Post on 18-Nov-2014
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Neuropharmacological Treatments of Drug Addiction
Brian J Piper, Ph.D., M.S.Department of Basic Pharmaceutical Sciences
Husson University, Bangor, Maine
Disclosures
• Research supported by NIH• No conflicts of interest
Importance• 18 million Americans are alcoholics (loss of control,
tolerance, physical dependence, or craving)-NIAAA, 2012
• 79,000 deaths are attributable to excessive alcohol/year: CDC, 2012
• 1.6 million hospitalizations and 4 million ER visits/year: CDC, 2012
Importance• Cigarette smoking results in 443,000
premature deaths/year• Smoking is the primary causal factor for at
least 30% of all cancer deaths• 8.6 million people suffer from a serious illness
caused by smoking/year
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5745a3.htm
Importance• 1.2 million regular heroin users in the U.S., 0.6% of adult
population (UNODC, 2010)• Economic costs due to nonmedical use of opioids is $53.4
billion/year (Smoking: $193B; Obesity: $139B)
Hansen et al. (2011) Clin J Pain, 27(3), 194-202.
Prenatal Drug Exposure
• Fetal Alcohol Syndrome– 2/1000 births in U.S.– 50/1000 births in South Africa
• Prenatal smoking is a risk for stillbirth, SIDS, ADHD
May et al. (2009). Dev Dis Res Review, 15, 1761-92, Arnold et al. (1994) Pediatrics, 93, 216-220.
Sex Differences
• Epidemiology: – opiates (1800s)– Amphetamines & barbiturates (1960s)
• Reasons for Use– Males: experimentation (substance abuse -> mood)
– Females: self-medication (mood -> substance abuse)
Becker et al (2012-in press). Biology of Sex Differences, 3, 14.
Paradigms
• Moral (Criminal) Model: only acceptable intervention is one that involves complete abstinence
• Harm-Reduction Model: any intervention that reduces harms to drug-user and society is worthy of consideration
Marlatt (1996) Addictive Behaviors, 21(6), 779-788.
Therapeutic Approaches• Pharmacodynamic: therapeutic drug blocks
the cellular response of a recreational drug• Pharmacokinetic: therapeutic drug interferes
with recreational drug metabolism or distribution
• Serendipity: biological mechanism not understood (yet)
Benjamin Rush
1746-1813
Charles Schuster
1930-2011
History
• Ernst von Fleischl-Marxow had his infected thumb amputated and subsequently became an opiate addict
• Sigmund Freud recommend cocaine as a treatment for heroin addiction
• Dr. Marxow developed a cocaine addiction and died at age 45
1846-1891
Goals
• Alcohol• Opiates• Nicotine• Other stimulants
– cocaine– methamphetamine
Alcohol Metabolism
Alcohol -------> Acetaldehyde ----------> Acetic Acid
Acetaldehyde is responsible for nausea, vomiting, skin flushing
1948: discovery that Antabuse inhibits acetaldehyde dehydrogenase1951: FDA approval for treatment of alcoholism
ACDH
Sounds good in theory but …
• Large, single-blind randomized controlled trial of:– Placebo – 1 mg disulfiram– 250 mg disulfiram
• Patients monitored by blood/urine analysis and by family intermittently for 1 year
Fuller et al. (1986) JAMA, 256(11), 1449-1455.
Importance of Motivation
Fuller et al. (1986) JAMA, 256(11), 1449-1455.
Compliance: 23% 17% 18%
Pharmacodynamics of Alcohol
• GABAA agonist• Glutamate (NMDA) antagonist
• Acamprosate – small molecule with an unclear mechanism
(possible inhibitor of glutamate release)– 2004: FDA approved for alcoholism
Meta-Analysis of Acamprosate
• 24 randomized controlled trials (N=6,894)– double-blind– Treatment duration of > 1
month– Relative risk of return to
drinking (RR = 0.86)
Rosner et al (2011) Cochrane Database of Systematic Reviews, 2011(2), 1-122.
Acamprosate: Statistically Significant
• Among patients both tolerating side-effects & completing psychosocial therapies:– Acamprosate patient complying with medication is
14% more likely to remain abstinent– “Acamprosate is expected to prevent drinking
after detoxification in one out of nine patients who would have otherwise relapsed.” (p. 25)
Rosner et al (2011) Cochrane Database of Systematic Reviews, 2011(2), 1-122.
Kudzu
• Pueraria lobata is a vine native to Japan (Kuzu) and China
• Extended history to treat inebriation and symptoms of hangover
Kudzu root• 14 volunteers with a history
of heavy drinking received placebo or kudzu extract (1000 mg x 3/day) for one week
• Drinking behavior in a naturalistic environment monitored
Lucas et al. (2005) Alcoholism: Clinical & Experimental Research, 29(5), 756-762.
Puerarin
• Isoflavones daidzin, daidzein, & puerarin have efficacy in animal models
• 600 mg puerarin x 2/day or placebo (N=10)
Penetar et al. (in press) Drug & Alcohol Dependence.
Drug Abuse Warning NetworkCountiesClackamasColumbiaMultnomahWashingtonYamhill
Drug Abuse Warning NetworkCountiesClackamasColumbiaMultnomahWashingtonYamhill
Multi-Drug (Single)Total: 233 (102)Heroin: 102 (45)Methadone: 54 (22)Other opiate: 59 (14)
Heroin for Heroin Addicts?!• Supervised heroin administration ongoing in
Canada, Spain, Germany for severely dependent long-term heroin addicts who have been unsuccessful with other treatment (e.g. methadone) options.
