Advances in Drug Abuse and Addiction from NIDA: Implications for Treatment

Transcription

1 Advances in Drug Abuse and Addiction from NIDA: Implications for Treatment Timothy P. Condon, Ph.D. Deputy Director National Institute on Drug Abuse National Institutes of Health Department of Health and Human Services Addiction Medicine: Improving Clinical and Teaching Skills for Generalists 2010 Chief Resident Immersion Training (CRIT) Program Cape Cod, Massachusetts May 3, 2010

2 NIDA Research From Molecules To Managed Care Drug Courts Community Coalitions

3 NEUROTOXICITY OBESITY AIDS CANCER MENTAL ILLNESS HEALTH CARE COSTS PRODUCTIVITY LOSS ACCIDENTS HOMELESSNESS CRIME VIOLENCE

4 Advances in Science Are Bringing Us New Understanding of Drug Abuse & Addiction AND This Knowledge Is Allowing Us To Develop More Targeted Strategies for Its Prevention and Treatment

5 Your Brain on Drugs - Then CRIT 2010

6 Infusion Rate VAS CRIT 2010

7 Your Brain on Drugs Now CRIT 2010 Source: Breiter & Rosen, Ann N Y Acad Sci 1999

8 What have we learned?

9 Drug Abuse is a Preventable Behavior Drug Addiction is a Treatable Disease Partnership for a Drug Free America

10 In 2008, an estimated 20.1 million Americans, or 8.0 percent of the population aged 12 or older, were current illicit drug users. Source: 2008 National Survey on Drug Use and Health (NSDUH), SAMHSA

11 Percent of Students Reporting Past Month Use of Any Illicit Drug Has Decreased 25% Decline 2001 to 2008* Percent * P <.001 SOURCE: University of Michigan, 2008 Monitoring the Future Study

12 Percent of Students Reporting Any Illicit Drug Use in Past Year, by Grade Percent th Grade 10th Grade 12th Grade SOURCE: University of Michigan, 2009 Monitoring the Future Study

13 Issues of Concern Percent of 12th Graders Reporting Nonmedical Use of OxyContin and Vicodin in the Past Year Remained High Percent OxyContin Vicodin No year-to-year differences are statistically significant. SOURCE: University of Michigan, 2008 Monitoring the Future Study

14 Prescription/Over-the-Counter Drugs Account for 7 Out of 11 of the Most Frequently Abused Drugs Percent Marijuana/Hashish Prevalence of Past Year Drug Use Among 12 th Graders Vicodin Amphetamines Sedatives Tranquilizers Cough Medicine Hallucinogens Cocaine (any form) OxyContin MDMA (Ecstasy) In 2008, 15.4% of 12 th graders reported abusing prescription drugs within the past year. Ritalin SOURCE: University of Michigan, 2008 Monitoring the Future Study

15 Source of Prescription Narcotics among those who used in the Past Year, 12 th grade Other 7% Bought from dealer/stranger 8% Took from friend/relative 12% Internet 0% Prescription 19% Given by friend/relative 33% Bought from friend/relative 21%

16 CRIT 2010

17 National Estimated Prevalence (Rate per 1,000 Population, aged 0 to 85+) of Persons with a Dispensed Opioid Prescription, by Specialty, 2007 Opioids Include Codeine & Comb NON-INJ (USC 02232), Morphine & Opium NON-INJ (USC 0222), Morphine & Opium INJ (USC 0221), Codeine & Comb INJ (USC 02231). CRIT 2010 Source: SDI Health, TPT Opiates and US Census

18 Why? Why do people take drugs?

19 Why do people take drugs? To feel good To have novel: Feelings Sensations Experiences AND To share them To feel better To lessen: Anxiety Worries Fears Depression Hopelessness Withdrawal Drawings courtesy of Vivian Felsen

20 Drug Abuse Risk Factors Community Peer Cluster Family Individual

21 A Major Reason People Take a Drug is they Like What It Does to Their Brains

22 Initial Drug Use Is A Voluntary Behavior A Person Chooses to Take a Drug for the First Time

23 Initially, A Person Takes A Drug Hoping to Change their Mood, Perception, or Emotional State Translation--- Hoping to Change their Brain

