Alcoholic Liver Disease Your Role Is Essential in Preventing, Detecting, and Co-Managing Alcoholic Liver Disease in Inpatient and Ambulatory Settings

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Preventing drinking relapse in patients with alcoholic liver disease Your role is essential in preventing, detecting, and co-managing alcoholic liver disease in inpatient and ambulatory settings

Gerald Scott Winder, MD lcohol use disorder (AUD) is a mosaic of psychiatric and Assistant Professor medical symptoms. Alcoholic liver disease (ALD) in its acute Department of Psychiatry University of Michigan Health System and chronic forms is a common clinical consequence of long- Ann Arbor, Michigan A standing AUD. Patients with ALD require specialized care from pro- Jessica Mellinger, MD, MSc fessionals in addiction, gastroenterology, and psychiatry. However, Clinical Lecturer medical specialists treating ALD might not regularly consider medi- Department of Internal Medicine University of Michigan Health System cations to treat AUD because of their limited experience with the Ann Arbor, Michigan drugs or the lack of studies in patients with significant liver disease.1 Robert J. Fontana, MD Similarly, psychiatrists might be reticent to prescribe medications for Professor of Medicine AUD, fearing that liver disease will be made worse or that they will Division of Gastroenterology cause other medical complications. As a result, patients with ALD Department of Internal Medicine University of Michigan Health System might not receive care that could help treat their AUD (Box, page 24). Ann Arbor, Michigan Given the high worldwide prevalence and morbidity of ALD,2 gen- Disclosures eral and subspecialized psychiatrists routinely evaluate patients with Dr. Winder and Dr. Mellinger report no financial AUD in and out of the hospital. This article aims to equip a psychia- relationships with any company whose products are mentioned in this article or with manufacturers of trist with: competing products. Dr. Fontana receives research • a practical understanding of the natural history and categoriza- funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation. tion of ALD • basic skills to detect symptoms of ALD • preparation to collaborate with medical colleagues in multi disciplinary management of co-occurring AUD and ALD • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD. continued

Current Psychiatry

JON KRAUSE FOR CURRENT PSYCHIATRY Vol. 14, No. 12 23 Box patients who have a MELD score >15 ben- Box Key points about treating efit from transplant. To definitively determine the severity of ALD, a liver biopsy is liver disease in patients required but usually is not performed in with alcoholism clinical practice. Collaborative management of medical, All patients who drink heavily or suffer substance-related, and psychiatric symptoms with AUD are at risk of developing AH; of ALD offers medical and psychiatric benefits Alcoholic liver women and binge drinkers are particu- Psychiatrists are essential for successful 4 disease monitoring and treatment of ALD. They larly vulnerable. Liver dysfunction and should be knowledgeable about its signs and malnutrition in ALD patients compromise symptoms the immune system, increasing the risk of In ALD, there is a role for AUD infection. Patients hospitalized with AH pharmacotherapy despite the risk of adverse have a 10% to 30% risk of inpatient mor- effects tality; their 1- and 2-month post-discharge More research is needed to describe (1) the efficacy of AUD pharmacotherapy for survival is 50% to 65%, largely determined preventing relapse in this population, (2) how by whether the patient can maintain sobri- Clinical Point these medications can be effectively and ety.5 Psychiatrists’ contribution to ALD safely used in ALD patients, and (3) what care A psychiatrist coordination strategies can make best use of treatment therefore has the potential to multidisciplinary management of patients with save lives. evaluating comorbid ALD and AUD a jaundiced patient ALD: alcoholic liver disease; AUD: alcohol use disorder who continues to Screening and detection of ALD drink should arrange Because of the high mortality associated with AH and cirrhosis, symptom recogni- urgent medical Categorization and clinical tion and collaborative medical and psy- evaluation features chiatric management are critical (Table 2, Alcoholic liver damage encompasses a page 28). A psychiatrist evaluating a jaun- spectrum of disorders, including alcoholic diced patient who continues to drink should fatty liver, acute alcohol hepatitis (AH), arrange urgent medical evaluation. While and cirrhosis following varying durations gathering a history, mental health providers and patterns of alcohol use. Manifestations might hear a patient refer to symptoms of of ALD vary from asymptomatic fatty gastrointestinal bleeding (vomiting blood, liver with minimal liver enzyme eleva- bloody or dark stool), painful abdominal tion to severe