WHY DO MY PATIENTS KEEP RELAPSING? The Neurobiology of Addiction

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1 WHY DO MY PATIENTS KEEP RELAPSING? The Neurobiology of Addiction Kevin Wandler, M.D., Dip ABAM, F.iaedp Chief Medical Officer Advanced Recovery Systems

2 Goals and Objectives After this presentation the attendee will: Understand at least 3 neurotransmitters in the brain and how they relate to addiction, mood and anxiety. Be able to describe the areas of the brain involved in reward, happiness and memory. Describe medication interventions that can contribute to alcohol and opioid use disorder recovery and how they work.

3 New York Times September 2017 Drug overdoses killed ~64,000 people in the US last year ~52,400 people died from drug overdoses

6 Drug-Overdose Deaths Involving Opioids, by Type of Opioid, US

7 Age-Adjusted Rates of Death Related to Prescription Opioids and Heroin Drug Poisoning in US Compton WM et al. N Engl J Med 2016, 374:

8 Drug Overdose Deaths by Major Drug Type, US

10 Dr William Oshler Father of Modern Medicine?? The good physician treats the disease, the great physician treats the patient who has the disease The first duties of the physician is to educate the masses not to take medicine If there are more than one treatment for an illness, then most are insufficient

11 YOUR BRAIN ON DRUGS--1980

12 YOUR BRAIN ON DRUGS 2017!!

13 The Neurobiology of Addiction

14 ASAM Definition Short Definition of Addiction: ADDICTION is a primary, CHRONIC DISEASE of BRAIN reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors.

15 ASAM Definition Short Definition of Addiction (cont.): Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. WITHOUT TREATMENT or engagement in recovery activities, ADDICTION is progressive and CAN RESULT IN disability or premature DEATH.

16 DSM-V Definition: Substance Use Disorders 1. Using larger amounts or over a longer period of time than intended. 2. Persistent desire or unsuccessful efforts to cut down or control 3. Great deal of time spent in obtaining, using, and recovering from 4. Craving or a strong desire or urge to use 5. Recurrent use resulting in failure to fulfill major role obligations 6. Continued use despite persistent or recurrent social or interpersonal problems caused or exacerbated by use 7. Important social, occupational, or recreational activities are given up or reduced because of use 8. Recurrent use in physically hazardous situations 9. Continued use despite knowledge of having a persistent or recurrent physical or psychological problems that is caused or exacerbated by use. 10. Tolerance defined by need for increased amounts to achieve desired effect or markedly diminished effect with continued use of the same amount 11. Withdrawal either with withdrawal symptoms, or continued use to relieve or avoid withdrawal

17 DSM-V Definition: Substance Use Disorder Mild: Presence of 2-3 symptoms Moderate: Presence of 4-5 symptoms Severe: Presence of 6 or more symptoms

18 DSM-V Definition: Substance Use Disorders If the narcotics are prescribed, example for chronic pain, then we do not consider these two items even when present. 1. Tolerance defined by need for increased amounts to achieve desired effect or markedly diminished effect with continued use of the same amount 2. Withdrawal either with withdrawal symptoms, or continued use to relieve or avoid withdrawal

JAMA, 284:1689-1695, 2000 Relapse does not deem treatment a failure!

19 JAMA, 284: , 2000 Relapse does not deem treatment a failure! Successful treatment for Diabetes, Hypertension and Addiction requires continual evaluation and modification, reinstatement of treatment (as appropriate) for the treatment plan.

20 QUESTION OF THE DAY: We know that Addictions are chronic illnesses. Why is Addiction treated differently than hypertension, diabetes and asthma?

