Medication and Addiction Treatment

1. Medication and Addiction Treatment Karen Miotto, M.D. UCLA School of Medicine Addiction Studies Program for Journalists December 2005

2. Does Treatment forSubstance Abuse Work? Treatment

3. Detoxification Narcotic Treatment Programs Pharmacotherapy Residential treatment Therapeutic community Sober living Motivational Enhancement Cognitive behavioral therapy (CBT) Relapse prevention 12-Step oriented support Individual therapy: supportive Brief intervention Group therapy Couple/family therapy Network therapy Vocational Training Treatment Interventions

4. “Self-Directed Cessation” or “Natural Recovery” Factors • Recognition of health/legal/family hazards • Financial considerations • Conflict with career goals • Social mores and peer pressure • Reduced access/availability of drugs • Conflict with personal values • “Maturation”

5. INTERVENTION Professional Family Consequential No Further Problem Drug use Successful Continuing Problem Drug Use Continued Problem Drug Use Unsuccessful

6. “Interventions”Professional • Primary care physicians • Mental health professionals • EAP’s • Clergy • Law enforcement personnel • School counselors

7. “Interventions”Family • Any family member or friend

8. “Intervention”Consequential • Accident • Arrest • Job loss (last chance agreements) • Relationship loss • Work place drug test • Negative drug experience • Sanctions in school • Loss of health

9. Factors AffectingTreatment Consideration • Recognition of drug use as a problem • Medical/legal/financial problems • Employer influence (EAP) • Family influence • Awareness of treatment • Perception of treatment

10. Factors AffectingTreatment Participation • Access issues (time of day, transportation, child care, etc) • Treatment environment • Treatment context • Treatment content • External pressure • Participant need/treatment service match • Family participation

11. Effective Treatment Strategies • Accurate information • Contingency management techniques • Cognitive-Behavioral approaches • Family participation • Drug and alcohol testing • Self-help support • Adequately trained staff • Medication/Detoxification

12. Role of Pharmacotherapy • “Cure” of withdrawal or overdose • To increase the holding power of outpatient treatment and thus reduce costs • To create a “window of opportunity” during which patients can receive psycho-social intervention to decrease the risk of relapse • To serve as a long-term maintenance agents for patients who can’t function without them, but can lead productive lives with them

13. Types of Pharmacotherapy • Anti-withdrawal • Agonists • Antagonists • Anti-craving • Treatment of co-morbid disorders

14. When Drugs Make You Feel NormalNo Drugs = Danger • Alcohol withdrawal – DT’s and seizures • GHB – “I go crazy when I stop” • Sedatives – “crawling out of my skin” • Heroin - kicking with medication or cold turkey • Stimulants – sad and fat • Marijuana – “wet dog shakes” • Nicotine – irritable and fat

15. GHB marketed to bodybuilders in 1980’s • Purported effects of muscle mass increase and fat loss • Euphoric and sexual effects led to more widespread use as a “party drug” • No data at that time about addictiveness or lethality of GHB

16. Opiate Addiction Pharmacotherapy • Agonists: Methadone • Partial Agonists: Buprenorphine • Antagonists: Naltrexone • Anti-Withdrawal &Anti-Craving: • Methadone • Buprenorphine • Clonidine

17. Locus Coeruleus in Opiate Withdrawal • located in the pontine tegmentum • largest group of NE-containing neurons • activated by pain, blood loss and cardiovascular collapse • LC hyperactivity - neural substrate for opiate withdrawal • clonidine or lofexidine (alpha-2 agonist) and opiates inhibit the LC

18. Opiate DetoxificationAnesthesia-aided Rapid Opiate Detoxification (AROD) Shortens withdrawal to 4-6 hours • especially useful for “detox phobic” • controlled study of risk/benefit ratio • withdrawal symptoms can persist for significant period post detoxification • expensive • large increase in stress hormones

