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NICOTINE ADDICTION

NICOTINE ADDICTION. Neal L. Benowitz, MD University of California San Francisco February 8, 2017. The Problem. WHAT IS DRUG ADDICTION?. The essence is loss of control of drug use. WHAT IS DRUG ADDICTION?. The essence is loss of control of drug use.

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NICOTINE ADDICTION

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  1. NICOTINE ADDICTION Neal L. Benowitz, MD University of California San Francisco February 8, 2017

  2. The Problem

  3. WHAT IS DRUG ADDICTION? • The essence is loss of control of drug use.

  4. WHAT IS DRUG ADDICTION? • The essence is loss of control of drug use. • A disease of brain reward centers (Dackis and O’Brien, 2005)

  5. DEFINITION OF A DRUG “…Articles other than food intended to affect the structure or any function of the body of man…” (F.D.A., 1938)

  6. CRITERIA FOR ADDICTION:1988 SURGEON GENERAL’S REPORT

  7. CRITERIA FOR ADDICTION:WORLD HEALTH ORGANIZATION “A behavioral pattern in which the use of a given psychoactive drug is given a sharply higher priority over other behaviors which once had a significantly higher value.”

  8. 57 yo smoker with coronary heart disease, recent bypass surgery, and severe hypertension, on multiple antihypertensive medications. Compliant with medications and office visits, but… “If I don’t have a cigarette, I can’t think, I can’t read, I become disoriented… If I can’t smoke, I don’t care if I live or die.” SFGH Cardiac Clinic - May 1, 1996

  9. DIAGNOSINGTOBACCOADDICTION:DSM-V(Tobacco UseDisorder) A problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: • Tobacco is often taken in larger amounts or over a longer period than was intended. • There is a persistent desire or unsuccessful efforts to cut down or control tobacco use. • A great deal of time is spent in activities necessary to obtain or use tobacco. • Craving, or a strong desire or urge to use tobacco. • Recurrent tobacco use resulting in a failure to fulfill major role obligations at work, school or home (e.g., interference with work). • Continued tobacco use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of tobacco (e.g., arguments with others about tobacco use.

  10. Important social, occupational, or recreational activities are given up or reduced because of tobacco use. • Recurrent tobacco use in situations in which it is physically hazardous (e.g., smoking in bed). • Tobacco use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by tobacco. • Tolerance, as defined by either of the following: • A need for markedly increased amounts of tobacco to achieve the desired effect. • A markedly diminished effect with continued use of the same amount of tobacco. • Withdrawal, as manifested by either of the following: • The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of the criteria set for tobacco withdrawal). • Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid withdrawal symptoms. Data from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

  11. DIAGNOSINGTOBACCOWITHDRAWAL:DSM-V(Tobacco UseDisorder) • Daily use of tobacco for at least several weeks • Abrupt cessation of tobacco use, or reduction in the amount of tobacco used, followed within 24 hours by four (or more) of the following signs or symptoms. • Irritability, frustration, or anger • Anxiety • Difficulty concentrating • Increased appetite • Restlessness • Depressed mood • Insomnia. • The signs of symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. • The signs or symptoms are not attributed to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance. Data from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

  12. SEVERITY OF ADDICTION: FAGERSTROM TEST FOR CIGARETTE DEPENDENCE ItemsResponse options Points1. How soon after you wake up do yousmoke your first cigarette?* Within 5 minutes 3 6± 30 minutes 2 31± 60 minutes 1 After 60 minutes 02. Do you find it difficult to refrain fromsmoking in places where it is Yes 1forbidden, e.g. in a church, at the library,in cinema, etc.? No 03. Which cigarette would you hate most to give up? The first one in the morning 1 All others 04. How many cigarettes/day do you smoke?* 10 or less 0 11± 20 1 21± 30 2 31 or more 35. Do you smoke more frequently during the firsthours after waking than Yes 1during the rest of the day? No 06. Do you smoke when your are so ill that you arein bed most of the day? Yes 1 No 0*HSI items.

  13. Neuroscience of Nicotine Addiction Nicotinic Receptors in Brain Neurochemical Effects The Cigarette as a Drug Delivery System Neuroadaptation Conditioned Behavior Genetics of Nicotine Addiction

  14. Nicotine Receptors and Neurochemistry

  15. pore z acetylcholine   z z   z z  x     y y     x ion y    neuronal type nicotinic receptors muscle type nicotinic receptor Structure of Nicotinic ACh Receptors Picciotto M. Emerging neuronal nicotinic receptor targets. SRNT 9th Annual Meeting; February 2003;New Orleans, La.

