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New Developments in the Treatment of Alcoholism

New Developments in the Treatment of Alcoholism. Hugh Myrick, MD Ralph H. Johnson VAMC Medical University of South Carolina Charleston, South Carolina. Disclosure of Financial Interests or Other Affiliations. Abbott: grant funding and speakers’ bureau Alkermes: speaker’s bureau

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New Developments in the Treatment of Alcoholism

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  1. New Developments in the Treatment of Alcoholism Hugh Myrick, MD Ralph H. Johnson VAMC Medical University of South Carolina Charleston, South Carolina

  2. Disclosure of Financial Interests or Other Affiliations • Abbott: grant funding and speakers’ bureau • Alkermes: speaker’s bureau • AstraZeneca: speaker’s bureau • Bristol-Myers Squibb: grant funding, speaker • Forest Laboratories: grant funding, speaker • Ortho-McNeil: grant funding, speaker • Pfizer: grant funding • Hythiam: grant funding • NIAAA and NIDA: grant funding

  3. Prevalence of Alcohol Abuse/Dependence • Estimated 14-18 million alcohol-abusing or alcohol-dependent individuals • Approximately half are alcohol dependent • Prevalence similar to other chronic diseases such as asthma, diabetes, and depression • Economic loss of $134 billion in productivity • Causes many other health problems either directly or indirectly Sources: National Institute on Alcohol Abuse and Alcoholism (1994, 2000a, 2000b); Centers for Disease Control and Prevention (1999); National Center for Health Statistics (no date: a, b, c); McLellan et al. (2000); American Lung Association (no date); American Heart Association and National Pharmaceutical Council (2000).

  4. Unmet Needs in Alcoholism 14 M (to 18 M) • Only 10% of those in the treatment system are receiving pharmacologic therapy Abusers Dependents Treated 1.4 M 140 K Prevalence SeekingTreatment Rx

  5. Phases of Alcoholism Treatment • Detoxification: • Primary goal is to achieve an alcohol-free state • Wide spectrum of severity • Drug-specific syndromes: opiates, cocaine, alcohol, benzodiazepines • Relapse prevention: • Primary goal is to maintain an alcohol-free state • Chronic treatment

  6. Alcohol Withdrawal Treatment • Substitute cross-dependent drug (BZ) • Gradually withdraw substitute drug • Supplement vitamins and minerals • thiamine • folic acid • multi-vitamin • Supportive treatment • decrease stimulation, • Increasingly an outpatient procedure increase fluid and caloric intake

  7. Benzodiazepines: Can they Prime Alcoholics to Drink? • Design: • Double-blind, placebo controlled, counterbalanced • Diazepam (DZ) 5mg vs placebo • 12 problem drinkers (41.6 std. drinks/week) • Results: • DZ increased alcohol consumption • DZ increased desire for alcohol • DZ decreased response latency to alcohol vs neutral words Poulos & Zack, Behav Pharm, 2004

  8. Anticonvulsants as Alcohol Detoxification Agents Advantages No abuse liability Seizure medication Neuroprotective Cognition • Disadvantages • Limited clinical experience • Hematological side effects • Liver toxicity

  9. Carbamazepine vs. Lorazepam in Alcohol Withdrawal • Double-blind, outpatient trial (n=136) • CIWA-AR ≥ 10 for inclusion • 5 day tapering dose • CBZ = 600-800 mg/d tapered to 200mg by day 5 • LZ = 6-8 mg/d tapered to 2 mg by day 5 • Compared single (0-1) vs. multiple (≥ 2) medicated detoxifications Malcolm, Myrick et al. J Gen Intern Med. 2002;17:349-355.

  10. * 6 n=11 5 4 3 n=40 n=30 2 n=8 1 0 CBZ/≥2 LZP/≥2 CBZ/0-1 LZP/0-1 Drinks per Drinking Day: Day 6 to Day 12 Least Square Mean for Follow-up Drinks per Drinking Day *P=.044. Drug main effect, P=.0032; Drug x Detox Hx, P=.0333. Malcolm R et al. J Gen Intern Med. 2002;17:349-355.