19. Opiate Detoxification:Pros & Cons of Various Techniques • Methadone taper • Pro: • Simple to use • few side effects • Con: • Requires special license • longest withdrawal • rebound symptoms associated with relapse

20. Maintenance Opiate Agonist • Reduce medical complications and death • Satisfy drug hunger, reduce craving, prevent withdrawal • Blocks effects of abused opiates • Reduce medical care burden and costs • Reduce crime rate • Reduce “hassle” of addict lifestyle • Social rehabilitation (e.g. tax eater to tax payer)

21. Methadone Maintenance • Best studied & most effective opiate treatment program so far, but also most controversial • Treatment provided in licensed clinics • Methadone is an orally effective, 24-hour opioid drug used to maintain heroin or other opiate addicts • Patients maintained usually several years, but many need maintenance for many years

22. How Long Does OAT Last? Long Enough!! . . . As long as patient desires and benefits from continued treatment 21 Opioid Agonist Treatment of Addiction - Payte - 1998

23. Maintenance Opiate Agonist • Reduce medical complications and death 8-10 fold reduction in death rate • Satisfy drug hunger, reduce craving, prevent withdrawal • Blocks effects of abused opiates • Reduce medical care burden and costs • Reduce crime rate • Reduce “hassle” of addict lifestyle • Social rehabilitation (e.g. tax eater to tax payer)

24. Buprenorphine • Detoxification or Maintenance • Treatment – Physician Office Based • High affinity partial mu agonist & kappa antagonist • Reduced opioid agonist effects, with less respiratory depression • Withdrawal easier than from methadone or heroin • Combo form (buprenorphine/naloxone) may further decrease diversion potential & will be main maintenance form

25. Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone) 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

26. Naltrexone • Opioid antagonist approved by FDA in 1984 • Blocks opioids without agonist effects • Need to be off opiates to begin • Can be abruptly stopped without withdrawal • No tolerance to antagonist effect even after years • “Ideal” drug but most addicts uninterested in using it

28. Ideal ‘Anti-Cocaine’ Medication • In active users it will induce abstinence (or significantly decrease cocaine use) • It will decrease withdrawal dysphoria in binge users • In abstinent patients it will attenuate the reactivity to drug-related cues • In abstinent patients who lapse it will block the progression to the full relapse • Safe in combination with cocaine, low abuse potential, no dysphoric effects

29. Treatment of Stimulant Addiction: Current Status • There are several effective psychotherapies for stimulant dependence but no effective medication • Medication development was predominantly centered on dopamine receptor and models of drug reinforcement • Medication that may prevent relapse in abstinent patients may be a more viable option • Stimulant Addiction is a behavioral disorder and behavioral interventions must play a major role in any treatment paradigm

30. Determinants of Stimulant Use • Euphoria and reinforcement • Effect of Cues • Exteroceptive (environmental) • Interoceptive (stress, emotions, drug euphoria) • Availability of alternative reinforcers • Presence of psychopathology • Withdrawal dysphoria

32. Amphetamine-Induced Disorders • 292.89 Amphetamine Intoxication • 292.0 Amphetamine Withdrawal • 292.81 Amphetamine Intoxication Delirium • 292.11 Amphetamine-Induced Psychotic Disorder, With Delusions • 292.12 Amphetamine-Induced Psychotic Disorder, With Hallucinations • 292.84 Amphetamine-Induced Mood Disorder • 292.89 Amphetamine-Induced Anxiety Disorder

33. Alcohol Pharmacotherapy • Agonists: None yet • Antagonists: Disulfiram (Antabuse) • Anti-withdrawal: Benzodiazepines Anti-convulsants • Anti-craving: Naltrexone (ReVia), Campral Ondansatron, Topamax

35. Antabuse (disulfiram) • Helpful in maintaining abstinence • Inhibits aldehyde dehydrogenase • Leads to the accumulation of acetaldehyde if alcohol is consumed • Acetaldehyde is toxic and produces nausea and hypotension • Daily dose 250 mg, or 3-4 day interval dosing

36. Disulfiram • Use for cocaine and methamphetamine dependence • Inhibits Dopamine beta Hydroxylase (catalyzing the synthesis of NE from DA) • Indirectly increases the ratio of DA to NE • Increasing the dopamine availability , enhances the aversive effects of stimulants.

