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

Transcription

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

2 Medications Currently Available For Nicotine Addiction Nicotine Replacement Therapies (NRT) Bupropion Varenicline For Alcoholism Disulfiram Naltrexone Acamprosate Naltrexone Depot Topiramate For Opiate Addiction Methadone Naltrexone Buprenorphine Buprenorphine/Naloxone

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4 Therapies for Smoking Cessation 7 FDA approved pharmaco-therapies: - 5 NRT and 2 non-nrt Cessation treatment has limited efficacy after 6 months 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% * Treating Tobacco Dependence in Light of the 2008 US Department of Health and Human Services Clinical Practice Guideline

5 7-day point-prevalence smoking abstinence rates Varenicline & Bupropion SR Combination Therapy for Smoking Cessation % 58% Gonzales et al., 2006;Jorenby et al., % reported smoking % 36% 25% 3 months 6 months Varenicline + Bupropion Varenicline Bupropion Ebbert JO et al., Nic Tobacco Research 2009;11(3):

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7 Full and Partial Agonists vs Antagonists Treatment Strategies for Opioid Addiction Opioid Effect agonist antagonist Full Agonist (Methadone) effect an agonist drug has an active site of similar shape to the endogenous ligand so binds to the receptor and produces the same effect no 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 Log Dose Partial Agonist (Buprenorphine) Antagonist (Naloxone)

8 Specific Binding [ 18 F]cyclofoxy (m ligand) Specific Binding [ 11 C]carfentail (m ligand) Normal Control Methadone Maintained Patient % receptor occupancy for methadone doses > 80 mg a day Source: Kling et al., JPET, % occupancy for 2mg Bup 85-92% occupancy for 16 mg Bup 94-98% occupancy for 32 mg Bup Greenwald, MK et al., Neuropsychoph, 2003.

9 Treatment Linkage & Days Used Heroin 6 Months Post-release 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 11% C 85% 64% 46% C + M % of 180 days postrelease on treatment % of 180 days postrelease used heroin C = Counseling Only C+M = Counseling & Methadone Started in Prison Gordon, MS et al., Addiction 103: , 2008.

10 Percent Treatment Retention in HIV-Infected Patients Receiving Buprenorphine/Naloxone (n=303) % Retained % Not Retained % Lost to Follow-Up Fiellin DA et al., JAIDS 2011; 56(Suppl 1) S33-S38.

11 Number of Patients IMPLANTABLE buprenorphine -- Probuphine Delivers buprenorphine for 6 months Retention of Patients Through the Trial Buprenorphine Placebo Week Ling, W. et al. JAMA 2010;304: Trials required for FDA approval finished; could be available in 2013 (Titan Pharmaceuticals)

12 Although We Do Have Treatments That Work We Face Some Major Challenges in Using Them Criminal Justice System s Reluctance to Use Many Countries Reluctance to Use

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

14 NO Medications to Treat Addictions to: Cocaine Addiction Methamphetamine Addiction Marijuana Addiction Vaccines as a promising strategy

15 Mechanism of Action of Vaccine Against Cocaine Addiction B cells produce antibodies Cocaine bound to cholera toxin B No vaccine: Quick absorption at the Blood-brain barrier Antibodies enter the bloodstream When cocaine is introduced into the bloodstream, antibodies bind it Vaccine-stimulated antibodies delay absorption Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1):

16 Targeting Brain Circuits Involved in Addiction EXECUTIVE FUNCTION INHIBITORY CONTROL MOTIVATION/ DRIVE PFC OFC ACG D. Striatum NAcc Amyg Hipp VP REWARD MEMORY/ LEARNING

17 Potential Targets for Medications Development Kappa opioid receptor antagonists (JDTic) Dopamine (D 3 ) receptor antagonists (Buspirone) 5HT 2A receptor antagonists 5HT 2C receptor agonists (Lorcarserin) mglur 5 receptor antagonists (Fenobam) mglur 2/3 allosteric modulators CRH 1 antagonists FAAH inhibitors Orexin antagonists NK-1 antagonists Biologics (vaccines, mabs, engineered enzymes)

18 Pharmaceutical Companies that have Reduced or Eliminated Psychiatry Research from their Portfolios within the Past 3 Years GlaxoSmithKline Novartis Astra-Zeneca Sanofi-Aventis Cephalon

19 IOM Recommendations: Overcome Critical Market Barriers Government Funding of New Drug Development Expansion and Enhancement of Substance Abuse Treatment System Guaranteed Market Extended Market Exclusivity

20 Vaccines Human studies Nicotine vaccine Cocaine vaccine Preclinical studies Heroin vaccine Methamphetamine vaccine

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22 Rates (%) of Positive Urines for Cocaine Metabolites Mu Opioid Receptors BPND Mu Opioid Receptors are Increased in Cocaine Abusers and this is Associated with more Cocaine Use during Tx Cubic-root transformed longest duration of cocaine abstinence Ghitza et al 2010 Naltrexone & Buprenorphine for the TX of Cocaine Naltrexone Alone --Naltrexone + Buprenorphine Week 1 Week 4 Week 12 Gerra G et al., J Psychopharmacol Online First January 9,

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24 Testing Positive for Methamphetamines,% Clinical Trials for Medications for METH BUPROPION Percentage of Patients with METH-Free Urine Week Baseline Low Meth Use p= Study week elapsed since randomization GEE fitted lines Bupropion Placebo Group means Bupropion Placebo Mirtazapine (n=30) Observed Fitted Placebo (n=30) Observed Fitted MIRTAZAPINE (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) Elkashef et al., Neuropsychopharm 2008; 33: Colfax GN et al., Arch Gen Psychiatry 2011; 68:

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26 Retention Probability WDS score Retention Rates in Dronabinol Treated vs Placebo Withdrawal Discomfort Score in Dronabinol Treated vs Placebo Placebo Dronabinol 2 Placebo Dronabinol Week Visit Levin FR et al., Drug and Alcohol Dependence 2011; 116:

27 Current Status of Anti-cocaine/Anti-nicotine Vaccines in Clinical Trials 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 Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1):

28 Pharmacological Strategies to Attenuate Nicotine Reinforcement and Alleviate Withdrawal D Souza MS and Markou A. Addiction Science and Clinical Practice July 2011: 4-16.