21 Circuits Involved In Drug Abuse and Addiction Inhibitory/ Control PFC prefrontal cortex ACG anterior cingulate gyrus; Motivation/ Drive OFC orbitofrontal cortex SCC subcallosal cortex Reward/ Saliency NAc nucleus accumbens VP ventral pallidum; Memory/ Learning Hipp hippocampus; Amyg amygdala All of these brain regions must be considered in developing strategies to effectively treat addiction

22 Normal Pleasure Response nucleus accumbens YUM!! VTR substantia nigra Increased Dopamine Release locus coeruleus Pleasure/Motivation Response

23 Brain Reward Pathway substantia nigra locus ceruleus Psychoactive Addictive Drugs Act on this Pathway

24 Brain Reward Pathway Wow!!! substantia nigra locus ceruleus Drug Dopamine surge!!!

25 Brain Reward Pathway Wow!!! substantia nigra locus ceruleus Drug Dopamine surge!!! Dopamine, Serotonin, Norepinephrine

26 Reward Pathway Drugs act on the Brain Reward Pathway The Wow!!! is a big reason people take drugs but other things also happen

27 Reward Pathway Areas Emotional & behavioral learning Control of body movement Early learning and memory processing Attention states and automatic function

29 Continued Drug Use Spine Development Wow!!! Structural changes locus ceruleus substantia nigra Drug

30 Continued Drug Use Wow!!! substantia nigra locus ceruleus A molecular switch is thrown in the brain Sensitization, Craving and Relapse Loss of control over drug use Compulsive drug seeking behavior

31 Natural Rewards and Dopamine Levels Adapted from: DiChiara et at, Neuroscience, 1999 Adapted from Fiorino and Phillips, J Neuroscience, 1997

32 Effects of Drugs on Dopamine Levels Adapted from: DiChiara and Imperato, Proceedings of the National Academy of Sciences USA, 1988, courtesy of NoraD Volkow, MD

33 Effects of Amphetamines on Dopamine Levels Adapted from: DiChiara and Imperato, Proceedings of the National Academy of Sciences USA, 1988, courtesy of NoraD Volkow, MD

34 Dopamine vs. Serotonin Pleasure(WOW!!!) vs. Happiness(YUM!) Dopamine produces a feeling of pleasure Serotonin produces a feeling of well being Difference between pleasure and happiness (short lived vs big picture) Happiness--Developing skills, interest, relationships, meaning ( getting a life )

35 Pleasure Scale Dysphoria Anhedonia Bored NORMAL RANGE Interested Pleasure Euphoria I feel negative I feel good

NEOCORTEX LIMBIC SYSTEM REPTILIAN COMPLEX Limbic and Reptilian (beast) Neocortex (modern man) 1. Survival 2. Emotions 3. Autonomic functions 4. Reward and appetite 5. Reliable and rigid 6.

36 NEOCORTEX LIMBIC SYSTEM REPTILIAN COMPLEX Limbic and Reptilian (beast) Neocortex (modern man) 1. Survival 2. Emotions 3. Autonomic functions 4. Reward and appetite 5. Reliable and rigid 6. Only able to execute yes 7. Always on Hijacked Brain!! 1. Reasoning and learning 2. Consciousness 3. Motor and sensory 4. Memory 5. Language 6. Abstract thought 7. Flexible and plastic 8. Able to execute both yes and no 9. Both on and off

Circuits Involved In Drug Abuse and Addiction Inhibitory/ Control PFC prefrontal cortex ACG anterior cingulate gyrus; Motivation/ Drive OFC orbitofrontal cortex SCC subcallosal cortex Reward/

37 Circuits Involved In Drug Abuse and Addiction Inhibitory/ Control PFC prefrontal cortex ACG anterior cingulate gyrus; Motivation/ Drive OFC orbitofrontal cortex SCC subcallosal cortex Reward/ Saliency NAc nucleus accumbens VP ventral pallidum; Memory/ Learning Hipp hippocampus; Amyg amygdala All of these brain regions must be considered in developing strategies to effectively treat addiction

38 Inside the brain: Brian cells called neurons send chemical messages Neurotransmitter - chemical messenger which are electrical signals. Synapse - Space between neurons where neurotransmitters travel Millions of electrical signals cause brain waves (measured by EEG)

