MAT: Medication Assisted Treatment for Alcohol Dependence

Transcription

1 MAT: Medication Assisted Treatment for Alcohol Dependence Maritza Lagos, MD, DABAM WMU Homer Stryker MD, School of Medicine - Psychiatry February 2015

2 Case 44 y.o. Divorced, Caucasian male with strong family history of alcohol use disorder. Presents to the outpatient clinic reporting that despite of several inpatient rehab treatments for alcohol dependence he has not been able to stay sober for a long time. What else could we do for this patient? 3/24/2015 2

3 Alcohol abuse/depend ence Alcohol dependence Seeking treatment Millions millions Treating with medication millions alcohol abuse/dependence alcohol dependence seeking treatment treating with medication Grant B.F et al. Arch Gen Psychiatry 2004; 61: SAMHSA 3/24/2015 3

4 In the 21 st century Adding pharmacotherapy to traditional treatment approaches is an option 3/24/2015 4

5 MEDICATIONS FOR PATIENTS WITH ALCOHOL DEPENDENCE 1. Extended-Release Naltrexone (IM): Vivitrol** 2. Naltrexone (oral): ReVia** 3. Disulfiram: Antabuse** 4. Acamprosate: Campral** 5. Topiramate: Topamax* 6. Baclofen* *Not FDA approved for alcoholism **FDA labeling on these medications is clear: These medications should be used in combination with behavioral treatments for addiction. 3/24/2015 5

6 NALTREXONE: ReVia, Depade World Health Organization (1996) safe and effective treatment for alcohol dependence 3/24/2015 6

7 The happy natural substances of the brain: Endorphins and Dopamine Alcohol increases endorphins in certain parts of the brain endorphin activity release of dopamine dopamine drinker feels good Alcohol also reduces anxiety The brain remembers the good feelings caused by alcohol (dopamine) The brain desires to repeat the behavior again to get the same good feelings relapse or continued ingestion. 3/24/2015 7

8 Naltrexone: Mechanism of action Blocks the action of endorphins by blocking their specific receptors (opioid receptors) No dopamine is released reduce reward in response to drinking By blocking the pleasure from alcohol: also may reduce the amount of heavy drinking in those who do drink With no endorphins in the receptors reduces craving By craving: may enhance the ability of patients to abstain from drinking. (Monti et al., 1999, 2001). 3/24/2015 8

9 NA naltrexone Endogenous opioids Endogenous opioids receptors dopamine 3/24/2015 9

10 Effectiveness of Naltrexone Reduces drinking frequency Reduces likelihood to relapse to heavy drinking Reduces reinforcing response to alcohol Safety and efficacy: > 8 double-blind RCT Naltrexone IM: Those who had a 7 days abstinence period prior to treatment had a greater reduction in the number of heavy drinking days during the entire study (Paille, et al., 1994; Pelc, et. al, 1997; Sass, et al., 1996) 3/24/

11 Naltrexone: side effects Most Common Fatigue Nausea Vomiting Headache Dizziness Less Common Diarrhea, constipation, stomach pains, cramps, loss of appetite Chest pain, joint/muscle pain Rash Difficulty sleeping Sweating, Excessive thirst, Increased tears Somnolence Anxiety Nervousness Mild depression Delayed ejaculation 3/24/

12 Acamprosate: Campral 3/24/

13 Alcohol: Chemical balance GABA (-) and Glutamate(+) Systems GABA: major inhibitory neurotransmitter (NT) in the brain: Alcohol GABA Glutamate: the major excitatory NT in the brain. Alcohol glutamate Good for agitation induced relapses 3/24/ Source: Littleton J. Alcohol Health Res World. 1998;22:13-24.

14 AWS: GABA vs GLUTAMATE Normal Alcohol Intake Inhibition (GABA) Excitation (Glutamate) Alcohol Tolerance Adaptation Acute Withdrawal 3/24/

15 Pathophysiology of Potential Relapse Ca 2+ Glutamate NMDA Receptor mglur5 3/24/

16 How Does Acamprosate Work? (Hypothesis) Reduces the pathological overactivation of the glutamate system to counteract the maladaptive changes associated with alcohol dependence Reduces the release of glutamate from the presynaptic nerve terminal Reducing the overactivation of NMDA receptors postsynaptically Similarities in molecular structure between Campral and glutamate suggest weak inhibitory effects at several points within glutamate synapses The cumulative effect seems to be weak inhibitory modulation rather than strong antagonism Moderation of prolonged withdrawal: cushions the brain against the stimuli and symptoms responsible for relapse. 3/24/