  16. Nicotinic Receptors in the Brain • 11 subunits (α2 – α9 and β2 – β4) • Α4β2 – high affinity, most prevalent, linked to addiction • α3β4 - cardiovascular • α7 homomeric – rapid synaptic transmission; learning, sensory gating

  17. Genetic Studies of Nicotinic Receptor Subtypes • β2 – Dopamine release, self-administration (Picciotto) • α4 – Nicotine sensitivity (Tapper) • α5, α6– Combine with α4 and β2; associated with human dependence

  18. DOPAMINE Pleasure, Appetite Suppression NOREPINEPHRINE Arousal, Appetite Suppression ACETYLCHOLINE Arousal, Cognitive Enhancement GLUTAMATE Learning, Memory Enhancement SEROTONIN Mood Modulation, Appetite Suppression BETA-ENDORPHIN Reduction of Anxiety and Tension GABA Reduction of Anxiety and Tension NICOTINE

  19. b2 b2 a4 a4 b2 4b2 nAChR Dopamine GABA GLU Nicotine Addiction: Reinforcing Behavior nicotine • Nicotine activates nAChRs on DA and GABA neurons (VTA) and Glu neurons • Net result of stimulatory and inhibitory effects and differential desensitization of nAChRs is enhanced DA release in the n. accumbens • Studies in transgenic mice: crucial role of a4 and b2 nAChR subunits - courtesy of H. Rollema, Pfizer

  20. The Cigarette as a Drug Delivery System

  21. Neuroadaptation

  22. Neuroadaptation and Nicotine Dependence • Upregulation of nicotinic receptors • Neuroplasticity • Induction of gene products (c-Fos) • Changes in protein expression • Altered cell signaling

  23. NICOTINIC RECEPTOR UPREGULATION IN SMOKERS

  24. TOBACCO ABSTINENCE SYMPTOM CLUSTERS(Gross and Stitzer) • PSYCHOLOGICAL DISTRESS: Irritability, Anger, Impatience, Anxiety • DIFFICULTY CONCENTRATING: Cognitive and Performance Impairment • HUNGER AND EATING: Weight Gain • TOBACCO CRAVING

  25. Hedonic Dysregulation(Koob and LeMoal, Science 278:52, 1997) Negative Affect State Common To Abstinence From All Drugs Of Abuse • Dysphoria • Depression • Irritability • Anxiety • Anhedonia

  26. MAINTAINING NICOTINE ADDICTION • Positive reinforcement – Liking a drug is part of addiction • Physical dependence – Avoiding withdrawal symptoms

  27. Is Tobacco Addiction Only Due to Nicotine?Monoamine Oxidase

  28. MAO A Activity Figure

  29. Monoamine Oxidase and Tobacco Addiction • Smoking inhibits brain MAO-A and MAO-B • Effect due to benzoquinones, 2-naphylamine, harmon and other chemicals, but not nicotine • MAO inhibition enhances nicotine self-administration in animals • MAO inhibitors may be useful in treating nicotine addiction

  30. Enhancement of Nicotine Self-Administration by Tranylcypromine Pre-treatment Fig

  31. Tobacco Smoking & Co-morbidity

  32. Tobacco Addiction is Frequently Co-morbid with Alcoholism Drug Abuse Depression Schizophrenia

  33. Cigarette Smoking and Depression • History of major depression more common in smokers • More dependent smokers have higher rates of depression • Smokers with depression history have more severe withdrawal symptoms, including severe depression symptoms

  34. Smoking and Conditioned Behavior

  35. OVERT BEHAVIOR SITUATIONS ASSOCIATED WITH SMOKING SMOKING STATUS COGNITIVE BEHAVIOR SMOKE CIGARETTE URGE TO SMOKE CURRENT SMOKER LAPSE OR RELAPSE MEAL COFFEE ALCOHOL PARTY TELEPHONE DRIVING FRIENDS SMOKING URGE TO SMOKE RECENTLY ABSTAINING SMOKER MAINTAINED ABSTINENCE NO URGE TO SMOKE LONG-TERM ABSTINENT SMOKER NO CIGARETTE

  36. Things Go Better with Nicotine Nicotine increases the rewarding value of non-nicotine stimuli (such as food).

  37. The Health Consequences ofSmoking: NICOTINE ADDICTIONA Report of the Surgeon General, 1988 • Cigarettes and other forms of tobacco are addicting. • Nicotine is the drug in tobacco that causes addiction. • The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.

  38. COMPARISON OF NICOTINE DEPENDENCE AND DEPENDENCE ON OTHER DRUGS OF ABUSE

  39. Public Health Implications of Nicotine Addiction: The Low Yield Cigarette Story

  40. FTC Machine Test Method

  41. LOW YIELD CIGARETTES • Smokers take in same amount of nicotine and tar as from regular cigarettes. • This “compensation” behavior is a reflection of nicotine addiction. • Tobacco industry advertisements imply lower risk. • Industry knew but never informed consumers about compensation.

  42. “FREE CHOICE” TO SMOKE OR NOT TO SMOKE

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