The Neurobiology of Addiction & the Pharmacology of Suboxone Presented by: Alan P. Agins, Ph.D. President, PRN Associates, Ltd Continuing Medical Education Tucson, AZ

Addiction (ASAM definition) 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.

Addiction (ASAM definition) 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.

Three “C’s” of Addiction Control Early social / recreational use Eventual loss of control Cognitive distortions (“denial”) Compulsion Drug-seeking activities Continued use despite adverse consequences Chronicity Natural history of multiple relapses preceding stable recovery Possible relapse after years of sobriety Slide Source: Peter Banys, M.D., Assoc. Clinical Prof. of Psychiatry, University of California at San Francisco, VA Medical Center, San Francisco.

Drug Addiction: A Complex Disorder Physiological Historical Genetics Disease states Gender Age Drugs - Past experience - Expectation - Memory Brain Mechanisms Behavior Environment Social interactions - Stress Conditioned stimuli 5

It all starts in the VTA with Dopamine

Dopamine and Reward Behavior which stimulates the release of dopamine in the nucleus accumbens is associated with the sensation of pleasure. People seek out experiences which provide pleasure and reward. These natural rewards act upon the dopamine reward pathway. The pleasure that is experienced when there is an increase in dopamine in the nucleus accumbens is a powerful motivator for behavior. Activities which are naturally reinforcing, like having sex or eating food, have been demonstrated to activate this dopamine reward pathway. ----------------------------------- Martel P, Fantino M. Mesolimbic dopaminergic system activity as a function of food reward: a microdialysis study. Pharmacol Biochem Behav. 1996;53:221-6. Fiorino DF, Coury A, Phillips AG. Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats. J. Neurosci. 1997;17:4849-55. Image: NIA.NIH.gov

Natural Rewards and DA Sex Food DA Concentration in NAc Copulation Initiated Introduce Food Introduce Female Time Time Learning in relation to natural rewards stimulates LTP – imparts survival of the individual / survival of the species

Why Do People Take Certain Drugs in the First Place? To feel good To have novel feelings, sensations, experiences of altered states of consciousness and to share them To feel better To lessen anxiety, worries, fears, depression, hopelessness Research has shown that people generally take drugs to either feel good (sensation seekers, or anyone wanting to experiment with feeling high or feeling different) or to feel better (self-medicators, or individuals who take drugs in an attempt to cope with difficult problems or situations, including stress, trauma, and symptoms of mental disorders). 9

Risk Factors for Addiction Genetics neurophysiology, receptors, transporters, etc Age of substance abuse (younger worse) Childhood trauma (emotional, violence, sexual) Comorbid psychiatric disorders: Most prevalent Mood disorders Anxiety disorders Personality disorders Psychotic disorders Slide Source: “Alcohol and Other Drugs and the Courts” curriculum, Judge Peggy Fulton Hora, Alameda County Superior Court, Hayward, CA and Peter Banys, M.D., Assoc. Clinical Prof. of Psychiatry, University of California at San Francisco, VA Medical Center, San Francisco.

Circuits involved in Addiction Prefrontal cortex and the anterior cingulate gyrus provide inhibitory control and emotional regulation Orbitofrontal cortex is involved in decision‐making and determining the expected rewards and punishments of an action Nucleus accumbens assesses reward and salience Amygdala and hippocampus involved in forming memories of the stimulus/reward relationship Higher Cortical Processes Limbic System: Basal emotion, memory and arousal “Survival”

The Road to Addiction In the beginning, the nucleus accumbens in the ventral striatum and its functional interaction with the basolateral amygdala are responsible for developing voluntary drug-seeking behavior The NA plays an important role in dopamine-dependent reward circuits that turn motivation into action, while the BLA provides positive consolidation of drug-associated memories with environmental cues

The Road to Addiction All addictive drugs release dopamine via different mechanisms, which enables the individual to flag an environmental stimulus or event as important to survival

