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Nora D. Volkow, M.D. Director @NIDAnews National Institute on Drug Abuse Addressing the Opioid Crisis: A Key Role for Translational Science
Nora D. Volkow, M.D.Director
@NIDAnews
National Instituteon Drug Abuse
Addressing the Opioid Crisis: A Key Role for Translational Science
Overdose Death Rates
1999 2016
Source: https://www.cdc.gov/nchs/data-visualization/drug-poisoning-mortality/index.htm
Analgesic & Reward Mechanisms of Mu Opiate Drugs (Heroin, Vicodin, Morphine)
Thalamus(pain)
ACC(pain) PAG
(pain)Accumbens(reward)
Cocaine
Alcohol
Heroin
Meth
control addicted
Decreased Levels of DA D2 Receptors in Drug Addicted Individuals
DA
DA
DA
DA DADA
DA
DADA DADA
DA
DA
DA
DA
DA DA
DA
Drug Abuser
Non-Drug Abuser
Volkow et al., PNAS 2011
Opioid Prescriptions 1991-2011
76 78 80 86 91 96100109120
131139144151158169
180192201202210
219
0
50
100
150
200
250
91 93 95 97 99 01 03 05 07 09 11
Pres
crip
tions
(mill
ions
)
IMS’s Source Prescription Audit (SPA) &Vector One®: National (VONA)
Opioids Hydrocodone Oxycodone
266 260 253242 234
222
0
50
100
150
200
250
300
2010 2011 2012 2013 2014 2015
OPI
OID
MM
E IN
BIL
LIO
NS
IMS Health, U.S. Outpatient Retail Setting
Opioid morphine milligram equivalents (MME) dispensed fell by over 15% from 2010-2015
Evolution of the Opioid CrisisOverdose Fatalities
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.
8521275 1434
4527
6643
8029
4124
3599
4116
294 453 524
2642
2033
2890
3672
1187
1994
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
PRESCRIPTION OPIOIDS HEROIN SYNTHETIC OPIOIDSMale 15-24 Male 25-44 Male 45-64Female 15-24 Female 25-44 Female 45-64
Overdose Deaths Involving Opioids, U.S., 2016
(other than methadone)
Puja Seth et al., MMWR, Weekly / March 30, 2018 / 67(12);349–358.
PAIN MANAGEMENTSafe, more effective strategies
OPIOID ADDICTION TREATMENT
New and innovative medications and
technologies
OVERDOSE REVERSALInterventions to reduce
mortality and link to treatment
Using Research to End the Opioid Crisis
NIH OPIOID RESEARCH INITIATIVE
Safe, More Effective Strategies for Pain Management
Non-pharmacological treatmentNeural stimulation;
Surgical interventions; Meditation
Non-Opioid AnalgesicsCannabinoids;Inflammatory mediators; Ion channel blockers
Targeted Opioid Analgesicswith reduced potential for addiction and overdose
Soergel DG et al., Pain 2014; 155(9):1829–1835.
Biased Mu-Opioid Receptor Ligands: New Generation Of Pain Therapeutics
Biologicse.g. antibodies that bind to pain producing cytokines
Williams AR, Nunes E, Olfson M. Health Affairs Blog, 2017
OUD Cascade of Carein USA
Opi
oid
Effe
ct
Full Agonist(Methadone: Daily Dosing)
Partial Agonist(Buprenorphine: 3-4X week)
Antagonist(Naltrexone: ER 1 month)Log Dose
DECREASES:• Opioid use• Opioid-related overdose deaths• Criminal activity• Infectious disease transmission
INCREASES• Social functioning• Retention in treatment
MAT is highly underutilized!Relapse rates are very high (50% in 6 months)
Medication Assisted Treatment (MAT)
Expand access to MATHealthcare systemCriminal Justice system
Medication developmentExtended release formulationsDrug combinationsNew Targets, Vaccines others
Extended Release Formulations• Vivitrol®
Rosenthal et al., Addiction 2013;105.
