Objectives. Why pharmacotherapy is required? Neuro-biology of Alcohol addiction 5/21/2013

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1 Muhammad A. Ghazi MD Fellow Addiction Medicine University at Buffalo Objectives Understand the basic patho-physiology of Alcohol addiction Enlist the drugs available for alcohol dependence detoxification and relapse prevention Know the evidence based guidelines to use these drugs in clinical practice. Summarize the common side effects and contraindications of Alcohol pharmacotherapy. Alcohol Consumption Alcohol abuse and Dependence WHO (2004) 2 billion people consumed alcohol, 76.3 million have alcohol use disorder. 2 million deaths each year 4 percent of global disease burden The prevalence of alcohol use in primary care settings ranges from 20 to 36 percent. Why pharmacotherapy is required? Up to 70% relapse rate with psychosocial therapy alone. Neuro-biology of Alcohol addiction Corticomesolimbic dopamine (CMDA) pathway, which can mediate reinforcement. Many available or promising compounds appear to act by modulating the function of opioids, glutamate (with or without gamma aminobutyric acid, GABA), and serotonin (5-HT). 1

2 Neuro-anatomy of Brain Reward System Neurotransmitters and receptors associated with Alcohol dependence Neurotransmitters Receptors Gamma-aminobutyric acid GABA a, GABA b, Glutamate Dopamine Serotonin NMDA, AMPA kinate receptors D1, D2, D3,D4 Several esp. 5HT3 Other Neurotransmitters Corticotropin-releasing factor (CRF) CRF levels increase in rat amygdala during withdrawal CRF antagonists can be used to decrease anxiety during withdrawal Neuropeptide Y NPY decreases the alcohol intake in the alcohol preferring rats Low NPY, increased alcohol consumption Endogenous Opioids Mu, kappa, delta Opioid receptors Alcohol dependence Maladaptive pattern of alcohol use associated with three or more of the following: 1) Tolerance 2) Withdrawal 3) Substance taken in larger quantity than intended 4) Persistent desire to cut down or control use 5) Time spent in obtaining, using or recovering from substance dependence Alcohol dependence Social, occupational, or recreational tasks are sacrificed Use continues despite physical and psychological problems 2

3 Goals of therapy Complete abstinence Reduction in amount of drinking Alcohol Detoxification Symptom triggered FDA-approved: chlordiazepoxide (Librium); initial dose of 50 to 100 mg, followed by repeated doses as needed until agitation is controlled, up to 300 mg per day. Off-label: chlordiazepoxide; 25 to 100 mg every hour when CIWA-Ar score > 8. Front loading FDA-approved: diazepam (Valium); 10 mg 3 or 4 times in first 24 hours, then 3 or 4 times daily as needed. Off-label: diazepam; 20 mg every 1 to 2 hours at first sign of withdrawal until symptoms are improved. Alcohol detoxification Fixed schedule Off-label: chlordiazepoxide; 50 mg every 6 hours for four doses, then 25 mg every 6 hours for eight doses. Short-acting benzodiazepine* FDA-approved: oxazepam (Serax); 15 to 30 mg 3 or 4 times daily. Off-label: lorazepam (Ativan); 0.5 to 1 mg 3 or 4 times daily on a scheduled basis, plus 1 mg every 4 hours if needed for mild symptoms (e.g., CIWA-Ar score between 8 and 14) or 2 mg every 2 hours if needed for moderate symptoms (e.g., CIWA-Ar score > 15). Blondell R. Ambulatory Detoxification of Patients with Alcohol Dependence, Am Fam Physician Feb 1;71(3): Alcohol Pharmacotherapy Non-FDA Approved Topiramate Baclofen Ondansetron Nalmefene 1949 FDA Approved 1994 ER injectable 2006 Acamprosate 2004 Screening for Alcohol pharmacotherapy Patient should be motivated to use drugs to reduce alcohol consumption, along with or instead of the psychosocial intervention. There is no contraindication of particular drug for alcohol pharmacotherapy. INITIATION OF THERAPY Post hospitalization for alcohol intoxication or withdrawal can be initiated when the patient is still drinking therefore can be used safely in the outpatient setting if there is no contraindication. must be use only after abstinence is achieved. Acamprosate should also be used once abstinence is achieved. *Gastfriend DR, Garbutt JC, Pettinati HM, Forman RF. Reduction in heavy drinking as a treatment outcome in alcohol dependence. J Subst Abuse Treat 2007; 33:71. 3

