine
Clarithromycin
Fluvoxamine
Cyclosporine
Grapefruit
Danazol
Indinavir
Delaviridine
Isoniazid
Diltiazem
Itraconazole
Erythromycin
Ketaconazole
Ethinyl Estradiol Metronidazole
Fluconazole
Mibefradil
Miconcazole
Prednisone
Nefazodone
Quinine
Nelfinavir
Ritonavir
Nicardipine
Saquinavir
Nifedipine
Trolandeomycin
Norethindrone Valproic acid
Norfloxacin
Verapamil
Omeprazole
Zafirlukast
Oxicanozole
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Saskatoon, 08 Dec 2012
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Methadone Dosing 2012.
• 5. 3A4 Decrease, can increase Meth effect
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Macrolides
Hormones (BCP)
Ca Channel Blockers
Antifungals
Most HIV drugs
Fluoxetine
Fluvoxamine
Valproic Acid
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Saskatoon, 08 Dec 2012
35
Methadone Dosing 2012.
• 5. Meth Interactions in Practice :
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1. Maintain a stable Methadone dose.
2. Add the other drug - effect is unpredictable.
3. Avoid telling the patient it may affect dose.
4. Wait a few days to assess effect.
5. Adjust methadone dose if need be.
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Saskatoon, 08 Dec 2012
36
Assessment for Methadone 2012.
• Basic Opioid Principles Summary :
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1. Opiates are largely interchangeable
2. Opioid dependency is irreversible
3. Opiates and methadone chemically unrelated
4. Opiates and methadone have no equivalents
5. Opiate and methadone combos work well
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
37
Methadone Dosing 2012.
• Induction Summary :
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1. Meth & opiates unrelated, no equivalents.
2. Combinations work well.
3. EHL and DSM IV confuse the issues.
4. Never exceed 30 mg initial doses.
5. Supplement Kadian for new patients.
6. 10 % rule for most adjustments, up or down.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
38
Methadone Dosing 2012.
• Objectives met ?
• Intent - conversion or introduction to methadone
•
•
•
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1. Basic opioid agonist principles
2. Induction Phase dosing
3. Maintenance Phase dosing
4. Medically Supervised Withdrawal dosing
5. Special dosing issues (mainly P450).
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
39
Methadone Dosing 2012.
Many thanks for your attention.
I trust the objectives were covered
and have provided some
understanding of the intent and
processes of MMT.
Copyright (c) Meth Made Easy, FML,
Saskatoon, 08 Dec 2012
40