Indiana CTSI Retreat 2018Medical(Science(Solutions(to(Indiana’s(Opioid(Crisis

Indiana(University(Bloomington

Wednesday,(April(25,(2018

Wilson'Compton,'M.D.

Keynote'Lecture'4'Advancing'Addiction'Science'to'Address'the'

Opioid'Crisis:'Science'='Solutions”

Advancing)Addiction)Science)to)Address)the)Opioid)Crisis

Advancing)Addiction)Science

Wilson'M.'Compton,'M.D.,'M.P.E.Deputy'Director

National'Institute'on'Drug'Abuse

Science)=)Solutions

ADDICTIONS)as)Diseases)of)Gene$Environment$Development

Environment))))

Addiction

DRUG/ALCOHOL))

Brain)Mechanisms)))

BiologyGenes/Development

1

2.3 2.73.5 3.4

7.7

0123456789

0 1 2 3 4 ≥5

Adjusted

3Odd

s3Ratio,3p<.05

ACE+Score

Ever+AddictedN=8613

Adverse'Childhood'Experiences''(ACE)&Associated&with&Increased&Illicit&Drug&Use

SR#Dube,#et#al.#PEDIATRICS#111:#5648572,#2003

IndividuallyHoused

D.0Morgan0et0al.0Nature0Neuroscience0(2002)

**

S.003 .01 .03 .10

10

20

30

40

50

Reinforcers

(per0session)

Cocaine0(mg/kg/injection)

DominantSubordinate

Social0Setting0Can0Change0Neurobiology

Effects0of0a0Social0Stressor on0Brain0Dopamine0D20Receptors0and0Propensity0to0Administer0Drugs

GroupHoused

Becomes0Subordinate

Becomes0Dominant

Stress0remains

No0longer0stressed

Social0Status0Is0Correlatedwith0D2/30Receptor0Binding

Martinez0D.0et0al.,0Bio0Psychiatry02010.

Brody GH, et al. JAMA Pediatr, 2017.

The$Environment$MattersA$recent$study$shows$that$a$Family8Based$intervention$for$

young$teenagers$can$help$brain$development

Science&= Solutions

More%years%in%poverty%as%a%teen%=%smaller%brain%volumes.

More%years%in%poverty%as%a%teen%=%smaller%brain%volumes.

With%the%SAAF%intervention,%no%difference%in%brain%volume.%%

With%the%SAAF%intervention,%no%difference%in%brain%volume.%%

Figure: Effect of Family Poverty on Youth Brain Region by Intervention Status. SAAF=Strong African American Families intervention.

Virtually)All#of#the#U.S.#Have)Increased)Drug)Overdoses:))Estimated#Age3adjusted#Death#Rates#per#100,000#for#Drug#Poisoning#by#County

Source:(https://www.cdc.gov/nchs/data5visualization/drug5poisoning5mortality/index.htm

1999 2016

Evolution)of)the)Opioid)OD)Crisis:

Source:(NCHS(WONDER,(NCHS(Data(Brief(294

05,00010,00015,00020,00025,00030,00035,00040,00045,000

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

Any/OpioidCommonly/Prescribed/Opioids/(natural/&/semisynthetics/and/methadone)HeroinSynthetic/Opioids/Other/Than/Methadone/(i.e.//Fentanyl/and/Related)

42,249/Any/Opioid

17,087/Rx19,413/“Fentanyl”

15,469/Heroin

Analgesics**********Heroin**********Fentanyl

1. Over'prescription'of'opioid'medications'led'to'misuse2. Addiction'to'prescription'opioids'led'to'heroin3. Emergence'of'fentanyl(s),'with'higher'potency'and'greater'profitability'in'

the'black'market'than'heroin.'