• PROBUPHINE®
FDA approval – May 26, 2016Krupitzky et al., Lancet 2011
Placebo: N=124XR-NTX: N=126
IM Injection q 4 weeks for 24 weeks
Median % Opioid-Negative Urines
Perc
ent o
f Wee
kly
Urin
e Te
sts 100%
80%
60%
40%
20%
0% PLACEBO XR-NTX
Opportunities for Partnership in the Development of Longer Acting Formulations and/or Drug Combinations to Improve Treatment Compliance and Retention
SUBLOCADE™ (Buprenorphine ER), Once-Month InjectableFDA Approval 11.30.2017
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90 100
RBP-6000 300/100 mg + IDC
RBP-6000 300/300 mg + IDC
Placebo + IDC
% urine samples negative for opioids (Weeks 5 to 24)
Perc
enta
ge o
f sub
ject
s
>% Abstinence (opioid-free weeks)
**
Heidbreder et al., CPDD 2017
Weekly or monthly injection
CAM2038: Subcutaneous ER Buprenorphine
0
20
40
60
80
100
≥ 0% ≥ 10% ≥ 20% ≥ 30% ≥ 40% ≥ 50% ≥ 60% ≥ 70% ≥ 80% ≥ 90% 100%
p=0.004
% P
artic
ipan
ts% Negative Urine
Comparison CAM2038 versus Daily SL BPN
Target Selection on the Basis of the Neurocircuitry of Addiction
Targets to reduce cue-induced drug seeking and to improve executive function
Targets to reduce stress-induced drug seeking and to improve mood
Compounds targeted to neurocircuitry could be beneficial not just to addiction but also to diseases for which such circuits are disrupted (i.e., ADHD, depression)
Diagram: Koob GF, Volkow ND. Neuropsychopharmacol Rev, 2010
Targets to interfere with drug reward
Antibodies reduce amount of drug in the brain
CapillaryBlood Flow
Brain
Targets drugs, not receptors
CapillaryBlood Flow
Brain
Antibodies
Vaccine
Binding sites
Immunotherapies for Opioid Use Disorder
Hwang et al., Efficacious Vaccine against Heroin Contaminated with Fentanyl. ACS Chem. Neurosci. 2018
Expand access to MATHealthcare systemCriminal Justice system
Medication developmentExtended release formulationsDrug combinationsNew Targets, Vaccines others
In 2016 An Estimated 20.1 Million Americans12 or Older Were Dependent On Any Illicit Drugs or Alcohol
But…Only 3.8 Million (19%)of These Individuals HadReceived Some Type ofTx In the Past Year and few involved Health Care Systems
Source: 2016 NSDUH, National Findings, SAMHSA, OAS, 2017.
Self Help Group
Outpatient Rehab
Outpatient MentalHealth Center
Inpatient Rehab
Doctor’s Office
Hospital Inpatient
Emergency Room
Prison or Jail
Numbers in Millions0 .5 1.0 1.5 2.0 2.5
1.8
1.5
1.1
0.9
0.5
Location TX Received
0.9
0.3
Opportunities with Health Care Reform to Expand Involvement of the Health Care System
in Treatment of SUD
0.9
0.7
Adapted from Morgan et al., 2017; permission for use of data provided by Dr. J.R. Morgan.Morgan JR, Schackman BR, Leff JA, et al. J Subst Abuse Tx, 2017.
5.4 5.4 5.6
0.9
2.3 2.4
0
1
2
3
4
5
6
Buprenorphine Referral Brief Intervention
Baseline 30 days
Improving Treatments for Addiction:Implementing Medication-Assisted Treatment
•Emergency department-initiated buprenorphine • Reduced self-reported, illicit opioid use• Increased engagement in addiction treatment; decreased use of inpatient
addiction treatment services
Day
s
Self-Reported Illicit Opioid Use in the Past 7 Days
D’Onofrio G et al., JAMA April 28, 2015.
Overdoses in 78 weeks:
Control: 7Naltrexone: 0
Naltrexone Trial in CJ 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 Suboxone
(encouraged)
O’Brien et al., Poster presentation at the Annual Meeting of the College on Problems of Drug Dependence, June 2015.
Relapse Frequency
Prob
abili
ty o
f No
Rel
apse
Weeks
Treatment as usual
Naltrexone
Lee et al. NEJM March 31, 2016.
Improving Treatments for Addiction:
Marsden J et al., Addiction 2017; 112:1408-1418.
Opioid Medication Therapy (OMT) In Prison
Mortality Post Release
OMT unexposedOMT exposed
Days since prison release
Surv
ival
pro
babi
lity
Postincarceration Overdose Deaths After Implementing OMT in a Statewide Correctional System (Rhode Island)
Green TC and Clarke J. JAMA Psychiatry 2018;75(4).
179 157
0
50
100
150
200
250
Num
ber O
D F
atal
ities
12.5%decrease
Statewide Overdose Deaths
1/1 to 6/302016
1/1 to 6/302017
OMT resulted in a 75% reduction in mortality (85% reduction in overdoses) in the first monthpost release
Survival Curve During the Year Following Release (Drug-Poisoning Mortality)
OD fatalities in those who had been incarcerated in 2017 decreased by 60% compared to 2016(5.7% vs 14.5%)
PAIN
ORWHOBSSRNIDANIDCRNINDS
NIANINRNICHDNIAMSNCCIH
NIH Pain Consortium Centers of Excellence in Pain Education
Goal: Improve pain treatment through education
EducationSUD
Goal: Prevent SUD and improve outcomes in addiction through education of health care providers
Source: CDC NCHS, census.gov
Drug Poisoning Deaths 2016 All Ages in Poverty
Adapted from Morgan et al., 2017; permission for use of data provided by Dr. J.R. Morgan.Morgan JR, Schackman BR, Leff JA, et al. J Subst Abuse Tx, 2017.
XR-NTX and BUP-NX Were Equally Safe andEffective In Preventing Relapse
Relapse-free survival and treatment effect over time for the XR-NTX and BUP-NX treatment groups
Opioid craving during the trial
In this population it was more difficult to initiate patients to XR-NTX thanBUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective.
Lee JD et al., Lancet 2017, November 14 (E-pub ahead of print.)
