Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 2012 Dosing of patients considered appropriate for Methadone Therapy. Regina 08 Dec 2012

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing Credentials / Conflicts : 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 Methadone Dosing 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).

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing Opioid Agonist Principles : 1. Opioids are dosed to SUBJECTIVE EFFECT We do not have an objective test for it.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 Methadone Dosing 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 Methadone Dosing 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 Methadone Dosing Opioid Agonist Principles : 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 Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 Methadone Dosing 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 Methadone Dosing 2012.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing Example : 100 mg / day EHL = 24 hrs. EHLTotal on board is combo of :Total

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 Methadone Dosing EHL Examples : SbstEHLFull Effects Diazepam hours Elavil154-8 Weeks Morphine11-4 hours Methadone244-6 weeks Ventolin?Immediate Flovent?4-8 Weeks

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 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 Methadone Dosing Induction dosing : So never exceed 30 mg first few days. For pain30 mg may be OK at least as a test For tolerance10-30 clears narcosis and resp dep 10 days For withdrawal30 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 Methadone Dosing Induction typical scripts : 1. Methadone starts at mg / day three days 2. Methadone increases by 10 mg / day over time 3. Kadian starts at 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

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 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 Methadone Dosing 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 Methadone Dosing 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 Methadone Dosing Cytochrome P450 (CYP450) Enzymes : Discovered about 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 Methadone Dosing 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 Methadone Dosing 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”)

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 Methadone Dosing 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 Methadone Dosing Cytochrome P450 (CYP450) Enzymes : 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 Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing A4 Increase -> can reduce Meth effect : Aminoglutethimide Ethanol (chr)Nevirapine Barbiturates GlutethimidePhenytoin Carbamazepine GriseofulvinPrimidone Dexamethasone NafcillinRifabutin Efavirenz NalfinavirRifampin

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing A4 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

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing A4 Decrease, can increase Meth effect : MacrolidesMost HIV drugs Hormones (BCP)Fluoxetine Ca Channel BlockersFluvoxamine AntifungalsValproic Acid

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Assessment for Methadone 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

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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 % rule for most adjustments, up or down.

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing 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).

Copyright (c) Meth Made Easy, FML, Saskatoon, 08 Dec Methadone Dosing Many thanks for your attention. I trust the objectives were covered and have provided some understanding of the intent and processes of MMT.