  11. Gabapentin vs. Lorazepam in Alcohol Withdrawal • Double-blind, outpatient trial (n=101) • CIWA-AR ≥ 10 for inclusion • Tapering dose • GBP = 900-1200 mg/d tapered over 4 days • LZ = 6 mg/d tapered over 4 days • Acoustic Startle assessed on Days 0, 4, and 7 • Follow-up at Day 7 and 12 Myrick et al, ACER, 2009

  12. Alcohol Withdrawal Symptoms Baseline used as covariate GBP 900mg/day GBP 1200mg/day Lorazepam 1 2 3 4 5 7 12 Comparisons: GBP 900 vs 1200: t = 5.83, p = 0.019 GBP 900 vs Lorazepam: NS GBP 1200 vs Lorazepam: t = 6.86, p = 0.011

  13. Drinking Odds Comparisons NS ≤ .07 ≤ .05 Treatment Follow-up

  14. Acoustic Startle Response Startle Magnitude - Lorazepam Startle Magnitude - Gabapentin Trial Number Trial Number

  15. Alcohol DependenceFDA-Approved Treatments • Disulfiram (Antabuse) • Aldehyde dehydrogenase inhibitor • Aversive effect produced by acetaldehyde buildup after alcohol intake • Naltrexone (ReVia) • Opiate receptor antagonist • Blocks the “high” associated with alcohol intake • Acamprosate (Campral) • Glutamate receptor modulator • May interact with the glutamate neurotransmitter system and restore the normal neurotransmitter balance • Extended-Release Injectable Naltrexone (Vivitrol) • Opiate receptor antagonist • Monthly injection

  16. Predictors of Response to Disulfiram • Predictors of efficacy • High motivation • Married • Behavioral contracts • Compelled to comply (legally) • Targeted treatment • Take medication prior to high-risk situations • Greater efficacy has been shown with supervised disulfiram administration

  17. Predictors of Response to Naltrexone Greatest benefit is derived by patients • Receiving cognitive-behavioral therapies • With higher levels of craving • With higher compliance on medication • With a family history of alcoholism • Associated with lower baseline plasma beta-endorphin and an exaggerated response to an alcohol challenge1 • The A118G allele of OPRM1 • Associated with increased substance abuse risk, beta-endorphin binding and altered dopamine function • +/- association with naltrexone treatment2,3 OPRM1=opioid receptor mu 1 gene. 1. Gianoulakis C et al. Alcohol. 1996;13:19-23; 2. Rubio G et al. EurNeuropsychopharm. 2002;12:S398; 3. Oslin D et al. Neuropsychopharmacology. 2003;28:1546-1552.

  18. Rate of Relapse by Treatment Adherence and Medication Group 50 45 42.0 40.0 40 38.6 35 30 Placebo % Patients Relapsed 25 Oral Naltrexone 20 15 10.0 10 5 0 n = 44 n = 60 n = 50 n = 42 Nonadherent Adherent Pettinati et al. J Addict Dis. 2000;19:71

  19. Oral Naltrexone Discontinuation Rates Pharmacy claims for NTX-PO in a plan with 1.5 million insureds for 3 yrs (‘00-’02) Approximately 50% did not refill even once – despite having coverage • U.S. Dept of HHS/SAMHSA study Harris KM, et al. Psychiatr Serv. 2004;55:221:1229-1235 3. Stephenson et al. American Academy of Addiction Psychiatry. 2006

  20. Oral Naltrexone Adherence in Alcohol Dependence • Medstat MarketScan Insurance Claims Database (2000-2004) • Over 5 million employees from 50 large national employers • 1138 oral NTX patients • 52% did not refill even once (Median = 1 Rx) • Only 14% filled prescriptions for 6 months Nonadherent86% Adherent14% Stephenson et al., American Academy of Addiction Psychiatry, 2006

  21. Oral Naltrexone Adherence in Alcohol Dependence (continued) Non-adherent patients were significantly more likely to have … • Inpatient detoxification admissions • Non-alcohol specific hospital admissions • Non-alcohol specific ER visits • No counseling participation Stephenson et al., American Academy of Addiction Psychiatry, 2006

