Nora D. Volkow, M.D. Director National Institute on Drug Abuse

Nora D. Volkow, M.D. Director

For Opiate Addiction

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Medications Currently Available

For Nicotine Addiction

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Therapies for Smoking Cessation

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Only 20% using pharmacotherapy are abstinent for more than a year.

Treatment Abstinence Rate at 6 mo, %

Self-help and Quitline 8.5% and 12.7%

Counseling alone 14.6%

* Varenicline (2mg/day and 1 mg/day) 33.2% and 25.4%

* Bupropion SR 24.2% * Nicotine patch 23.4%

Medication and counseling 27.6%

Varenicline & Bupropion SR

Combination Therapy for Smoking Cessation

Ebbert JO et al., Nic Tobacco Research 2009;11(3):234-239.

0 10 20 30 40 50 60 70 80 Varenicline + Bupropion Varenicline Bupropion 3 months 6 months 7 -da y po int -p reval en ce smok ing ab stinence rat es 71% 58% 50% 33% 36% 25% reported smoking

Full and Partial Agonists vs Antagonists

Treatment Strategies for Opioid Addiction

effect

no effect agonist antagonist

an agonist drug has an active site of similar shape

to the endogenous ligand so binds to the receptor and produces the same effect

an antagonist drug is close enough in shape to bind to the

receptor but not close enough to produce an effect. It also takes up receptor space and so

prevents the endogenous ligand from binding

O pio id Effect Full Agonist (Methadone) Partial Agonist (Buprenorphine) Antagonist (Naloxone) Log Dose

Normal Control

Methadone Maintained Patient

Source: Kling et al., JPET, 2000. Specific Binding

[18_{F]cyclofoxy (}m _ligand)

30-35 % receptor occupancy for methadone doses > 80 mg a day

Specific Binding

[11_{C]carfentail (}m _ligand)

27-47 % occupancy for 2mg Bup 85-92% occupancy for 16 mg Bup 94-98% occupancy for 32 mg Bup

C = Counseling Only

C+M = Counseling & Methadone Started in Prison

11% 85% 80% C 64% 46% C + M % of 180 days post-release on treatment % of 180 days post-release used heroin

Gordon, MS et al., Addiction 103:1333-1342, 2008.

Treatment Linkage & Days Used Heroin

6 Months Post-release

Per

cent

Treatment Retention in HIV-Infected Patients Receiving Buprenorphine/Naloxone (n=303)

% Retained % Not Retained % Lost to

Follow-Up

IMPLANTABLE buprenorphine -- Probuphine™

Ling, W. et al. JAMA 2010;304:1576-1583

120 100 80 60 40 20 0 Nu mber of Pat ie nt s 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Week Buprenorphine Placebo

Retention of Patients Through the Trial

Trials required for FDA approval finished; could be available in 2013

Delivers buprenorphine for 6 months

Although We Do Have Treatments That Work

We Face Some Major

Challenges

in Using Them

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Krupitzky et al., unpublished Placebo: N=124 XR-NTX: N=126 IM Injection every 4 weeks for 24 weeks

NO Medications to Treat Addictions to:

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B cells produce antibodies Cocaine bound to cholera toxin B Antibodies enter the bloodstream When cocaine is introduced into the bloodstream, antibodies bind it

Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1): 60-70.

Mechanism of Action of Vaccine Against Cocaine Addiction

No vaccine:

Quick absorption at the Blood-brain barrier

Vaccine-stimulated antibodies delay absorption

Targeting Brain Circuits Involved in Addiction

Potential Targets for Medications Development

Kappa opioid receptor antagonists (JDTic)

Dopamine (D₃) receptor antagonists (Buspirone)

5HT_2A receptor antagonists

5HT_2C receptor agonists (Lorcarserin)

mGluR₅ receptor antagonists (Fenobam)

mGluR_2/3 allosteric modulators

CRH₁ antagonists

FAAH inhibitors Orexin antagonists NK-1 antagonists

Pharmaceutical Companies that have Reduced or Eliminated Psychiatry Research from their

Portfolios within the Past 3 Years

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IOM Recommendations:

Overcome Critical Market Barriers

Government Funding of New Drug Development Expansion and Enhancement of Substance Abuse Treatment System

Guaranteed Market

Vaccines

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Naltrexone & Buprenorphine

for the TX of Cocaine

R ates (% ) of Posit iv e Urines fo r Cocaine Me tab olit es

Gerra G et al., J Psychopharmacol Online First January 9, 2006. 0 5 10 15 20 25 30 35 40 45

Week 1 Week 4 Week 12

3₃₇ 40 42 18 33 9 --Naltrexone Alone --Naltrexone + Buprenorphine

Cubic-root transformed longest duration of cocaine abstinence

M u Op ioi d R ece ptors B P ND Ghitza et al 2010

Mu Opioid Receptors are Increased in Cocaine Abusers

and this is Associated with more Cocaine Use during Tx

Colfax GN et al., Arch Gen Psychiatry 2011; 68:1168-1175.

Clinical Trials for Medications for METH

Elkashef et al., Neuropsychopharm 2008; 33:1162-1170.

BUPROPION MIRTAZAPINE

Percentage of Patients with METH-Free Urine Week Baseline Low Meth Use

Study week elapsed since randomization

100 90 80 70 60 50 40 30 20 10 0 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 p=0.03

GEE fitted lines Bupropion Placebo Group means Bupropion Placebo

T es tin g P os itiv e fo r M et ha m ph et am in es ,% Mirtazapine (n=30) Observed Fitted Placebo (n=30) Observed Fitted 0 2 3 4 5 6 7 8 9 10 11 12 (30;30) (28;27) (25;23) (27;27) (27;22) (26;27) (26;25) (27;24) (26;24) (23;23) (23;23) (27;27)

Study Week (No. of Placebo Arm; Mirtazapine Arm Samples)

100 80 60 40 20 0

Re te n tion P rob ab il ity 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Placebo Dronabinol 0 1 2 3 4 5 6 7 8 Week 8 7 6 5 4 3 2 1 0 WDS sc or e Placebo Dronabinol 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Visit Retention Rates in

Dronabinol Treated vs Placebo

Withdrawal Discomfort Score in Dronabinol Treated vs Placebo

Current Status of Anti-cocaine/Anti-nicotine Vaccines in Clinical Trials

Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1): 60-70.

Vaccine Target Status Characteristics Company Country

TA-CD Cocaine

Cocaine Phase IIB Cholera toxin B conjugate

Celtic

Pharmaceuticals

United Kingdom NIC002 Nicotine Phase II Virus-like vaccine Cytos Biotechnology/

Novartis

Switzerland TA-NIC Nicotine Phase II A recombinant cholera

toxin conjugate

Celtic

Pharmaceuticals

United Kingdom NicVax Nicotine Phase III A bacterial exoprotein Nabi

Biopharmaceuticals/ GlaxoSmithKline

United States

Pharmacological Strategies to Attenuate Nicotine Reinforcement and Alleviate Withdrawal