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.