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Section 33: Addiction Medications

Section 33: Addiction Medications. Richard A. Rawson, Ph.D., Professor Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles. Alcohol and Benzodiazepines. Alcohol. Still the most popular ‘drug’ –

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Section 33: Addiction Medications

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  1. Section 33:Addiction Medications Richard A. Rawson, Ph.D., Professor Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles

  2. Alcohol and Benzodiazepines

  3. Alcohol • Still the most popular ‘drug’ – • In some societies over 80% of population drinks • 8% drink daily, peak in males +60 yrs (23%). 40% drink weekly • At-risk drinking now defined as: • risks of harm in the long term (chronic harm) • risks of harm in the short term (acute harm)

  4. Risky Drinking Levels (for chronic harm)

  5. Predisposing Factors for High Risk Drinking • Family history of alcohol problems • Childhood problem behaviours related to impulse control • Poor coping responses in the face of stressful life events • Depression, divorce or separation • Drinking partner • Working in a male dominated environment

  6. Alcohol: Effects on Brain • No single receptor - interacts with and alters function of many different cellular components • Primary targets are GABA, NMDA glutamate, serotonin and ATP receptors • Stimulates dopamine and opioid systems • Effects of chronic consumption are opposite to acute because of homeostatic compensation.

  7. Pharmacokinetics 5 minutes to affect brain • Metabolised by liver (95–99%) • alcohol acetaldehyde acetic acid & H2O CO2 2% excreted unchanged in sweat, breath & urine • Rapidly absorbed into blood by stomach (20%) and small intestine (80%) • Distributed in body fluids (not fat) • 1 standard drink per hour raises BAC by approx. 0.01–0.03 g%. Alcohol

  8. Effects of Alcohol Intoxication

  9. Binge Drinking Binge drinking can lead to: • increased risk taking • poor judgment/decision making • misadventure/accidents • increased risky sexual behaviour • increased violence • suicide

  10. Harms Associated with High-risk Alcohol Use • Hypertension,CVA • Cardiomyopathy • Peripheral neuropathy • Impotence • Cirrhosis and hepatic or bowel carcinomas • Cancer of lips, mouth, throat and esophagus • Cancer of breast • Fetal alcohol syndrome

  11. Alcohol-related Brain Injury • Cognitive impairment may result from consumption levels of >70 grams per day • Thiamine deficiency leads to: • Wernicke’s encephalopathy • Korsakoff’s psychosis • Frontal lobe syndrome • Cerebellar degeneration • Trauma

  12. Interventions and Treatment for Alcohol-related Problems • Screening and Assessment  individualised interventions • Brief intervention and Harm Reduction strategies • Withdrawal management • Relapse prevention / goal setting strategies • Controlled drinking programs • Residential programs • Self-help groups

  13. Brief Intervention Consider the patient’s: • perspective on drinking • attitudes to drinking goals • significant others • short-term objectives. Provide: • information on standard drinks, risks, and risk levels • encouragement to identify positive alternatives to drinking • self-help manuals • follow-up session

  14. Two Steps Towards Alcohol Brief Intervention (BI) 1. Screening • E.g. the alcohol AUDIT, a 10-item questionnaire 2. Intervention • Information • Brief counselling • Advice • Referral (if required)

  15. Harm Minimizing Strategies Benefits of cutting down or cutting out: • save money • be less depressed • lose weight • less hassles for family • have more energy • sleep better • better physical shape Reduce the risk of: • liver disease • cancer • brain damage • high blood pressure • accidents • injury • legal problems

  16. Withdrawal Severity depends on: • pattern, quantity and duration of use • previous withdrawal history • patient expectations • physical and psychological wellbeing of the patient (illness or injury) • other drug use/dependence • the setting in which withdrawal takes place. Usually occurs 6–24 hours after last drink: • tremor • anxiety and agitation • sweating • nausea and vomiting • headache • sensory disturbances - hallucinations.

  17. deCrespigny & Cusack (2003) Adapted from NSW Health Detoxification Clinical Practice Guidelines (2000–2003)

  18. Home-based Withdrawal Medications for Symptomatic Treatment • Diazepam • Thiamine 100mg daily & multivitamins • Antiemetic • Analgesia (e.g. paracetamol) • Antidiarrhoeal.