  22. Extended Release Injectable Naltrexone • Design: 6-month, randomized, double-blind, placebo-controlled trial at 24 sites • Dosing: • 380 mg (n=205) • 190 mg (n=210) • Placebo (n=209) • Results: • 380 mg had 25% reduction in heavy drinking days • 190 mg had 17% reduction in heavy drinking days • Males and pre-treatment abstinence had greater tx effects Garbutt et al., JAMA 2005;293:1617-1625

  23. XR-NTX 380 mg Response Among patients who were abstinent for 4 or more days prior to treatment initiation XR-NTX prolongs initial abstinence 32% 11% XR-NTX 380 mg (N=28) Placebo (N=28) O’Malley SS, et al. J Clin Psychopharmacol. 2007;27:507-512

  24. Persistence of Monthly RefillsPrivate national pharmacy claims data in all Alcohol Use Disorder patients who filled an initial Rx N=133 N=3012 N=1006 N=1135 XR-NTX Un H, Addiction Health Services Research Conference, Boston 2008

  25. Acamprosate • Not metabolized by the liver • Acamprosate does not inhibit or induce CYP450 • Acamprosate is primarily excreted unchanged by the kidneys • Safe concomitant administration with disulfiram and naltrexone • Can be used in patients with hepatic impairment • No evidence of abuse or dependence liability

  26. The COMBINE Study • Design: • Randomized, 16-week controlled trial conducted in 11 US sites (n=1,383) • 8 groups received medical management (MM) with or without combine behavioral intervention (CBI): • Naltrexone 100 mg/day • Acamprosate 3 gm/day • Naltrexone + Acamprosate • Placebo • 9th group received CBI only (no pills) The COMBINE STUDY, JAMA 295;17:2003-2017, 2006

  27. COMBINE Interpretation • In the context of MM, naltrexone and/or CBI improve clinical outcomes • Acamprosate alone or in combination had no effect on clinical outcomes • Naltrexone with MM should be easy to implement in healthcare settings

  28. What is fMRI? • Infer brain activity by measuring changes in blood flow • neuronal activity= oxygen demand • Hemoglobin • Diamagnetic when oxygenated • Paramagnetic when deoxygenated • Difference lead to MR signal • BOLD (Blood Oxygen Level Dependent) imaging

  29. fMRI Imaging and Finger-Tapping

  30. Importance of Imaging Research • Aid in understanding the neurobiological substrates underlying craving • Aid in the evaluation of potential medication treatments • Aid in understanding neurobiology of relapse

  31. Standard Methodology • Subject is presented a cue • Pictures or video • Handling paraphernalia • Imagery • Odor • Sip or infusion • Craving rated • Images obtained

  32. Cue Paradigm Alcohol (A) Beverage (B) Visual Control (C) Rest (R) Time Course of the Presentation of Stimuli During fMRI Sip of Preferred Beverage C A B C B A C B A A C B B C A B C A R R R R R R 0 1 2 3 4 5 6 7 8 9 10 11 12 Post-sip craving rating Time (min) Pre-sip craving rating Post scan craving rating Comparisons: Alcohol - Beverage Beverage - Vis Ctrl Alcohol - Vis Ctrl Beverage - Rest Vis Ctrl - Rest

  33. Subjects • ALCOHOLICS • Current DSM-IV alcohol dependence or abuse • Meet “loss of control” dependence criteria • Consume at least 20 drinks per week • Non-treatment seeking • Medically healthy, psychiatrically stable • No current psychoactive medications or illicit drug use • SOCIAL DRINKERS • Never met DSM-IV alcohol dependence (or abuse) • Consume less than 14 drinks per week • Consumed 2 drinks on at least one occasion in past 30 days • Medically healthy, psychiatrically stable • No current psychoactive medications or illicit drug use

  34. Demographics/Drinking Variables

  35. Alcohol - Beverage Condition Cingulate 82 82 Insula Ventral Striatum Alcoholics (n=10) Controls (n=10) Z=1.645 Ex .05

  36. Alcohol - Beverage Condition 107 107 Cingulate Ventral Tegmental Area Alcoholics (n=10) Controls (n=10) Z=1.645 Ex .05

