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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