Medicines for the Treatment of Drug Addiction

Transcription

1 Recovery Happens! Current Trends in Substance Abuse Treatment September 29, 2009 Medicines for the Treatment of Drug Addiction Mark Stanford, Ph.D.

2 Objectives Highlight the effective primary medications to treat alcoholism and drug addiction Critically appraise the efficacy of medications for treating substance use disorders Medications are reviewed by neurotransmitter system Each section begins with a mechanistic overview New vistas for the future

3 about Contemporary Addiction Treatment

4 How Long Do They Stay? More than 50% of outpatients drop out within one month.

5 Do They Stay Sober? About 60% use drugs/alcohol within 6 months after treatment

6 Do They Return to Tx? About 45% apply for re-treatment within 12 months

7 The Problem With Addiction Treatment It s the Patients They Won t Do What You Ask! Won t Attend - They Drop Out Won t Change Behaviors, People, Places & Things They relapse all the time!

8 Re-Considering Addiction Treatment Have We Been Thinking Correctly?

9 Treatment Works! Compulsive drug use decreases by 87% following Tx, & substance related problems Decrease by 60% following Tx (Miller, et al, 2001). Lives of individuals and families transformed by addiction treatment. Treatment Works, BUT

10 The majority of our efforts focus on attracting, engaging and retaining clients in treatment. Attracting Clients: Drug Court Readmissions Word of mouth Provider referrals Websites EAP referrals Advertising Engaging/Retaining: NiaTx MI, MET, CBT, 12-Step Staged-Based Tx Session rating scales Therapeutic alliance Meeting client where they re at

11 Treatment services needs to add the piece that helps the client sustain recovery after treatment has completed. Attracting, Engaging, Retaining Sustaining

12 What is Addiction? Addiction is A Brain Disease Characterized by: Compulsive Behavior Continued abuse of drugs despite negative consequences Persistent changes in the brain s structure and function

13 Advances in science have revolutionized our fundamental views of drug abuse and addiction and allowed for the development of improved treatments.

14 Neurobiology of addiction Disease model 1930 AA is founded by a physician and business man 1956 AMA released formal statements supporting the definition of alcoholism as a disease Reward center of brain (Olds and Milner, 1954) Identified from work performed in animals Further Experimental results Stimulation Ablation Blockade studies Neuroimaging studies (PET Scans, SPECT scans)

15 Neural circuitry of reward Present in all animals Produces pleasure for behaviors needed for survival: Eating Drinking Mating Nurturing

16 Behaviors that result in the experience of release from a biological tension (i.e. eating) make us feel good. This feel good response is registered in a certain part of the brain.

17 Behaviors experienced as pleasurable are processed in certain areas of the brain called the brain reward pathway. The fancy name for this brain area is called the mesocorticolimbic pathway.

18 Brain areas involved in the reward pathway, and in addiction Ventral tegmental area (VTA) Nucleus accumbens (NA) Prefrontal cortex (PC) Locus coeruleus (LC) Thalamus

19 Natural Rewards The brain's reward pathway is necessary for survival since it motivates important activities such as food seeking and eating, mating, and parenting. Food Water Sex Nurturing

20 Natural Rewards Elevate Dopamine Levels % of Basal DA Output Food Time (min) NAc shell DA Concentration (% Baseline) Sample Number Sex Female Present Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.

21 Self-stimulation studies Will work for stimulation of the VTA or NA

22 Will work for morphine or cocaine

23 All drugs of abuse bind to the neural circuitry of reward

24 Drugs of abuse hijack the Reward Center Instead of eating, drinking and making love, drugs tell you that you need to take them in order to survive. This is obviously a lie, and one that leads to sickness and death.