  19. Post-withdrawal Management Treatment options: • retain in treatment, ongoing management • seek referral Considerations: • patient’s wants (abstinence or reduced consumption, remaining your patient) • severity of problems Pharmacotherapies: • acamprosate • naltrexone • disulfiram (not PBS listed)

  20. Naltrexone and Acamprosate • Effective • Work well with variety of supportive treatments e.g. brief intervention, CBT, supportive group therapy • Start following alcohol withdrawal – proven efficacy where goal is abstinence, uncertain with goal of moderation • No contraindication while person is still drinking, although efficacy uncertain • Generally safe and well tolerated

  21. Clinical Guidelines Naltrexone 50mg daily: • indicated especially where strong craving for alcohol after a priming dose •  likelihood of lapse progressing to relapse • LFTs < x3 above normal • side effects: nausea & headache. Acamprosate 600 mg (2 tabs) tds: • indicated especially where susceptible to drinking cues or drinking triggered by withdrawal symptoms • low potential for drug interactions • need normal renal function • side effects: diarrhoea, headache, nausea, itch.

  22. Disulfiram • Acetaldehyde dehydrogenase inhibitor – 200mg daily •  unpleasant reaction with alcohol ingestion • Indications: alcohol dependence + goal of abstinence + need for external aid to abstinence • Controlled trials:  abstinence rate in first 3–6 months • Best results with supervised ingestion & contingency management strategies

  23. VIVITROL A Brief Clinical Overview

  24. Comprehensive Alcohol Dependence Treatment Psychosocial Treatment and Medication • Limbic Region • Role: • Drive generation • VIVITROL • Cortex • Role: • Decision making • Thinking • Reasoning • Rationalizing • Psychosocial treatments • 12-step fellowships • Faith-based support 25

  25. Oral Naltrexone Discontinuation Rates Pharmacy claims for NTX-PO 1,4 Guidelines recommend treatment from 3-6 months to 2 years1 The vast majority did not persist in refills for a reasonable course of treatment 1,4 Both analyses show that approximately 50% failed to refill even beyond 30 days1,4 Two additional independent studies obtained similar discontinuation rates2,3 US Department of Health and Human Services/SAMHSA study (2004)1 Kranzler et al., Addiction 20084 26 • 1. Harris KM, et al. Psychiatr Serv. 2004;55:221. • 2. Hermos JA, et al. Alcohol Clin Exp Res. 2004;28:1229-1235. • 3. Un H, Addiction Health Services Research Conference, Boston 2008 • 4. Kranzler HR, et al. Addiction. 2008:103(11):1801-1808.

  26. Medications for Alcohol Dependence Antabuse®(disulfiram)1 ReVia®(naltrexone)2 Campral® (acamprosate)3 VIVITROL®(naltrexone for extended-release injectable suspension)4 30 tabs/month*(1 tab/day) 180 tabs/month*(2 tabs, 3x/day) 30 tabs/month*(1 tab/day) 1/month 2006 1951 1994 2004 1. Antabuse full Prescribing Information. Odyssey Pharmaceuticals, Inc. 2. ReVia full Prescribing Information. Duramed Pharmaceuticals, Inc. 3.Campral full Prescribing Information. Merck Santé s.a.s. 4.VIVITROLFull Prescribing Information. Alkermes, Inc. *Based on a month with 30 days. 27

  27. What is VIVITROL? VIVITROL is NOT1: Addictive Aversive (e.g. disulfiram) Euphorigenic (i.e. pleasure producing) VIVITROL is1: An opioid blocker (i.e. antagonist) Extended-release (30 days) Compatible with psychosocial treatments, antidepressants and Alcoholics Anonymous2 Administered by a healthcare professional (use can be monitored) VIVITROL Full Prescribing Information. Alkermes, Inc. Gromov, I., et al. AMERSA, Washington, DC, November 8, 2007. 28

  28. VIVITROL Indication VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration. Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support. VIVITROL[full prescribing information]. Cambridge, MA: Alkermes, Inc; May 2009. 29

  29. Opioid Receptors and Alcohol Dependence 1.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210. 2. Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003:101-118. 30

