Pharmacological Treatment of Stimulants Addiction

Transcription

1 Pharmacological Treatment of Stimulants Addiction Ahmed Elkashef, M. D. Head, Research and Clinical Studies Section National Rehabilitation Center, Abu Dhabi, UAE Associate Professor of Psychiatry George Washington Medical School Washington, D.C. 1

2 2

3 3

4 How Many Of These Illicit drugs Users Eventually Develop The Dependence Syndrome? Psychedelic drugs, 1 in 20 Analgesic Drugs, 1 in 11 Inhalant drugs, 1 in 20 Anxiolytic, sedative, & hypnotic drugs, 1 in 11 Tobacco, 1 in 3 Heroin, 1 in 4-5 Crack + HCl, 1 in 5 (??) Estimated Cocaine HCl, 1 in 6 fraction of drug users who have become drug dependent Alcohol, 1 in 7-8 Cannabis, 1 in 9-11 Stimulants other than cocaine, 1 in 9 (Adapted from Anthony et al., 1994; Chen & Anthony, 2004)

5 Two decades of treatment seeking for substance use disorders in Saudi Arabia: Trends and patterns in a rehabilitation facility in Dammam Mahdi S. AbuMadini a,, Sheikh I.A. Rahima, Mohamed A. Al-Zahrani b, Abbdalla O. Al-Johi b a Department of Psychiatry, King Faisal University, P.O. Box 40101, Al-Khobar 31952, Saudi Arabia b Amal Hospital Dammam, Ministry of Health, Eastern Province, P.O. Box 2801, Dammam 31461, Saudi Arabia Drug and Alcohol Dependence 97 (2008) ٥

6 Crystalline Methamphetamine ٦

7 Meth lab in Stanton County, Nebraska 8/11/06 Stanton County Sheriff s Office ٧

8 ٨

9 Various Illicit Methamphetamine Syntheses Pseudoephedrine (the active ingredient in Sudafed, etc) can be used to make d-methamphetamine [Ephedrine was banned by the FDA for other reasons in 2004] Mendelson et ٩al (2006) Clin Pharmacol Ther 80:403-20

10 Methamphetamine Licit d- Schedule II ١٠ d-methamphetamine (marketed as Desoxyn ) is used for ADD, narcolepsy & obesity

11 Licit l-methamphetamine Vicks calls it: Levmetamfetamine Nasal Decongestant Vicks Vapor Inhaler (Procter & Gamble) contains 50 mg l-methamphetamine ١١

12 What Are the Long-Term Effects of Chronic Methamphetamine Abuse?... Multnomah County Sheriff s Office Faces of Meth Mug Shots ١٢

13 Meth Mouth Source: Richards, Brofeldt (2000) J Periodontol 71: ١٣

14 Sores on the face and body ("crank bugs") Source: ١٤

15 Cocaine and Methamphetamine Effects Compared Cocaine Methamphetamine 15

16 Meth-Induced Degeneration of Dopaminergic Axons Representative DA neuron in control culture DA neuron in culture after 100 µm meth for 6 days Cubells, Rayport, Rajendran & Sulzer (1994) J Neurosci 14: ١٦

17 Partial Recovery of DAT in an Abstinent Methamphetamine Abuser 3 Normal Control METH Abuser METH Abuser ml/gm Normal Control Meth Abuser Same Meth Abuser 1 month detox 2 years detox 0 Volkow et al (2001) J Neurosci 21:

18 Addiction Pharmacological Treatment Strategies Facilitation of Abstinence: Restore Homeostasis (Agonist Therapy: Nicotine, Methadone) Co-morbid conditions (depression, ADD) Relapse Prevention: - Stress reduction (CRF antagonist, Lofexidine/clonidine) - Cues/Craving (D3 agonists) - Cognitive/Decision (D1 Agonist) - Block Action (Antagonist Therapy: Nalotrexone) 18

