Treating DRUG ADDICTION: What Do We Know? What More Should We Do? National Institute on Drug Abuse Bringing the full power of science to bear on drug abuse and addiction Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institute on Drug Abuse Bringing the full power of science to bear on drug abuse and addiction Nora D. Volkow, M.D. Director National Institute on Drug Abuse Nora D. Volkow, M.D. Director

ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Control Cocaine Abuser Decreased Brain Metabolism in Drug Abuse Patient High Low Decreased Heart Metabolism in Heart Disease Patient Healthy Heart Diseased Heart Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.6% Prefrontal Cortex Amygdala 1.4% 1.2% 1.0% % in each age group who develop first-time cannabis use disorder 0.8% 0.6% Brain areas where volumes are smaller in adolescents than young adults 0.4% 0.2% Sowell, E.R. et al., Nature Neuroscience, 2, 859-861, 1999 0.0% 5 10 15 18 25 30 35 40 45 50 55 60 65 70 Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

Drugs and Natural Rewards ACTIVATE Dopamine in Reward Regions VTA/SN nucleus accumbens frontal cortex 100 200 300 400 500 600 700 800 900 1000 1100 1 2 3 4 5 hr Time After Amphetamine % of Basal Release AMPHETAMINE 50 100 150 200 60 120 180 Time (min) % of Basal Release Empty Box Feeding Di Chiara et al. FOOD Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction

Repeated Drug Use Changes the Brain Weakens the Brain Dopamine System Control Cocaine Abuser T Y R O S I N E D A P DA COCAINE T Y R O S I N E D A P DA T Y R O S I N E D A P DA PLEASURE REPEATED USE OF COCAINE OR OTHER DRUGS REDUCES LEVELS OF DOPAMINE D2 RECEPTORS

Dopamine D2 Receptors are Lower in Addiction Normal Controls 1.5 2 2.5 3 3.5 4 4.5 15 20 25 30 35 40 45 50 DA D2 Receptors (Ratio Index) Cocaine Abusers Cocaine Meth DA D2 Receptor Availability 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2` Alcohol Bmax/Kd Heroin 20 25 30 35 40 45 50 control addicted Volkow et al., Neuro Learn Mem 2002.

Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors Overexpression of DA D2 receptors reduces alcohol self-administration 60 1st D2R Vector p < 0.0005 2nd D2R Vector 50 p < 0.0005 40 p < 0.005 p < 0.005 Percent Change in D2R 30 20 p < 0.10 10 Null Vector 4 6 8 10 24 -20 DA DA % Change in Alcohol Intake -40 p < 0.01 DA DA p < 0.01 DA -60 DA p < 0.001 DA DA -80 p < 0.001 p < 0.001 -100 4 6 8 10 24 Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001. Time (days)

Brain glucose metabolism Low Levels of Striatal D2 Receptors Are Associated with Impaired Activity in Frontal Regions Control Cocaine Abuser 30 40 50 60 70 80 90 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 D2 Receptors (BPND) 35 45 55 65 1.8 2 2.2 2.4 2.6 2.8 control addicted Brain glucose metabolism Controls Methamphetamine Abusers umol/100gr/min OFC 4 Controls Alcoholics Volkow et al., PNAS 2011 108(37): 15037-42 DA D2 receptors

ADDICTION CAN BE TREATED Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 ml/gm Normal Control METH Abuser (1 month detox) METH Abuser (14 months detox) Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

Opportunities with Health Care Reform to Expand Involvement of the Health Care System in Treatment of SUD In 2012 An Estimated 22.2 Million Americans 12 or Older Were Dependent On Any Illicit Drugs or Alcohol But …Only 4 Million (18%) of These Individuals Had Received Some Type of Tx In the Past Year and Few involved Health Care Systems Location TX Received Self Help Group Outpatient Rehab Inpatient Rehab Outpatient Mental Health Center Hospital Inpatient Doctor’s Office Emergency Room Prison or Jail 2.1 1.5 1.0 1.0 0.8 0.7 0.6 0.4 0 .5 1.0 1.5 2.0 2.5 Numbers in Millions Source: 2012 NSDUH, National Findings, SAMHSA, OAS, 2013.

Pre - - Post During Pre - - - - - - - - - - - - Post Evaluation of A Hypothetical Treatment 10 HYPERTENSION 9 8 Pre - - Post During 7 Symptom Severity 6 5 4 3 2 Just Like Hypertension, Addiction Is A Chronic Disease That Requires Continued Care 1 Pre During During During Post 10 ADDICTION 9 Pre - - - - - - - - - - - - Post 8 7 6 Symptom Severity 5 4 3 2 1 Pre During During During Post Stage of Treatment Source: McLellan, AT, Addiction 97, 249-252, 2002.

ADDICTION TREATMENT Addiction is a chronic disease and requires continued care No single treatment is appropriate for everyone  Medications are an important element of treatment for many patients,   Drug use during treatment must be monitored continuously, as lapses during treatment occur and need to be addressed  Attends to multiple needs of the individual, including co-morbid mental illness and infectious diseases (HIV, HCV, HBV, TB) Treatment does not need to be voluntary to be effective 

Medications for Opioid Addiction antagonist agonist Full Agonist (Methadone) Opioid Effect no effect Partial Agonist (Buprenorphine) effect an antagonist drug is close enough in shape to bind to the receptor but not close enough to produce an effect. It also takes up receptor space and so prevents the endogenous ligand from binding an agonist drug has an active site of similar shape to the endogenous ligand so binds to the receptor and produces the same effect Antagonist (Naloxone) Log Dose Source: SAMHSA, 2012 National Survey on Drug Use and Health, 2013.