25 Effects of Drugs on Dopamine Release % of Basal Release % of Basal Release Amphetamine Accumbens DA DOPAC HVA hr Nicotine hr Time After Drug Di Chiara and Imperato, PNAS, 1988 Accumbens Caudate % of Basal Release % of Basal Release Accumbens Cocaine DA DOPAC HVA hr Accumbens Morphine Dose 0.5 mg/kg 1.0 mg/kg 2.5mg/kg 10 mg/kg hr Time After Drug

26 Neuroadaptation Drugs change the brain s balance The brain has mechanisms to oppose this change The balancing action overshoots : The stronger the drug, the higher the dosage and the longer the use, the more the opposing change

27 Neuroadaptation: Example: alcoholism Long term adaptive changes to the inhibitory GABAergic system and to the excitatory glutamatergic systems are thought to underlie the development and maintenance of alcohol dependence

28 Neuroadaptation: alcoholism To compensate for the sedative effects of alcohol there occurs an up-regulation of the excitatory system and a downregulation of the inhibitory system

29 Neuroadaptation: alcoholism In withdrawal the CNS is left in a hyperexcitable state: anxious sleepless tremulous tachycardic/hypertensive

30 Neuropeptides which activate receptors and act on the reward pathway Serotonin Affects Mood Receptor 5HT3 Dopamine Affects Mood D1, D2 Cannibinoids Pain Multiple cannibinoids receptors identified Endorphins, Enkephalins, Dynorphins Mood, pain 5 types of Mu, Delta, Kappa

31 Evidence for reward pathway Stimulation (electrical or chemical) of NA & VTA is intrinsically rewarding. Stimulation elsewhere is not Reward can be interrupted by Severing NA-FC fibers Using dopamine blocker Blocking can interrupt naturally rewarded behaviors Patients on drugs that block dopamine look flat to us and experience decreased emotions

32 Reward pathway Dopamine is the primary transmitter that is the final activation chemical in all rewards Activates D1 receptors D2 receptors are also activated Responsible for reinforcing behavior

33 All drugs act via dopaminergic pathways Dopamine

34 Drugs can be Imposters of Brain Messages

35 If taking drugs make people feel good or better, what s the problem?

36 Repeated use of drugs and alcohol saturate the brain s reward pathway to the point that: the person becomes conditioned to the intense level of drug-induced pleasure, the normal level of natural rewards are no longer experienced as very pleasurable, and after chronic use, the brain s reward pathway becomes drained so that nothing is pleasurable not even the drugs!

37 Development of addiction Increasing use of the substance to feel high Gradual increase in number of receptors Gradual decrease in amount of normal transmitter by drug induced depletion Gradual decrease in reinforcing properties of drug (loss of high or rush ) Tolerance as neuroadaptation Increase in need for drug to maintain normalcy Beginning of dependence

38 Science Has Generated Much Evidence Showing That Prolonged Drug Use Changes the Brain In Fundamental and Long-Lasting Ways

39 AND We Have Evidence That These Changes Can Be Both Structural and Functional

40 DA D2 Receptor Availability Structurally... Dopamine D2 Receptors are Decreased by Addiction Cocaine Meth Alcohol Heroin Control Addicted

41 Functionally: Loss of Dopamine Transporters Normal Control Methamphetamine Abuser Dopamine Transporter Bmax/Kd Time Gait (seconds) Delayed Recall (words remembered) Volkow et al., Am. J. Psychiatry, Motor Task Loss of dopamine transporters in methamphetamine abusers may result in slowing of motor reactions. Memory Task Loss of dopamine transporters in methamphetamine abusers may result in memory impairment.

42 Drug Mechanism of Action: Direct action Some of the actions of drugs of abuse are due to direct action on a psychoactive receptor Example: opioid (pain medications) binding to mu or endorphin receptors Effect limited by the number of receptors present Direct action continues as long as drug is present

43 Indirect action: Mechanisms Alcohol as an example: Binds to receptors GABA A, NMDA, endorphin Activates receptor-coupled adenyl cyclase systems. Downstream effects on dopamine from above systems In high doses affects membrane lipid