acute AH with jaundice, distension, fevers, or confusion that should coagulopathy, and high short-term mor- prompt a referral to a gastroenterologist or tality (Table 1, page 26). Symptoms seen in the emergency department. Testing for uri- patients with AH include fever, abdominal nary ethyl glucuronide—a direct metabolite pain, anorexia, jaundice, leukocytosis, and of ethanol that can be detected for as long coagulopathy.3 as 90 hours after ethanol ingestion—is use- Patients with chronic ALD often develop ful in detecting alcohol use in the past 4 or cirrhosis, persistent elevation of the serum 5 days. aminotransferase level (even after pro- longed alcohol abstinence), signs of portal hypertension (ascites, encephalopathy, var- Medical management of ALD iceal bleeding), and profound malnutrition. Corticosteroids are a mainstay in pharma- Discuss this article at The survival of ALD patients with chronic cotherapy for severe AH. There is evidence www.facebook.com/ liver failure is predicted in part by a Model for improved outcomes in patients with CurrentPsychiatry for End-Stage Liver Disease (MELD) score severe AH treated with prednisolone for that incorporates their serum total biliru- 4 to 6 weeks.5 Prognostic models such as bin level, creatinine level, and international the Maddrey’s Discriminant Function, Lille normalized ratio. The MELD score, which Model, and the MELD score help determine ranges from 6 to 40, also is used to gauge the need for steroid use and identify high- Current Psychiatry 24 December 2015 the need for liver transplantation; most risk patients. Patients with active infection or bleeding are not a candidate for steroid because of their additive interactions with treatment. An experienced gastroenterolo- alcohol, cognitive and psychomotor side gist or hepatologist should initiate medical effects, and abuse potential.9,10 Many of intervention after thorough evaluation. these drugs are cleared by the liver and generally are not recommended for use in Liver transplantation. A select group of patients with ALD. patients with refractory liver failure are con- sidered for liver transplantation. Although Other agents, further considerations. transplant programs differ in their criteria Drug trials in AUD largely have been con- for organ listing, many require patients to ducted in small, heterogeneous populations demonstrate at least 6 months of verified and revealed modest and, at times, con- abstinence from alcohol and illicit drugs as flicting drug effect sizes.6,11,12 The placebo well as adherence to a formal AUD treat- effect among the AUD population is pro- ment and rehabilitation plan. The patient’s nounced.6,7,13 Despite these caveats, several psychological health and prognosis for sus- agents have been studied and validated by tained sobriety are central to candidacy for the FDA to treat AUD. Additional agents organ listing, which highlights the key role with promising pilot data are being inves- Clinical Point 1,7,10,11,13-43 of psychiatrists. tigated. Table 3 (page 30) summa- Alcohol abstinence rizes drugs used to treat AUD—those with Further considerations. Thiamine and and without FDA approval—with a focus remains central to folate often are given to patients with ALD. on how they might be used in patients with survival because Abdominal imaging and screening for HIV ALD. Of note, several of these agents do not relapse increases and viral hepatitis—identified in 10% to 20% rely on the liver for metabolism or excretion. the risk of recurrent, of ALD patients—is routine. Alcohol absti- There is no agreed-upon algorithm or severe liver disease nence remains central to survival because safety profile to guide a prescriber’s deci- relapse increases the risk of recurrent, severe sion making about drug or dosage choices liver disease. Regrettably, many physical when treating AUD in patients with ALD. symptoms of liver disease, such as portal Because liver function can vary among hypertension, ascites, and jaundice, can take patients as well as during an individual months to improve with abstinence. patient’s disease course, treatment decisions should be made on a clinical, collaborative, and case-by-case basis. Treating AUD in patients with ALD That being said, the AUD treatment liter- Successful treatment is multifaceted and ature suggests that specific drugs might be includes more than just medications. Initial more useful in patients with varying sever- management often includes addressing ity of disease and during different phases of alcohol withdrawal in dependent patients.6 recovery: • Acamprosate has been found to be Behavioral interventions are effective effective in supporting abstinence in sober and indispensable components in prevent- patients.14,44 ing relapse,7 including a written relapse • Naltrexone has been shown to be use- prevention plan that formally outlines the ful in patients with severe alcohol cravings. patient’s commitment to change, identi- By modulating alcohol’s rewarding