Morphine)equivalent0(mg/patient0in0need0of0care),0and0estimated0percentage0of0need0that0is0met

Knaul&FM&Lancet&2017

Over%reliance%on%opioids%for%pain%management

People&Misusing&Analgesics&Obtain&them&Directly)&)Indirectly)by&Prescription&

Source)where)pain)relievers)obtained)for)most)recent)misuse

10%

36%87%

10%

3%

54%

Friend/Relative

Prescription

Other

Their&Prescription

Their&Friend/RelativeOther

Source:((Han,(Compton,(et(al.(Annals(of(Internal(Medicine(2017;167(5):293E301

Source)where)pain)relievers)obtained)for)most)recent)misuse

10%

36%87%

10%

3%

54%

Friend/Relative

Prescription

Other

Their&Prescription

Their&Friend/RelativeOther

Source:((Han,(Compton,(et(al.(Annals(of(Internal(Medicine(2017;167(5):293E301

Doctors'Continue'to'Prescribe'Opioids'for'Ninety5one'Percent'of'Overdose'Patients

Source:(Larochelle et(al.(Ann#Intern#Med.(2016;164(1):179.

high(dose moderate(doselow(dose none

63%$of$high*dose$opioid$pts$still$on$high$dose$31*90$days$after$OD$

17%of'high5 dose'

patients'overdosed'again'within'two'years

In#a#25year'follow5up'of'2848'commercially'insured'patients'who'had'a'nonfatal'opioid'overdose during#long0term#opioid#therapy#:

!33539%'of'those'with'active'opioid'prescriptions'during'follow5up'also'were'prescribed'benzodiazepines.

Analgesic*Mechanisms*of*Mu*Opiate*Drugs*(Heroin,*Vicodin,*Morphine)

Thalamus(pain)

ACC(pain)

PAG(pain)

Accumbens(reward)

ECONOMICS:))Heroin'Increases'Due'to'Lower'Price'and'Greater'Availability

!$#

!$500

!$1,000

!$1,500

!$2,000

!$2,500

!$3,000

!$3,5001981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

"Retail"!Price!Per!Pure!Gram

National(Drug(Control(Strategy11Data(Supplement(2014.(https://www.whitehouse.gov/sites/default/files/ondcp/policy1and1research/ndcs_data_supplement_2014.pdf

ECONOMICS:))CHEAP&Fentanyl&Precursor&Chemicals

Heroin'Contaminated'with'Fentanyl'Dramatically'

Enhances'Brain'Hypoxia

Solis&et&al.,&2017,&eNeuro

Fentanyl’s*higher*potency*contributes*to*its*lethality*and*when*combined*with*heroin this*might*enhance*their*toxicity

National'Forensic'Laboratory'Information'System'(NFLIS).''Fentanyl'ORANGEFentanyl'analogues'RED

More'than'double'of'the'drugs'seized'by'DEA'tested'positive'for'fentanyl'from'2015'to'2016

Counties)Deemed)Highly)Vulnerable to)Rapid)Dissemination)of)HCV)or)HIV

Source:)Van)Handel)et)al,)JAIDS)2016

Rising)rates)of)HCV

HIV (and%Hepatitis)C)%Outbreak%Linked%to%Oxymorphone Injection%

Use%in%Indiana,%2015Peters%et%al.%%

The New England Journal ofMedicine 2016;375:229I239

0

500

1,000

1,500

2,000

2,500

3,000

3,500

20002002200420062008201020122014

Number-of-cases

National(Notifiable(Diseases(Surveillance(System((NNDSS)

• ~31,000%new%HCV%infections%in%2015

• 1:1%male:%female%ratio,%predominantly%white

Science&=&Solutions:"NIDA,"CDC,"SAMHSA,"ARC"Partnering"to"Combat"HIV"and"Viral"Hepatitis"in"Rural"Areas

New$England

Ohio

West$Virginia

Kentucky

North$Carolina

Illinois

WisconsinOregon

Science&=&Solutions&:""Opioid"Use"and"Misuse"During"Pregnancy"

Increasing*NICU*Admissions*for*Neonatal*Abstinence*Syndrome*NAS*(per%1000%%

Admissions)

Source:((Tolia VN,(Patrick(SW,(et(al.,(NEJM 2015;372:2118=2126.

Buprenorphine resulted(in(a(shorter,durationof,NAS,treatment,and(length,of,hospital,stay

than(treatment(with(morphineSource:((Kraft(WK(et(al.,(NEJM 2017;376:2341=2348.

Buprenorphine*for*NAS*Tx

Source:((Winkelman(TNA,(Villapiano N,(Kozhimannil KB,(Davis(MM,(Patrick(SM..(Pediatrics.+2018;141(4):e20173520

Increasing&Costs&for&Neonatal&Exposure

Prevention)

Research(on(the(Neurobiology(of(Pain

• Males&had&higher&K&opioid&receptor&availability&than&females&presumably&from&increased&dynorphin.&&• Could&this help&explain&gender&differences&in&pain&catastrophizing??