44 Withdrawal from alcohol and drugs Tolerance: a physiologic adaptation of the organism to the presence of a drug. Upon abrupt discontinuation of the drug, a recognizable syndrome develops Always involves autonomic disturbance Activation of thalamus Activates the Locus coeruleus LC has projections to frontal cortex, limbic cortex, and amygdala Individual feels dysphoric, depressed, angry, and irritable

45 Case example: Asian-American male age 23 Started tobacco age 13, cannabis age 15 Never liked alcohol because of flushing On weekends started snorting heroin, gradual increase to three nights/week Added crack cocaine, rapid deterioration Increasing cost led to switch to opioid pills, crack, low grade dealing Increasing availability led to escalating use Began injecting opioids/ cocaine Admitted for treatment

46 Case example: Neurotransmitter issues Depletion of dopamine Anergic, anhedonic, irritable Depletion of endorphins Poor sleep, anhedonic, decreased pain tolerance Apparent depletion of serotonin Depression, increased impulsivity

47 We Are Using Science to Develop Even Better Treatments Genetics Mechanisms Treatments

48 What Is Drug Addiction Treatment? Medication Assisted CBT MI 12 Steps Contingency management

49 All Treatments Work For Some People No One Treatment Works for All People Alan I. Leshner, Ph.D Former Director NIDA

50 How can medications help treat drug addiction? Different types of medications may be useful at different stages of treatment to help a patient stop compulsive drug use, stay in treatment, and avoid relapse.

51 Treating Withdrawal. When patients first stop abusing drugs, they can experience a variety of physical and emotional symptoms, including depression, anxiety, and other mood disorders; restlessness; and sleeplessness. Certain treatment medications are designed to reduce these symptoms, which makes it easier to stop the abuse. Staying in Treatment. Some treatment medications are used to help the brain adapt gradually to the absence of the abused drug. These medications act slowly to treat cravings and to have a calming effect on body systems. They can help patients focus on counseling and other psychotherapies related to their drug treatment. Preventing Relapse. Science has taught us that stress, cues linked to the drug experience (e.g., people, places, things, moods), and exposure to drugs is the most common triggers for relapse. Medications are being developed to interfere with these triggers to help patients sustain recovery.

52 Goals of Medication Tx in Addictions 1. Abstinence (or Reduction) 2. Treat or prevent withdrawal symptoms 3. Reduces urges/cravings 4. Diminish the high / make it less worthwhile 5. Minimize relapses time and intensity 6. Treat comorbid disorders 7. Stabilize to enhance counseling therapy

53 Medication Strategies 1. Agonist Substitute effects of drug. Produces an increase in neural activity. 2. Antagonist Block the effects of drug. Produces a decrease in neural activity 3. Deterrent Medications (aversive) 4. Reduce Drug Intake Target cravings, reinforcement

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55 Best Practice Standard! Medications Plus Psychosocial Intervention

56 Medications To Treat Addictions Alcohol: Opiates: Nicotine: Stimulants: Naltrexone, Disulfiram, Acamprosate, Topamax Naltrexone, Methadone, Buprenorphine (Suboxone, Subutex) Nicotine replacement (gum, patches, spray), bupropion (Zyban), Chantix, Acomplia None to date (3 in research)

57 Alcohol Addiction Disulfiram (Antabuse) Naltrexone (Revia, Vivitrol) Topiramate (Topamax) Acamprosate (Campral)

58 Disulfiram (Antabuse) Oldest drug treatment for alcohol dependence through blockade of aldehyde dehydrogenase Limited double-blind, placebo controlled studies New role: treatment of cocaine dependence by increasing cocaine-induced dysphoria Challenges: Toxicity Adherence

59 Antabuse (disulfiram) When patients are taking Antabuse, they experience great discomfort should they drink. The medicine works by inhibiting liver enzyme - aldehyde dehydrogenase, thereby increasing acetaldehyde. A recent study has demonstrated that disulfiram is also effective in reducing cocaine abuse. See Carrol KM.et al. Efficacy of Disulfiram and Cognitive Behavior Therapy in Cocaine-Dependent Outpatients: A Randomized Placebo-Controlled Trial. Archives of Gen Psych. 61: , 2004.