effects, fies triggers, and outlines a discrete plan naltrexone also reduces heavy alcohol con- of action. Primary psychiatric pathology, sumption in patients who are drinking.14,15,44 including depression and anxiety, often are • Disulfiram generally is not recom- comorbid with AUD; concurrent treatment mended for use in patients with clinically of these disorders could improve patient apparent hepatic insufficiency, such as outcomes.8 decompensated cirrhosis or preexisting jaundice. Benzodiazepines often are used during Although alcohol abstinence remains the acute alcohol withdrawal. They should treatment goal and a requirement for liver Current Psychiatry not be used for relapse prevention in ALD transplant, providers must recognize that Vol. 14, No. 12 25 Table 1 Table 1 Clinical and laboratory picture of alcoholic liver disease Disease phenotype Clinical features Objective laboratory and prognostic markers Asymptomatic Incidence: 2% to 5% of U.S. adult population Labs: hepatic steatosis • Serum AST and ALT may be mildly elevated Symptoms: Often asymptomatic, well-nourished, occasional or >2:1 ratio (outpatient) hepatomegaly/RUQ pain, impaired cognition, appear medically well • CBC shows mild macrocytosis without anemia Alcoholic liver Risk factors: Daily alcohol consumption >2 to 3 drinks/d, female sex • Urine ethyl glucuronide to verify alcohol use in past disease Prognosis: Generally favorable and reversible with abstinence 5 days • Normal albumin, bilirubin, and INR Treatment: Alcohol detoxification to sobriety, multivitamin, counseling, psychiatric medications to prevent relapse Imaging: Increased hepatic steatosis on CT and MRI might be seen Biopsy: Variable amount of steatosis with mild inflammation and pericellular fibrosis Prognosis: Might improve/resolve with abstinence or lead to progressive liver damage/fibrosis with continued alcohol use Clinical Point Alcoholic hepatitis syndrome Incidence: 5 to 10 per 100,000 Labs: • Serum AST:ALT > 2:1 often seen but both (hospitalized) Symptoms: Acute jaundice, nausea, abdominal pain, fever, Psychiatric pathology, <1,000 IU/mL encephalopathy including depression • Urinary ethyl glucuronide to verify alcohol use Risk factors: Binge intake >4 weeks in chronic user, younger age, in past 3 to 5 days and anxiety, often genetic polymorphisms • CBC: Moderate to severe macrocytosis with are comorbid with Prognosis: 10% to 30% 1-month mortality; 50% 1-year mortality anemia, frequent thrombocytopenia, leukocytosis with abstinence; 90% mortality without abstinence with left shift if severe AUD; concurrent • Moderate to severely elevated bilirubin and INR, Treatment: low albumin always seen treatment could • Manage acute alcohol withdrawal improve outcomes • Thiamine, folate Imaging: Hepatic steatosis in CT or MRI +/- • Enteral nutrition hepatosplenomegaly, +/- ascites and venous collaterals • Steroids for 6 weeks in selected patients could improve short-term Biopsy: Steatosis with neutrophilic inflammation, survival cirrhosis in 40% to 60% • Alcohol abstinence Prognosis: Discriminant function ≥32 has 30% to 50% • Management of encephalopathy, bleeding, ascites mortality at 1 month • Not candidates for liver transplant at most centers Decompensated alcoholic cirrhosis Incidence: Unknown but 10% to 15% of patients with heavy alcohol Labs: (chronic liver failure) use will develop cirrhosis • Serum AST and ALT often normal or minimally elevated Symptoms: Anorexia, weight loss, cachexia, ascites, muscle • CBC: Moderate to severe macrocytosis with wasting/weakness anemia, low WBC and platelets because of portal Risk factors: Lifetime alcohol consumption exceeding 4 drinks/d HTN over ≥10 years • Bilirubin and INR may only be mildly elevated; low Prognosis: Determined by severity of portal HTN complications albumin (variceal bleeding, ascites, encephalopathy). If MELD >20, then • CTP score ranges from 5 to 15 approximately 70% 1-year survival even with abstinence • 1 to 3 points for albumin, bilirubin, INR, and ascites and encephalopathy Treatment: • CTP A = 5 to 6 points • Thiamine, folate, and multivitamins • CTP B = 7 to 9 points • Medical management of ascites with diuretics • CTP C ≥10 points • Lactulose/rifaximin for encephalopathy • Endoscopy for varices Imaging: Small shrunken, nodular liver with ascites, • Transplant in selected patients with favorable prognosis for collaterals, and splenomegaly long-term abstinence, favorable compliance Biopsy: Cirrhosis with minimal steatosis/inflammation Prognosis: MELD score predicts mortality at 3 months: • <9 = ~2% mortality • 10 to 19 = 6% mortality • 20 to 29 = 20% mortality • 30 to 39 = 53% mortality • >40 = 71% mortality ALT: alanine transaminase; AST: aspartate transaminase; CBC: complete blood count; CTP: Child-Turcotte-Pugh score; HTN: hypertension; INR: international normalized ratio; MELD: Model for End-Stage Liver Disease; RUQ: right upper quadrant; Current Psychiatry WBC: white blood cell count 26 December 2015 some