  30. VIVITROL: A Targeted Approach The mechanism by which VIVITROL exerts its effects in alcohol-dependent patients is not entirely understood. 1. VIVITROL full Prescribing Information. Alkermes, Inc. 2. Oswald LM, et al. PhysiolBehav. 2004;81:339-358. 3.Kenna GA, et al. Am J Health Syst Pharm. 2004;61:2272-2279. 4.Gianoulakis C. Alcohol Health Res World. 1998;22:202-210. 31

  31. VIVITROL Eliminates DailyAdherence Decisions1 VIVITROL utilizes a delivery system that Provides a month of medication in a single dose Adherence to any treatment program is essential for successful outcomes Administration by a healthcare provider ensuresthat the patient receives the medication as directed “…addressing patient adherence systematically will maximize the effectiveness of these medications.”2 –Updated NIAAA Clinician’s Guide 1. Dean RL. Front Biosci. 2005;10:643-655. 2. NIAAA. 2007. NIH publication 07-3769. 32

  32. VIVITROL Provided Rapid Results When VIVITROL was added to counseling*… Reductions were rapid1 • Post hoc analysis of a randomized, double-blind, placebo-controlled study. Patients had ≥2 heavy drinking episodes/week during the month prior to screening. Inclusion did not require detoxification, abstinence or intent to abstain from alcohol1 • VIVITROL is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration2 • Approval of VIVITROL was based on a subset of patients who were able to abstain for 7 days prior to treatment initiation1 Counseling* with PLACEBO (n=209) Counseling* with VIVITROL (n=205) *The counseling used with all subjects was BRENDA, a low-intensity intervention designed to facilitate direct feedback of alcohol-related consequences. BRENDA consists of biopsychosocial assessment, reporting the assessment to the patient, an empathetic approach, identified and stated patient needs, direct advice regarding drinking behavior, and assessment of treatment adherence. • Ciraulo D et al. J Clin Psychiatry. 2008;69(2):190-195. • VIVITROL Full Prescribing Information. Cambridge, MA. Alkermes, Inc.; 2008. 33

  33. VIVITROL Significantly Reduces Drinking Days1,2 Reductions were substantial1† Counseling with VIVITROL (n=28) Counseling with PLACEBO (n=28) Baseline (n=56) • According to the SAMHSA/CSAT, 4 days is the US norm (median duration) for detoxification2 • Approval of VIVITROL was based on a subset of patients who were able to abstain for 7 days prior to treatment initiation1 • † These results are from a post hoc subgroup analysis of a 6-month, multicenter, double-blind, placebo-controlled clinical trial of alcohol dependent patients. This subset analysis evaluated patients who were abstinent for 4 or more days prior to treatment initiation1 • O’Malley SS et al. J ClinPsychopharmacol. 2007;27(5):507-512. • Drug and Alcohol Services Information System. The DASIS report: discharges from detoxification: 2000. http://oas.samhsa.gov/2K4/detoxDischarges/detoxDischarges.pdf. Published July 9, 2004. Accessed January 23, 2008. . 34

  34. VIVITROL Sustained Abstinence1 VIVITROL maintained 6-month abstinence Nearly three times as many patients remained abstinent 32% 11% VIVITROL prolonged initial abstinence • Results are from a post hoc subgroup analysis of a 6-month multicenter, double-blind, • placebo controlled clinical trial of alcohol dependents who were abstinent for 4 or more days • prior to treatment initiation. • The approval of VIVITROL was based on a subset of patients who were able to • abstain for 7 days prior to treatment initiation. 1. O’Malley SS, et al. J ClinPsychopharm. 2007;27:507-512. 35

  35. VIVITROL Sustained Reduction in Heavy Drinking Among patients receiving VIVITROL or placebo in the 6-month trial Data on file. Alkermes, Inc. 36

  36. Rapid results Substantial reduction in drinking days Prolonged initial abstinence Sustained continuous abstinence through the 6-month study Sustained reduction in heavy drinking days through 18 months Substantial reduction in holiday drinking Summary of Efficacy Results1,2 In clients who were abstinent during the week before treatment initiation, VIVITROL and counseling, as compared to placebo and counseling, provided: 1. O’Malley SS, et al. J ClinPsychopharmacol. 2007;27:507-512. 2. VIVITROL Full Prescribing Information. Alkermes, Inc. 37