Neurotransmitters implicated in the Motivational Effects of Drugs of Abuse Positive Hedonic Effects Dopamine Endorphins Serotonin GABA KoobG/NP/wor2/030104jh 14

Natural Reward vs. Drug-Induced Reward Drugs of abuse also have some effects on the dopamine pathway. Many drugs of abuse increase the transmission of dopamine in the nucleus accumbens. The magnitude of dopamine transmission associated with consuming some drugs is estimated to be as much as 3 to 5 times greater than the transmission of dopamine derived from natural rewards. Drugs of abuse may be preferred over natural rewards because of the instant and intense pleasure associated with high levels of dopamine transmission. ----------------------------------- Volkow ND, Wang GJ, Fischman MW, et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature. 1997;386:827-30. Volkow ND, Fowler JS, Wang, GJ. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav. Pharmacol. 2002;13:355-66. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci. 1988;85:5274-8. Food, Sex, Excitement Addictive Drugs

Effects of Drugs on Dopamine Release Cocaine Amphetamine % Increase in Nac DA Concentration Nicotine Alcohol Time after Administration

The Road to Addiction Continued exposure to opioids stimulates neuroplastic changes in the striatum, with control passing to the anterior dorsolateral striatum (decision region). This functional shift in neural control, from habitual to compulsive drug-seeking behaviour, is greatly influenced by drug-associated Pavlovian conditioned stimuli that induce drug-cravings and even relapses after abstinence

Natural Reward Drug The reduction of dopamine availability is a change in brain chemistry that can have significant implications for clients in early recovery and who are facing the daily challenge of making choices to avoid substance use. Clients in early recovery sometimes become discouraged when they find that non-substance reinforcers do not provide the level of pleasure or reward that they did before substance use became a problem. This is, in part, a direct result of changes to the dopamine reward pathway. Even when clients are determined to not use and to make greater efforts to return to activities in life that provide natural reward and pleasure, they may find themselves being drawn back to substance use if the healthy activities are not experienced as pleasurable. ----------------------------------- Fiorino DF, Phillips AG. Facilitation of sexual behavior and enhanced dopamine efflux in the nucleus accumbens of male rats after D-amphetamine behavioral sensitization. J Neurosci. 1999;19:456-63. Di Chiara G, Tanda G, Cadoni C, et al. Homologies and differences in the action of drugs of abuse and a conventional reinforcer (food) on dopamine transmission: an interpretive framework of the mechanism of drug dependence. Adv Pharmacol. 1998;42:983-7 Repeated release of DA will continually promote new learning (long-term potentiation – LTP) - therefore consolidating drug-seeking and drug-taking behaviors more rapidly and to a greater degree than physiological rewards

Down-Regulation of Dopamine Acute Substance-Induced Chronic Substance Use Normal Continual activation of the pathway alters the availability of DA Reduction and/or down-regulation in dopamine availability has a blunting effect on the natural reward circuit Leads to neuroplastic changes at higher cortical sites One of the changes seen in the brain with repeated use of substances is a reduction in the transmission of dopamine in response to natural rewards. Through a reduction in the number of dopamine receptor sites and a decrease in the production of dopamine, there is less availability of dopamine for transmission when a natural reinforcer is encountered. The reduction, or down-regulation, in dopamine availability has a blunting effect on the natural reward circuit. With limited dopamine availability, clients may not experience strong feelings of pleasure from engaging in everyday natural-reward activities, like eating and having sex. ----------------------------------- Balldin JI, Berggren UC, Lindstedt G. Neuroendocrine evidence for reduced dopamine receptor sensitivity in alcoholism. Alcoholism, Clinical and Experimental Research. 1992;16:71-4. Volkow ND, Wang GJ, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:830-3. Volkow ND, Wang GJ, Fowler JS, et al. Cocaine abusers show a blunted response to alcohol intoxication in limbic brain regions. Life Sciences. 2000;66:PL161-7.