24 What have we learned about Vulnerability? Why do some people become addicted while others do not?

25 We Know There s s A Big Genetic Contribution To Drug Abuse and Addiction And the Nature of this Contribution Is Extremely Complex

26 Genetic component of common traits Trait Heritability Type II (adult-onset) diabetes Type I (insulin-dependent) diabetes Hypertension Peanut allergy Cataract (age-related) Alcoholism Nicotine Cocaine and stimulants Heroin and opiates Marijuana

27 DA Receptor Levels and Response to MP Subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant 2.5 unpleasant response 0 pleasant response

28 Some Gene Variants Implicated in Addiction FAAH - associated with drug dependence OPRM1 - associated with opiates and alcoholism CYP2A6, CYP2B6 - associated with smoking and smoking cessation ALDH2 - associated with protection against alcoholism DBH (Dopamine beta-hydroxylase) cocaine-induced paranoia DRD2, DRD4 (Dopamine receptors) - reward, craving NrCAM, neurexins (Cell adhesions genes) - assoc with drug abuse and addiction Prodynorphin gene - associated with protection against cocaine dependence Nicotinic alpha 7 promoter assoc. with decreased expression of its message in different brains regions and with sensory gating defects in schizophrenics -- Alpha 5 and beta 3 (nicotinic receptors) assoc. with nicotine dependence -- 5HT1B (serotonin receptor) - associated with conduct disorder and alcoholism

29 Initial p values of Top 40 K SNPs Non-coding SNP Coding SNP Expected: 44 SNPs at 10-4 Observed: 81 SNPs at 10-4 Chromosome

30 Epigenetic Mechanisms Regulate How Genetic Information Is Expressed Across Development, Tissue, Environment and Disease States Citations for Epigenetics l DNA Methylation silences gene l Histone Modification methylation, acetylation, or phosphorylation l Non coding RNA Epigenetics Epigenetics + Disease

31 Epigenetic Mechanisms Regulate How Genetic Information Is Expressed Across Development, Tissue, Environment and Disease States l DNA Methylation silences gene l Histone Modification methylation, acetylation, or phosphorylation l Non coding RNA

32 Genetics Gene/ Environment Interaction Environment

33 ENVIRONMENT Risk Factors Poor Family Support Drug availability Poverty Crime Insufficient number of of students in in this area. No No students in in this area. Neighborhood #3 Neighborhood #1 Neighborhood #2 John John A. A. Pollard, Pollard, Ph.D. Ph.D. Developmental Research Research and and Programs

34 What have we learned about other aspects of vulnerability?

35 Addiction Is a Developmental Disease starts in childhood and adolescence % in each age group to develop first-time dependence TOBACCO THC ALCOHOL Age Age at tobacco, at alcohol and at cannabis dependence, as per DSM IV National Epidemiologic Survey on Alcohol and Related Conditions, 2003

36 Right Lateral and Top Views of the Dynamic Sequence of GM Maturation Over the Cortical Surface Source: Gogtay, Nitin et al. (2004) Proc. Natl. Acad. Sci. USA 101, Copyright 2004 by the National Academy of Sciences

37 Exposure to drugs of abuse during adolescence could have profound effects on Brain Development & Brain Plasticity Understanding drug abuse and addiction from a Development Perspective has important implications for their Prevention & Treatment

38 K. Winters Maturation starts at the back of the brain... Construction Ahead and moves to the front Amygdala Judgment Emotion Prefrontal Cortex Motivation Physical coordination, sensory processing Nucleus Accumbens Cerebellum Notice: Judgment is last to develop!