patients might not be able to maintain Table 1 Clinical and laboratory picture of alcoholic liver disease long-term sobriety. Therefore, harm reduction models are important companions to Disease phenotype Clinical features Objective laboratory and prognostic markers abstinence-only models of AUD treatment.45 Asymptomatic Incidence: 2% to 5% of U.S. adult population Labs: The array of behavioral, pharmacologi- hepatic steatosis • Serum AST and ALT may be mildly elevated Symptoms: Often asymptomatic, well-nourished, occasional cal, and philosophical approaches to AUD or >2:1 ratio (outpatient) hepatomegaly/RUQ pain, impaired cognition, appear medically well • CBC shows mild macrocytosis without anemia treatment underlines the need for an indi- Risk factors: Daily alcohol consumption >2 to 3 drinks/d, female sex • Urine ethyl glucuronide to verify alcohol use in past vidualized approach to relapse prevention. Prognosis: Generally favorable and reversible with abstinence 5 days • Normal albumin, bilirubin, and INR Treatment: Alcohol detoxification to sobriety, multivitamin, counseling, psychiatric medications to prevent relapse Imaging: Increased hepatic steatosis on CT and MRI might be seen Collaboration between medicine and psychiatry Biopsy: Variable amount of steatosis with mild inflammation and pericellular fibrosis When AUD and ALD are comorbid, psychiatrists might worry about making the Prognosis: Might improve/resolve with abstinence or lead to progressive liver damage/fibrosis with continued patient’s medical condition worse by pre- alcohol use scribing additional psychoactive medica- Alcoholic hepatitis syndrome Incidence: 5 to 10 per 100,000 Labs: tions—particularly ones that are cleared Clinical Point • Serum AST:ALT > 2:1 often seen but both (hospitalized) Symptoms: Acute jaundice, nausea, abdominal pain, fever, by the liver. Remember that AUD confers <1,000 IU/mL The patient’s encephalopathy a substantial mortality rate that is more • Urinary ethyl glucuronide to verify alcohol use psychological health Risk factors: Binge intake >4 weeks in chronic user, younger age, in past 3 to 5 days than 3 times that of the general population, genetic polymorphisms • CBC: Moderate to severe macrocytosis with along with severe medical46 and psycho- and prognosis for Prognosis: 10% to 30% 1-month mortality; 50% 1-year mortality anemia, frequent thrombocytopenia, leukocytosis social31 effects. Although prescribers must sustained sobriety with left shift if severe with abstinence; 90% mortality without abstinence remain vigilant for adverse drug effects, • Moderate to severely elevated bilirubin and INR, are central to Treatment: medications easily can be blamed for what low albumin always seen candidacy for organ • Manage acute alcohol withdrawal might be the natural progression and symp- • Thiamine, folate Imaging: Hepatic steatosis in CT or MRI +/- 26 listing • Enteral nutrition hepatosplenomegaly, +/- ascites and venous collaterals toms of AUD in patients with ALD. This • Steroids for 6 weeks in selected patients could improve short-term Biopsy: Steatosis with neutrophilic inflammation, erroneous conclusion can lead to premature survival cirrhosis in 40% to 60% medication discontinuation and under- • Alcohol abstinence Prognosis: Discriminant function ≥32 has 30% to 50% treatment of AUD. • Management of encephalopathy, bleeding, ascites mortality at 1 month • Not candidates for liver transplant at most centers In the end, keeping the patient sober Decompensated alcoholic cirrhosis Incidence: Unknown but 10% to 15% of patients with heavy alcohol Labs: and mentally well might be more beneficial (chronic liver failure) use will develop cirrhosis • Serum AST and ALT often normal or minimally than eliminating the burden of any medica- elevated Symptoms: Anorexia, weight loss, cachexia, ascites, muscle tion side effects. Collaborative medical and • CBC: Moderate to severe macrocytosis with wasting/weakness psychiatric management of ALD patients anemia, low WBC and platelets because of portal Risk factors: Lifetime alcohol consumption exceeding 4 drinks/d HTN can ensure that clinicians properly weigh over ≥10 years • Bilirubin and INR may only be mildly elevated; low the risks, benefits, and duration of treat- Prognosis: Determined by severity of portal HTN complications albumin ment unique to each patient. • CTP score ranges from 5 to 15 (variceal bleeding, ascites, encephalopathy). If MELD >20, then Starting AUD treatment promptly after approximately 70% 1-year survival even with abstinence • 1 to 3 points for albumin, bilirubin, INR, and ascites and encephalopathy alcohol relapse is essential and entails a Treatment: • CTP A = 5 to 6 points multidisciplinary effort between medicine • Thiamine, folate, and multivitamins • CTP B = 7 to 9 points and psychiatry, both in and out of the hos- • Medical management of ascites with diuretics • CTP C ≥10 points • Lactulose/rifaximin for encephalopathy pital. Because the relapsing, ill ALD