  37. What can imaging tell us about treatment? • Alcohol and alcohol cues stimulate dopamine release in the ventral striatum • This effect may underlie cue-induced craving • Neuroimaging techniques such as fMRI have been used to illicit cue-induced brain activation • Dopamine stabilization could potentially reverse or block cue-induced ventral striatum activation • Blunting of the ventral striatum activation could reduce craving and relapse behavior

  38. Medication Treatment of Cue-Induced Brain Activation • Explore the effects of combining medications on altering alcohol cue-induced craving and brain activity in non-treatment seeking alcoholics • Medication Groups: • Naltrexone • Ondansetron • Naltrexone/Ondansetron • Placebo • Medication treatment for seven days Myrick et al, Archives Gen Psych, 2008

  39. Cue Paradigm Alcohol (A) Beverage (B) Visual Control (C) Rest (R) Time Course of the Presentation of Stimuli During fMRI Sip of Preferred Beverage C A B C B A C B A A C B B C A B C A R R R R R R 0 1 2 3 4 5 6 7 8 9 10 11 12 Post-sip craving rating Time (min) Pre-sip craving rating Post scan craving rating Comparisons: Alcohol - Beverage Beverage - Vis Ctrl Alcohol - Vis Ctrl Beverage - Rest Vis Ctrl - Rest

  40. Demographics and Drinking Characteristics Differences between treatment conditions were non-significant. Drinking history and Obsessive Compulsive Drinking Scale (OCDS) score in the control group was significantly different than treatment groups (p<.01).

  41. Placebo 7 days Naltrexone 7 days Ventral Striatum Nal + Ond 7 days Ondansetron 7 days Areas of Activation During Alcohol CuesAlcohol - Beverage Condition Social Drinkers Alcoholics Brain regions with significantly increased activation in one task (alcohol) compared with another (beverage) are depicted in color on coronal structural magnetic resonance imaging scans (p ≤.001).

  42. Alcohol Cue-induced Brain Activity Area indicates greater activation to alcohol cues than neutral beverage cues Non-treatment Seeking Alcoholics Placebo – 7 days Naltrexone – 7 days Social Drinkers occipital occipital ventral striatum nucleus accumbens medial prefrontal occipital

  43. Aripiprazole on Cue-Induced Brain Activation in Alcoholics Aripiprazole is a partial dopamine agonist Open-label data suggested use in alcoholism Multi-site trial found decrease in drinks per drinking day Clinical lab study found a dose-dependent reduction in euphoric effects of alcohol Exact mechanism of action in alcoholism unknown: dopamine stabilization could potentially reverse or block cue-induced ventral striatum activation. Blunting of ventral striatum activation could reduce craving and relapse behavior

  44. Cue Paradigm Alcohol (A) Beverage (B) Visual Control (C) Rest (R) Time Course of the Presentation of Stimuli During fMRI Sip of Preferred Beverage C A B C B A C B A A C B B C A B C A R R R R R R 0 1 2 3 4 5 6 7 8 9 10 11 12 Post-sip craving rating Time (min) Pre-sip craving rating Post scan craving rating Comparisons: Alcohol - Beverage Beverage - Vis Ctrl Alcohol - Vis Ctrl Beverage - Rest Vis Ctrl - Rest

  45. Demographics

  46. fMRI Response to Alcohol Craving Cues by Medication Condition Placebo Aripiprazole Nucleus Accumbens Insula

  47. Naltrexone Study Aripiprazole Study Placebo Naltrexone Placebo Aripiprazole Ventral Striatum Ventral Striatum Insula fMRI Response to Alcohol Craving Cues by Medication Condition

  48. Alcohol Cue-induced Brain Activity Aripiprazole Placebo Social Drinking Controls Middle Cingulate Ventral Striatum P = 0.005, vox = 15 • Decrease in percent days abstinent (p=.05) • Decrease in percent heaving drinking days (p=.05)

  49. What can imaging tell us about relapse? • Seven-week, RCT • Treatment seeking alcoholics (n=48) • Scanning • fMRI 10-21 days after treatment starts • Philips 3.0 Tesla scanner • Cue-induction paradigm • Imaging data analysis not complete

  50. Brain Activity and Alcohol Relapse Areas of activation that differ between alcoholics who did and did not relapse to heavy drinking No Relapse Relapse medial prefrontal

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