Advantages Disadvantage
New (last?) option Politics
Less likelihood of over-dose relative to street heroin
Less safety than methadone, etc.
Possible reduction in criminal activity?
Trial• Heroin dependent patients (N=1,015) were
randomized to receive methadone or supervised heroin injections (3x/day; upto 1,000 mg/day).
Hassen et al. (2007). British Journal of Psychiatry, 191, 55-62.
Results
• Adverse events: Heroin: 32.8%; Methadone: 10.9%
Hassen et al. (2007). British Journal of Psychiatry, 191, 55-62
Meta-Analysis
• Heroin administration (iv or oral), relative to methadone, resulted in: – greater likelihood (44%) of completing treatment– reduced mortality (23%)– decreased criminal behavior (possibly)
• Prescription heroin may be an option for addictions that have failed other interventions.
Ferri et al. (2012). Cochrane Reviews, 2012(3), e1-e57.
Nicotine
• Nicotine: active ingredient of tobacco leaves with half-life of 2 hours
• Cotinine: inactive metabolite (?) of nicotine with half-life of 20 hours
Nicotiana
1530-1600
Acetylcholine Pathways
Meyer & Quenzer (2005). Psychopharmacology, p. 145.
The nicotinic cholinergic receptor
Varenicline: partial α4β2 agonistCytisine: partial α4β2 agonistBupropion: nACh antagonistNicotinic Replacement Therapy (NRT): nACh agonist
Cytisine• Cytisus Laburnum L. (Golden
rain) is native to central and southern Europe
• Tabex® developed in 1964
Cytisine Trial
• Regular smokers (N=740) randomized to cytisine (step-down dosing) or placebo for 4 weeks and followed for 1 year
• Minimal counseling
West et al. (2011). New England Journal of Medicine, 365, 1193-1200.
Cytisine Trial
• Regular smokers (N=740) randomized to cytisine (step-down dosing) or placebo for 4 weeks and followed for 1 year
• Minimal counseling
West et al. (2011). New England Journal of Medicine, 365, 1193-1200.
6 month abstinence 12 month abstinence
Varenicline• Partial agonist for α4β2, full agonist
α7• Approved in 2004; suicidal ideation • Meta-analysis (20 trials, 17 by Pfizer,
N=12,000)• Relative Risk = 2.27
Calhill et al. (2012) Cochrane Review, 2012(4), 1-114.
6 month abstinence with 1 mg x 2/day
Nicotine Vaccine
• Rationale: nicotine conjugate produces antibodies which prevent distribution to brain
Maurer et al. (2005). European Journal of Immunology, 35, 2031-2040.
Immunopharmacotherapy for Addiction
Advantages• No neurobiology knowledge• Limited side effects• No drug interactions
Disadvantages• Switching• Motivation• Withdrawal/craving
Gorelick (2012). Future Medical Chemistry, 4(2), 227-243.
Nicotine QB trial
• Regular smokers (1/2 pack/day for 3 years, N = 239) were randomized to receive 100 μg Nicotine QB (week 0, 4, 8, 12, 16) or adjuvant
• Counseling at week 3, target quit date of week 4
• Followed for 8 months after last dose• Smoking status determined based on self-
report and carbon monoxide
Cornuz (2008). PLOS ONE, 3(6), e2547.
Limited Efficacy• No compensatory increase in smoking• Mild (flu like) Adverse Events: V-96.5%, P-84.8%)• % Abstainers (2-6): H-56.6%, P-31.3% but no
difference after
Cornuz (2008). PLOS ONE, 3(6), e2547.
Immunopharmacotherapy PipelineTarget Company Product Immunization Statusnicotine Cytos Biotech Nic002(QB) Active Phase II
nicotine Nabi Biopharm NicVAX Active Phase III
PCP InterveXion mAB6B5 Passive preclinical
cocaine Xenova TA-CD Active Phase III
oxycontin Minneapolis MRF ‘OXY-KLH’ Active preclinical
morphine Minneapolis MRF ‘M-KLH’ Active preclinical
Methamphetamine InterveXion mAb4G9 Passive Phase I
Raupach et al. (2012). Drugs, 72(4), e1-e16.
Ethics
• Assuming safety, should these vaccines be administered to women with a drug abuse history planning on becoming pregnant?
• What about children (i.e. prior to drug experimentation)?
• Confidentiality of prolonged high levels of antibodies?
Conclusions
• Multimodal & Interdisciplinary• Reasonable expectations• Sensitivity to sex differences
Pre-cessation Early Middle Late
Key ReferencesBecker J. B. et al. (2012-in press). Sex differences in the neural mechanisms mediating addiction: A new synthesis and hypothesis. Biology of Sex Differences, 3, 14.
Etter J. F. (2008). Cytisine for smoking cessation: A research agenda. Drug & Alcohol Dependence, 92, 3-8.
Lu L. et al. (2009). Traditional medicine in the treatment of drug addiction. American Journal of Drug & Alcohol Abuse, 35, 1-11.
Marlatt G. A. (1996). Harm reduction: Come as you are. Addictive Behavior, 21, 779-788.
McCaul, M. (2001). Women and drug abuse: Prevalence, problems and treatments. NIH Videocast at:http://videocast.nih.gov/launch.asp?10712
Meyer J. S. & Piper B. J. (2012). Developmental neurotoxicology of abused drugs. . In Reproductive & Developmental Toxicology (Edited by Ramesh C. Gupta), Elsevier: Amsterdam, 341–353.