patient Small shrunken, nodular liver with ascites, • Endoscopy for varices Imaging: most often will be admitted to a medical • Transplant in selected patients with favorable prognosis for collaterals, and splenomegaly specialist, AUD might not receive enough long-term abstinence, favorable compliance Biopsy: Cirrhosis with minimal steatosis/inflammation attention during the medical admission. Prognosis: MELD score predicts mortality Psychiatrists can help in initiating AUD at 3 months: • <9 = ~2% mortality treatment in the acute medical setting, • 10 to 19 = 6% mortality which has been shown to improve the out- • 20 to 29 = 20% mortality patient course.6 For medically stable ALD • 30 to 39 = 53% mortality patients admitted for inpatient psychiatric • >40 = 71% mortality care or presenting a clinic, the mental health ALT: alanine transaminase; AST: aspartate transaminase; CBC: complete blood count; CTP: Child-Turcotte-Pugh score; HTN: hypertension; INR: international normalized ratio; MELD: Model for End-Stage Liver Disease; RUQ: right upper quadrant; clinician should be aware of key laboratory Current Psychiatry WBC: white blood cell count and physical exam findings. Vol. 14, No. 12 27 continued Table 2 Table 2 Diagnosis and management of acute alcoholic hepatitis Lab tests • Serum AST:ALT ratio of 2:1 (Variable albumin and total bilirubin) • Basic metabolic panel (kidney injury common) and INR (often elevated) • CBC: Frequent leukocytosis with neutrophilia • Toxicology: Positive blood alcohol level or urine ethyl glucuronidea Alcoholic liver • Abdominal ultrasonography (to exclude other causes of jaundice) disease • Screen for HBV and HCV with HBsAg, anti-HBc, anti-HBs and anti-HCV, respectively • Screen for infection (blood and urine cultures, ascitic fluid cultures, chest radiography) Medical • Referral to gastroenterologist/hepatologist for evaluation therapy • Consider prednisolone or pentoxifylline • Candidates for treatment, including steroids: Recent jaundice, history of alcohol use disorder, no recent (<15 days) GI hemorrhage, labs consistent with AH, prognostic scores, no infection • Enteral nutrition for protein-calorie malnutrition • Vitamin supplementation (thiamine, folate) Clinical Point • Consider pharmacologic treatment for AUD Harm reduction • Substance abuse treatment referral for AUD treatment models are aUrine ethyl glucuronide is a direct metabolite of ethanol that can be detected in urine for up to 90 hours AH: alcoholic hepatitis; ALT: alanine transaminase; AST: aspartate transaminase; AUD: alcohol use disorder; important GI: gastrointestinal; HBc: hepatitis B core antibodies; HBs: hepatitis B surface antibodies; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; INR: international normalized ratio companions to abstinence-only models of AUD References in patients with alcohol dependence and comorbid 1. Gache P, Hadengue A. Baclofen improves abstinence in psychiatric disorders. Biol Psychiatry. 2005;57(10): treatment alcoholic cirrhosis: still better to come? J Hepatol. 2008; 1128-1137. 49(6):1083-1085. 14. Maisel NC, Blodgett JC, Wilbourne PL, et al. Meta-analysis 2. Rehm J, Mathers C, Popova S, et al. Global burden of disease of naltrexone and acamprosate for treating alcohol use and injury and economic cost attributable to alcohol use and disorders: when are these medications most helpful? alcohol-use disorders. Lancet. 2009;373(9682):2223-2233. Addiction. 2013;108(2):275-293. 3. Singal AK, Kamath PS, Gores GJ, et al. Alcoholic hepatitis: 15. Pettinati HM, O’Brien CP, Rabinowitz AR, et al. The status current challenges and future directions. Clin Gastroenterol of naltrexone in the treatment of alcohol dependence: Hepatol. 2014;12(4):555-564; quiz e31-32. specific effects on heavy drinking. J Clin Psychopharmacol. 2006;26(6):610-625. 4. Becker U, Deis A, Sørensen TI, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective 16. Anton RF, Myrick H, Wright TM, et al. Gabapentin population study. Hepatology. 1996;23(5):1025-1029. combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011;168(7):709-717. 5. Mathurin P, Lucey MR. Management of alcoholic hepatitis. J Hepatol. 2012;56(suppl 1):S39-S45. 17. Srisurapanont M, Jarusuraisin N. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 6. Mann K, Lemenager T, Hoffmann S, et al; PREDICT 2005(1):CD001867. Study Team. Results of a double-blind, placebo-controlled pharmacotherapy trial in alcoholism conducted in Germany 18. Naltrexone. 2014. http://www.micromedexsolutions.com. and comparison with the US COMBINE study. Addict Biol. Accessed January 31, 2015. 2013;18(6):937-946. 19. Soyka M, Chick J. Use of acamprosate and opioid antagonists 7. 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Efficacy and safety of 376. oral naltrexone treatment for pruritus of cholestasis, a 10. Furieri FA, Nakamura-Palacios EM. Gabapentin reduces crossover, double blind, placebo-controlled study. J Hepatol. alcohol consumption and craving: a randomized, 2002;37(6):717-722. double-blind, placebo-controlled trial. J Clin Psychiatry. 