Opioid Drug Abuse: NIH ResearchFrancis S. Collins, M.D., Ph.D.

Director, National Institutes of Health5th Annual National Rx Drug Abuse and Heroin Summit

March 29, 2016

NIH: Steward of Medical and Behavioral Research for the Nation

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

...

NIH Funds Scientists Across The U.S.

NIH Research: Opioid Drug Abuse

Pursuing fundamental knowledge of pain Developing alternatives for pain management Limiting abuse of opioids

– Enhancing safety– Predicting addiction– Improving treatments for addiction and overdose

Knowledge of Pain Pathways – New Biomarkers for Pain?New study to determine role of glial cells in pain Pairs patients with low back pain (LBP) and

healthy controls – Uses imaging to detect levels of specific glial protein – Paradoxically, higher levels = less subjective pain

Demonstrates role of glial activation in human pain – Possible biomarker– May suggest new treatments for chronic pain

Loggia et al., Brain 2015;138.

NIH Research: NIH Pain Consortium

NIH-wide effort to enhance pain research, including: Centers of Excellence in Pain Education (CoEPEs) Task Force on Research Standards for Chronic Low Back Pain Pathways to Prevention: Efficacy of Opioids for Chronic Pain NIH Blueprint for Neuroscience Research’s Grand Challenge on the

Transition from Acute to Chronic Neuropathic Pain RFA

2011: Institute of Medicine calls for coordinated approach to relieving burden of pain in U.S.– Tasked Health & Human Services to develop plan

2012: HHS created the Interagency Pain Research Coordinating Committee (IPRCC)

IPRCC: chaired by NIH, brought together nearly 80 experts from public and private sectors– Received public comment on draft Strategy

March 2016: National Pain Strategy released

NIH Research: A National Strategy for Reducing Pain

Department of Health and Human Services

Public Education &

Communication

Disparities

Care & Prevention

Service Delivery & Reimbursement

Focuses on Six Key Areas

Major Objectives: Develop methods to improve pain prevention, management Devise system of patient-centered integrated pain management

practices Reduce barriers to, improve quality of, pain care - particularly for

vulnerable or underserved populations Increase awareness of pain, care options - for public, patients,

health care workforce

NIH Research: Opioid Drug Abuse

Pursuing fundamental knowledge of pain Developing alternatives for pain management Limiting abuse of opioids

– Enhancing safety– Predicting addiction– Improving treatments for addiction and overdose

Transcranial Magnetic Stimulation shown to diminish pain of– Headaches related to mild traumatic brain injury – Post-herpetic neuralgia

Spinal Cord Stimulation indications include– Painful diabetic neuropathy– Chronic painful radiculopathy

Acupuncture– Meta-analysis suggests role for managing chronic pain– Improvement with headache; musculoskeletal,

osteoarthritis pain

Developing Non-Medication Strategiesfor Pain Management

Lamer et al., Mayo Clinic Proceedings 2016; 91.

Spinal Cord Stimulation

©Mayo 2015

Transcranial Magnetic Stimulation

Leung et al., Pain Physician 2016;19.

Study of Rare Disease Points toNew 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– NIH grantees developing new, more selective drugs to block Nav1.7

NIH Research: Opioid Drug Abuse

Pursuing fundamental knowledge of pain Developing alternatives for pain management Limiting abuse of opioids

– Enhancing safety– Predicting addiction– Improving treatments for addiction and overdose

Limiting Abuse by Enhancing Safety

Opioid deterrent formulations Pro-drugs Tamper resistance Drug combinations with adverse effects if injected

Enhancing Safety: Prodrugs Problem: changing method of taking opioids – i.e., crushing, injecting –

increases euphoria and abuse Challenge: develop drugs that resist tampering Research response: oxycodone prodrug BIO-MD™

– Inactive compounds metabolized in the body to produce active drug– Has broad potential across all known prescription opioid drugs

• Achieved human proof of concept with PF329, hydromorphone prodrug• PF614 is lead abuse-resistant opioid drug program

Limiting Abuse by Predicting Addiction OPRM1 encodes for the target of

opioids – and varies from person to person– Can variants predict likelihood of

addiction? OPRM1 variant

– Affects specific receptor levels in brain– Associated with increased risk for

addiction, overdose severity

Hancock et al., Biol Psychiatry 2015; 78. Manini et al., J Med Toxicol 2013; 9.Peciña et al., Neuropsychopharmacology 2015; 40.

Variant Common Type

Mapping the differences

Rosenthal et al., Addiction 2013;105.

Improving Treatments for Addiction:Extended Release Medications Improve Compliance Buprenorphine: partial opioid agonist

– Has lower abuse potential – Suppresses symptoms of

withdrawal– Helps people stay in treatment

Implanted buprenorphine may improve compliance– Trial: buprenorphine implants

vs. placebo for 6 months

EVA polymer Probuphine®Buprenorphine

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Buprenorphine Referral Brief Intervention0

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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

Improving Treatments for Pregnant Women Addicted to Opioids Methadone: recommended treatment for addiction in pregnant

women; however, prenatal exposure associated with neonatal abstinence syndrome (NAS)– Often requires extended hospitalization– Incidence almost doubled in 4 years

Buprenorphine: alternative treatment? Trial: offspring of mothers receiving buprenorphine compared to

methadone had:– Shorter hospital stays (10 vs 17.5 days) – Shorter duration of NAS (4.1 vs 9.9 days)

Using Research to Improve Opioid Intervention ServicesNIH is partnering with the Appalachian Regional Commission to fund grants to address increased opioid injection drug use in the region One-year research planning grants to:

– Improve understanding problem’s scope; contributing health trends– Identify resources, obstacles

Goal: build foundation for better intervention programs, larger-scale research efforts to address this public health threat

Applications now being accepted– RFA-DA-16-015: Due April 28

http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-16-015.html

Improving Treatments for Addiction:Naltrexone Naltrexone: opioid antagonist related to naloxone Extended release formula (Vivitrol) approved by FDA in 2006 for

alcohol dependence; approved for opioid addiction in 2010– First non-narcotic, non-addictive extended release medicine for

treatment of opioid dependence Multiple NIH-supported

clinical trials now underway…

Overdoses in 78 weeks:Control: 7

Naltrexone: 0

Improving Treatments for Addiction:Naltrexone Trial Shows Promise 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

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Treatment as usualNaltrexone

Naloxone: medication that can halt an opioid overdose– Original formulation delivered by injection

Lay-friendly administration: intranasal naloxone– NIH and FDA supported development – Overdose education and naloxone distribution (OEND)

programs demonstrated to be effective NARCAN Nasal spray device

– $37.50 per 4mg Approved by FDA, November 2015

Improving Treatments for Overdose:Naloxone

Image courtesy of ADAPT Pharma, Inc.

Coming soon: the Precision Medicine Initiative® An opportunity to advance research on common U.S.

medical problems – including opioids

www.nih.gov/precisionmedicine

“We lose almost a hundred Americans a day from overdoses of prescription medicine and heroin…. We need a holistic, multipronged approach to the epidemic.”

~Rep. Hal RogersAppropriations Hearing

March 16, 2016

NIH… Turning Discovery Into Healthdirectorsblog.nih.gov @NIHDirector