Neurotransmitters implicated in the Motivational Effects of Drugs of Abuse Negative Hedonic Effects of Withdrawal Dopamine Endorphins Pain Serotonin Dysphoria GABA Anxiety Glutamate Craving KoobG/NP/wor2/030104jh 20

Neuroplastic Changes in Addiction

The Road to Addiction Addiction tricks the brain into believing that drugs are necessary for survival. The drive to use becomes as powerful as the drive to find food and water. The executive system’s longer term goals such as maintaining healthy relationships, pursuing educational or professional objectives, or maintaining one’s reputation and legal status are all overridden by the drive to use.

The Road to Addiction Self-Control Loss of Self-Control Don’t Go

Pharmacological Options for Treatment

Medication Strategies (MAT) Agonist / Partial Agonist Substitute effects of drug Harm Reduction Buprenorphine +/- naloxone, Methadone Antagonist Block the effects of drug Reduce cravings Naltrexone / Vivitrol Deterrent Medications (aversive) Naloxone in Suboxone

Buprenorphine Semisynthetic opioid Partial agonist at Mu receptors Antagonist at Kappa receptors Less euphoria Produces feelings of euthymia - a general feeling of good mood, not a euphoria like with an opioid Suppresses cravings for opiates and prevents withdrawal symptoms when taken as prescribed orally

Buprenorphine 25 to 50 times more potent than morphine Poor oral absorption Significant 1st-Pass effect (CYP3A4) Which is why sublingual route is used Maximal effects peak slower than morphine Slow dissociation from receptor, extended duration of action, less/milder withdrawal when discontinued Primary side effects: nausea and constipation like other mu agonist opioids, but may be less severe and more self-limiting

Buprenorphine First therapy approved for in-office prescribing for opioid dependence under the Federal Drug Addiction Treatment Act of 2000 Subutex (buprenorphine sublingual tablets) Useful for detox (esp Pregnant women) Slow dissociation from receptor, extended duration of action, less/milder withdrawal when discontinued Suboxone (+ naloxone / sublingual tablets) Useful for maintenance - preferred for use when patients will be unsupervised in drug administration Sublocade – Monthy SC injection, ER buprenorphine following induction and dose adjustment with transmuscosal buprenorphine  Schedule III

Suboxone Buprenorphine – poor oral / good SL bioavailabilty Naloxone - limited bioavailibility both PO and SL When taken sublingually Buprenorphine will be well absorbed Naloxone absorption will be minimal If taken intravenously Naloxone becomes 100% bioavailable Can attenuate effect of buprenorphine Can precipitate withdrawal in opioid-dependency

Suboxone The combo product, if crushed, dissolved and injected the: naloxone may cause initial withdrawal if the person is opioid physically dependent. decreasing diversion and misuse naloxone will block, or attenuate, the opioid agonist effect of the buprenorphine therefore safer if diverted

Overdose Risk Minimal Low risk of clinically significant problems Pre-clinical studies suggest high doses of buprenorphine should not produce respiratory depression No reports of respiratory depression in clinical trials Overdose and misuse (e.g., injecting) of buprenorphine combined with other CNS depressants result in respiratory depression and risk overdose In Europe IV buprenorphine + high potency benzodiazepines  deaths

Abuse Potential of Buprenorphine Euphoria in non-opioid dependent individuals Abuse potential less than full opioid agonists Abuse among opioid-dependent individuals is relatively low Burprenorphene is weaker opioid but with higher Mu affinity which can act like narcan leading to withdrawal Combination product (Suboxone) theoretically less likely to be abused by IV route Most common use in addicts is to prevent or treat withdrawal and cravings (already in withdrawal)

Who Might Abuse Suboxone? Can be abused Risk may be greatest in new opioid abusers Untreated Opioid Addicts Treated Opioid Addicts Methadone maintenance patients Buprenorphine treated patients Buprenorphine stabilized addicts will not experience adverse effects injecting Suboxone Buprenorphene has higher Mu affinity than naloxone Will not have pleasurable effects either Suggests low abuse liability in this population

Thanks for listening . . . Alan Questions? Thanks for listening . . . Alan