60 Disulfiram

61 Disulfiram (Antabuse ) Contraindications: Concomitant use of alcohol, heart diseases. Precautions: High impulsivity likely to drink while using it; psychosis (current or history), diabetes, epilepsy, liver disease, hypothyroidism, renal impairment, rubber contact dermatitis. Common side effects: metaliic aftertaste; dermatitis. Oral dose 250 mg/daily (range 125 to 500 mg) Follow-up: monitor liver function tests periodically. Antabuse ; Florham Park, NJ: Odyssey Pharmaceuticals, Inc.

62 Naltrexone (for Alcohol) 3 kinds of effects: 1)Anti-craving, 2) increased number of days abstinence, and 3) reduced number of days of drinking if a relapse does occur. Dulls alcohol s rewarding effects and results in longer periods of abstinence compared to patients on placebo. Anton, RF. Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence. JAMA. 295(17): Vivitrol ( a newer long-lasting naltrexone product). A monthly injection. Garbutt, J., et al. Efficacy and tolerability of Long-Acting Injectable Naltrexone for Alcohol Dependence: A Randomized Controlled Trial. JAMA. 293(13):

63 Naltrexone Alcohol produces its positive reinforcing effects through the opioid system Pure opioid antagonist Effective in treatment of alcoholism and opiate addiction Blocks cue-triggered craving Blocks the high and increases the negatives

64 How Is An Opiate Antagonist Also an Alcohol Anti Craving Medicine? THPs (tetrahydropapaverolines) Etoh Opioids Increase THPs = decrease in endorphins. Low level of endorphins = increased in receptor sites Increased receptor sites = craving behavior THPs and the Robin Meyer Study Myers, RD. Alcohol drinking: abnormal intake caused by tetrahydropapaveroline in brain. Science, Vol 196, Issue 4289,

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66 Naltrexone Naltrexone can decrease: The percentage of days spent drinking The amount of alcohol consumed on a drinking occasion Relapse to excessive and destructive drinking

67 Naltrexone Oral (Revia) and an injectable depot formulation (Vivitrol) Primary drug-drug interaction: Opioids Challenges Side effects (nausea in small percentage) Adherence Physician awareness and knowledge Integration with psychosocial treatment Optimal duration of treatment unknown

68 Naltrexone (ReVia ) Contraindications: Currently using opioids or in acute opioid withdrawal; Precautions: Other hepatic disease; renal impairment; history of suicide attempts. Common side effects: Nausea; abdominal pain; constipation; dizziness; headache; anxiety; fatigue Oral dose: 50 mg daily Follow-up: Monitor liver function tests periodically ReVia ; Wilmington, De: DuPont Pharmaceuticals.

69 Research shows that Topiramate : reduces drinking days and produces anti-craving responses Topiramate (Topamax) An anti-epileptic drug that works through GABA and glutamate systems. Blocks sodium channels, augments GABA, and inhibits glutamate.

70 Topiramate Anti-convulsant: glutamate antagonist and GABA (inhibitory) promoter Anti-craving agent for alcohol, cocaine and cannabis Increases alcohol abstinence rates by 50% Patients reports enhanced sense of well-being

71 Topiramate Decreases both the acute reinforcing effects of alcohol and cocaine and the longer term sensitization that leads to craving and relapse Challenges: Metabolic

72 Acamprosate (Campral) No direct effect on acute alcohol withdrawal but shows anti-craving properties in newly abstinent alcoholics. Chemical structure similar to neurotransmitters GABA and glutamate. As a GABA agonist, acts as a stabilizer to erratic system in early recovery Many studies showing an increase number of abstinence days compared to placebo.

