VOLUME C Pharmacological Treatment for Drug Use Disorders Drug Treatment for Special Populations Module 2 Basics of opioid dependence Pharmacotherapy options Opioids: Opioid Opioid Opioid Definition, dependence dependence antagonist effects and treatment with treatment with treatment treatment Methadone Buprenorphine implications Workshop 2 Opioid dependence treatment with Methadone Training objectives At the end of this workshop, you will be able to: ► Explain the rationale for opioid agonist therapy ► Understand medical withdrawal protocols using Methadone ► Explain the basic principles of maintenance treatment with Methadone ► Identify effective practices in the implementation of Methadone treatment ► Explain how to address concurrent use of other drugs and alcohol during Methadone treatment ► Determine the contraindications and medical interactions with Methadone Let‘s discuss! ► What do you know about methadone for treatment? ► What are your personal views about treatment with methadone? 5 Opioid withdrawal & management Opioid withdrawal Signs Symptoms • Yawning • Anorexia and nausea • Lacrimation, mydriasis • Abdominal pain or cramps • Diaphoresis • Hot and cold flushes • Rhinorrhea, sneezing • Joint and muscle pain or • Tremor twitching • Piloerection • Insomnia • Diarrhoea and vomiting • Drug cravings • Restlessness/anxiety 7 Progress of the acute phase of opioid withdrawal since last dose Withdrawal from heroin Withdrawal from methadone Onset: 6–24 hrs. Onset: 24–48 hrs., sometimes more Duration: 4–10 days Duration: 10–20 days, sometimes more Severity of signs and symptoms and signs of Severity 8 Opioid withdrawal complications ► Anxiety and agitation ► Low tolerance to discomfort and dysphoria ► Drug-seeking behaviour (requesting or seeking medication to reduce symptom severity) ► Muscle cramps ► Abdominal cramps ► Insomnia 9 Opioid withdrawal management Withdrawal management aims to: ► Reverse neuroadaptation and reduce withdrawal symptoms ► Promote the uptake of post- withdrawal treatment options 10 Opioid withdrawal treatment Involves: ► Reassurance and supportive care ► Information ► Hydration and nutrition ► Opioid pharmacotherapies e.g., Methadone ► Symptomatic treatment e.g., Clonidine 11 Treatment of opioid dependence: Methadone Methadone ► Methadone is a synthetic opioid medication developed in 1939 in Germany ► Introduced to the USA in 1947 ► Widely used for treatment of opioid addiction & as analgesic ► Dole and Nyswander first used methadone in maintenance treatment for opioid addiction in 1964 & published results of clinical trial in 1965 ► Numerous studies over 49 yrs consistently support clinical & cost effectiveness of methadone for opioid dependence ► Evidence also for ↓ illicit opioid use, risk of HIV, mortality, crime & ↑ social functioning 13 Medical basis of treatment with methadone The treatment (with Methadone) is corrective, normalizing neurological and endocrinologic processes in patients whose endogenous ligand-receptor function has been deranged by long-term use of powerful narcotic drugs. Why some persons who are more susceptible and whether long-term drug users can recover without maintenance therapy are questions for the future. At present, the most that can be said is that there seems to be a specific neurological basis for the compulsive use of heroin by drug users and that methadone taken in optimal doses can correct the disorder. (Vincent Dole, 1988) 14 Methadone: clinical properties The “Gold Standard” treatment ► Synthetic opioid with a long half-life ► μ Agonist with morphine-like properties/actions ► Action – CNS depressant ► Effects usually last about 24 hours ► Daily dosing (same time, daily) maintains constant blood levels and facilitates normal everyday activity ► Adequate dosage prevents opioid withdrawal and reduces craving without intoxication 15 Intrinsic activity: full agonist, partial agonist and antagonist 100 90 Full Agonist (Methadone) 80 70 Intrinsic Activity 60 Partial Agonist 50 (Buprenorphine) 40 30 20 10 Antagonist (Naloxone) 0 -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid 16 Methadone: pharmacokinetics ► Good oral bioavailability ► Peak plasma concentration after 2-4 hrs. ► 96% plasma protein bound ► Mean half-life around 24 hrs. ► Steady state after 3-10 days ► Metabolism ► Cytochrome P450 mediated ► CYP3A4 main ► Also CYP2D6, CYP1A2, CYP2C9 and CYP2C19 ► Genetic variability ► Risk of drug interactions 17 Methadone pharmacodynamics ► Full opioid agonist ► Main action on mu receptors – Inhibit adenylyl cyclase = cAMP – Potassium channel opening – Calcium channel opening ► Inhibit serotonin reuptake ► Non-competitive antagonist NMDA receptor 18 Methadone: recommended formulation ► Methadone should normally be prescribed as a 1 mg in 1 