Outline of the lecture

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1 Outline of the lecture Treatment of Substance Use Disorders in Primary and Integrated Care Elena Volfson, MD, MPH DSM V vsdsm IV substance use disorders Current epidemiology of substance use in the US from NSDUH 2013 Neurobiology of substance use Current review of treatment strategies by substances : alcohol, tobacco, opiates, cannabis DSM-IV and DSM-V Substance Use Disorders Past month alcohol consumption in >12 in 2012 Added craving criterion Eliminated dependence and abuse distinction Eliminated legal problems as criterion Mild (2-3), moderate (4-5) and severe (>6) out of 11 Past month alcohol use by race 2012 Past month tobacco use >

2 Tobacco use by women > Past month cigarette use over age Past month illicit drug use by age 2012 Daily or almost daily cannabis use > Initiation of use by substances 2012 (excluding tobacco) Goal of Addiction Treatment Recovery as "a voluntarily maintained lifestyle characterized by sobriety, personal health, and citizenship (J Subst Abuse Treat. 2007;33(3):221) Restoration of medical and social well-being Acquiring or regaining cortical/executive control over one s behavior and life 2

3 Proprietary Recipe: Most Effective Treatments for Any Mental Illness by Dr. Volfson Brain transplant Re-parenting Injection of common sense and perspective Emotion Temporal - Parietal Model of Addiction Control Orbital Prefrontal Cortex Psychotherapy is the best treatment unless the patient is actively psychotic, demented or mentally retarded. Functional frontal lobes are required for therapy. Ventral Tegmentum Reward / Euphoria Memory Craving Hippocampus Nucleus Accumbens 14 Used with permission from David Oslin, 2012 Model of Addiction Addiction is a Compulsive Relapsing Disorder Emotion Antidepressants Mood Stabilizers Therapy Reward / Euphoria Craving Control 12 Step / CBT Two essential features: impaired ability to regulate the drive to obtain and use substances reduced drive to obtain natural rewards Naltrexone Acamprosate Memory Naltrexone Acamprosate Change in the reward circuitry : substances usurp normal learning circuitry to create the pathology of addiction 15 Used with permission from David Oslin, 2012 Kalivas and O Brien, 2008 Vulnerabilities in Development of Addiction Core Addiction Syndrome Genetic Developmental Social Drug-induced brain plasticity Common neuroplasticchanges in response to chronic administration of different substances of abuse Addiction is overlearned with repeated associations between substances and life events mediated by dopamine release Addictive behaviors and chronic relapse vulnerability are maintained by glutamatergic neurotransmission Kalivas and O Brien,

4 Core Addiction Syndrome Hypofrontality- subcortical glutamatergic connections assume primacy and reduce cortical control over drug-seeking (automatic behavior) Drug-associated stimuli activate PFC excessively, whereas natural reinforcers(sex, food, danger etc.) elicit poor response - maladaptive process Staged Neuroplasticity of Addiction Abstinence Social Use Chronic Use Regulated relapse conscious choice Compulsive relapse-inability to make a conscious choice (Kalivas and O Brien 2008) Neurobiological Changes with Chronic Substance Use Motivation/reward system DA/endorphine Glutamate/GABA dysregulation HPA axis dysregulation Hypofrontality Sex hormones dysregulation Cravings Relapse Pharmacologic Strategies to Treat Addiction Dopaminergic (D1-D5) Glutamatergic(NMDA, AMPA, KA, metabotropic) GABA ergic(gaba A and B) Cholinergic (Ach M and N) Noradrenergic (Alpha and beta) Serotonergic (14 subtypes) Endogenous opioids (mu, delta, kappa, OFQ-N) Endogenous cannabinoids (CB1 and CB2) Many others (NPY, DARPP-32, galanin, orexin, CRF, substance P, melanocortins, leptin, BDNF etc.) Most Effective Treatment for Substance Abuse Disorders Combination of medications and therapy Treatment of co-morbid mood and anxiety disorders Free up the frontal lobes by quieting subcortical areas for the therapy Therapy: relapse prevention, motivational interviewing, 12-step facilitation, CBT, family therapy etc. Addiction Therapy may be related to activation of Frontal Cortex (Boettiger, et.al. 2009) (Crews and Boettiger et.al. 2009) 4