39 Do all drugs of abuse work the same? No / Yes / Maybe? Each substance mimics a particular neurotransmitter Each of these trigger a cascade/ series of chemical events that results in activation of the VTA and NAc Most likely, if the event did not end up in the VTA/NAc, it wouldn t be addicting

40 Receptors/ Neurotransmitters: Excitatory vs. Inhibitory Excitatory: Tends to increase action potential firing. Inhibitory: Tends to decrease or block action potentials. Receptors are classified as excitatory or inhibitory. Some neurotransmitters can be classified this way, but many are both. 2013, CC-BY, by Zak Fallows,

41 Agonist vs. Antagonist Agonist: Binds to a receptor and sends the normal signal (either excitatory or inhibitory). Antagonist: Binds to a receptor and does not send a signal. Antagonists block receptors and prevent agonist binding. 2013, CC-BY, by Zak Fallows,

42 One Synapse Presynaptic cell Postsynaptic cell 2013, CC-BY, by Zak Fallows,

43 One Synapse Action potential Postsynaptic cell 2013, CC-BY, by Zak Fallows,

44 One Synapse Action potential Receptor binding 2013, CC-BY, by Zak Fallows,

45 Agonist vs. Antagonist Neurotransmitter Agonist (drug) Antagonist (drug) 2013, CC-BY, by Zak Fallows,

46 2 2 Table Quiz Excitatory receptor: Inhibitory receptor: Agonist: More Signal Less Signal Antagonist: Less Signal More Signal , CC-BY, by Zak Fallows,

47 Agonist: Excitatory receptor: Drugs here may be stimulants, promoting wakefulness, alertness, and fast thinking, but also seizures. Inhibitory receptor: Drugs here may be sedatives, promoting relaxation and sleep. Antagonist: May be sedatives. May be stimulants. 2013, CC-BY, by Zak Fallows,

48 Agonist: Excitatory receptor: Stimulants of this type: Nicotine Psychedelics (LSD, psilocybin mushrooms, mescaline) Inhibitory receptor: Sedatives of this type: Ethanol (alcohol) Barbiturates Benzodiazepines (Valium, Klonopin, Xanax, Ativan) Antagonist: Sedatives of this type: Diphenydramine (Benadryl) Antipsychotics (Haldol, Thorazine, Seroquel) Caffeine 2013, CC-BY, by Zak Fallows,

49 Neuro- Transmitters Dopamine (pleasure, learning) Serotonin (emotional stability) Norepinephrine (behavioral & physical activity) Glutamate GABA Normal Functions Pleasure (hunger/thirst/sexual), attention, organization of thought, muscle control and motor function Regulates mood, emotions, thought processes, sleep, and appetite Energy, motivation, attention span, alertness, pleasure, assertiveness, confidence, heart rate, blood pressure, etc. Excitatory Inhibitory

50 How Drugs of Abuse Effect Dopamine Inhibit Reuptake of Dopamine (stimulate release of Dopamine as well to a lesser extent) Cocaine Stimulate Dopamine transporter (release of Dopamine) Amphetamine, Methamphetamine Modulate firing of Dopamine releasing cells by actions on GABA and Glutamate Nicotine, alcohol, opiates, cannabis Cocaine, Amphetamine, Methamphetamine

51 When COCAINE is present: COCAINE blocks the reuptake of dopamine (And to a lesser extent releases DA) Synapse is flooded with dopamine, causing feeling of euphoria When AMPHETAMINES ARE present: AMPHETAMINES release dopamine Synapse is flooded with dopamine, causing feeling of euphoria

(enhance DA release) Licit use: schedule II (ADHD, narcolepsy, weight loss) Amphetamine Dextroamphetamine Methamphetamine