39 What Else Have We Learned?

40 Substance Abuse Is Commonly Linked To A Variety of Other Medical & Mental Health Conditions MAJOR PSYCHOSES ANXIETY DEPRESSION LOWER BACK PAIN HEADACHE ARTHRITIS ASTHMA Source: Mertens JR et al. Arch Intern Med, 163, November 10, Odds of Substance Abuse Patients Having Condition Compared to Controls Odds of Substance Abuse Patients Having Condition Compared to Controls INJURIES/ OVERDOSES

41 ADDICTIVE DISORDERS OFTEN CO-EXIST WITH MENTAL DISORDERS Mental Disorder Comorbid Disorders Addictive Disorder

42 Drug Users have a Higher Risk of Developing Mental Disorders Psychosis Depression Anxiety Panic attacks

43 Co-Occurrence of Serious Psychological Distress and Substance Use Disorder in the Past Year among Adults Aged 18 or Older: Million Substance Use Disorder (SUD) Only 5.6 Million 19.3 Million Serious Psychological Distress (SPD) Only National Survey on Drug Use and Health, SAMHSA Co-Occurring SUD and SPD

44 Many Common Factors Are Involved in Addiction and Mental Illness Addiction: Early Physical or Sexual Abuse Stress Family History Mental Illness Mental Illness: Early Physical or Sexual Abuse Stress Family History Drug and Alcohol Abuse Peers who use Drugs

45 Why do Mental Illnesses and Substance Abuse Co-occur? Self-medication hypothesis substance abuse begins as a means to alleviate symptoms of mental illness Causal effects of substance abuse Substance abuse may increase vulnerability to mental illness Common or correlated causes the life processes and risk factors that give rise to mental illness and substance abuse may be related or overlap

46 Comorbidity is a Reality

47 So What have learned about how drugs work?

48 We Now Know That Despite Their Many Differences, Most Abused Substances Enhance the Brain s Reward Pathway

49 A Major Reason People Take a Drug is they Like What It Does to Their Brains

50

51 Dopamine Pathways striatum frontal cortex hippocampus Functions reward (motivation) pleasure, euphoria motor function (fine tuning) compulsion perseveration nucleus accumbens CRIT 2010 substantia nigra/vta

52 We Know That In Combination with Many Other Transmitter Systems, and Despite Their Many Differences, Most Abused Substances Enhance Dopamine Activities

53 Nuclear Circuitry Mediating the Activation of Goal-Directed Behavior Medial dorsal thalamus Ventral pallidum Nucleus accumbens core Prefrontal cortex Enter basal ganglia motor generator Dopamine Glutamate GABA GABA/Neuropeptide Cannabinoid receptors??? Ventral tegmental area Extended amygdala Central amygdala nucleus, bed nucleus of the stria terminalis nucleus accumbens shell Basolateral amygdala Adapted from Kalivas and Volkow, Am J Psychiatry 162:8, Aug 2005 Hippocampus

54 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL OFC PFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING CRIT 2010

55 Science Has Generated A Lot of Evidence Showing That Prolonged Drug Use Changes the Brain In Fundamental and Long-Lasting Lasting Ways

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

57 Normal Cocaine Abuser (10 Days) Cocaine Abuser (100 Days) Sources: Volkow, et al., Synapse, 11: , 1992 & Volkow, et al., Synapse, 14: , 1993

58 Dopamine D2 Receptors are Lower in Addiction DA D2 Receptor Availability Cocaine DA DA DA DA DA DA DA DA DA DA DA DA Meth Reward Circuits Non-Drug Abuser Alcohol DA DA DA DA DA DA Heroin control addicted Reward Circuits Drug Abuser

59 Effect of Cocaine Abuse on Dopamine D2 Receptors normal subject cocaine abuser (1 month post) cocaine abuser (4 months post)

60 Chronic cocaine increases density of dendritic spines and neuronal branching in the nucleus accumbens Branches 50 COC 8 CTL COC CTL COC 45 CTL COC CTL Robinson, T.E. & Kolb, B. Eur. J. of Neuro Ferrario, C.R. et al. Biol. Psychiatry, 2005.

61 Repeated drug exposure (e.g., via neurotrophic factors, ΔFosB, CREB?) Normal responses to drugs Use-dependent plasticity leading to sensitized responses to drug and environmental cues CRIT 2010 Nestler, 2001

62 Repeated Drug Abuse Increases Genetic Transcription Resulting in Long-term Structural Changes Dopamine Dendritic Spines Adapted from Nestler E.J. Science & Practice Perspectives, 5(1) 2005.