  37. Safety Profile During clinical trials: Treatment with extended-release naltrexone was generally well tolerated Safety profile is based on more than 900 patients Adverse events in the majority of patients were mild or moderate Discontinuation rates due to adverse events: 9% in patients treated with VIVITROL 7% in patients treated with placebo The safety profile of patients treated with VIVITROL concomitantly with antidepressants was similar to that of patients taking VIVITROL without antidepressants1 No significant increase in mean AST or ALT levels2 • VIVITROL Full Prescribing Information. Alkermes, Inc. • Garbutt JC, et al. JAMA.2005;293:1617-1625. 38

  38. Most Common Adverse Events Occurring in >10% of patients *Injection site reaction (ISR) included tenderness, induration, pain, and pruritus. The dropout rate due to ISR was 3%. 39 VIVITROL Full Prescribing Information. Alkermes, Inc.

  39. Dosage and Administration VIVITROL is given as an intramuscular (IM) gluteal injection every 4 weeks or once a month VIVITROL should not be given subcutaneously or in the adipose layer VIVITROL must not be administered intravenously VIVITROL should be administeredby a healthcare professional, into alternating buttocks each month VIVITROL should be injected into the upper outer quadrant of the buttock, deep into the muscle-not the adipose. Epidermis Dermis Adipose Muscle VIVITROL Full Prescribing Information. Alkermes, Inc. 40

  40. Questions? Comments?

  41. Benzodiazepines “Benzodiazepines:the opium of the masses” Malcolm Lader, Neuroscience, 1978

  42. Medical Indications for Use • Anxiolytic– chronic / phobic anxiety & panic attacks • Sedative and hypnotic – sleep disturbance & anaesthesia / premed • Anticonvulsant – status epilepticus, myoclonic & photic epilepsy • Muscle relaxant – muscle spasm / spasticity • Alcohol withdrawal

  43. Patterns of Use • BZDs are one of the most prescribed drugs • 4% of all prescriptions from General Practitioners are for benzodiazepines (BZDs) • Predictors for BZD prescription include: • being female • being elderly • being an established patient • attending a busy doctor, or a doctor in inner urban area • Over 40% of prescriptions given to people >70 years • Night time use tends to increase with age • 58% of current users report daily use for >6 months.

  44. Benzos and Long-term Use • Long-term use is common and associated with: • altered use patterns (from night time to daytime use) • excessive sedation • cognitive impairment • increased risk of accidents • adverse sleep effects • dependence and withdrawal (even at therapeutic doses) • BZDs have an additive effect with alcohol / other CNS depressants, increasing the risk of harm • BZDs have limited long-term efficacy.

  45. Pharmacodynamics • Rapidly absorbed orally (slower rate of absorption IM) • Lipid soluble - differences determine rate of passage through blood brain barrier i.e.  lipophilic  speed of onset • Duration of action variable – lipophilic  duration of action due to distribution in adipose tissue.

  46. Metabolism • Metabolised in the liver – mostly oxidative transformation prior to conjugation with glucuronic acid for urinary excretion • Elimination half life (drug & active metabolites) ranges from 8 – >60 hours, if short half life & no active metabolites rapidly attains steady state with minimal accumulation.

  47. Neurotransmission • Potentiate neurotransmission mediated by GABA (main inhibitory neurotransmitter), therefore neurons are more difficult to excite • Specific neuronal membrane receptors for BZD closely associated with synaptic GABA receptors • Receptors distributed through CNS, concentrated in reticular formation & limbic systems, also peripheral binding sites • Further understanding of the effects of BZDs on receptor subgroups may lead to the development of non-sedating anxiolytic BZDs.

  48. Effects: Low Dose Other effects: • Drowsiness, lethargy, fatigue • Impaired concentration, coordination, memory • Reduced ability to think and learn • Emotional anaesthesia • Clumsiness, ataxia • Depression • Mood swings • Blurred vision and/or vertigo • Light-headedness • Nausea, constipation, dry mouth, loss of appetite. Short term: • Sedation • Anxiety relief • Anticonvulsant properties • Can usually attend daily business (though should not drive in first 2 weeks of treatment).

  49. Drug + Alcohol Interactions • CNS depressants e.g. Benzodiazepines • Antipsychotics, antidepressants • Opioid analgesics, antihistamines (some) • Hypoglycaemics (chlorpropamide), metronidazole, cephalosporins (some) Confusion, depressed respiration Decreased metabolism, toxicity & CNS depression CNS depression Facial flushing, headache

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