sign in sign up
<<
Home , Acamprosate, Alanine, Alcoholic hepatitis

Savvy Psychopharmacology

Pharmacotherapy for use disorder in patients with hepatic impairment

Courtney V. Eatmon, PharmD, BCPP, and Kelley Trent, PharmD

r. S, age 64, presents for an outpa- partially explain the higher prevalence of tient follow-up after a recent hospital viral among persons with alco- M discharge for . hol use disorder (AUD) compared with the He reports a long history of alcohol use, which general population. Alcoholic disease has resulted in numerous hospital admissions. (ALD) progresses through several stages, He has recently been receiving care from a beginning with hepatic and pro- gastroenterologist because the results of labo- gressing through alcohol-related hepatitis, Vicki L. Ellingrod, ratory testing suggested hepatic impairment , , and potentially hepatocel- PharmD, FCCP (Table 1,1 page 26). Mr. S says that an friend of lular carcinoma.3 Department Editor his was able to stop drinking by taking a medi- cation, and he wonders if he can be prescribed Liver markers of alcohol use a medication to help him as well. Although biological markers can be used A chart review shows that Mr. S recently in clinical practice to screen and monitor underwent paracentesis, during which 6 liters of fluid were removed. Additionally, an abdomi- Practice Points nal ultrasound confirmed hepatic cirrhosis. • The risk of alcoholic (ALD) increases with daily alcohol According to the World Health Organization, consumption; however, it is also alcohol consumption contributes to 3 mil- dependent on genetic predisposition, lion annually.2 The highest proportion age, gender, comorbid hepatitis B or C infection, and other risk factors. of these deaths (21.3%) is due to alcohol- associated gastrointestinal complications, •  must be interpreted including alcoholic and infectious hepati- carefully along with a full clinical picture because these tests are not specific to liver tis, , and cirrhosis. Because the injury, and the degree of liver liver is the primary site of metabo- elevation does not always correspond with lism, it sustains the greatest degree of tis- the degree of liver injury. sue injury with heavy alcohol consumption. • Although not specific, alterations in serum Additionally, the association of harmful use albumin level and international normalized of alcohol with risky sexual behavior may ratio are better correlated to actual liver Savvy Psychopharmacology function as the disease progresses. is produced in partnership Dr. Eatmon is Clinical Pharmacy Specialist, Substance Use with the College Disorders, Lexington Veterans Affairs Health Care System, and • Of the 3 FDA-approved medications for of Psychiatric Assistant Professor, Department of Pharmacy Practice and Science, the treatment of alcohol use disorder, only and Neurologic University of Kentucky, Lexington, Kentucky. Dr. Trent is a PGY-2 is considered safe for use in Pharmacists Psychiatric Pharmacy Resident, Lexington Veterans Affairs Health patients with severe ALD. cpnp.org Care System, Lexington, Kentucky. mhc.cpnp.org (journal) Disclosures • Baclofen is the only medication that has The authors report no financial relationships with any companies been tested specifically in patients with whose products are mentioned in this article, or with manufacturers advanced ALD and may promote abstinence of competing products. and reduce return to use. Current Psychiatry doi: 10.12788/cp.0068 Vol. 20, No. 1 25 Savvy Psychopharmacology