17 Balancing Pathophysiology Campral (acamprosate calcium) C Reduction in glutamate release C Reduction in postsynaptic effects C C NMDA Receptor Glutamate C Campral mglur5 3/24/ Campral is a registered trademark of Merck Santé s.a.s., subsidiary of Merck KGaA, Darmstadt, Germany. C

18 Research about Acamprosate European trials: When compared to placebo, participants treated with acamprosate: reduced drinking days Increased duration of complete abstinence lengthened time to relapse (Paille, et al., 1994; Pelc, et. al, 1997; Sass, et al., 1996) US trials: mixed results In Project COMBINE acamprosate did not perform as well as naltrexone 3/24/

19 From: Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial JAMA. 2006;295(17): doi: /jama Date of download: 2/8/2015 Copyright /24/2015 American Medical 19 Association. All rights reserved.

20 Antabuse: disulfiram 3/24/

21 Disulfiram Mechanism of action in the liver Alcohol dehydrogenase Aldehyde dehydrogenase Ethanol Acetaldehyde (hangover) 5-10x more than normal Disulfiram- Ethanol Reaction Disulfiram Acetic acid (harmless) 3/24/

22 Disulfiram: Antabuse Disulfiram + alcohol = DER (Disulfiram-Ethanol-Reaction). DER: aversive reaction that varies in intensity with the dose of disulfiram the volume of alcohol consumed The prospect of such a reaction deters drinking Efficacy???? The most rigorous study of disulfiram: controlled, blinded 1 year study. 605 men randomly assigned to 250 mg of disulfiram: 202 men 1 mg of disulfiram:204 men No pills: 199 men: control for the counseling that all received. Bimonthly treatment assessments Relative/friend interviews and blood and urine ethanol analyses were used to corroborate patients' reports. 1. Fuller RK, Branchey L, Brightwell DR, et al: Disulfiram treatment of alcoholism: A veterans administration cooperative study. JAMA 256: , /24/

23 Results There were no significant differences among the groups in total abstinence, time to first drink, employment, or social stability Among the patients who drank: The 250 mg disulfiram group: significantly fewer drinking day:49.0 +/- 8.4 The 1 mg disulfiram group: / No pills: / groups. There was a significant relationship between adherence to drug regimen and complete abstinence in pill taking groups. Almost 90% were not taking the pills when they decided to drink. Conclusion: disulfiram may help reduce drinking frequency after relapse, but does not enhance counseling in aiding alcoholic patients to sustain continuous abstinence or delay the resumption of drinking. 3/24/

24 As a deterrent, disulfiram helps those who are having trouble controlling their impulsivity around urges and relapses Disulfiram does not reduce craving The prefrontal cortex may use it to keep the midbrain reward center from winning the battle; it knows the consequences: disulfiram punishes relapses Spouses and judges may insist on observed adherence to taking the medicine daily Aspirin, ibuprofen or other NSAIDS may block the DER making disulfiram ineffective. 3/24/

25 DER Body part affected Moderate Severe Skin Respiratory system Head, neck, throat Sweating, warmth and flushing, particularly on upper chest and face Hyperventilation Respiratory difficulty/dyspnea Acetaldehyde breath odor Blurred vision Head and neck throbbing Thirst none Respiratory depression none Stomach, digestive system Nausea/vomiting None Chest, heart, circulatory system Brain/ nervous system Chest pain/palpitations Hypotension, light headed Tachycardia (rapid heart) Vertigo Syncope Marked uneasiness Confusion Other Weakness Death Arrhythmia MI: if preexisting CAD Acute CHF: if preexisting myocardial dysfunction Cardiovascular collapse Seizures Unconsciousness 3/24/

26 Normal sequence of DER Flushing of the face Headache Low Blood Pressure Racing Heart Dizziness Nausea and vomiting 3/24/

27 Other medications Not FDA approved for alcoholism Topiramate Reduces craving at GABA-B receptors 2 studies support efficacy Ondansetron Seems only to work in type 2 alcoholics Baclofen Reduces craving at GABA-B receptors Mixed results in studies. 3/24/

28 Case 44 y.o. divorced, Caucasian male with strong family history of alcohol use disorder. Presents to the outpatient clinic reporting that despite of several inpatient rehab treatments for alcohol dependence he has not been able to stay sober for a long time. What else could we do for this patient? 3/24/