Addiction Medicine 2014

Transcription

1 Addiction Medicine 2014 Update on Current/New/Anticipated Medications for Alcohol Use Disorders J.C. Garbutt, MD Department of Psychiatry and Bowles Center for Alcohol Studies School of Medicine, University of North Carolina at Chapel Hill

2 Objectives Provide a perspective on current efficacy of medications for alcohol use disorders and prescribing practices Briefly review basic science concepts that should drive the development of new medications Provide clinical trial data on medications in development that show promise for alcohol use disorders. Provide information on the emerging effort to use pharmacogenomics as a means to improve efficacy of medications for alcohol use disorders. Provide some clinical perspective on pulling this all together.

3 General Background

4 Alcohol Use Disorders DSM V no longer includes alcohol dependence as an alcohol use disorder, of interest to pharmacotherapy as all FDA medications have been approved for alcohol dependence as defined by DSM IV and DSM III R. Is equivalence moderate to severe alcohol use disorder? Use of pharmacotherapy for less severe alcohol use disorders (abuse, binge drinking) not clear though an important area of research

5 Barriers to Medication Use Of the estimated 10% of men and 5% of women who will experience alcoholism in their lifetime about 25% will receive treatment, but, of those, only about 10% will receive a medication for alcoholism. Mark et al (Drug and Alcohol Dependence 71:219, 2003) examined why so few patients with alcoholism receive an FDA approved medication

6 Reasons Given for Low Medication Use Mark et al Drug and Alcohol Dependence 71:219, 2003

7 How Do We Move Forward Education of physicians, counselors and patients New molecules preclinical research and serendipity. The challenge of alcohol clinical trials given disease heterogeneity and the issue of who should be studied.

8 New Molecules The Role of Basic Research

9 The Pathophysiology of Alcoholism and Addiction Koob & Volkow, Neurocircuitry of Addiction, Neuropsychopharm 35:217, 2010

11 Effects of Naltrexone on Cue Induced Activation of Ventral Striatum (Craving?) Myrick et al, Arch Gen Psychiatry. 2008;65(4):

12 Now or Later? An fmri study of the effects of endogenous opioid blockade on a decision making network Boettiger et al, Pharmacol Biochem Behavior 93:291, 2009

14 Withdrawal/Negative Affect Acamprosate? Improvement in sleep Staner et al, ACER, 30:1492, 2006 n=24

15 Potential New Medications for Alcohol Use Disorders Craving/Euphoria Anxiety/Withdrawal Baclofen ± + Gabapentin ± + Varenicline ± Ondansetron + ± Oxytocin? +

16 Baclofen First synthesized 1962 GABA B agonist approved by the FDA for treatment of spasticity. In human use for many years so safety profile well known Animal testing has shown: i) baclofen counters a variety of drinking behaviors ii)baclofen has anxiolytic properties and can prevent the anxiogenic effects of alcohol

17 Baclofen: Effects on Alcohol Withdrawal Addolorato et al, Am J Med 119: 276, 2006 N=37, alcohol dependent subjects with CIWA Ar scores of 10. BAC dose of 30 mg/d vs mg/kg diazepam. BAC equivalent to diazepam

18 Baclofen: Effects on Consumption/Anxiety Addolorato et al (2002) N=29, 4 week trial, 30 mg baclofen Drinking Anxiety P<.05 P<.005

19 Baclofen: Effects on Consumption Addolorato et al (2007) N=84, subjects had cirrhosis, 12 week trial, 30 mg baclofen Baclofen well tolerated in this population, no negative effects on liver function, no serious adverse events

20 Baclofen: Effects on Consumption/Anxiety Garbutt et al (2010) N=80, 12 week trial, 30 mg BAC Drowsiness (28% BAC, 10% PBO, p=.08) P=NS P=.02 Effect on Heavy Drinking Effect on Anxiety

21 Baclofen Status and Directions Are higher doses more effective? Case reports of improvement at higher BAC doses, up to 330 mg/d but more reports in the mg/d range BAC is 85% excreted by kidney with trials not showing liver damage agent of interest for patients with liver disease including cirrhosis? Is severity of alcoholism an indicator of response? Current trials: U.S. placebo 30 mg 90 mg/d Europe placebo 300 mg/d

22 Gabapentin Discovered over 40 years ago Complex mechanism of action may affect multiple ion channels, NMDA and GABA systems, evidence of specific binding site in brain. FDA approved for epilepsy and postherpetic neuralgia, safety profile relatively well known Renally excreted

23 A double blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Myrick et al, ACER 33:1582, subjects (lorazepam 8 mg, GBP 900mg, GBP 1200 mg tapered over 4 days) GBP, 1200 mg, statistically superior to lorazepam though clinically similar Post detox GBP subjects were less likey to drink than lorazepam subjects

24 Gabapentin combined with naltrexone for the treatment of alcohol dependence. Anton et al, Am J Psych 168:709, subjects, 16 wks (50 NTX 50 mg; 50 PBO; 50 NTX 50 mg + Gabapentin 1200 mg for first 6 wks) P=.03 Overall, the addition of gabapentin to naltrexone led to reductions in drinking which faded once gabapentin stopped. The presence of withdrawal sx or a history of inpatient detox was associated with positive response to naltrexone + gabapentin, effect continued after gabapentin stopped.