4 Duration of therapy The optimal duration of pharmacotherapy is not known. Most trials studied the effect of treatment over two to six months. Experts recommend at least six months of medication with an additional six months of follow-up. The efficacy of medication treatment wanes once medications are discontinued. Topiramate requires a taper of 1-2 weeks before discontinuation ACAMPROSATE Neuro-chemical mechanism of action involves the modulation of glutamate neurotransmission at metabotropic-5 glutamate receptors. GABA receptor agonist and NMDA receptor modulator. Acamprosate Usual dose : 666mg three times a day Acamprosate reduced the rate of patients returning to any drinking (relative risk=0.86, 95% CI 0.81 to 0.91; NNT=9) and increased the cumulative abstinence duration by an average of 11 percent. Not effective for heavy drinkers. Works for daily relief drinkers Acamprosate A 2004 meta-analysis of the 17 European trials found that Acamprosate increased six-month abstinence rates compared to placebo (36.1 versus 23.4 percent) Acamprosate The COMBINE Study, found Acamprosate (either alone or in conjunction with a psychosocial intervention) to be no more effective than placebo, while was significantly more effective than placebo. 4

5 Acamprosate: Side effects Diarrhea, nervousness, and fatigue, which usually subside with continued use. Excreted mainly unchanged through kidneys therefore contraindicated in patients with renal failure but requires dosage adjustment in patients with Chronic kidney disease. Predictors of therapeutic response to Acamprosate Increased levels of anxiety Physiological dependence (ie, severe symptoms of withdrawal) Negative family history Late age of onset Female gender. Acamprosate-other considerations Acamprosate should also be considered as an alternative to naltrexone for patients under concurrent treatment with Opioid. Acamprosate is not indicated in patients for the induction of abstinence in actively drinking patients Works by blocking the mu Opioid receptors. Endogenous Opioid are involved in modulating the expression of alcohol's reinforcing effects. also modifies the hypothalamic-pituitaryadrenal axis to suppress ethanol consumption Contra-indications: Patients taking Opioid Liver disease, liver failure Side effects: Nausea, headache and dizziness. Elevation of Liver function tests (LFTs) Dose: 50mg per day. Some patients may require 100mg per day. 5

6 efficacy A meta-analysis of 18 trials of naltrexone for alcohol dependence found the medication to decrease the risk of relapse in comparison to placebo (RR = % CI 0.51 to 0.82) as well as to reduce return to drinking and cravings, and to increase time to first drink. The effect size for reducing relapse was modest (NNT=7). : Genetic factors individuals with the Asp variant of the OPRM1 gene are less likely to experience relapse when receiving naltrexone Patients who were heterozygous for the Asp-40 allele were almost six times more likely to have a favorable outcome with naltrexone Predictors of therapeutic response to Works best for: type II binge drinkers males with positive family history of alcohol addiction. strong cravings for alcohol Consider in Bulemic patients, compulsive gamblers and cutters. Monitoring of patients on Baseline LFTs Period check of LFTs thereafter Depot Form Injectable formulations of naltrexone (Vivitrol, Naltrel, and Depotrex) Only Vivitrol is approved for use in the US Dose : 380 mg intramuscular injection to the gluteal area Side effects: injection site reactions, nausea (33 percent), fatigue (20 percent), and decreased appetite (13 percent) Rarely interstitial pneumonia, allergic type eiosinophilic pneumonia 6

7 Efficacy of injections Vivitrol 380 mg monthly had a 25 percent greater reduction in the rate of heavy drinking after 24 weeks compared to those receiving placebo (HR 0.75; 95% CI ) Cost analysis : injections may cost up $600 Depot naltrexone is an option for treatment of patients likely to be non-adherent to daily oral medication. Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration. (Spring 2007). for extended-release injectable suspension for treatment of alcohol dependence. Substance Abuse Treatment Advisory, 6(1). Ethanol Reaction (DER) Drinking alcohol while taking disulfiram results in the accumulation of acetaldehyde in the blood, causing unpleasant effects such as sweating, headache, dyspnea, lowered blood pressure, flushing, sympathetic over activity, palpitations, nausea, and vomiting. Ethanol Reaction (DER) DERs are self-limiting lasting 30 minutes. DER may be severe, with marked tachycardia, hypotension, cardiovascular collapse, congestive cardiac failure and convulsions. is initially dosed at 500 mg/day for one to two weeks, followed by an average maintenance dose of 250 mg/day with a range from mg based on the severity of adverse effects. The medication should not be used by patients with current alcohol intoxication. 7