Vijay&et&al.,&Am(J(Nucl(Med(Mol(Imaging. 2016&6(4):2055214.

Males

Females

Gender(Differences(in(Kappa(Opioid(Receptor(Availability

New$Target$for$Pain$Control• Congenital+analgesia:+rare+condition,+individuals+cannot+feel+pain+–Mutation+identified+in+gene+that+encodes+for+Nav1.7+– sodium+channel+that+regulates+pain>sensing+neurons

• Targeting+Nav1.7+to+produce+analgesia–Several+companies+now+have+drugs+in+pipeline+to+block+channel• Targeting+complications–Understanding+what+happens+when+Nav1.7+is+blocked

Science$= Solutions

Soergel DG,*et*al.,*Pain 2014.**Manglik A, et al., Nature 2016. DeWire SM, et al., JPET 2013. Bohn LM, et al., Science 1999

A"Promising"New"Generation"Of"Pain"Therapeutics

Science&= Solutions

Biased&Mu0Opioid&Receptor&Ligands

Resources(for(Medical(Students,(Resident(Physicians(&(Faculty

Web(training(on(pain(assessment(and(treatment

Archived(NIDA(CME(Courses:

Safe(Prescribing(for(PainManaging(Pain(Patients(Who(Abuse(Rx(Drugs

Opioid&Education&

Upcoming(NIDA(CME(Course:

Adolescent(Substance(Use((Prescription(Opioid(Module)

Bringing(NIDA(research(to(

clinical(practice

Medical(schools(have(developed(innovative(curriculum(resources(about(how(to(identify(and(treat(patients(with(substance(use(disorders

Universal*Drug*Abuse*Prevention*Reduces'Opioid'(and'other)'Prescription'Drug'Misuse

Notes:*General=Misuse*of*narcotics*or*CNS*depressants*or*stimulants.**Source:**R*Spoth et*al.*American*Journal*of*Public*Health*2013

In*this*study,*for*100*young*adults*in*general*population*starting*Rx*abuse,*only*35*young*adults*from*an*intervention*community**started.*

1.2**0.6***

5.4**4.7**

9.38.7

15.5

13.5

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

Age1211General Age1211Narcotics Age1251General Age1251Narcotics

Family1Program

Control

**p<.01;1***p<.001;1RRRs1=165G93%

Overall,*three*studies*now*suggest*the*impact*of*universal*prevention*on*prescription*drug*abuse.**

Science&="Solutions

Naloxone(Distribution for$opioid$overdose$victims.$$The$potential for$direct$intervention$to$save$lives.$$

! Nasal(spray(and$Auto3injector formulations$now$approved$by$the$FDA

Next(steps• Longer(acting(agents(to(

address(fentanyl(risks?• Respiratory(stimulation?(• Device(development?

Science(=(Solutions:$Direct$Overdose$Intervention

I,#Surgeon#General#of#the#United#States#Public#Health#Service,#VADM#Jerome#Adams,#am#emphasizing#the#importance#of#the#overdoseBreversing#drug#naloxone.#For#patients#currently#taking#high#doses#of#opioids#as#prescribed#for#pain,#individuals#misusing#prescription#opioids,#individuals#using#illicit#opioids#such#as#heroin#or#fentanyl,#health#care#practitioners,#family#and#friends#of#people#who#have#an#opioid#use#disorder,#and#community#members#who#come#into#contact#with#people#at#risk#for#opioid#overdose, knowing'how'to'use'naloxone'and'keeping'it'within'reach'can'save'a'life.

BE#PREPARED.#GET#NALOXONE.#SAVE#A#LIFE.

April#5,#2018Surgeon#General’s#Advisory#on#Naloxone#and#Opioid#Overdose

Retail'Pharmacy'Prescriptions'for$Naloxone$Increase$Markedly

• Retail'prescriptions'show'an'increase'of'9520% from'the'4thquarter'of'2013'to'2nd quarter'2016.''

• Outpatient'prescribing'of'naloxone'may'complement'communityAbased'distribution'and'first'responder'access.''