Opioid Agonist Treatments Decreased Heroin Overdose Deaths Baltimore, Maryland, 1995-2009 Overdose Deaths, No. Patients Treated, No. Heroin overdoses Buprenorphine patients Methadone patients Schwartz RP et al., Am J Public Health 2013;1 03: 917-922.

Methadone Maintenance Therapy Improves HIV Outcomes in IDU Methadone Maintenance Therapy Promotes Initiation Of Antiretroviral Therapy IDU Antiretroviral Adherence and HIV Treatment Outcomes Among HIV/HCV Co-Infected IDU: Role of Methadone Adjusted Odds Ratio Uhlmann S et al., Addiction 2010; 105(5):907-913. Palepu A et al., Drug and Alcohol Dependence 2006; 84: 188-194.

Implementation research Lack of uptake of medication-assisted treatment TOO FEW ARE TREATED Addiction Specialty Programs Offering Services As % of all programs surveyed (N=345) Within adopting programs, % of eligible patients receiving Rx Opioid Tx Meds: Methadone 7.8 41.3 Buprenorphine 20.9 37.3 Tablet naltrexone 22.0 10.9 Knudsen et al, 2011, J Addict Med; 5:21-27.

ED-initiated Buprenorphine Increased Engagement In Addiction Treatment, Reduced Self-reported Illicit Opioid Use, & Decreased Use Of Inpatient Addiction Treatment Services % engaged in treatment on the 30th day after randomization 5.4 2.3 Number of days of illicit opiate use per week 0.9 5.6 2.4 D’Onofrio JAMA. 2015.

Medications Are An Important Part Of Treatment For Many Drug Abusing Offenders Methadone Maintenance For Prisoners: Results At 12 Months Post-release In Treatment for one year at 12 months post-release The data are from the first 100 participants in the Prison Methadone study. The proportions of participants in treatment at 1-month post-release are: -Counseling only, 9% -Counseling+ Transfer, 42% -Counseling + Methadone, 65% Chi-square goodness-of-fit tests found that there were significant differences between Counseling Only and Counseling+Methadone (p<.001) and Counseling+Transfer (p<.01). The proportion of participants testing positive for opiates are: -Counseling only, 76% -Counseling + Transfer, 50% -Counseling + Methadone, 34% Chi-square goodness-of-fit tests found significant differences between Counseling Only and Counseling + Methadone (p<.05). Opiate + Urine Test at 12 months post release C = Counseling Only; C+T = Counseling & Transfer C+M = Counseling & Methadone Kinlock T, et al. J Subst Abuse Treatment 2009.

Challenge: How to Integrate Drug Abuse & Addiction Screening, Prevention & Treatment into the Healthcare System

Interventions Tailored to Severity In Treatment ~ 2,300,000 Addiction ~ 23,000,000 Before we talk about the specific priorities in the Strategy it is important to understand the full spectrum of the Substance USE problem in our country; different policies are needed for different parts of the overall problem This pyramid describes this very well 1 – As represented by the broad base of this pyramid –most people in the US either do not use substances or use them very very few times - Here the best policies are prevention – to keep use low 2 – As you go up the pyramid to the wavy dotted line – this shows when “use” becomes “harmful use” – either to an individual’s health or their productivity or their relationships. It is NOT a diagnosis and people can go back and forth across that line – but there are a lot of these folks about 65 – 70 million They are the people who drink and drive, or make their asthma problem worse by smoking marijuana, or are failing school because of too much weekend partying with drugs. Here we need convenient, attractive, potent but probably brief interventions to reduce use and prevent problems from becoming worse 3 –The bright solid line means that the frequency and intensity of use has reached a DIAGNOSTIC threshold – there are 23 – 25 million adults who meet diagnostic criteria for the most serious problems “SUSTANCE ABUSE AND DEPENDENCE” - Click – In comparison, most people think there is an “epidemic” of diabetes and there is - about 24 million people are diabetic. 4 - The orange pinnacle shows the number of people who are receiving any kind of treatment – about 2.3 – 2.5 million or only 1/10 of those who meet the diagnosis – even smaller proportion of those with “harmful use” – This is the “Treatment GAP” that we want to close – the worst in all of medicine 5 – The OVAL indicates that we need policies and interventions that will reach a FAR broader range of people with “substance use problems” Severity “Harmful – 40,000,000 Use” Little or No Use McLellan and Woodworth Journal of Substance Abuse Treatment, Volume 46, Issue 5, 2014, 541 - 545 20

Integration of Substance Use Disorders Into Healthcare System SUDs are too omnipresent, dangerous & expensive in healthcare to be ignored Market forces will accelerate integration 2008 Parity Law providing for coverage of SUD at level of other medical diseases 2010 Healthcare reform provides insurance to individuals with SUD that in the past would have not had access to healthcare Mainstream healthcare needs to prepare for this Integrate with specialty service

Resources for Medical Students, Resident Physicians & Faculty NIDA CoEs established in 2007 to help fill gaps in medical education curricula related to both illicit drugs and Rx drug abuse Medical schools at CoEs have developed a diverse portfolio of innovative curriculum resources about how to identify and treat patients struggling with SUD

GO Addicted Brain STOP Non-Addicted Brain Memory Memory Drive Drive Saliency Control Drive OFC Saliency NAc Memory Amygdala Control CG Drive Memory Saliency STOP GO Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.