Policy Implications of the Neurobiology of Addiction

Transcription

1 Policy Implications of the Neurobiology of Addiction Facilitator: Jay Butler, MD, President of ASTHO, Chief Medical Officer Alaska Department of Health and Social Services Director, Alaska Division of Public Health Wilson Compton, MD, MPE, Deputy Director National Institute on Drug Abuse

2 Advancing Addiction Science Science = Solutions Wilson M. Compton, M.D., M.P.E. Deputy Director National Institute on Drug Abuse

3 ADDICTIONS as Diseases of Gene-Environment-Development Biology Genes/Development DRUG/ALCOHOL Brain Mechanisms Environment Addiction Age

4 There are Multiple Environmental Influences Laws/Culture Neighborhood/ Community Family/Peers Biology Individual/ Genes Time/Age

5 Effects of a Social Stressor on Brain Dopamine D2 Receptors and Propensity to Administer Drugs Individually Housed Becomes Dominant No longer stressed Social Setting Can Change Neurobiology Becomes Subordinate Group Housed * Dominant Subordinate * Cocaine (mg/kg/injection) S Social Support Is Correlated with D2/3 Receptor Binding Stress remains D. Morgan et al. Nature Neuroscience (2002) Martinez D. et al., Bio Psychiatry 2010.

6 Genes for Serotonin Transporter Modulate Parenting s Impact on Substance Abuse Vulnerability Substance Use Rate of Increase No Genetic Risk (l-l allele) Genetic Risk (s-s or s-l allele) Low High Involved-Supportive Parenting High supportive parenting decreased substance use risk in those with low serotonin transporter expressing variants (high risk alleles) G. Brody et al. J Consulting Clinical Psychol (2009) Science = Solutions

7 Three Major Addiction Themes Where Science is Needed to Inform Policy MARIJUANA: The shifting legal landscape suggests possible population impacts E-CIGARETTES: Both potential promise for established tobacco users and concern for increasing adolescent use OPIOIDS: Impacts on public health in the USA starting with overexposure to prescription opioids

8 Status of Marijuana Laws in the USA

9 Percentage of U.S. 12 th Grade Students Reporting Past Month Use of Alcohol, Cigarettesand Marijuana Alcohol Marijuana Cigarettes SOURCE: University of Michigan, 2015 Monitoring the Future Study.

10 Marijuana Potency (% Δ-9 THC) Tripled in Past 20 Years 20-9 THC % THC SOURCE: University of Mississippi Marijuana Project (potency data) Science = Solutions

11 More Teenage Use of Marijuana Associated with Worse Outcomes in 20 s (3 Australia/New Zealand Studies) 1.2 O.R HS Complete 0 HS Complete Never < Monthly Monthly + Weekly + Daily 20 O.R O.R Other Illicit Drug O.R. Suicide Attempt 0 Cannabis Depend Silins, et al., Lancet Psychiatry 2014;1:

12 When MJ Sales Were Restricted in The Netherlands, University Grades Improved Marie O, Zollitz U, IZA Discussion Paper No. 8900, March 2015

13 Regular Marijuana Use Increases Schizophrenia Risk in those with AKT1 rs genotype High Potency Marijuana and Earlier Onset of Psychosis Odds Ratio Never used cannabis History of cannabis use AKT1(T/T) AKT1(C/T) AKT1(C/C) Odds Ratio Never used cannabis Used cannabis at week ends or less Used cannabis everyday 26.5* 25.2* AKT1(T/T) AKT(C/T) AKT1(C/C) AKT1 genotype does not predict History of Cannabis use (p=0.772) GXE multiplicative model: p*=0.014 Di Forti et al., Biological Psychiatry, None Weekly Hash Daily Hash Weekly Skunk Daily Skunk Di Forti M et al. Schizophr Bull 2013;schbul.sbt181

14 Early (<18y) Long-Term Cannabis Use Associated with Decreased Axonal Fiber Connectivity Precuneus to splenium Fimbria of hippocampus, hippocampal commissure and Splenium Axonal paths with reduced connectivity (measured with diffusion-weighted MRI) in cannabis users (n=59) than in controls (N=33). Zalesky et al Brain 2012.