63 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL OFC PFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING CRIT 2010

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

65 Dopamine Transporters in Methamphetamine Abusers 2.4 Normal Control Dopamine Transporters (Bmax/Kd) Normal Controls Meth Abusers Methamphetamine Abuser p < Methamphetamine abusers have significant reductions in dopamine transporters. BNL - UCLA - SUNY NIDA - ONDCP - DOE

66 Dopamine Transporters in Methamphetamine Abusers Dopamine Transporter Bmax/Kd Time Gait (seconds) Delayed Recall (words remembered) 4 Motor Task Loss of dopamine transporters in the meth abusers may result in slowing of motor reactions. Memory Task Loss of dopamine transporters in the meth abusers may result in memory impairment. BNL/UCLA/SUNY NIDA, ONDCP, DOE

67 Implication: Brain changes resulting from prolonged use of drugs may be reflected in compromised cognitive functioning Is there recovery?

68 [C-11]d-threo-methylphenidate Normal Control DAT Recovery with prolonged abstinence from methamphetamine Methamphetamine Abuser (1 month detoxification) Methamphetamine Abuser (14 month abstinent) Source: Volkow, N.D. et al., Journal of Neuroscience, 21(23), pp , December 1, 2001.

69 As We ve Seen, Drug Use Can Lead to Structural and Functional Changes in the Brain

70 Addiction is, Fundamentally, a Brain Disease

71 Addiction is Not Just a Brain Disease

72 Addiction Is A Brain Disease Expressed As Compulsive Behavior Both Developing and Recovering From It Depend on Behavior and Social Context

73 CRAVING INDUCTION IN PET SETTING 5 N = 13 CRAVING Neutral STIMULI Cocaine

74 Amygdala Conditioned Association Anterior Cingulate Source: Childress, et al., AJP, 1999 Nature Video Cocaine Video CRIT 2010

75 Memories Appear to Be A Critical Part of Addiction CRIT 2010

76 People, places and things

77 But Not Just Memories CRIT 2010

78 Drugs Usurp Brain Circuits and Motivational Priorities CRIT 2010

79 We Don t Know the Exact Switch BUT We Do Know that the Brain Circuitry Involved in Addiction Has Similarities to that of Other Motivational Systems CRIT 2010

80 Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine ) Cingulate Signal Intensity (AU) Cocaine Film Ant Cing IFG Controls Cocaine Users CRIT Garavan 2010 et al A.J. Psych 2000

81 Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Signal Intensity (AU) Cocaine Film Erotic Film Ant Cing IFG Controls Cocaine Users CRIT Garavan 2010 et al A.J. Psych 2000

82 This Results in Motivational Toxicity and Compulsive Drug Use (Addiction) CRIT 2010

83 So What?

84 Addiction is the Quintessential Biobehavioral Disorder

85 So...What Does This Mean For Treatment?

86 The Most Effective Intervention Strategies Will Attend to All Aspects Biology Behavior of Addiction: Social Context

87 Circuits Involved In Drug Abuse and Addiction CONTROL INHIBITORY CONTROL OFC PFC SCC MOTIVATION/ DRIVE ACG NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING CRIT 2010

88 Non Addicted Brain Addicted Brain Control STOP Control Saliency Drive Saliency Drive GO Memory Memory

89 Brain Glucose Metabolism in Cocaine Abusers (n = 20) and Controls (n = 23) CG micromol/100g/min micromol/100g/min Controls CG Abusers P < 0.01 OFC Controls Abusers P < 0.005

90 Treating the ADDICTED Brain REWARD CONTROL DRIVE Decrease the rewarding value of drugs MEMORY

91 Outpatient Study: Percent of Negative Urines After Depot Naltrexone Administration 80% 70% 60% 50% 40% 30% 20% 10% 0% Visits (2 per week) Placebo 192 mg Dose 384 mg Dose Comer, S. D., Sullivan, M. A., Yu, E., Rothenberg, J. L., Kleber, H. D., Kampman, K. et al. Arch Gen Psychiatry, 63, , 2006.