5 Importance of Simultaneous Treatment for All Substances Involved One craving breeds another One addiction drives another (priming effect) Very important to address tobacco dependence Stress increases cravings and relapse Low-risk drinking limits If no cardio-vascular disease Men: Not more than 2 standard drinks per day and not more than 4 drinks on an occasion and not more than 14 drinks per week Women and elderly: drinks per day Medications for alcohol dependence Disulfiram First medication approved for alcoholism Blocks acetaldehyde dehydrogenase Medications for Alcohol Use Disorders Disulfiram Acamprosate Naltrexone oral/injectable/implantable Topiramate Works best if dose observed Disulfiram Reduces Drinking Days Acamprosate Glutamate antagonist Reduced protracted withdrawal Reduces cravings * *p<.05 Fuller et al. JAMA Sep 19;256(11):

6 Acamprosate Promotes Abstinence Meta-Analysis of Acamprosate: Abstinence Improved Outcome: Abstinence Rate Treatment Study n/n Besson 1998 Chick 2000 Geerlings 1997 Gual 2001 Ladewig 1993 Paille 1995 Pelc 1997 Poldrugo 1997 Sass 1996 Tempesta 2000 Whitworth /55 35/289 14/128 49/141 12/29 45/361 52/126 53/122 54/136 62/164 27/224 Control n/n 3/55 32/292 7/134 38/147 7/32 16/177 9/62 37/124 23/136 48/166 11/224 Peto OR (95% CI Fixed) Weight % Peto OR (95% CI Fixed) 4.56 [1.63, 12.76] 1.12 [0.67, 1.86] 2.16 [0.89, 5.27] 1.52 [0.92, 2.52] 2.45 [0.83, 7.18] 1.41 [0.80, 2.48] 3.37 [1.76, 6.44] 1.79 [1.07, 3.01] 3.06 [1.81, 5.18] 1.49 [0.94, 2.35] 2.50 [1.29, 4.87] Total (95%CI) 417/ /1549 Test for heterogeneity: chi-square = 17.00; df= 10; P = Test for overall effect: z = 6.87; P< [1.57, 2.25] Sass et al. Arch Gen Psychiatry. 1996;53(8): Bouza et al. Addiction. 2004;99:811. CI = confidence interval; OR = odds ratio Medications for alcohol dependence Cumulative Rate of Alcohol Relapse Naltrexone HCl (N=35) Placebo (N=35) No. of Weeks Receiving Medication Naltrexone Blocks opiate receptors prevents endorphines from binding to GABAinterneurons Blocks subsequent dopamine release Effective is a subset of alcoholics Volpicelli et al., Arch Gen Psychiatry 1992;49(11): Meta-Analysis: Oral Naltrexone Reduces Relapse Naltrexone is effective in compliant patients Study Treatment n/n Control n/n Peto OR (95% CI Fixed) Weight % Peto OR (95% CI Fixed) Anton 1999 Chick 2000 Guardia 2002 Heinala 2001 Hersch 1998 Kranzler 2000 Krystal 2001 Latt 2002 Monti 2001 Morris 2001 Oslin 1997 O Malley 1992 Volpicelli 1995 Volpicelli /68 59/90 8/101 49/63 15/31 29/61 142/378 19/56 16/64 19/55 3/21 16/52 10/54 17/48 38/63 54/85 19/101 51/58 15/33 31/63 83/187 27/51 19/64 26/56 8/23 31/52 17/45 26/ [0.21, 0.82] 1.09 [0.59, 2.03] 0.39 [0.17, 0.88] 0.50 [0.19, 1.27] 1.12 [0.42, 2.98] 0.94 [0.46, 1.89] 0.75 [0.53, 1.08] 0.46 [0.22, 0.99] 0.79 [0.36, 1.72] 0.61 [0.29, 1.30] 0.34 [0.09, 1.33] 0.32 [0.15, 0.68] 0.38 [0.16, 0.93] 0.49 [0.22, 1.09] * Total (95%CI) 428/ /930 Test for heterogeneity: chi-square = 17.00; df=10; P = Test for overall effect: z = 6.87; P< Bouza et al. Addiction. 2004;99: Favors Naltrexone Favors Control 0.62 [0.52, 0.75] CI = confidence interval; OR = odds ratio *p =.002 Arch Gen Psychiatry 1997 Aug;54(8):