52 Stimulants: Cocaine & Amphetamines Cocaine (blocks DA reuptake) Licit use: schedule II (topical anesthetic) Illicit use: Salt (cocaine-hcl): powder Water-soluble Incinerates when heated Snorted or injected Base (freebase or crack ) Water-insoluble Amphetamines (enhance DA release) Licit use: schedule II (ADHD, narcolepsy, weight loss) Amphetamine Dextroamphetamine Methamphetamine Methylphenidate Dexmethylphenidate Illicit use: Abuse of above Vaporizes when heated Methamphetamine epidemic Able to be inhaled (smoked) Easy manufacture

53 VTA Amphetamines Opiates THC PCP Ketamine Nicotine Nucleus accumbens (NAc) Alcohol benzodiazepines barbiturates Dopamine Pathways

54 Stimulants- Withdrawal Dopamine Hypothesis Stimulants cause increased release and/or delayed reuptake of DA Chronic use downregulation of DA receptors An example of downregulation is the cellular decrease in the number of receptors to a drug, such as a neurotransmitter, which reduces the cell's sensitivity to the molecule. Relative depletion of dopamine is thought to be the etiology of stimulant withdrawal. Result is profound depression (NO PLEASURE)!!

55 Dopamine D2 Receptors are Lower in Addiction Down regulation!! Cocaine Meth DA DA DA DA DA DA DA DA DA DA DA DA Reward Circuits Non-Drug Abuser DA DA Alcohol DA DA DA DA Heroin control addicted Reward Circuits Drug Abuser Adapted from Volkow et al., Neurobiology of Learning and Memory 78: , 2002.

56 Stimulants Treatment of Withdrawal Supportive- rest, eat, sleep in safe environment Medications: Anxiety: rapid acting, intermediate to long-half life benzodiazepines (lorazepam, diazepam) Depression: may persist long enough to warrant treatment with SSRI Psychosis/mania: may require treatment Cocaine-induced psychosis usually self-limited Methamphetamine psychosis can be longer lasting and require medication (think atipsychotics)

57 Long-term Damage? Long-term drug use results in loss of dopamine receptors Users report constant depression, sadness, feelings of hopelessness Need more and more of the drug just to feel normal Potential for high is gone

58 Meth Brain Damage

59 DopAmine (DA) The Salience Neurotransmitter Rewards eating, sex Increases alertness, happiness, motivation

60 Opioids Relieve pain, anxiety Induce sleep Important for pleasure Slow the digestive tract

Perco-) Oxymorphone Methadone (Dolophine) Propoxyphene (Darv-) Illicit Agonists Heroin Opium Mixed Agonist/Antagonists

61 Opioids Licit Agonists Morphine (MS Contin, Kadian, Avinza, Oramorph, MSIR) Codeine (Tylenol #2,3,4) Fentanyl (Duragesic) Hydromorphone (Dilaudid) Hydrocodone (Lor-, Vico-) Levorphanol (Levo-Dromoran) Meperidine (Demerol) Oxycodone (OxyContin, Roxi-, Perco-) Oxymorphone Methadone (Dolophine) Propoxyphene (Darv-) Illicit Agonists Heroin Opium Mixed Agonist/Antagonists Buprenorphine (Buprenex, Suboxone) Pentazocine (Talwin) Butorphanol (Stadol) Nalbuphine (Nubain) Antagonists Naloxone (mostly IV) Naltrexone (mostly PO)

62 GABA GABA is the primary inhibitory neurotransmitter GABA stands for Gamma-AminoButyric Acid Sleep, muscle relaxation, anxiety relief, memory impairment

63 GABA Agonists: Sedatives GABA agonists are almost always sedatives. Here are some famous GABA agonists: Ethanol (alcohol) Note that ethanol has other mechanisms, it does not act solely through GABA. Barbiturates Examples include phenobarbital (Luminal ) and pentobarbital (Nembutal ). Benzodiazepines Examples include diazepam (Valium ), clonazepam (Klonopin ), alprazolam (Xanax ), and lorazepam (Ativan ).