73 Acamprosate (Campral) NMDA receptor antagonist Glutamatergic (excitatory) system Blocks craving: particularly context and stress-related cues Use in detoxified patients engaged in active psychosocial treatment Doubles abstinence rates Additive with naltrexone (Combine Study)

74 Acamprosate No liver metabolism or toxicity No drug-drug interactions Greater rates of complete abstinence Longer times to first drink Challenge: three time a day dosing

75 Acamprosate (Campral ) Contraindications: Severe renal impairment Side effects: Diarrhea; flatulence; nausea; abdominal pain; headache; back pain; infection; flu syndrome; chills; somnolence; decreased libido; amnesia; confusion Oral dose: 666 mg (two 333-mg tablets) three times daily Campral ; St. Louis, Mo: Forest Pharmaceuticals, Inc.

76 Opiate Addiction 1. Methadone 2. Buprenorphine 3. Naltrexone

77 Methadone best abstinence rates: 70-80% blocks craving blocks euphoria normalization of limbic function return to functionality

78 Methadone: therapeutic effects blocking effect on euphoria with administration of heroin blocking effect on withdrawal. relieves craving stabilization of brain function: decrease in HPA stress state improvement in mood and behavioral stability

79 Methadone death rates of patients not on mmt three times those on MMT reduction in HIV seroconversion from 50% to 2.5% of IVDU with MMT 95% prevalence hepatitis C in chronic IVDU

80 HIV CONVERSION IN TREATMENT 25% 20% 15% 10% Tx Status 5% 0% In Tx (N=95) Partial Tx (N=45) No Tx (N=55) Source: Metzger, D. et. al 18 month HIV conversion by treatment retention. J of AIDS 6:1993. p.1053

81 Buprenorphine A partial agonist/antagonist drug Ceiling effect and safety Displaced other opiates: withdrawal on induction Schedule 3 (methadone is 2) One form combined with naloxone (Suboxone) Office based use available Sublingual tablet in 2mg and 8 mg strengths

82 Buprenorphine/naloxone: Suboxone Partial agonist + pure antagonist t/2 >24 hours Blocks craving and euphoria Less physical dependence Combo decreases diversion risk

83 Suboxone: therapeutic effects Blocking effect on euphoria with administration of opiates Blocking effect on withdrawal. Relieves craving Stabilization of brain function: Decrease in HPA stress state Improvement in mood and behavioral stability

84 Buprenorphine s Ceiling Effect Full Agonist (e.g. methadone) % Mu Receptor Intrinsic Activity Partial Agonist (e.g. buprenorphine) Ceiling Effect 10 0 no drug low dose Antagonist (e.g. naloxone) high dose DRUG DOSE

85 Naltrexone (for Opiates) A complete opioid receptor site blocker. No receptor Site availability - no opioid action. (antagonist) Provides no narcotic effect. Is not an anti-craving medication. Clinical trials for efficacy show patients who received naltrexone were twice as successful in remaining abstinent and avoiding relapse as patients who received placebo

86 Nicotine Dependence 1. Gums 2. Lozenge 3. Inhalers 4. Nasal Spray 5. Patch 6. Bupropion (Zyban) 7. Varenicline (Chantix)

87 Nicotine Dependence Nicotine Replacement Therapies Increase quit rates 1.5 2x Meds + therapy = 15-30% quit rate Duration of therapy 8-12 weeks Effects of meds wane over time

88 Chantix and Zyban Inhaled tobacco produces nicotine that attaches to receptors in brain acetylcholine system which also triggers dopamine release. Chantix blocks nicotinic receptor sites. Thus, relapse to smoking will not stimulate receptors in the way it used to. Both Chantix and Zyban stimulate low levels of dopamine release to help ease the dysphoria associated with nicotine withdrawal.