15 Adolescent Brain Cognitive Development (ABCD) Study An NIH Collaboration: NIDA, NIAAA, NCI, NIMH, NIMHD, NICHD, NINDS, OBSSR Source:

16 More U.S. Youth Use E-Cigs Than Combustible Cigs 2014 Past Month E-Cig vs. Combustibles in USA Students Combustible Cigarettes E-Cigarettes 16% 14% 17% In a prospective study of 14 year old students, E-Cigarette use predicting onset of: Any combustible 2.75 AOR Combustible cigs 1.73 AOR Leventhal, et al. JAMA 2015;314(7): % 8% 7% 8th Grade 10th Grade 12th Grade Monitoring the Future Study 2014, University of Michigan U.S. study of year olds (n=13,561), first tobacco product was flavored among users: Cigarettes 50% Smokeless 69% E-Cigarettes 81% Ambrose, et al. JAMA, 26 October 2015

17 Nicotine Effects Particularly Impacts Adolescent Brain Nicotine up-regulates arc (involved in synaptic plasticity) in adolescents but not adults (rodent models) Adolescent Adult Nicotine enhances response to cocaine in adolescents but not adults (rodent models) Schochet AE, et al. Neuroscience 135 (2005) Levine A. et al., Sci Transl Med. 2011

18 Marked Increases in Prescription Opioid and Heroin Overdose Deaths in the USA 2000 to 2014 Number of Deaths 30,000 25,000 20,000 15,000 10,000 5,000 0 USA 2014 Overdose Deaths: 47,055 Any Drug 27,119 Any Opioid 18,893 Rx opioid 10,574 Heroin Any opioid Opioid Analgesics Heroin Source: CDC, NVSS

19 Marked Geographic and Temporal Variation in Mortality : Estimated Age-adjusted Death Rates for Drug Poisoning by County Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System; Tom Frieden Presentation at the Opioid Summit, Atlanta, April 2016

20 Outbreak of HIV Linked to IDU of Oxymorphone in Indiana, % 162 HIV Infections in a Community of % 17% (23) All reported injecting tablets of oxymorphone As drug of choice 84.4% 114 co-infected with Hepatitis C Injection Drug Use No Injection Drug Use Status Not Determined located Reported average of 9 syringe-sharing partners, sex partners, or other social contacts at risk for HIV infection 61.7% 4.6% 373 HIV- 230 tested % 47% syringe-sharing or sex partners contacts 74 HIV % 42.2% 128 not located social contacts regarded as at high risk for HIV

21 Science = Solutions: Using Research to Improve HIV and Hepatitis C in Rural Areas NIH is partnering with the CDC, SAMHSA and the Appalachian Regional Commission (ARC) to conduct research to address increased opioid injection drug use and resulting overdose, HIV and Hepatitis C infection. Improve understanding problem s scope; contributing health trends Identify resources, obstacles Develop intervention approaches to address these health threats

22 Similarities of Illicit & Prescription Opioids Source: Compton, Jones, Grant NEJM 2016; 374:

23 Most Heroin Users Report Previous Non-Medical Use of Prescription Opioids, BUT Only a Small Proportion of Non-Medical Users Progress to Heroin National General Population: Within 5 years, 3.6% of non-medical users of opioids progressed to heroin within 5 years (i.e. less than 1% per year) (Muhuri, Gfroerer, Davies. 2013) Local Longitudinal Study of Non-medical users: Within 3 years, 7.5% progressed to heroin (i.e. 2.8% per year) (Carlson, Nahhas, martins, Daniulaityte. 2015) Science = Solutions

24 Secretary Burwell s/hhs Opioid Priority Areas Opioid prescribing practices to prevent opioid use disorders and overdose The expanded use of naloxone, used to treat opioid overdoses Expanded use of medication assisted treatment (MAT) for opioid use disorders

25 Doctors Continue to Prescribe Opioids for Ninety-one Percent of Overdose Patients In a 2-year follow-up of 2848 commercially insured patients (from 2000 to 2012) who had a nonfatal opioid overdose during long-term opioid therapy : 14% 13% 10% 63% of high-dose opioid patients were still on a high dose days after overdosing 17% of high- dose patients overdosed again within two years high dose moderate dose low dose none 33-39% of those with active opioid prescriptions during follow-up also were prescribed benzodiazepines. Larochelle et al. Ann Intern Med. 2016;164(1):1-9.

26 Direct Overdose Intervention Naloxone Distribution for opioid overdose victims. The potential for direct intervention to save lives. Evzio naloxone auto-injector APPROVED BY FDA, April 3, 2014 Narcan Nasal Spray naloxone APPROVED BY FDA, November 18, 2015 Science = Solutions

27 Medications for Opioid Addiction Full Agonist: Methadone (daily dosing) Partial Agonist: Buprenorphine (3-4X week and 6 month Implant) Antagonists: Naltrexone (ER 1 month) agonist antagonist Full Agonist (Methadone) effect no effect Binds to receptor but has no effect. Prevents heroin from binding Binds to the receptor. Prevents Heroin from binding. Opioid Effect Log Dose Partial Agonist (Buprenorphine) Antagonist (Naltrexone) Source: National Institute on Drug Abuse, Science = Solutions

28 Accessing Medications Can Save Lives Opioid Agonist Treatments Decreased Heroin OD Deaths Baltimore, Maryland, Heroin overdoses Buprenorphine patients Methadone patients Schwartz RP et al., Am J Public Health Science = Solutions

29 ADDICTION: New Medications Challenge: Compliance with daily intake Solution: Develop long acting medications % of Patients Failing to Exceed Each Possible Criterion of Success Placebo Sublingual Buprenorphine Buprenorphine Implants Buprenorphine implants approved by FDA, May 27, 2016 % of Urines Negative (out of 72) for Opioids Across Weeks 1 to 24` Rosenthal RN et al., Addiction 2013;105: Science = Solutions

30 Prevention: Universal Drug Abuse Prevention Reduces Prescription Drug Misuse 16% 12% 8% 4% 0% ** p<.01; 15.5% 5.4% ** Age 25 General 13.5% 4.7% Age 25 Opioids Control Family Program ** In this study, for 100 young adults in general population starting Rx abuse, only 35 young adults from an intervention community started. Overall, three studies now suggest the impact of universal prevention on prescription drug abuse. Notes: General=Misuse of narcotics or CNS depressants or stimulants. Source: R Spoth et al. American Journal of Public Health 2013 Science = Solutions

31 Prevention: Less Abusable Medications Uptake in Striatum (nci/cc) Slow!! Time (minutes) Develop medications with lower abuse potential including drugs that don t cross the Blood-Brain-Barrier (i.e., CbR2 agonist) Develop slow release formulations (low dose and long duration) and prodrug formulations (only activated with digestion) Develop novel formulations to reduce abuse liability including mixture formulations (e.g., naloxone and buprenorphine) Science = Solutions

32 PAIN: Non-Medication Treatments for Pain and Addiction Transcranial Magnetic Stimulation (TMS) Left periventricular gray Left sensory thalamus Deep Brain Stimulation (DBS) Stereotaxtic implantation of electrodes that emit electrical stimulation to a targeted neuronal region High-Definition transcranial Direct Current Stimulation (HD-tDCS) Transcranial Direct Current Simulation (tdcs) Gray AM et al., J Pain 2014; 15(3): Morena-Duarte I et al., Neuroimage 2014; 85(3): Science = Solutions

33 Novel Treatment Sites: Access to Buprenorphine in Emergency Department Increased Engagement In Addiction Treatment & Reduced Self-reported Illicit Opioid Use % engaged in treatment on the 30 th day after randomization D Onofrio, et al. JAMA % % 45% Buprenorphine Referral Brief Intervention Number of days of illicit opiate use per week Science = Solutions

34 Improving Treatments for Addiction: Extended Release Naltrexone in Criminal Justice Involved Populations Participants: parolees/probationers with opioid addiction all volunteers received either Monthly injections of extended release naltrexone for 6 months Community treatment, including methadone or buprenorphine and naloxone (encouraged) Relapse Frequency Probability of No Relapse Naltrexone Treatment as usual ODs in 78 weeks: Control: 7 Naltrexone: 0 Lee et al. NEJM March 31, O Brien et al., Poster presentation Weeksat the Annual Meeting of the College on Problems of Drug Dependence, June Science = Solutions

35 Conclusions/Summary MARIJUANA and E-Cigarettes: Neuroscience is especially needed to understand the impacts of marijuana and nicotine exposure on the developing brain. OPIOIDS: The development of non-opioid pain treatments and new treatments for opioid addiction depend on a full understanding of opioid neuroscience

36 Science = Solutions