92 Disulfiram and Naltrexone for the Treatment of Co-occurring Cocaine and Alcohol Dependence Percent of Cocaine-Alcohol Dependent Patients that Achieved at Least 3 Consecutive Weeks of Abstinence from both Cocaine and Alcohol in an 11 Week Trial % Patients w/ 3 consecutive abstinent wks 40% 35% 30% 25% 20% 15% 10% 5% 15.0% 17.0% 17.3% 34.7% 0% Placebo Disulfiram Naltrexone Disulfiram- N=54 N=53 N=52 Naltrexone N=49 Source: Pettinati, HM et al., Addictive Behaviors, 33, pp , 2008.

93 Antibodies can reduce brain concentrations Capillary Blood Flow Antibody holds drmcg in blood stream Brain

94 Fewer cocaine urines at higher Vaccine Dose Vaccination makes antibodies by Week 4 (n=11) 60 Percent Positive Urines mcg grp 2000 mcg grp Z= -3.17, p= Week Kosten, et al, unpublished

95 Treating the ADDICTED Brain REWARD CONTROL DRIVE Decrease the rewarding value of drugs REWARD CONTROL DRIVE Increase the rewarding value of non-drug reinforcers MEMORY MEMORY

96 Contingency Management for the Treatment of Methamphetamine Use Disorders Roll, J.M. et al., AJP 163(11) pp , November 2006.

97 Treating the ADDICTED Brain REWARD CONTROL DRIVE Decrease the rewarding value of drugs REWARD CONTROL DRIVE Increase the rewarding value of non-drug reinforcers MEMORY MEMORY REWARD CONTROL DRIVE Weaken learned positive associations with drugs and drug cues MEMORY

98 Medications Biofeedback Coping Skills Desensitization Other behavioral strategies

99 Time-dependent increases in cue-induced cocaine seeking after withdrawal from drug self-administration Cocaine selfadministration (10 days) Withdrawal period (1 to 180 days) Extinction tests for cocaine seeking in a drug-free state Lever presses (6 h) * * * Withdrawal day * Lever presses (6 h) * * Withdrawal day * Grimm et al. Incubation of cocaine craving after withdrawal. Nature, 2001 CRIT 2010 Lu et al. Psychopharmacology, 2004

100 Summary of neuropharmacological findings Incubation of cocaine craving: Associated with increases in peptide levels of BDNF in VTA, accumbens and amygdala (Grimm et al. J Neurosci 2003; Lu et al. J Neurosci 2004) Mediated by time-dependent increases in responsiveness of central amygdala ERK and glutamate to cocaine cues (Lu et al. Nat Neurosci 2005; Lu et al. Biol Psychiatry 2007) AP-5 or LY NMDA NMDA receptor AMPA receptor Kv4.2 potassium channel subunit Raf U0126 MEK ERK Nucleus Activity-dependent genes (c-fos, zif268) CRIT 2010 ERK=extracellular signal-regulated kinase

101 AMYGDALAR CONNECTIVITY during brief.5 sec Cocaine Cues Placebo Drug 2 amyg conx (n=7) Source: Childress, et al, unpublished

102 AMYGDALAR CONNECTIVITY during brief.5 sec Cocaine Cues Placebo Drug 2 amyg conx (n=7) Baclofen blunts AMYGDALAR CONNECTIVITY Baclofen Source: Childress, et al, unpublished

103 Treating the ADDICTED Brain REWARD CONTROL DRIVE Decrease the rewarding value of drugs REWARD CONTROL DRIVE Increase the rewarding value of non-drug reinforcers MEMORY MEMORY REWARD CONTROL DRIVE Weaken learned positive associations with drugs and drug cues REWARD CONTROL DRIVE Strengthen frontal control MEMORY MEMORY

104 Behavioral Interventions Medications Biofeedback

105 Abstinence Rates Following Behavioral Treatments for Marijuana Dependence Kadden et al, Addictive Behaviors 32 (2007)