89 Zyban - bupropion antidepressant decreases craving decreases withdrawal can increase abstinence rates side effects: GI, anxiety, headaches

90 On the Horizon: Other Medications to Treat Addictions

91 On the horizon: Other Medications to Treat Addictions Baclofen: GABA agonist Reduces cocaine self-administration in animal models Reduces cue-induced craving in humans May be most effective in heaviest cocaine users Ondansetron Early onset drinking Blocks serotonin receptors and then to decrease in dopamine release

92 On the horizon Modafinil: decreases cocaine high and increases abstinence rates May also improve executive function in ADHD patients Cocaine vaccine GVG (Vigabatrin) Tiagabine: GABA uptake inhibitor Anti-seizure medication Positive study in reducing cocaine use in randomized, placebo-controlled study in methadone patients

93 Novel Approaches Vaccinations Bayor College of Medicine working on the first vaccine for cocaine addiction. The vaccine stimulates the immune system to deactivate cocaine molecules before they reach the brain. To help the immune system distinguish cocaine, scientists have attached inactivated cocaine to inactive proteins. In response, the immune system makes antibodies that bind to cocaine and prevent it from reaching the brain, thus rendering it inactive.

94 Stimulant Addiction 1. Cocaine Disulfiram, topiramate 2. Amphetamines - Vigabatrin Reference Sources: J Clin Psych 2004:65-:84-86 Gabapentin Reduces Cocaine use Among Addicts From A Community Sample. J Clin Psych. 2003:64: Randomized Placebo-Controlled trial for Cocaine Dependence. Shoptaw, S. Kampman KM. A pilot trial of topiramate for the treatment of cocaine dependence. Drug and Alcohol Dependence. 2004; 75(3): Carrol KM.et al. Efficacy of Disulfiram and Cognitive Behavior Therapy in Cocaine- Dependent Outpatients: A Randomized Placebo-Controlled Trial. Archives of Gen Psych. 61: , 2004.

95 Stimulant Addiction A strong candidate medication so far: Vigabatrin (gamma-vinyl-gaba) (Sabril) An anti-craving medication for methamphetamine addiction. Also blocks the euphoria induced by methamphetamine s strong dopamine actions. A GABA agonist and dopamine antagonist drug Also approved as an anti-seizure drug and for infantile spasms.

96 Cannabinoid Addiction No RCT trials Anecdotes with fluoxetine, nefazadone. Interesting: bupropion actually worsened cannabinoid withdrawal symptoms! In the Pipeline: CB1 Antagonists as anti-craving medications

97 Conclusions Addiction is a treatable brain disease Research is edifying the biological mechanisms involved

98 Conclusions Increased understanding of neurobiology is allowing for the development of effective, targeted pharmacotherapies State of the art, evidenced-based treatment must combine behavioral and medical therapies to produce the best outcomes.

99 Medications are an important element of treatment for many patients, especially when combined with counseling and other Behavioral treatments. From Principles of Drug Addiction Treatment: A Research- Based Guide (second edition). NIDA. April, 2009.

100 Paths to recovery are unique and achieving sustained recovery requires the addicted person to be motivated to change their readiness to be engaged in a process of change. Medications may make it easier for individuals to transition from stage to stage during recovery. Pharmacotherapy offers new hope especially to those who have been discouraged about initiating change. Carol DiClemete, Ph.D. Integrating Pharmacologic and Psychosocial Approaches. ASAM

101 A recent study of acamprosate found that patients who are motivated to become abstinent had significantly more abstinence days when they received acamprosate compared with motivated patients receiving placebo. Mason BJ, Goodman AM, et al. Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res. 2006:40(5):

102 Challenges: Coverage Limited private insurance coverage for anti-addiction medication State did not include a category for antiaddiction medication for new Medi-Cal benefits Parity Act?

103 Challenges: Medications Bias Myths and Misunderstanding still pervasive: Total abstinence from all mind altering substances is the goal of treatment Recovery not possible if taking meds Meds conflicts with AA and NA philosophy and principles of recovery And, despite the evidence, many programs still maintain anti-medication policies!

104 Targeting Future Treatments Developing improved treatments for addiction is becoming easier because of continued scientific research. Every new discovery about the neurobiology of addiction allows for a potential new treatment approaches. The more we understand about the biopsychosocial aspects of addiction, better and more effective treatments can be developed.

105 Thank you! And, be sure to visit my website at: