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Addiction Pharmacotherapy for Alcohol Use Disorders

David A. Frenz, M.D. dafrenz@healtheast.org 26 September 2010

Positive cravings

Acute drinking

Reward circuitry activated

Chronic drinking

Reward circuitry dysregulated

Withdrawal Negative cravings

Relapse Pregabalin

Oxcarbazepine

Topiramate

Acamprosate

Ondansetron

Aripiprazole

Naltrexone

Varenicline

Baclofen

Disulfiram

Disease of Addiction Medication Options

Adapted from: Cleve Clin J Med 2006;73:641.

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Psychopharmacology 101 for the LADC!

David A. Frenz, M.D.!Mental Health & Addiction Services!

St. Josephʼs Hospital!

Disclosures!

•  I am employed by the HealthEast Care System!•  I do not have any financial relationships with the

pharmaceutical or medical device industries!•  I will be discussing the “off label” use of medications!

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Lecture outline!

•  General structure of the nervous system!•  Neurons!•  Action potentials, synapses and neurotransmission!•  Putting it all together with some examples!

Structural divisions of the nervous system!

•  Central nervous system!–  Brain!–  Spinal cord!

•  Peripheral nervous system!–  Everything else!

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Functional divisions of the nervous system!

•  Somatic—“voluntary”!–  Sensory!–  Motor!

•  Autonomic—“involuntary”!–  Sensory!–  Motor!

Rizzo D. Fundamentals of anatomy & physiology, 2d ed. Thomson Delmar Learning, 2006.!University of Minnesota—full-text electronic resource.!

Autonomic nervous system!

•  Sympathetic—“fight or flight”!•  Parasympathetic—“rest and digest”!

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Autonomic nervous system!

Organ! Sympathetic! Parasympathetic!

Eyes (pupils)! Dilate! Constrict!

Salivary glands! More saliva! More saliva!

Heart! Increased rate! Decreased rate!

GI tract! Decreased activity! Increased activity!

Bladder! Fill! Empty!

Penis! Erection! Ejaculation!

Skin! Sweating, goosebumps!

Key concept!

•  Many unintended (“side”) effects of psychotropic medications occur in the autonomic nervous system!

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Autonomic nervous system!

Organ! Sympathetic! Parasympathetic!

Eyes (pupils)! Dilate! Constrict!

Salivary glands! More saliva! More saliva!

Heart! Increased rate! Decreased rate!

GI tract! Decreased activity! Increased activity!

Bladder! Fill! Empty!

Penis! Erection! Ejaculation!

Skin! Sweating, goosebumps!

Neurons!

•  The nervous system is composed of various specialized cells!

•  Neurons process and transmit information by electrochemical signaling!

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Neuron!

http://www.drugabuse.gov/jsp/MOD3/page3.html!

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Stahlʼs Essential Psychopharmacology (online edition).!

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Neuron!

Cell body! Axon! Axon terminals!

Action potentials!

•  Are electrochemical impulses (waves) that transmit information within neurons!

•  Cause neurotransmitter release into the synapse!

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Action potential!

Signal!

Synapse!

•  Synapses are specialized junctions were neurons communicate with each other and other tissues(e.g., muscles, glands)!

•  Each neuron has up to 15,000 synapses!•  Each cubic millimeter of cerebral cortex contains

about 1 billion synapses!•  There are roughly 100–500 trillion synapses in the

brain!

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Synapse!

http://www.drugabuse.gov/jsp/MOD3/page3.html!

Neurotransmitters!

•  Are chemicals that transmit information from neurons to others cells!–  Other neurons!–  Muscles, glands!

•  Are stored in vesicles in the presynaptic neuron!•  Are released into the synapse by action potentials!•  Act upon the postsynaptic tissue!

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Receptors!

•  Are molecules to which ligands bind!•  Ligands include!

–  Neurotransmitters!–  Hormones!–  Medications and substances that are abused!–  Poisons and toxins!

•  Receptor-ligand relationships are very specific—“lock and key”!

Receptor-ligand!

http://www.drugabuse.gov/jsp/MOD3/page3.html!

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Wikimedia!

Neurotransmission!

Action potential!

Neurotransmitterreleased into the synapse!

Neurotransmitters!

•  Can be excitatory or inhibitory!•  Excitatory neurotransmitters!

–  Make postsynaptic action potentials more likely!•  Inhibitory neurotransmitters!

–  Make postsynaptic action potentials less likely!

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Neurotransmission—excitation!

Action potential! Action potential!

Excitatory neurotransmitterreleased into the synapse!

Muscle,!gland, et cetera!

Neurotransmission—inhibition!

Action potential!

Inhibitory neurotransmitterreleased into the synapse!

Muscle,!gland, et cetera!

Key concept!

•  Psychotropic medications and substances that are abused exert their effects—both intended and unintended—by affecting neurotransmission at the synaptic level!

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http://www.asylumprojects.org/!

http://www.asylumprojects.org/!

Putting it all together!

•  Symptoms → brain regions → neuronal circuits → neurotransmitters → medications!

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Example—Major Depressive Episode!

Stahlʼs Essential Psychopharmacology (online edition).!

Example—Major Depressive Episode!

Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

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Monoamine hypothesis!

•  Major depressive disorder is felt to be due to a relative deficit of serotonin, norepinephrine and dopamine!

Stahlʼs Essential Psychopharmacology (online edition).!

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Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

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Stahlʼs Essential Psychopharmacology (online edition).!

Stah

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Stahl SM. J Clin Psychiatry 2007;58:520.!

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Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

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Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

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Treatment for depression!

•  Involves medications that increase serotonin, norepinephrine and/or dopamine!

Selective serotonin reuptake inhibitors!

Generic name! Trade name!

Citalopram! Celexa!

Escitalopram! Lexapro!

Fluoxetine! Prozac!

Fluvoxamine! Luvox!

Paroxetine! Paxil!

Sertraline! Zoloft!

Nat Rev Drug Discov 2005;4:764.!

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Stahlʼs Essential Psychopharmacology (online edition).!

Dual reuptake inhibitors!

Generic name! Trade name!

Desvenlafaxine! Pristiq!

Duloxetine! Cymbalta!

Milnacipran*! Savella!

Sibutramine*! Meridia!

Venlafaxine! Effexor!

* FDA approved but not as an antidepressant.!

Stahlʼs Essential Psychopharmacology (online edition).!

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Atypical antidepressants!

Generic name! Trade name!

Atomoxetine*! Strattera!

Bupropion! Wellbutrin!

Mirtazapine! Remeron!

Nefazodone! Serzone!

Trazodone! Desyrel!

* FDA approved but not as an antidepressant.!

Stahlʼs Essential Psychopharmacology (online edition).!

Stahlʼs Essential Psychopharmacology (online edition).!

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Drugtext Internet Library!

Putting it all together!

•  Symptoms → brain regions → neuronal circuits → neurotransmitters → medications!

Example—Addiction!

•  A disorder of reward characterized by continuing compulsive substance use despite harm!

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Symptoms and behaviors!

•  As per DSM-IV-TR!•  Poor self-awareness!•  Low frustration tolerance!•  Dysregulated emotions!•  Impaired interpersonal skills!•  Impulsivity!•  Cravings!

Example—Addiction!

Stahlʼs Essential Psychopharmacology (online edition).!

www.crystalmethsolutions.org.!

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Seeking and experiencing reward!

“Go”! “Stop”!

Reward circuitry! Executive function!

Mesolimbic pathway! Prefrontal cortex!

Dopamine! Serotonin!

Glutamate! Gamma-aminobutyric acid!

Risk taking! Risk avoidance!

Experimentation! Harm reduction!

Am J Addict 2008;17:6.!

Neuron 2002;34:13.!

Pharmacol Ther 2005;108:18.!

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Big Book insights!

“ !They are restless, irritable and discontented, unless they can again experience the sense of ease and comfort which comes at once by taking a few drinks… After they have succumbed to the desire again, as so many do, and the phenomenon of craving develops… ”!

Alcoholics Anonymous (“Big Book”), 3rd ed (7th imp), 1980, page xxvi.!

“ !Memory of the rewarding aspects of drug use superimposed on a negative emotional state ”!

Craving!

Annu Rev Psychol 2008;59:29.!

www.crystalmethsolutions.org.!

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Nat Rev Neurosci 2007;8:844.!

Blue: glutamate; Red: dopamine; Orange: GABA; Green: orexin.!

Brain Res 2009;1293:61.!

Cravings!

Positive!Desire to get intoxicated or “high”!

Negative!Desire to relieve uncomfortable emotional symptoms!

Type 1!Induced by drugs or stimuli that have been paired with prior drug use!

Type 2!Negative emotional state, combined with Type 1, that causes drug seeking!

Cleve Clin J Med 2006;73:641 § Annu Rev Psychol 2008;59:29.!

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Cravings!

Positive!Desire to get intoxicated or “high”!

Negative!Restless, irritable and discontended!

Type 1!People, places and things!

Type 2!Restless, irritable and discontended!

Neurotransmitters—Addiction!

Dopamine!

Serotonin!

Gamma-aminobutyric acid (GABA)!

Neuropeptide Y!

Dopamine!

Corticotropin-releasing factor (CRF)!

Norepinephrine!

Glutamate!

Annu Rev Psychol 2008;59:29.!

Integrated addiction treatment!

Treatment goals! PT! ER! RX!

Mindfulness! ×!

Distress tolerance! ×!

Emotion regulation! ×! ×!

Interpersonal effectiveness! ×!

Impulse control! ×! ×!

Craving reduction! ×! ×! ×!

PT = Psychological Therapies; ER = Environmental Restructuring; RX = Pharmacotherapy!

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Naltrexone (ReVia, Vivitrol)!

•  Alcohol increases the activity of the reward pathway by increasing endogenous opioids!

•  Naltrexone blocks the effects of endogenous opioids!–  Reduces reward!

•  Naltrexone may also reduce “positive” cravings!

Naltrexone!

Pharmacol Ther 2005;108:18.!

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Stahlʼs Essential Psychopharmacology (online edition).!

Acamprosate (Campral)!

•  Alcohol alters the balance between glutamate and gamma-aminobutyric acid (GABA)!

•  Acamprosateʼs exact mechanism of action is somewhat uncertain but likely affects the glutamate system and possibly GABA!

•  Acamprosate is felt to reduce “negative” cravings, especially in early recovery!

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Glutamate and GABA!

Pharmacol Ther 2005;108:18.!

Stahlʼs Essential Psychopharmacology (online edition).!

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Contact information!

David A. Frenz, M.D.!Mental Health & Addiction Services!HealthEast St. Josephʼs Hospital!45 West 10th Street!St. Paul, MN 55102!dafrenz@healtheast.org!651-232-3640 (department)!651-326-3730 (voice mail)!