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/yearhttp://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, ADHDMay 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 considerationMarlatt (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 Charles understood (yet) SchusterBenjamin Rush 1746-1813 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
Alcohol Metabolism ACDHAlcohol -------> Acetaldehyde ----------> Acetic AcidAcetaldehyde is responsible fornausea, vomiting, skin flushing1948: discovery that Antabuse inhibits acetaldehyde dehydrogenase1951: FDA approval for treatment of alcoholism
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 yearFuller et al. (1986) JAMA, 256(11), 1449-1455.
Importance of Motivation Compliance: 23% 17% 18%Fuller et al. (1986) JAMA, 256(11), 1449-1455.
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 monitoredLucas 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 NetworkCountiesClackamas Multi-Drug (Single)Columbia Total: 233 (102)Multnomah Heroin: 102 (45)Washington Methadone: 54 (22)Yamhill 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 DisadvantageNew (last?) option PoliticsLess likelihood of over-dose relative to Less safety than methadone, etc.street heroinPossible 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 Nicotiana nicotine with half-life of 20 hours 1530-1600
Acetylcholine PathwaysMeyer & Quenzer (2005). Psychopharmacology, p. 145.
The nicotinic cholinergic receptorVarenicline: 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 counselingWest 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 6 month abstinence 12 month abstinenceWest et al. (2011). New England Journal of Medicine, 365, 1193-1200.
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 = 2.27Calhill et al. (2012) Cochrane Review, 2012(4), 1-114.
Nicotine Vaccine • Rationale: nicotine conjugate produces antibodies which prevent distribution to brainMaurer et al. (2005). European Journal of Immunology, 35, 2031-2040.
Immunopharmacotherapy for Addiction Advantages Disadvantages • No neurobiology knowledge • Switching • Limited side effects • Motivation • No drug interactions • Withdrawal/cravingGorelick (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 monoxideCornuz (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 afterCornuz (2008). PLOS ONE, 3(6), e2547.
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 IRaupach 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 differencesPre-cessation Early Middle Late
Key ReferencesBecker J. B. et al. (2012-in press). Sex differences in the neural mechanisms mediating addiction: A newsynthesis 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?10712Meyer J. S. & Piper B. J. (2012). Developmental neurotoxicology of abused drugs. . In Reproductive &Developmental Toxicology (Edited by Ramesh C. Gupta), Elsevier: Amsterdam, 341–353.