19 Modafinil Increases Abstinence Rates Dackis, et al 2005 (30), Neuropsychopharmacology 19

20 Mean (SE) Percent Non-use Days Modafinil for Cocaine Percent Non-use Days in Non-Alcohol Dependent Patients Anderson et al, Drug Alcohol Depend Jun 25. Placebo 200mg 400mg N Placebo: 200mg: 400mg: Study Week

21 A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Shearer J, Darke S, Rodgers C, Slade T, van Beek I, Lewis J, Brady D, McKetin R, Mattick RP, Wodak A. Addiction Feb;104(2):

22 Modafinil for the treatment of methamphetamine dependence. Anderson AL, Li SH, Biswas K, McSherry F, Holmes T, Iturriaga E, Kahn R, Chiang N, Beresford T, Campbell J, Haning W, Mawhinney J, McCann M, Rawson R, Stock C, Weis D, Yu E, Elkashef AM. Drug and Alcohol Dep: 2011 Aug 11 Analysis 3b: Top quartile of urine compliance (>85%) vs. all others -- Max number of consecutive days of abstinence Variable: maxdays N Mean Std Dev Top quartile Lower 3 quartiles Method Variances DF t Value Pr > t Satterthwaite Unequal

23 Bupropion For Methamphetamine Addiction Elkashef, et al: Neuropsychopharmacology Apr;33(5): Epub 2007 Jun 20.

24 Bupropion vs Placebo Weekly % Clean UA Samples by Condition Light Users (Top Panel) Heavy Users (Bottom Panel)

25 Naltrexone for the Treatment of Amphetamine Dependence: A Randomized, Placebo-Controlled Trial Nitya Jayaram-Lindström, et al, 2008, AJP. DBPC,Naltrexone 50mg + RP therapy, for 12 wks. FIGURE 2. Percentage of Negative Urine Samples in the FIGURE 3. Percentage of Negative Urine Samples in the Naltrexone and Placebo Groups During the 12-Week Trial Naltrexone and Placebo Groups During the 12-Week Trial (Intention-to-Treat Analysis) (Completer Analysis)

26 A pilot trial of topiramate for the treatment of cocaine dependence. Kampman KM, Pettinati H, Lynch KG, Dackis C, Sparkman T, Weigley C, O'Brien CP. Drug Alcohol Depend Sep 6;75(3): % BE Negative Urine Samples p =.06 Kyle M. Kampman, M.D. Baseline Neg Baseline Pos

27 Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial. Elkashef et al, Addiction 2012 Jul;107(7):

28 Addiction Jan 8. doi: /add [Epub ahead of print] Extended release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomised, double-blind, placebo controlled trial. Miles SW, Sheridan J, Russell B, Kydd R, Wheeler A, Walters C, Gamble G, Peta H, Maree J, Kuoppasalmi K, Tuomola P, Föhr J, Kuikanmäki O, Vorma H, Salokangas R, Mikkonen A, Kallio M, Kauhanen J, Kiviniemi V, Tiihonen J. Source Waitemata District Health Board, New Zealand; University of Auckland, New Zealand. Abstract AIMS: To assess the efficacy of methylphenidate as a substitution therapy for amphetamine/methamphetamine dependence in Finland and New Zealand. DESIGN: parallel group, double-blind, randomised placebo controlled trial. SETTING: outpatient care. PARTICIPANTS: amphetamine/methamphetamine dependent, aged MEASUREMENTS: The primary outcome measure was presence/absence of amphetamine/methamphetamine in urine samples collected twice weekly. Secondary measures included treatment adherence, alterations in craving scores and self-reported use. Primary analysis was by intention to treat (ITT). Study drug: methylphenidate (as Concerta( ) ) was up-titrated over two weeks to a maximum dose of 54 mg daily and continued for a further 20 weeks. Doses were given under daily supervision at the clinics. FINDINGS: Seventy nine participants were randomised (40 methylphenidate; 39 placebo); 77 received allocated treatment and 27 completed the trial. ITT analysis (N=78) showed no statistically significant difference in the percentage of positive urines between the methylphenidate and placebo arms (OR 0(.) 95, 95% CI 0(.) 83-1(.) 08). However, there was a significant difference (p< 0(.) 05) between the active and placebo arms in retention, the placebo arm displaying a significantly lower retention from six weeks that persisted until trial end. CONCLUSIONS: The trial failed to replicate earlier findings suggesting that methylphenidate was superior to placebo. The low retention rate confounded the ability to draw firm conclusions about efficacy. The higher retention rate was observed in the methylphenidate arm. Any replication of this work would need to consider alternatives to the rigid clinic attendance criteria, and consider an increased dose The Authors, Addiction 2013 Society for the Study of Addiction

