copyright (c) meth made easy, fml, saskatoon, 08 dec 2012 1 methadone dosing 2012 dosing of patients...

1Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec 2012

Methadone Dosing 2012

Dosing of patients considered appropriate for Methadone

Therapy

.

Regina 08 Dec 2012


Methadone Dosing 2012.

• Credentials / Conflicts :

• Qualifications – mainly experience• Conflicts – talks for the College• Drug companies – fed and watered - rarely• Opioid companies – no involvement.



• Objectives :

• Intent - conversion or introduction to methadone

• 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).



• 1. Opioid Agonist Principles :

• 1. Opioids are dosed to SUBJECTIVE EFFECT

• We do not have an objective test for it.




• 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.




• 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.




• 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.




• 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.



• 2. Elimination Half Lives :

• 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.


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• 2. EHL and Steady State :

• Definition : The time it takes for half the substance to be eliminated from the

blood stream.


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• 2. EHL and Steady State :

• Any substance at steady dose builds rapidly for 3-4 half lives then levels off to

steady state.


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• 2. Example : 100 mg / day EHL = 24 hrs.

EHL Total on board is combo of : Total

1 50 50

2 25 + 50 75

3 12.5 + 25 + 50 87.5

4 6.25 + 12.5 + 25 + 50 93.75

5 3.12 + 6.25 + 12.5 + 25 + 50 96.87

6 1.5 + 3.12 + 6.25 + 12.5 + 25 + 50 98.37

7 0.75 + 1.5 + 3.12 + 6.25 + 12.5 + 25 + 50 99.12


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• 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.


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• 2. EHL Examples :

• 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



• 3. Tolerance :

• 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.



• 4. Induction dosing :

• Intent - safely introduce / convert opiate to methadone

• 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.



• 4. Induction dosing :

• 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.



• 4. Induction typical scripts :

• 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



• 4. Induction Process is the same for :

• 1. Palliative care• 2. Chronic Pain• 3. Opioid Dependency• 4. Chronic Pain and Opioid Dependency

• All patients start at < 35 mg per day.



• 5. Maintenance (fixed dose) dosing :

• 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



• 6. MSW dosing :

• 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.



• 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.



• 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.



• 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.




• 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.




• 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”)



• 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.



• 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.



• 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.




• 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.



• 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.



• 5. 3A4 Increase -> can reduce Meth effect :

• Aminoglutethimide Ethanol (chr) Nevirapine

• Barbiturates Glutethimide Phenytoin

• Carbamazepine Griseofulvin Primidone

• Dexamethasone Nafcillin Rifabutin

• Efavirenz Nalfinavir Rifampin



• 5. 3A4 Decrease -> can increase Meth effect :

• Cimetidine Fluoxetine Miconcazole Prednisone

• Clarithromycin Fluvoxamine Nefazodone Quinine

• Cyclosporine Grapefruit Nelfinavir Ritonavir

• Danazol Indinavir Nicardipine Saquinavir

• Delaviridine Isoniazid Nifedipine Trolandeomycin

• Diltiazem Itraconazole Norethindrone Valproic acid

• Erythromycin Ketaconazole Norfloxacin Verapamil

• Ethinyl Estradiol Metronidazole Omeprazole Zafirlukast

• Fluconazole Mibefradil Oxicanozole



• 5. 3A4 Decrease, can increase Meth effect :

• Macrolides Most HIV drugs• Hormones (BCP) Fluoxetine• Ca Channel Blockers Fluvoxamine• Antifungals Valproic Acid



• 5. Meth Interactions in Practice :

• 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.


Assessment for Methadone 2012.

• Basic Opioid Principles Summary :

• 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



• Induction Summary :

• 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.



• Objectives met ?

• Intent - conversion or introduction to methadone

• 1. Basic opioid agonist principles• 2. Induction Phase dosing• 3. Maintenance Phase dosing• 4. Medically Supervised Withdrawal dosing• 5. Special dosing issues (mainly P450).



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 1 methadone dosing 2012 dosing of patients...

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