7 Extended Release Injectable Naltrexone Extended-release Injectable Naltrexone: Pivotal Trial Naltrexone embedded in microspheres Elimination: polymer eventually metabolized and eliminated as CO 2 and H 2 O Hydration Diffusion Erosion Dean. Front Biosci. 2005;10:643. Multicenter study, 624 patients 3 groups: placebo, 190 mg, and 380 mg All patients received BRENDA About 8% of patients were abstinent for 1 week prior to treatment 6 months of treatment Garbutt et al. JAMA 2005;293:1617 Reductions in Heavy Drinking with Naltrexone All Patients Patients Without Lead-in Abstinence Patients With Lead-in Abstinence Family History Predicts Naltrexone Response Percent Reduction Relative to Placebo P = 0.02 vs PBO P = 0.05 vs PBO PBO = placebo P = vs Garbutt et PBO al. JAMA. 2005;293:1617 Monterosso et al. Am J Addict. 2001;10: Mu Receptor Polymorphism Predicts Naltrexone Response * Pharmacology of Topiramate Antagonist at AMPA and kainate receptors Allosteric agonist at the GABA-A receptor Blocks voltage-dependent Na and l-type voltage-gated Ca channels Inhibits carbonic anhydrase Enhances K+ conductance * p=.04 Oslin et al. Neuropsychopharmacology 2003;28(8):

8 Medications for alcohol dependence Meta-analysis by Blodgett et al. (2014) Topiramate Promotes Abstinence From Alcohol Johnson et al. Lancet. 2003;361(9370): Placebo-Controlled Trial of Topiramateto Reduce Heavy Drinking Study Design 12-week study of 138 heavy drinkers whose goal was to reduce drinking to safe levels Topiramate 100 mg twice daily (N=67) or matching placebo (N=71) with dosage increased gradually over 6 weeks Brief behavioral counseling at each visit Moderator analysis of rs in GRIK1 Kranzler et al., Am J Psychiatry, 2014 Screenin g (n=200) Baseline (n=138) 12-Week Treatment Topiramate (n=67; 82.1% completed tx) 12-Week Treatment Placebo (n=71; 87.3% completed tx) 3-month Follow-up Topiramate (n=60; 90%) 3-month Follow-up Placebo (n=63; 88.7%) 6-month Follow-up Topiramate (n=59; 88.1%) 3-month Follow-up Placebo (n=59; 83.1%) Kranzler et al., Alcohol Clin Exp Res, in press Within-Treatment Heavy Drinking Days/Week Within-Treatment Abstinent Days/Week 8