Sources:'Jones'CM,'Lurie'PG,'Compton'WM.'Am'J'Public'Health.'2016;106(4):689J690;

Science&='Solutions

0

5000

10000

15000

20000

25000

30000

35000

1Q2010

3Q2010

1Q2011

3Q2011

1Q2012

3Q2012

1Q2013

3Q2013

1Q2014

3Q2014

1Q2015

3Q2015

1Q2016

20142015

2016

Medications+are+Effective+for$Opioid$Use$Disorder

Medication+Assisted+Treatment+(MAT)+can$DECREASE:• Opioid$use• Opioid4related$overdose$deaths• Criminal$activity• Infectious$disease$transmission

And$INCREASE• Social$functioning• Retention$in$treatment

Kakko J+et+al.,+The+Lancet+2003.

Jones&C&et&al.,&Am&J&Public&Health&2015.

In#48#states#and#D.C.,#Opioid#Use#Disorder#Rates#Exceed#Buprenorphine#Treatment#Capacity#

Medications+are+Underused

25%

9%17%

9%16% 19%

0%10%20%30%40%50%60%70%80%90%100%

Buprenorphine

Methadone

Tablet<naltrexone

Injectable<naltrexone

Disulfiram

Acamprosate

%<Treatment<Programs<Offering<FDAJapproved

SUD<Medications

Knudsen&et&al.,&J&Addict&Med&2011

25%

75%

In#2014,#only#25%#of#opioid#admissions#had#treatment#plans#that#included#receiving#medications.

Treatment&Episode&Data&Set&

(TEDS):&2004H2014.

MAT No+MAT

• Initiating'buprenorphine'treatment'in'the'emergency(department(improves'treatment'engagement'and'reduces'illicit'opioid'use

• Extended'release'naltrexone'initiated'in'criminal(justice settings'lowers'relapse'rates'and'overdoses

• XR:Naltrexone'and'BUP:Nx Equally(Safe(and(Effective((After'Induction)

• Lofexidine for'opioid'withdrawal'treatment'recommended'by'FDA'Advisory'Committee'March'29,'2018

Science(=(Solutions:""Improving"Addiction"Treatment

Lee'JD,'et'al.,''Addiction'2015;100:1005:1014'

and'New'Eng J'Med'2016;374:1232:1242

Relapse6free"survival

Lee#JD#et#al.,#The$Lancet Nov.#14,#2017

Antibodies*reduce*amount*of*drug*in*the*brain

CapillaryBlood*Flow

Brain

Targets(drugs,(not(receptors

CapillaryBlood*Flow

Brain

AntibodiesVaccine

Binding(sites

Immunotherapies(for(Opioid(Use(Disorder

Hwang&et&al.,&Efficacious&Vaccine&against&Heroin&Contaminated&with&Fentanyl.&ACS&Chem.&Neurosci.&2018&

Non$Pharmacological.Treatments.for$Addiction

Salling and$Martinez,$2016.

Transcranial Direct$Current$Simulation$(tDCS)

Deep$Brain$Stimulation$(DBS)Implanted$electrodes$emit$electrical$stimulation$to$targeted$brain$region

Transcranial Magnetic$Stimulation$(TMS)

Using&Research&to&End&the&Opioid&CrisisNIH$Opioid$Research

PAIN$MANAGEMENTSafe,$effective,$non=addictive$strategies

OPIOID$ADDICTION$TREATMENT

New,$innovative$medications$and$technologies

OVERDOSE$REVERSAL

Interventions$to$reduce$mortality$

and$link$to$treatment

Non=Opioid$Analgesics

Biomarkers$For$Pain$

Opioid$Vaccines

Nonpharmacological$Treatments$(e.g.$TMS)

Respiratory$Stimulation$Devices

New$NIH$Initiative$to$Address$the$Crisis:$HEAL:$Helping$to$End$Addiction$Long:term

• Collaborative,,cross/cutting,research• From,basic,to,behavioral,– and,everything,between• Innovative,partnerships,– across,agencies,,sectors,,

organizations,– will,ensure,rapid,progress,• $500M%just%added%by%Congress• Adds,to,$600M,current,funds,=,$1.1B,for,FY18• Will,propel,HEAL,

• Advances,national'priorities'for'pain,'addiction'research

• Complex(biological,(developmental(and(social(aspects(of(substance(use(and(addiction(suggest(multipronged-responses.• The(severity(of(the(opioid(crisis(demands(urgent-action.-

Summary:Advancing)Addiction)Science

www.drugabuse.gov

www.nih.gov/opioid7crisis

Science)="Solutions