106 Brief Motivational Intervention at a Clinic Visit Reduces Cocaine and Heroin Use Abstinence Among Those Screening Positive At Baseline 100% 80% % 60% 40% 20% 0% Cocaine ** 22.3% 16.9% 40.2% Opioids *** 30.6% 17.4% 12.8% Both * Intervention Control * p =.052 ** p =.045 *** p =.050 Bernstein et al. Drug and Alcohol Dependence 2005;77:49-59

107 Can We Predict Whether or Not a Treatment Will Work?

108 Insula Brain Network For Recovery? Monitor internal body state (Visceral sensory) Register and Predict Adverse Events Anterior Cingulate Drives body states (Viscero-motor) Error Detection Monitor (resolve) Conflicts Stroop Task ( Blue Blue ) Cognitive Dissonance Predicts Treatment Adherence Slips, Relapse, Abstinence

109 Predictors of Nonresponse to Cognitive Behavioral Therapy or Venlafaxine in MDD Ventral anterior cingulate cortex hypermetabolism in non-responders to either treatment Konarski et al, J Psychiatry Neurosci May; 34(3):

110 Brain Regions Predictive of Smoking Relapse Relapses > Non-Relapsers during Emotional Stroop with Smoking Words Relapsers < Non-Relapsers Functional Connectivity Janes et al., 2010

111 Brain Predictor of Relapse Paulus, 2005

112 Drug Addiction: A Complex Behavioral and Neurobiological Disorder HISTORICAL - previous history - expectation - learning ENVIRONMENTAL - social interactions - stress - conditioned stimuli DRUGS BRAIN MECHANISMS PHYSIOLOGICAL - genetics - circadian rhythms - disease states - gender BEHAVIOR ENVIRONMENT

113 The Brains of Addicts Are Different From the Brains of Non-Addicts And Those Differences Are An Essential Element of Addiction

114 That s s Why Addicts Can t t Just Quit That s s Why Treatment Is Essential!

115 Treating A Biobehavioral Disorder Must Go Beyond Just Fixing The Chemistry

116 The Most Effective Treatment Strategies Will Attend to All Aspects Biology Behavior of Addiction: Social Context

117 Drug Abuse Treatment Core Components and Comprehensive Services Financial Medical Mental Health Housing & Transportation Core Treatment Intake Assessment Group/Individual Counseling Abstinence Based Urine Monitoring Case Management Vocational Child Care Treatment Plans Pharmaco-therapy Self-Help (AA/NA) Continuing Care Educational Family AIDS / HIV Risks Legal Etheridge, Hubbard, Anderson, Craddock, & Flynn, 1997 (PAB)

118 In Treating Addiction We Need to Keep Our Eye on the Real Target Abstinence Functionality Functionality Functionality in in in Family, Family, Family, Work Work Work and and and Community Community Community

119 We Need to Treat the Whole Person!

120 We Need to View and Treat Addiction As A Chronic, Relapsing Illness

121 After 5 years if you are sober, you probably will stay that way. Longitudinal Trends in Recovery (Pathways N=1326) It takes a year of abstinence before less than half relapse Pathways Dennis, ML Foss MA & Scott CK (2007). An eight-year perspective on the relationship between the duration of abstinence and other aspects of recovery. Eval. Rev.

122 Percent of Patients Who Relapse Relapse Rates Are Similar for Drug Dependence and Other Chronic Illnesses to 60% Drug Dependence 30 to 50% Type I Diabetes 50 to 70% Hypertension 50 to 70% Asthma Source: McLellan, A.T. et al., JAMA, Vol 284(13), October 4, 2000.

123 10 Outcome In Diabetes Pre During Post Treatment Research Institute

124 10 Outcome In Hypertension Pre During Post Treatment Research Institute

125 10 Outcome In Addiction Pre During Post Treatment Research Institute

126 If we treat a diabetic and symptoms don t subside.what do we do? Would we increase the dose? Would we change medications? Would we change treatment approaches? Would we fail to provide ongoing treatment for a diabetic?

127 NIDA Physician Outreach Research Practice

128

129

130 Where Do We Need to Go From Here? We Need to Advance the SCIENCE and to End the STIGMA and Discrimination

131 NATIONAL INSTITUTE ON DRUG ABUSE

132

133 65 min Keynote