23. Skinner MD, Lahmek P, Pham H, et al. Disulfiram 2007;68(11):1691-1700. efficacy in the treatment of alcohol dependence: a meta- 11. Blodgett JC, Del Re AC, Maisel NC, et al. A meta-analysis analysis [published online February 10, 2014]. PLoS One. of topiramate’s effects for individuals with alcohol use 2014;9(2):e87366. doi: 10.1371/journal.pone.0087366. disorders. Alcohol Clin Exp Res. 2014;38(6):1481-1488. 24. Disulfiram. 2014. http://www.micromedexsolutions.com. 12. Krystal JH, Cramer JA, Krol WF, et al; Veterans Affairs Accessed January 31, 2015. Naltrexone Cooperative Study 425 Group. Naltrexone 25. Björnsson E, Nordlinder H, Olsson R. 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Drug Saf. 1999;20(5):427-435. continued on page 30 continued from page 28 TableTable 3 3 Medications used to treat alcohol use disorder: Indications, mechanism of action, and use Metabolism (M)/ Medication Indications and use Dosing excretion (E) Mechanism of action Advanced liver disease Other medication features Naltrexonea Reduce reinforcing 50 mg/d13,18 or M: Hepatic18 Opioid receptor Dose modification: Not required in patients with mild • Concomitant opioids are contraindicated18 aspects of alcohol, 100 mg/d antagonist7,16,19 to moderate hepatic impairment18,20 E: Mostly renal, • Opioid-free period of 7 to 10 days is required18 Alcoholic liver 7 drinking cues, and orally, 380 mg fecal 2% to 3%15,18 Hepatotoxicity: Hepatotoxicity in <5% at doses disease 13-17 • Used in the treatment of cholestasis-related heavy drinking subcutaneous 7-times recommended daily dose15; use of naltrexone 18 pruritis22 once monthly injection in patients with severe hepatic impairment has not been studied18; most transaminase elevations • Injectable form can boost adherence and bypass during therapy are mild, self-limited, and resolve with hepatic first-pass metabolism continued therapy21 Other toxicities: Nervousness, restlessness, nausea, headache, anxiety, depression, vomiting, diarrhea, somnolence7,13,15 Clinical Point Disulfirama Promotion of alcohol Commonly M: Hepatic24 Primarily psychological— Dose modification: Associated with hepatotoxicity • Drug’s effect size increased with close supervision 13 abstinence 250 mg/d but E: Renal 70% to anticipation of and should be used cautiously, if at all, in hepatic of disulfiram compliance and patient awareness of 24 23 Keeping the patient has been used in 76%, fecal 20%, disulfiram-ethanol insufficiency drug’s effect higher and lower 24 reaction (tachycardia, sober and mentally lung 20% to 30% Hepatotoxicity: Dose-dependent, rapid- • Preexisting liver pathology predisposes to bad dosages13,23,24 flushing, nausea, onset hepatitis (leukocyte infiltration, high outcomes in disulfiram-induced hepatitis25 well might be more vomiting) aminotransferases—ALT predominant) in <1% with • Immediate drug discontinuation after jaundice beneficial than Blocks aldehyde onset often 1 to 2 months after drug initiation25 appears reduces morbidity and mortality24 eliminating dehydrogenase resulting Other toxicities: Nausea, abdominal pain13; rarely in accumulation of psychosis, confusion, peripheral neuropathy, optic • Small amounts of alcohol in over-the-counter drugs 23 the burden of acetaldehyde neuritis26 or household items can trigger symptoms medication side effects Acamprosatea Promotion of 666 mg, 3 times M: None27 Antagonist at the NMDA Dose modification: None27 • Reduces “negative cravings” (negative feelings 27 7 19 abstinence by reducing daily ; 3 g/d orally E: Renal27 receptor although Hepatotoxicity: None27 arising in the absence of alcohol) cravings14,19 mechanism of action is Other toxicities: Diarrhea, abdominal discomfort, not fully understood7,19 anxiety7,19

Gabapentin Promotion of 600 to 1,800 mg/ M: None30 Modulates GABA Dose modification: None30 • No adverse interactions with alcohol16 10,16,28,29 abstinence in patients d deficits (via action at 30 E: Renal 75%, fecal Hepatotoxicity: None • Additive efficacy when used with naltrexone16 with protracted alcohol 30 pre-synaptic calcium 25% Other toxicities: Somnolence, dizziness, headache, withdrawal, reduction channels) and glutamate • Might be helpful for treating comorbid indigestion, myalgias, altered mental status, 16,28,29 10,29 of alcohol craving10,16 excess16,29 insomnia, mood and anxiety insomnia10,28,29 • Withdrawal symptoms if stopped abruptly

Topiramate Promotion of 75 to M: Not extensively Decreases dopamine Dose modification: Clearance may be reduced • May be particularly useful in patients who also abstinence, 400 mg/d11,31-33 metabolized34 activity after alcohol use in hepatic insuffiency34 abuse stimulants36 reduction in alcohol 34 through enhancement E: Renal Hepatotoxicity: None • Can improve mood during abstinence32 reinforcement, reduce of GABA action, Other toxicities: Paresthesias, numbness, 32 heavy drinking and some glutamate • Low dosages might be effective (75 mg/d) cognitive impairment, headache, dizziness, cravings, reduction in antagonism11,31,32,35 32 psychomotor slowing, weight loss, nausea/vomiting, • Useful in addressing impulsivity total drinking days11,31 somnolence11,31-33

