This talk was given July 13, 2012 at the Women's Health & Integrative Medicine conference in Portland, Oregon by Brian J. Piper, PhD.

1. Neuropharmacological
Treatments of Drug Addiction
Brian J Piper, Ph.D., M.S.
Department of Basic Pharmaceutical Sciences
Husson University, Bangor, Maine

2. Disclosures
• Research supported by NIH
• No conflicts of interest

3. 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

4. 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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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
Charles
understood (yet) Schuster
Benjamin Rush
1746-1813 1930-2011

10. 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

11. Goals
• Alcohol
• Opiates
• Nicotine
• Other stimulants
– cocaine
– methamphetamine

12. Alcohol Metabolism
ACDH
Alcohol -------> Acetaldehyde ----------> Acetic Acid
Acetaldehyde is responsible for
nausea, vomiting, skin flushing
1948: discovery that Antabuse inhibits acetaldehyde dehydrogenase
1951: FDA approval for treatment of alcoholism

13. 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.

14. Importance of Motivation
Compliance: 23% 17% 18%
Fuller et al. (1986) JAMA, 256(11), 1449-1455.

15. 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

16. 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.

17. 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.

18. Kudzu
• Pueraria lobata is a vine native to Japan (Kuzu)
and China
• Extended history to treat inebriation and
symptoms of hangover

19. 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.

20. 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.

21. Drug Abuse Warning Network
Counties
Clackamas
Columbia
Multnomah
Washington
Yamhill

22. Drug Abuse Warning Network
Counties
Clackamas Multi-Drug (Single)
Columbia Total: 233 (102)
Multnomah Heroin: 102 (45)
Washington Methadone: 54 (22)
Yamhill Other opiate: 59 (14)

23. 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 Less safety than methadone, etc.
street heroin
Possible reduction in criminal activity?

24. 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.

25. Results
• Adverse events: Heroin: 32.8%; Methadone: 10.9%
Hassen et al. (2007). British Journal of Psychiatry, 191, 55-62

26. 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.

27. Nicotine
• Nicotine: active ingredient of tobacco
leaves with half-life of 2 hours
• Cotinine: inactive metabolite (?) of Nicotiana
nicotine with half-life of 20 hours
1530-1600

28. Acetylcholine Pathways
Meyer & Quenzer (2005). Psychopharmacology, p. 145.

29. The nicotinic cholinergic receptor
Varenicline: partial α4β2 agonist
Cytisine: partial α4β2 agonist
Bupropion: nACh antagonist
Nicotinic Replacement Therapy (NRT): nACh agonist

30. Cytisine
• Cytisus Laburnum L. (Golden
rain) is native to central and
southern Europe
• Tabex® developed in 1964

31. 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.

32. Cytisine Trial
• Regular smokers (N=740) randomized to
cytisine (step-down dosing) or placebo for 4
weeks and followed for 1 year
• Minimal counseling
6 month abstinence 12 month abstinence
West et al. (2011). New England Journal of Medicine, 365, 1193-1200.

33. Varenicline
6 month abstinence with
• Partial agonist for α4β2, full agonist 1 mg x 2/day
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.

34. Nicotine Vaccine
• Rationale: nicotine conjugate produces
antibodies which prevent distribution to brain
Maurer et al. (2005). European Journal of Immunology, 35, 2031-2040.

35. Immunopharmacotherapy for
Addiction
Advantages Disadvantages
• No neurobiology knowledge • Switching
• Limited side effects • Motivation
• No drug interactions • Withdrawal/craving
Gorelick (2012). Future Medical Chemistry, 4(2), 227-243.

36. 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.

37. 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.

38. Immunopharmacotherapy Pipeline
Target Company Product Immunization Status
nicotine 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.

39. 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?

40. Conclusions
• Multimodal & Interdisciplinary
• Reasonable expectations
• Sensitivity to sex differences
Pre-cessation Early Middle Late

41. Key References
Becker 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.