25 Gabapentin Treatment for Alcohol Dependence A Randomized Clinical Trial Mason et al, JAMA Int Med 174:70, randomized subjects placebo gabapentin 900 mg/d (300 mg tid) gabapentin 1800 mg/d (600 mg tid) Subjects with CIWA scores >9 were excluded 12 week trial with follow up at 24 weeks

26 Gabapentin Treatment for Alcohol Dependence A Randomized Clinical Trial Mason et al, JAMA Int Med 174:70, 2014 Drinking Outcomes:

27 Gabapentin Treatment for Alcohol Dependence A Randomized Clinical Trial Mason et al, JAMA Int Med 174:70, 2014 Effects on craving, sleep and mood Gabapentin well tolerated

28 Alcohol and Nicotine Alcohol Dependence associated with higher rates of nicotine dependence in general population (50%) and in treatment samples (90%) compared to overall general population (21%). Rates of nicotine dependence in general population have dropped substantially but are not dropping as fast in the alcohol dependent population.

29 Possible Link Between Alcohol, Dopamine Release and Nicotine Receptors Hendrickson et al, Frontiers in Psychiatry 4:1, 2013 In the VTA, alcohol stimulates DAergic neurons at least, in part, via nachr activation. Ethanol increases ACh release (red arrow, presumably through cholinergic projection from the LDT/PPTg) which in turn activates nachrs on DAergic neurons driving activity. In addition, ethanol potentiates Ach activation at high affinity a4b2* nachrs (red plus sign).

30 Varenicline: A Nicotine Receptor Partial Agonist/Antagonist Rollema et al, Trends Pharmacol, 28:316, 2007 Multiple forms of nicotinic Ach receptor, α4β2 activates dopamine release Varenicline designed to target α4β2 and provide low level DA activation while antagonizing nictoine

31 A Double Blind, Placebo Controlled Trial Assessing the Efficacy of Varenicline Tartrate for Alcohol Dependence. Litten et al, J Addict Med 7: N=200, PBO vs 1 mg bid of varenicline. Randomization by smoking. P=.011 Drinking improved in both smokers and non smokers. Cigarettes/day dropped from 12 to 7 p=.002

32 Oxytocin Nonapeptide released by posterior pituitary for uterine contraction, milk ejection. Oxytocin in brain associated with prosocial and anxiolytic properties and can counteract physical dependence to opiates and alcohol.

33 Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects Pedersen et al, ACER 37:484, 2013 Placebo controlled clinical trial Hospitalized subjects at risk for alcohol withdrawal; CIWA Ar triggered lorazepam Oxytocin 24 IU intranasally bid (n=7), PBO (n=4) Followed for 3 days with CIWA Ar ratings

34 Intranasal Oxytocin Blocks Alcohol Withdrawal in Human Subjects Pedersen et al, ACER 37:484, 2013 Metric P<.0001 CIWA-Ar Day 1 P=.0015 Lorazepam total mg Placebo Oxytocin

35 Alcoholism comes in many forms How do we identify responders?

36 Response to Naltrexone and Polymorphism of the µ Opioid Receptor A single nucleotide polymorphism in the µ opioid receptor gene, Asn40Asp or G allele, confers change in the response to ethanol: N=28 (12 AG; 16 AA) Dopamine response to ethanol assessed with PET scans. Ramchandani et al, Mol Psych 16: 809, 2011 Frequencies of AG/GG Genotype: Caucasian % African American 0 5% Asian 25 47%

37 Response to Naltrexone and AG/GG Allele Oslin et al, Neuropsychopharm 28:1546, 2003

38 Clinical and Biological Moderators of Response to Naltrexone in Alcohol Dependence: A Systematic Review of the Evidence. Garbutt et al, submitted

39 Topiramate s actions involve modulation of glutamate receptors including the kainate receptor of which GRIK1 codes a subunit.

40 Response to Topiramate by GRIK1 Polymorphism: Kranzler et al, Am J Psych 2014

41 Ondansetron 5 HT3 antagonist approved for nausea. Johnson et al (JAMA 284:963, 2000 and Am J Psych 168:265, 2011) found efficacy in early onset alcoholism and in patients with L L variant of serotonin transporter. Dose 4 μg/kg bid (about ¼ mg bid) with current formulation being 4 mg for nausea, will need compounding pharmacy if wish to use.

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43 Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5 HT3 Antagonist Ondansetron Johnson et al, Am J Psych 170:1020, 2013

44 Summary in Broader Context of Recovery The use of medications should be considered when treating the patient with alcoholism. It makes sense to start with FDA approved medications: disulfiram for the motivated patient who wants sobriety naltrexone for most patients and can consider long acting naltrexone if affordable acamprosate may be considered for the patient with some established sobriety, may help with post withdrawal sleep problems as well. Off label medications topiramate is top choice given evidence for efficacy gabapentin is emerging as a potential good option either alone or as an adjunct to naltrexone and may help with sleep/anxiety/withdrawal baclofen has mixed evidence but only drug with evidence in patients with cirrhosis and may benefit anxiety/withdrawal, dose may need to be titrated up to mg/d, cautiously and can t stop abruptly varenicline data is still early but could consider in alcoholic patient with interest in smoking cessation ondansetron has some positive evidence but may be limited to specific genetic pattern and not straightforward to formulate. Pharmacogenomics an exciting new option but not quite ready for routine clinical use. Medications are one tool in recovery. Patients should be encouraged to engage in counseling, attend AA or other meetings and realize recovery is more than taking a medication.