Baclofen Reduction in 30 to 60 mg/d in 3 M: Liver, limited38 GABA-B receptor Dose modification: None38 • Potential increased efficacy with higher doses1 38 alcohol craving divided doses 38 agonist mediating E: Renal Hepatotoxicity: Has not been linked to any clinically • Improves abstinence and some liver function tests and consumption,1 reinforcing effects significant liver injury, including encephalopathy in hepatitis C patients41 promotion of of alcohol through and hyperammonemia39,40 abstinence37 action in ventral • No inherent pleasurable or reinforcing properties37 Other toxicities: Drowsiness, weakness, fatigue, tegmental area37 myalgia37 • Withdrawal when stopped abruptly • Overdose has been documented in alcohol- dependent patients42 • Might reduce comorbid anxiety43

aFDA-approved for treatment of AUD

Current Psychiatry ALT: alanine transaminase: AUD: alcohol use disorder; GABA: γ-aminobutyric acid; NMDA: N-methyl-d-aspartate 30 December 2015 Table 3 Medications used to treat alcohol use disorder: Indications, mechanism of action, and use Metabolism (M)/ Medication Indications and use Dosing excretion (E) Mechanism of action Advanced liver disease Other medication features Naltrexonea Reduce reinforcing 50 mg/d13,18 or M: Hepatic18 Opioid receptor Dose modification: Not required in patients with mild • Concomitant opioids are contraindicated18 aspects of alcohol, 100 mg/d antagonist7,16,19 to moderate hepatic impairment18,20 E: Mostly renal, • Opioid-free period of 7 to 10 days is required18 7 drinking cues, and orally, 380 mg fecal 2% to 3%15,18 Hepatotoxicity: Hepatotoxicity in <5% at doses 13-17 • Used in the treatment of cholestasis-related heavy drinking subcutaneous 7-times recommended daily dose15; use of naltrexone 18 pruritis22 once monthly injection in patients with severe hepatic impairment has not been studied18; most transaminase elevations • Injectable form can boost adherence and bypass during therapy are mild, self-limited, and resolve with hepatic first-pass metabolism continued therapy21 Other toxicities: Nervousness, restlessness, nausea, headache, anxiety, depression, vomiting, diarrhea, somnolence7,13,15 Disulfirama Promotion of alcohol Commonly M: Hepatic24 Primarily psychological— Dose modification: Associated with hepatotoxicity • Drug’s effect size increased with close supervision Clinical Point 13 abstinence 250 mg/d but E: Renal 70% to anticipation of and should be used cautiously, if at all, in hepatic of disulfiram compliance and patient awareness of 24 23 has been used in 76%, fecal 20%, disulfiram-ethanol insufficiency drug’s effect Because an ill ALD higher and lower 24 reaction (tachycardia, lung 20% to 30% Hepatotoxicity: Dose-dependent, rapid- • Preexisting liver pathology predisposes to bad patient often will be dosages13,23,24 flushing, nausea, onset hepatitis (leukocyte infiltration, high outcomes in disulfiram-induced hepatitis25 vomiting) aminotransferases—ALT predominant) in <1% with admitted to a medical • Immediate drug discontinuation after jaundice Blocks aldehyde onset often 1 to 2 months after drug initiation25 specialist, AUD might appears reduces morbidity and mortality24 dehydrogenase resulting Other toxicities: Nausea, abdominal pain13; rarely not receive enough in accumulation of psychosis, confusion, peripheral neuropathy, optic • Small amounts of alcohol in over-the-counter drugs 23 acetaldehyde neuritis26 or household items can trigger symptoms attention during the

Acamprosatea Promotion of 666 mg, 3 times M: None27 Antagonist at the NMDA Dose modification: None27 • Reduces “negative cravings” (negative feelings medical admission 27 7 19 abstinence by reducing daily ; 3 g/d orally E: Renal27 receptor although Hepatotoxicity: None27 arising in the absence of alcohol) cravings14,19 mechanism of action is Other toxicities: Diarrhea, abdominal discomfort, not fully understood7,19 anxiety7,19

ALT: alanine transaminase: AUD: alcohol use disorder; GABA: γ-aminobutyric acid; NMDA: N-methyl-d-aspartate Current Psychiatry Vol. 14, No. 12 31 continued 34. Topamax [package insert]. Titusville, NJ: Janssen Related Resources Pharmaceuticals; 2009. 35. De Sousa AA, De Sousa J, Kapoor H. An open randomized • Khan A, Tansel A, White DL, et al. Efficacy of psychosocial trial comparing disulfiram and topiramate in the treatment interventions in inducing and maintaining alcohol absti- of alcohol dependence. J Subst Abuse Treat. 2008;34(4): nence in patients with chronic liver disease: a systematic re- 460-463. view [published online August 6, 2015]. Clin Gastroenterol 36. Kampman KM, Pettinati HM, Lynch KG, et al. A double- Hepatol. doi: 10.1016/j.cgh.2015.07.047. blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence.

• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for Drug Alcohol Depend. 2013;133(1):94-99. alcoholic patients with alcoholic liver disease. Am J Health 37. Addolorato G, Leggio L, Ferrulli A, et al. Dose-response Alcoholic liver Syst Pharm. 2014;71(15):1265-1276. effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, Drug Brand Names disease double-blind, placebo-controlled trial. Alcohol Alcohol. Acamprosate • Campral Pentoxifylline • Trental 2011;46(3):312-317. Baclofen • Lioresal Prednisolone • Prelone 38. Balcofen [package insert]. Concord, NC: McKesson Packing Disulfiram • Antabuse Rifaximin • Xifaxan Services; 2013. Gabapentin • Neurontin Topiramate • Topamax 39. United States National Library of Medicine. Baclofen. Naltrexone • ReVia, Vivitrol 2015. http://livertox.nlm.nih.gov/Baclofen.htm. Accessed November 7, 2015. 40. Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007;370(9603): Clinical Point 27. Campral [package insert]. St. Louis, MO: Forest 1915-1922. Pharmaceuticals, Inc.; 2012. 41. Leggio L, Ferrulli A, Zambon A, et al. Baclofen promotes 28. Brower KJ, Myra Kim H, Strobbe S, et al. A randomized alcohol abstinence in alcohol dependent cirrhotic patients For medically stable double-blind pilot trial of gabapentin versus placebo to treat with hepatitis C virus (HCV) infection. Addict Behav. alcohol dependence and comorbid insomnia. Alcohol Clin 2012;37(4):561-564. ALD patients, the Exp Res. 2008;32(8):1429-1438. 42. Franchitto N, Pelissier F, Lauque D, et al. Self-intoxication 29. Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment with baclofen in alcohol-dependent patients with co- mental health clinician for alcohol dependence: a randomized clinical trial. JAMA existing psychiatric illness: an emergency department case should be aware Intern Med. 2014;174(1):70-77. series. Alcohol Alcohol. 2014;49(1):79-83. 30. Neurontin [package insert]. New York, NY: Pfizer; 2015. 43. Brennan JL, Leung JG, Gagliardi JP, et al. Clinical of key laboratory 31. Johnson BA, Ait-Daoud N, Akhtar FZ, et al. Oral topiramate effectiveness of baclofen for the treatment of alcohol reduces the consequences of drinking and improves dependence: a review. Clin Pharmacol. 2013;5:99-107. and physical exam the quality of life of alcohol-dependent individuals: 44. Rösner S, Leucht S, Lehert P, et al. Acamprosate supports a randomized controlled trial. Arch Gen Psychiatry. abstinence, naltrexone prevents excessive drinking: findings 2004;61(9):905-912. evidence from a meta-analysis with unreported outcomes. 32. Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. Treatment J Psychopharmacol. 2008;22(1):11-23. of alcohol dependence with low-dose topiramate: an open- 45. Marlatt GA, Witkiewitz K. Harm reduction approaches to label controlled study. BMC Psychiatry. 2011;11:41. alcohol use: health promotion, prevention, and treatment. 33. Rubio G, Ponce G, Jiménez-Arriero MA, et al. Effects Addict Behav. 2002;27(6):867-886. of topiramate in the treatment of alcohol dependence. 46. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver Pharmacopsychiatry. 2004;37(1):37-40. disease. Am J Gastroenterol. 2010;105(1):14-32; quiz 33.

Bottom Line Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy Current Psychiatry 32 December 2015 decisions should be made case by case.