Advancing Pain Relief, Preventing Abuse Francis S. Collins, M.D., Ph.D.

Director, National Institutes of Health National Rx Drug Abuse Summit

April 22, 2014

“Science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce illness and disability.”

...

NIH: Steward of Medical and Behavioral Research for the Nation

NIH: Advancing Pain Relief; Preventing Abuse of Pain Relievers   NIH supports wide array of programs and projects that

–  Enhance our understanding and treatment of pain –  Improve our ability to monitor and prevent abuse of pain

relievers   Examples include:

–  NIH Pain Consortium –  “Monitoring the Future” study –  Supporting research to curb

epidemic of opioid abuse

NIH Pain Consortium Centers of Excellence in Pain Education

12 CoEPEs in 9 states, >100 schools

“Monitoring the Future”

  Survey measures drug, alcohol, and cigarette use and related attitudes among adolescent students nationwide –  Started in 1975 –  Conducted at the University of Michigan –  Supported by NIH’s National Institute on

Drug Abuse (NIDA)

  2013 survey included 41,675 students from 389 public and private schools

Percent of Students Reporting Nonmedical Use of Vicodin in Past Year, by Grade

0

5

10

15

20

02 03 04 05 06 07 08 09 10 11 12 13

8th Grade 10th Grade 12th Grade

SOURCE: University of Michigan, 2013 Monitoring the Future Study

*Denotes significant difference between 2012 and 2013

*

Year

Percent of Students Reporting Nonmedical Use of OxyContin in Past Year, by Grade

0

5

10

15

20

02 03 04 05 06 07 08 09 10 11 12 13

8th Grade 10th Grade 12th Grade

SOURCE: University of Michigan, 2013 Monitoring the Future Study

Year

Research: Finding New Responses to Opioid Abuse   Develop abuse-resistant drug formulations   Devise user-friendly methods of antidote (naloxone)

administration   Create mHealth interventions to help prevent opiate

overdose   Produce new immunotherapies to treat addiction

Abuse-Resistant Drug Formulations: Prodrugs   Problem: changing method of taking opioids – i.e.,

crushing, injecting – increases euphoria; abuse   Challenge: develop drugs that resist tampering; abuse   Research response: oxycodone prodrug

–  Prodrugs: inactive compounds metabolized in the body to produce active drug

–  NIH-supported Signature Therapeutics’ Bio-MD™ opioid prodrug •  Resists extraction, tampering •  2 prodrug types, for:

-  Hydromorphone -  Oxycodone: priority

Abuse-Resistant Drug Formulations: Oxycodone Prodrug   Two-step activation process in the body

–  Taken orally, bioactivation by trypsin in GI tract –  Cyclization release reaction

  Without activation, very little active opioid released   NIH support:

–  NIDA –  National Center for Advancing Translational Sciences’ “Bridging

Interventional Development Gaps” (BrIDGs) program •  Supports application to FDA

User-Friendly Antidote Administration: Naloxone   Opioid overdose antidote: naloxone

–  Effective: reversed >10,000 overdose cases, 1996–2010* –  Until recently, only available in injectable formulation

•  Practically, limited use to emergency medical personnel

  New formulation, Evzio, approved April 3, 2014 –  Hand-held auto-injector quickly delivers single dose –  Facilitates use by family members, caregivers

  Simpler systems could expand availability even further –  NIH/NIDA supporting development of intranasal delivery systems

*Centers for Disease Control and Prevention

User-Friendly Antidote Administration: NIH-Supported Naloxone Nasal Sprays AntiOp   Developing single-dose, disposable nasal spray

–  Combines proven nasal spray device with stable, concentrated, specially-formulated naloxone solution

–  Investigational New Drug (IND) application filed with FDA in 2012

–  Could be on the market ~18 months

Lightlake Therapeutics   Conducting clinical trials with intranasal naloxone for

treatment of binge eating disorder –  Applying technology to treatment of opioid overdose –  Clinical trials began last fall

mHealth Interventions May Help Prevent Opiate Overdose

Wireless Sensors •  Respiration •  Oximeter •  Arrhythmias

Naloxone Delivery •  Automatic •  Patient •  Third party

Alarm •  Set up delivery •  Alert patient •  Alert third party

A Shift from Abuse of Prescription Pain Relievers to Heroin

Cicero TJ et al. N Engl J Med 2012;367:187-189.