64 Serotonin (5-HT) The Satiety Neurotransmitter 5-HT stands for 5-HydroxyTryptamine Feelings of fullness, contentment Relieves depression

65 Serotonin Agonists Selective Agents Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression. The triptans for the treatment of acute migraine headaches. Imitrex, Maxalt, Zomig. Trazodone is used generally as a sleeping agent. Non-selective agonists Ergotamine used for migraine attacks. LSD

66 NorepinEphrine (NE) The Fight-or-Flight Neurotransmitter Also called noradrenaline Excitement, fear, alertness As a hormone, it increases heart rate, blood pressure, and blood sugar

67 AcetylCholine (ACh) Nicotine is an agonist of the nicotinic cholinergic receptor Curare blocks this receptor (Used in anesthesia and is quickly reversible) Chantix is a partial agonist of this ACh receptor Bupropion (Wellburtrin and Zyban are nicotinic cholinergic receptor and increases release of Dopamine

68 Incentive Salience Wants/ Cravings Incentive salience is a type of motivation created in the brain because it has developed an association between a certain stimuli and reward. I want and I want it now!! In the case of addiction this stimuli will be whatever drug the individual is using. Incentive salience is a far greater incentive than merely liking something.

69 Incentive Salience Wants/ Cravings Previously neutral stimuli are assigned incentive salience. Smelling cigarette smoke can trigger a craving for nicotine Drug paraphernalia now trigger drug craving. Driving in or near a neighborhood where drugs were purchased triggers craving Thus, if a person's addiction subsides and the individual subsequently encounters one of these secondary reinforcers, a craving for that drug may reappear.

70 Non-Addicted Brain Addicted Brain Control Control CG STOP Saliency NAc Drive OFC Saliency Drive GO Memory Amygdala Memory Adapted from: Volkow et al., J Clin Invest 111(10): , 2003.

71 Medications for Relapse Prevention Non-Addicted Brain Control Strengthen reinforcing effects of non-drug reinforcers Strengthen inhibitory control Saliency Drive Drive Memory STOP GO Strengthen prefrontalstriatal communication Interfere with conditioned memories (craving) Counteract stress responses that lead to relapse Adapted from: Volkow et al., J Clin Invest 111(10): , 2003.

72 Many of my patients just want a pill.. Sorry, there are no magic pills.

73 Medications for Recovery from Substances Alcohol: (Data Conflicting on efficacy for AUD) Naltrexone(ReVia)/ Depot Naltrexone (Vivitrol) Acamprosate (Campral) Disulfiram (Antabuse) Naltrexone (ReVia) Opiates: (Does patient need/ want to be off opiates?) Naltrexone(ReVia)/ Depot Naltrexone (Vivitrol) Buprenorphine/ Subutex (Depot Buprenorphine 2018) Buprenorphine + Naloxone/ Suboxone Methadone Nicotine: (Great evidence of helping!!) Varenicline(Chantix) Buproprion (Wellbutrin/ Zyban Nicotine-gum, patch, lozenge, inhaler

80 Opioid Full vs. Partial Agonist Levels

82 Sublocade Buprenorphine Like Probuphine Subdermal Implant, for individuals who have achieved and sustained a low to moderate dose of buprenorphine ie not more than 8 mg of buprenorphine daily. Once a month injection of Buprenorphine 300mg month one 300mg month two Then 100mg monthly

83 Thank you for all you do!! Questions? Answers!

84 Kevin Wandler, MD Chief Medical Officer

85 Resources Advanced Recovery Systems: National Institute on Drug Abuse (NIDA): Substance Abuse and Mental Health Services Administration (SAMHSA) American Society of Addiction Medicine (ASAM)

86 Resources Advanced Recovery Systems: Academy of Eating Disorders: Binge Eating Disorders Association: International Association of Eating Disorder Professionals: National Eating Disorders Association:

I Gave Up Opiates and Alcohol, Now I m Addicted To Food?

I Gave Up Opiates and Alcohol, The Neuroscience of Substance Use Disorders and Food Addiction. Chief Medical Officer Advanced Recovery Systems Chief Medical Officer KWandler@AdvancedRecoverySystems.com