9 Genotype Groups We genotyped participants for rs in GRIK1 as a moderator of topiramate s adverse effects and effects on drinking behavior. The genotypes in European Americans (n=122) were in Hardy- Weinberg Equilibrium: CC (n=51) AC (n=53) AA (n=18) Kranzler et al., Am J Psychiatry, 2014 Heavy Drinking Days by Medication and Genotype Groups Abstinent Days by Medication and Genotype Groups The population of veterans Figure : Main effect of medication group (A), and moderating effect of rs (B and C) Prevention only Heavy Drinking Addiction 52 Brief Interventions Heavy Drinking Brief Advice/Intervention Shown to decrease drinking and adverse health outcomes for non dependent individuals Two components: Advice Link drinking to health PCMHI staff Provide training Provide Brief interventions Assess for comorbidities Integrating treatment for addiction The BHL Model Stepped Care Approach Strong ties to mental health supervision Initial decisions and prescribing in primary care Assessment based Tracking important need informatics support Emphasis on patient self-management support Behavioral Health Provider facilitates communication and education of team Offer telephone contacts Much appreciated by patients 9

10 Alcohol Care Management - Dependence Provider: BHS nurse, psychologist, SW BHS meets with patient for 18 sessions over 6 months either in person or by telephone Collaborates with PCP to: Increase motivation to abstain Be supportive and optimistic Encourage naltrexone Encourage AA attendance Provide education (health risks and detrimental outcomes) Subjects engaged in treatment (%) Drinking Outcomes Alcohol Care Management Specialty Addiction care Relapse to heavy drinking Tobacco Use Disorder Treatment Percent days of heavy drinking Alcohol Care Management Specialty Addiction care No contraindications for NRT (ICU, CVD, pregnancy) Patients may smoke while using the patch Gradual replacement of cigarettes may work better than fixed quit date Combination NRT beats varenicline (Surgeon General Report on Tobacco, 2008) Need to give enough of NRT (2-4 mg per cigarette) Many patients need long term NRT (up to 6 months or longer) Women metabolize nicotine faster need higher doses 57 Nicotine Replacement Treatment Nicotine Levels Obtained by Various Forms of Replacement Pre-Cessation NRT Meta-analysis (2008): Effectiveness of and abstinence rates for smokers not willing to quit (but willing to change their smoking patterns or reduce their smoking) after receiving NRT compared to placebo (n = 5 studies) Placebo 3.6 % (OR1) Nicotine replacement (gum, inhaler,or patch) 8.4% ( ) (OR 2.2)

11 Treatment of Tobacco Dependence with Antidepressants Bupropion(36 trials, N = 11,140, risk ratio [RR] 1.69; 95% confidence interval [CI] 1.53 to 1.85) and nortriptyline(six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) both significantly increased long term cessation From the available data bupropionand nortriptylineappear to be equally effective and of similar efficacy to nicotine replacement therapy.the mode of action of bupropionand nortriptylineis independent of their antidepressant effect. SSRIs not effective, MAOIs (moclobemide, selegiline) and venlafaxine(snri) not effective Treatment of Tobacco Dependence with Varenicline(Partial Nicotinic Agonist) RR for continuous abstinence at six months for vareniclinevsplacebo was 2.33 (95% confidence interval [CI] 1.95 to 2.80). The pooled RR for vareniclineversus bupropion at one year was 1.52 (95% CI 1.22 to 1.88). The RR for vareniclineversus NRT at one year was 1.31 (95% CI 1.01 to 1.71) Varenicline vs.bupropion Comparable in efficacy (a bit higher with varenicline) Agonist (?) and partial agonist on nicotinic receptor 2008 FDA suicidal warning on both: 90% of suicides on varenicline, 7% on bupropion and 3% on NRT (Moore,T et al,2011) Varenicline may exacerbate CVD (FDA, 2011) but 2012 meta-analysis does not confirm it (Prochaska,J et al, 2012) Varenicline is contraindicated in pilots and traffic controllers (FAA) Both can be safely used in combination (Ebbert,Jet al, 2008) Cannabis: Clinical Issues 60 cannabinoids and cannabinoid-antagonists, one of them is THC Associated with early onset of psychosis (Large,M et all, 2011), may be causal Causes neuropsych decline (Meier,Met al,2012); amotivational syndrome ( s); lower educational attainment; lower income (Gruber,Aet al,2003); lower life satisfaction (Fergusson,D et al, 2008) Respiratory effects comparable to tobacco (Moore, B et al, 2005), more carcinogens Use declines with age Cannabis: Treatment No FDA approved meds Oral THC 10 mg 5 times daily and Divalproex 1500 mg daily (Haney, M et al, 2004) Dronabinol (Levin,F et al,2008) Gabapentin 1200 mg daily (Mason,B et al, 2012) Mirtazapine mg nightly (Benyamina,A 2008) NAC (N-Acetylcysteine) : 1200 mg twice daily for 8 weeks and contingency management beats placebo in negative urines OR 2.4 (Gray, K et al, 2012) Cannabis: Clinical Pearls Rimonabant(CB 1 blocker) off the market Medical marijuana Decriminalization vs. legalization debate 11