8 Patient education should address "hidden" forms of ethanol (e.g., tonics and mouthwashes) and the duration of the drug's activity (up to 14 days after stopping). A large study, 52-weeks, multi-site trial of 605 US veterans, found disulfiram to be no more effective than placebo in maintaining abstinence or in time to first drink, but it may have reduced drinking days in a subgroup that drank during the study. A high rate of non-compliance with medication was seen. Aversive medication is usually effective in medication compliant patients and in those whose medication taking can be supervised. In general, negative re-inforcers are a weaker way to change behavior. Works better in Employ assisted programs and impaired physician programs. side effects Hepatitis Hepatic failure in patients with baseline abnormal LFTs Depression Psychosis Peripheral neuropathy Optic neuritis Topiramate Not FDA approved for alcohol dependence Mechanism of action: 1) Antagonizing alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors and kainate glutamate receptors. 2) Facilitating inhibitory GABA(A)-mediated currents at non-benzodiazepine sites on the GABA(A) receptor Topiramate Dose It is generally initiated at 50 mg/day and increased to a maximum dose of 150 mg twice daily 8

9 Topiramate efficacy In a multi-site US trial, topiramate reduced the percentage of heavy drinking days compared to placebo (43.8 versus 51.8 percent) among 371 men and women with alcohol dependence over 14 weeks Adverse effects Fetal anomalies (cleft lip/palate) Numbness and tingling Metabolic acidosis Loss of appetite Suicidal thoughts or actions Renal calculi Acute angle closure glaucoma Baclofen GABA (b) receptor agonist and CMDA system modulator, has been shown in animal studies to reduce voluntary ethanol intake and rebound to drinking following the ethanol-deprivation effect. Superior to placebo for alcohol dependence. Baclofen Individuals receiving baclofen were more likely to achieve and maintain abstinence compared with placebo. The cumulative duration of abstinence was also greater with baclofen (63 versus 31 days) Addolorato G et al., Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial. Alcohol Alcohol May-Jun;46(3): Baclofen Baclofen treatment was well tolerated, with no abuse liability. No serious adverse effects were seen, including hepatotoxicity, encephalopathy, or hyperammonaemia. Mild-to-moderate side effects included nausea, vertigo, transient sleepiness, and abdominal pain. Baclofen appears safe and effective for alcoholdependent patients with cirrhosis. Nalmefene Nalmefene, an opioid antagonist, has several potential advantages over naltrexone, including : absence of dose-dependent liver toxicity longer-acting effects more effective binding to central opiate receptors. 9

10 Nalmefene Three of four trials comparing oral nalmefene to placebo have shown modest benefits on the primary outcomes of relapse rates and heavy drinking day. Side Effects of Nalmefene Nausea, insomnia, fatigue, dizziness, and malaise. Rarely psychosis or dissociation. Selective serotonin reuptake inhibitors SSRI do not effectively treat alcohol dependence in patients who do not have a comorbid mental disorder. Preliminary evidence suggests that SSRIs may be more effective for a late-onset subtype and comorbid depression. Ondansetron 5-HT3 receptor antagonist, appears to be selectively efficacious for alcohol dependence in patients with an early-onset subtype of the disorder and, in a separate study, in patients with a specific genetic variant of the serotonin transporter (5-HTT) gen Ondansetron A randomized trial that differentiated subjects by onset of alcohol dependence found that early-onset alcoholics were more likely than late-onset alcoholics to respond therapeutically to ondansetron. Johnson BA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial. JAMA Aug 23-30;284(8): Other drugs under investigation anticonvulsants like Valproate, carbamezipine antipsychotics dopamine antagonists CRF antagonists neuropeptide Y antagonists varenicline cannabinoid receptor antagonist rimonabant. 10

11 Combinations Two trials compared the combination of oral naltrexone and acamprosate, finding mixed results. In a trial of 160 individuals with alcohol dependence, the group receiving naltrexone and acamprosate experienced fewer relapses and a longer time to first drink than those receiving acamprosate alone. However, the combined medications were no more effective than naltrexone alone. Combinations The COMBINE Study did not find an advantage to combined naltrexone-acamprosate treatment compared with either the individual agents or placebo. Reasons of Underutilization Lack of healthcare providers skills and knowledge Lack of confidence in the treatment effectiveness Low patient demand Pharmacy regulations formulary restrictions Conclusions, and Acamprosate are FDA approved medications available for the alcohol relapse prevention and addiction treatment. Patient participation should be encouraged through proper education and discussions. Physicians should be aware of the indications and contra-indications of the alcohol pharmacotherapy. Harris, HS Alex et al., Pharmacotherapy for Alcohol Dependence: Perceived Treatment Barriers and Action Strategies Among Veterans Health Administration Service Providers. Psychological Services, Jan 28, Questions 11