37. Adjunctive medication for alcohol craving - naltrexone • Opiate antagonist • Proposed mechanism of action • Dosing and side effects • Clinical efficacy

38. Topiramate • Inhibition of mesocortical dopamine release via facilitation of GABA activity • Inhibition of glutamate function • Hypothesis: • Decreases mesocorticolimbic dopamine activity after alcohol intake • Antagonize chronic changes induced by alcohol in the glutamate system

39. Oral Topiramate for Treatment of Alcohol Dependence Bankole Johnson et al (2003) • Abstinence-initiation trial N=150 • N=150 Double-blind randomized control trial 12 week • Topiramate (up to 300 mg per day) • Outcomes • 2.9 fewer drinks per day • 3.1 fewer drinks per drinking day • 27.6% fewer drinking days • 26.2% more abstinent days • Reduced craving

40. Acamprosate • Amino acid derivative - acetyl-homotaurine • similar to homocysteic acid (NMDA receptor) • mimics GABA (GABAA receptor) • interacts with calcium channel proteins • Reduces alcohol craving (conditioned withdrawal) • Reduces severity and frequency of relaspe • Suppress physical signs of withdrawal in animal models • (J Littleton Addiction 1995)

41. Acamprosate • Amino acid derivative - acetyl-homotaurine • similar to homocysteic acid (NMDA receptor) • mimics GABA (GABAA receptor) • interacts with calcium channel proteins • Reduces alcohol craving (conditioned withdrawal) • Reduces severity and frequency of relaspe • Suppress physical signs of withdrawal in animal models • (J Littleton Addiction 1995)

42. CAMPRAL NORMAL EQUILIBRIUM-Glutamate and GABA balanced This figure represents the brain (triangle) in a regular state of equilibrium with regard to excitation and inhibition processes. Excitation Inhibition Alcohol ACUTE ALCOHOL INTAKE-Increased levels of GABA Acute alcohol intake disrupts the equilibrium by exaggerating the inhibitory processes Excitation Inhibition Neuro- Adaptation Alcohol CHRONIC ALCOHOL CONSUMPTION-Increased levels of glutamate Chronic alcohol consumption induces neuroadaptation (increase in glutamate) to counteract the inhibitory action of alcohol. Excitation Inhibition

43. CAMPRAL ACUTE WITHDRAWAL AND POST-ACUTE WITHDRAWAL-Increased glutamate Acute Withdrawal of alcohol triggers a hyperexcitatory state because of the excess of glutamate present dur to the neuroadaptation. This results in withdrawal symptoms. Post-Acute Withdrawal stage follow. Environmental of learned cues associated with alcohol intake may trigger a hyperexcitatory state similar to acute withdrawal in abstinent patients. This precipitates mini-withdrawal symptoms in the post-acute stage-eg, anxiety tremors, sweating-that may contribute to relapse. Environmental/ Learned Cues No Alcohol Excitation Inhibition Environmental/ Learned Cues CAMPRAL CAMPRAL-Modulation of glutamate restores balance CAMPRAL interacts with the glutamate neurotransmitter system to block the response to environmental and learned cues. CAMPRAL is though to restore the normal balance. The mechanism of action of CAMPRAL is believed to address the biochemical aspect of alcohol dependence, complementing psychosocial therapy that targets the emotional and behavioral components of the disease. Excitation Inhibition

47. Conclusion • Addiction is a complex chronic medical disorder • Opioid - methadone, buprenorphine • Stimulants - vaccine • Alcohol - campral • New developments in medication for addiction