12 Opiate relapse prevention medications What is goal of pharmacological treatment? Relapse prevention Methadone Buprenorphine The Ideal Medication Stops withdrawal Reduces craving Blocks the high from abused drugs Naltrexone Opiate relapse prevention medications Methadone Maintenance Treatment is Effective Methadone Maintenance Stops withdrawal Reduces craving Blocks the high from heroin Saves lives ADMISSION Pre- 1st Year 2nd Year 3rd Year 4th Year Admission * * Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance Treatment, 1991 Problems with Methadone Methadone is a full opiate agonist Strict federal state and local controls Limited to methadone clinics Too little availability Buprenorphine Partial mu opiate agonist, kappa antagonist Parenteral analgesic (Buprenex ) Available for opiate dependence since

13 Opiate relapse prevention medications The Advantage of Buprenorphine Buprenorphine Is As Effective as Methadone Not improved efficacy but increased availability Buprenorphine is available for office use Johnson et al. N Engl J Med. 2000;343(18): Opiate relapse prevention medications Naltrexone Blocks opiate receptors Compliance impacts effectiveness It does not stop withdrawal Its anti-craving effect is weak Very effective in certain populations Opiate relapse prevention medications Extended release naltrexone in Russia 250 patients 6 month trial Double blind placebo controlled 380 mg extended release naltrexone monthly Krupitsky et al. Lancet 2011; 377: Response Profile Cumulative % of Participants at Each Rate of Weekly Confirmed Abstinence: XR-NTX 380 mg vs. Placebo Cocaine: Treatment No FDA approved meds Disulfiram(250 mg daily) was effective in four trials (Carroll,K et al, 2004), not effective in one (Olivetto,Aet al, 2011) Modafinil( mg daily) decreased cocaine intake in one controlled clinical trial (Dackis,C et al,2005) but not in a second larger trial (Anderson,A et al, 2009) Anticonvulsants are effective: topiramate(200 mg daily) (Kampman,K 2004), tiagabine (12 mg or 24 mg daily) (Gonzales, 2007), and vigabatrin(3 g/day) (Brodie, 2009) Gabapentin (1800 to 3200 mg/day) not effective (Brodie,2009) Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 (35.7%) of subjects in the XR-NTX group versus 28 (22.6%) subjects in placebo group (P=0.0224). 13

14 Cocaine: Treatment Citalopram 10 mg daily (Moeller,F et al,2007) Ondansetron 4 mg twice daily (Johnson,B et al,2006) Agonist substitution with amphetamines (Mooney et al,2009; Shearer,J 2008) Bupropion 300 g daily with contingency management (Poling,J 2006) Naltrexone 100 mg daily (Schmitz,J et al,2009; Pettinati,H et al, 2008; Schmitz,J et al, 2003, Hersh D, 1998) Buprenorphine/Naloxone mg daily (Montoya,I et al,2004) Beta-blockers (Propranolol) reduces cravings (Leri, 2002),reinforcing effects (Sofuoglu, 2000), withdrawal (Kampman,2001) Cocaine vaccine Acupuncture, herbal remedies not effective 14