29 Randomized controlled trial of dexamphetamine maintenance for the treatment of methamphetamine dependence. Longo M, Wickes W, Smout M, Harrison S, Cahill S, White JM. Addiction Jan;105(1): doi: /j x. Epub 2009 Oct mg/day sustained-release dexamphetamine (n = 23) or placebo (n = 26) for a maximum of 12 weeks, with gradual reduction of the study medication over an additional 4 weeks. Medication was taken daily under pharmacist supervision. Methamphetamine Concentration from Baseline to Follow-Up/ Hair Analysis Significant reduction in concentration from baseline to follow-up within each group (p<0.001) but not significant between groups

30 Craving Methamphetamine Withdrawal Stabilisation: Significantly greater reduction in withdrawal and Craving in d-amphet group

31 A Randomized, Placebo-Controlled Trial of Sustained-Release Dextroamphetamine for Treatment of Methamphetamine Addiction GP Galloway1, R Buscemi1, JR Coyle1, K Flower1, JD Siegrist1, LA Fiske1, MJ Baggott1, L Li1, D Polcin2, CYA Chen1, and J Mendelson1, Clin Pharmacol Ther February ; 89(2): doi: /clpt Proportions of methamphetamine-negative urine samples by time and group. d-amp, dextroamphetamine.the subjects took 60 mg sustained-release d-amp for 8 weeks ٣١

32 Mirtazapine to Reduce Methamphetamine Use: A Randomized Controlled Trial Grant N. Colfax, MD, Arch Gen Psychiatry November ; 68(11): doi: /archgenpsychiatry ٣٢

33 Bupropion and Contingency Management Poling et al, 2006 ٣٣

34 Desipramine and Contingency Management Kosten T, ٣٤

35 Targeting the drugs not the receptors * Drug Overdose * relapse Prevention Capillary Blood Flow Brain (Owens & Gentry 2002)

36 Potential Therapeutic Applications METH & MDMA Overdose Protection Relapse/Prevention

37 Advances in the Development of Biologics to Treat Drug Addictions and Overdose IVÁN D. MONTOYA, ADICCIONES, 2012 VOL. 24 NÚM. 2 PÁGS Nicotine: NicVAX: No effect in two phase III trials (ongoing trial in combination with varenicline) NIC002: Subgroup effect in patients with high titers SEL-068:phase I TAC-NIC: No effect in proof of concept trial IP18-KLH: Cocaine: -TA-CD: Subgroup effect in subjects with high titers - Monoclonal Antibodies Methamphetamine: - Vaccine and Monoclonal antibodies Opiates: - Morphine/Herion vaccine - OXY(Gly)4-KLH ٣٧

38 Conclusions Promising medications for Stimulants include (Provigil, Bupropion, Naltrexone, Topiramate, Mirtazapine). Amphetamines possible withdrawal medication. Immunotherapies are in early stages. CM may potentiate medication effect. For reviews on Medications: Elkashef A, et al 2008, Subst Abus. 2008;29(3): Karila L, et al 2010, BJCP, 69:6, Brackins T, et al J Pharm Pract Dec;24(6):