A recent increase in heroin use accompanied a downward trend in OxyContin abuse – following introduction of an abuse-deterrent formulation of OxyContin.

Antibodies reduce amount of drug in the brain

Capillary Blood Flow

Brain

Immunotherapies to Treat Addiction: Vaccines

Targets drugs, not receptors

Capillary Blood Flow

Brain

Antibodies

Vaccine

Binding sites

  Vaccines using immune molecules to diminish effects of abused drugs have been developed

  Heroin vaccine development trickier –  Heroin is metabolized into many substances –

each with psychoactive effects   NIH-supported researchers used dynamic approach to

develop heroin vaccine –  Targets not only heroin, but chemicals into which it degrades

  Recent tests promising   George Koob, co-PI, now at NIH….

Immunotherapies to Treat Addiction: Heroin Vaccine

Learning the Language of the Brain

New Insights on the Horizon? “The Next Great American Project”

BRAIN Buzz 2014

2013 Monitoring the Future Study Prevalence of Past Year Drug Use Among 12th graders

Drug Prev. Drug Prev. Alcohol 62.0 Sedatives* 4.8 Marijuana/Hashish 36.4 Tranquilizers* 4.6 Hookah 21.4 Hallucinogens 4.5 Small cigars 20.4 MDMA (Ecstasy) 4.0 Amphetamines* 8.7 Hall other than LSD 3.7 Synthetic Marijuana 7.9 OxyContin* 3.6 Snus 7.7 Salvia 3.4 Adderall* 7.4 Cocaine (any form) 2.6 Narcotics o/t Heroin* 7.1 Inhalants 2.5 Vicodin* 5.3 Ritalin* 2.3 Cough Medicine* 5.0 LSD 2.2

* Nonmedical use Categories not mutually exclusive

Percent of Students Reporting Use of Heroin in Past Year, by Grade

0

5

10

15

20

95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13

8th Grade 10th Grade 12th Grade

Year

SOURCE: University of Michigan, 2013 Monitoring the Future Study

Percent of High School Seniors Reporting Use of Narcotics Other than Heroin

0

5

10

15

20

91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12

12th grade

SOURCE: University of Michigan, 2013 Monitoring the Future Study

Year

Percent Reporting Narcotics Other Than Heroin as ‘fairly easy’ or ‘very easy’ to Obtain, by Grade

0

20

40

60

80

100

92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13

8th Grade 10th Grade 12th Grade

SOURCE: University of Michigan, 2013 Monitoring the Future Study

*Denotes significant difference between 2012 and 2013

*

•  Collaborator: Signature Therapeutics (Palo Alto, CA)

•  Compound: Oral prodrug formulation of oxycodone   Tamper-resistant - Common methods of tampering do not

release appreciable amounts of the active opioid.

•  Novel Project Intake Model   MOU between NIDA and NCATS   3-way CRADA including Signature

•  Pending BrIDGs Studies:   GMP synthesis   Packaging of drug supply   PK/ADME and GLP toxicology studies

•  IND Goal: End of 2014

Binding Site

Capillary Blood Flow

Brain

Antibodies

VACCINE Antibodies Can Reduce Brain Concentrations

Immunotherapies for Addiction Treatment (i.e., Vaccines)

Capillary Blood Flow

Brain

Targeting the drugs, not the receptors

##p<0.01, ###p<0.001, significant reduction of analgesia vs. Control/KLH group, ### p<0.001, significant reduction of analgesia vs. Control/KLH group

Heroin  1  mg/kg,    s.c.  

30  min  

Hot Plate Test

The Vaccine(s)

Immunotherapies to Treat Addiction: Heroin Vaccines

*K.D. Janda & G.F. Koob Laboratories at TSRI Dr. Koob now at NIH