ml oral solution ► Oral concentrates, containing methadone hydrochloride 10 mg/ml or 20 mg/ml, should normally be dispensed only after dilution, as appropriate ► Methadone tablets are not licensed for the treatment of drug dependence and should not normally be prescribed due to the increased potential for diversion 19 Methadone: safety overview ► Respiratory depression & overdose – ↑ Risk in low opioid tolerance and/or combination with other sedative drug use – ↑ Mortality in 1st fortnight of treatment, following treatment cessation, diversion to those not in treatment ► Adverse events – Side effects most common early in treatment: constipation, nausea, sweating – Less common: lowered androgens in men, sleep apnoea, osteoporosis, QTc prolongation 20 Methadone and prolonged QTc Methadone and QTc prolongation ► Methadone ↓ cardiac hERG voltage-gated potassium channels (repolarization) ► ↓ Potassium channel may ↑ the QT interval ► ↑ QT interval & torsades de pointes reported ► More common with higher dose > 200 mg/day ► Most treated with large, multiple daily doses for pain ► Also at doses commonly used for OST ► In OST other medications, ↓ potassium contribute 22 Methadone and prolonged QTc recognised risks ► Advanced Heart Disease, IHD, Conduction defects, ↑ QT ► Liver disease ► Electrolyte abnormalities (↓K, Mg) ► Family h/o sudden death ► Treatment with medicines that ↑QT / ↕Electrolyte ► Treatment with CYP 3A4 inhibitors ► Dose >100 mg/day 23 Methadone and prolonged QTc management ► Patients with recognised risk factors for ↑QTc: – ECG before starting & at stabilisation ► No risk factors for ↑ QT: – ECG before dose titration > 100mg & – 7 days after titration 24 Drug interaction – metabolism Methadone ► Metabolism Cytochrome P450 mediated – CYP3A4 main – Also CYP2D6, CYP1A2, CYP2C9 and CYP2C19, genetic variability ► CYP3A4 breaks down 50% of drugs – Methadone mixed inhibitor may increase other drug levels, e.g., Nifidepine, etc. 25 Opioids: drug interactions Respiratory Toxicity/ Hypotension Coma depression risk of death CNS depressants MAOIs TCAs Betablockers BZDs 26 Methadone: advantages of treatment ► Suppresses opioid withdrawal ► Reduces craving and blocks effects of Heroin ► Pure – no “cutting agents” present ► Oral administration (syrup or tablet forms used) ► Once-daily doses enable lifestyle changes ► Slow reduction and withdrawal can be negotiated with minimal discomfort ► Minimal reinforcing properties, relative to heroin ► Counselling and support assists long-term lifestyle changes ► Legal and affordable – reduced participation in crime ► Few long-term side effects 27 Methadone: disadvantages of treatment ► Initial discomfort to be expected during stabilisation phase ► Physical opioid dependence is maintained ► Slow withdrawal (preferably) negotiated and undertaken over a period of months ► Protracted withdrawal symptoms ► Can overdose, particularly with polydrug use ► Daily travel and time commitment ► Variable duration of action ► Diversion 28 Maximising treatment adherence ► Address psychosocial issues as first priority – Emotional stability – “Chaotic" drug use – Accommodation – Income ► Opioid agonist pharmacotherapy can: – Address psychosocial instability – Increase opportunities to directly observe the administration of various HIV therapies 29 Assessment objectives ► Clarify nature and severity of problems ► Establish a therapeutic relationship ► Formulate problems into a treatment plan 30 Key features of assessment ► History – Patient self-report – Collateral history ► Examination ► Investigations 31 Remember: TRAPPED ► Treatment History ► Route of administration ► Amount of drug used ► Pattern of use ► Prior abstinence ► Effects (medical, psychiatric, social) ► Duration of use TRAPPED 32 Approximate durations of detectability of selected drugs in urine *Duration of Drug or its metabolite(s) detection Amphetamines including methylamphetamine and MDMA 2 days Benzodiazepines: Ultra-short-acting (e.g. midazolam) 12 hours Short-acting (e.g. triazolam) 24 hours Intermediate-acting (e.g. temazepam, chlordiazepoxide) 2–5 days Long-acting (e.g. diazepam, nitrazepam) 7 days + Buprenorphine and metabolites 8 days Cocaine metabolite 2-3 days Methadone (maintenance dosing) 7-9 days Codeine, dihydrocodeine, morphine, propoxyphene (heroin detected as the 48hrs metabolite morphine) Cannabinoids: 3-4 days-up to 45 Single use – chronic heavy use days 33 Where are we so far? ► What does opioid withdrawal management aim? ► What does this process involve? ► What is Methadone and why it is considered a “Gold Standard” treatment? ► What are some advantages and disadvantages of MMT? 34 Break Methadone induction overview Guidelines and procedures for Methadone maintenance treatment 1. Induction 2. Stabilization 3.