Table 1 advanced cirrhosis may have liver enzyme levels that appear normal. However, the Hepatic laboratory values for Mr. S pattern of elevation in can Liver Mr. S’s Reference be helpful in making a diagnosis of liver function test values range dysfunction; using the ratio of AST to ALT AST 216 U/L 17 to 59 U/L may aid in diagnosing ALD, because AST ALT 99 U/L 20 to 35 U/L is elevated more than twice that of ALT in ALP 194 U/L 44 to 147 U/L >80% of patients with ALD.1,3,4 GGT 76 U/L 9 to 48 U/L Table 2,1,3,4 (page 27) shows the pro- Total 1.6 mg/dL 0.2 to 1.3 mg/dL gression of ALD from to ALP: alkaline phosphatase; ALT: aminotransferase; to cirrhosis. In steatohep- AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase atitis, transaminitis is present but all other Source: Reference 1 biomarkers normal. In alcoholic hepatitis, Clinical Point transaminitis is present along with elevated The risk of alkaline phosphatase, elevated bilirubin, and elevated international normalized alcoholic liver for , making a diagnosis of ratio (INR). In alcoholic cirrhosis, the AST- disease increases ALD can be challenging. Typically, a history to-ALT ratio is >2, and hypoalbuminemia, with daily alcohol of heavy alcohol consumption in addition to hyperbilirubinemia, and coagulopathy consumption, but certain physical signs and laboratory tests for (evidenced by elevated INR) are present, liver disease are the best indicators of ALD. consistent with long-term liver damage.1,3,4 also depends on However, the clinical assessment can be con- other risk factors founded by patients who deny or minimize FDA-approved medications how much alcohol they have consumed. Three medications—acamprosate, naltrex- Furthermore, physical and laboratory find- one, and —currently are FDA- ings may not be specific to ALD. approved for treating AUD.5,6 Additionally, Liver , including aspartate ami- several other medications have shown notransferase (AST), alanine aminotransfer- varying levels of efficacy in treating patients ase (ALT), and gamma-glutamyltransferase with AUD but are not FDA-approved for (GGT), have historically been used as the this indication (Table 3,5-8 page 28). basis of diagnosing ALD. In addition to ele- Acamprosate is thought to create a bal- vated bilirubin and evidence of macrocytic ance of inhibitor and excitatory neurotrans- anemia, elevations in these enzymes may mitters by functioning as a glutamate suggest heavy alcohol use, but these val- antagonist and gamma-aminobutyric ues alone are inadequate to establish ALD. (GABA) agonist. This is speculated to aid Gamma-glutamyltransferase is found in cell in abstinence from alcohol. Data suggests membranes of several body tissues, includ- that acamprosate may be more effective ing the liver and spleen, and therefore is not for maintaining abstinence than for induc- specific to liver damage. However, elevated ing remission in individuals who have not GGT is the best indicator of excessive alcohol yet detoxified from alcohol. Because of its consumption because it has greater sensitiv- renal , acamprosate is the only ity than AST and ALT.1,3,4 FDA-approved medication for AUD that is Discuss this article at Although these biomarkers are helpful in not associated with liver toxicity. The most www.facebook.com/ diagnosing ALD, they lose some of their util- commonly reported adverse effect with MDedgePsychiatry ity in patients with advanced liver disease. acamprosate use is . Patients with severe liver dysfunction may , a mu- antago- not have elevated serum aminotransferase nist, is available in both tablet and long-act- levels because the degree of liver enzyme ing IM injection formulations. Naltrexone elevation does not correlate well with the blocks the binding of endorphins created by Current Psychiatry 26 January 2021 severity of ALD. For example, patients with alcohol consumption to opioid receptors. Savvy Psychopharmacology

Table 2 Progression of Liver function test Alcoholic steatohepatitis Alcoholic hepatitis Alcoholic cirrhosis AST 174 U/L (H) 260 U/L (H) 109 U/L (H) ALT 86 U/L (H) 94 U/L (H) 39 U/L ALP 87 U/L 192 U/L (H) 169 U/L (H) GGT 52 U/L (H) 94 U/L (H) 204 U/L (H) Total 6.6 gm/dL 8.6 gm/dL (H) 6.7 gm/dL Albumin 3.7 g/dL 4.6 g/dL 2.8 g/dL (L) Total bilirubin 1.0 mg/dL 1.8 mg/dL (H) 3.8 mg/dL (H) INR 1.11 1. 3 (H) 2.45 (H) ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma- glutamyltransferase; INR: international normalized ratio Clinical Point Source: References 1,3,4 Liver function tests must be interpreted carefully along with This results in diminished release Off-label medications for AUD a full clinical picture and is speculated to decrease reward and Additional pharmacotherapeutic agents because these tests positive reinforcement with alcohol con- have been evaluated in patients with AUD. are not specific to sumption, leading to fewer heavy drinking , , gabapentin, and days. Due to hepatic , naltrex- ondansetron have shown varying levels liver injury one use carries a risk of liver injury. Cases of efficacy and pose minimal concern in of hepatitis and clinically significant liver patients with ALD. dysfunction as well as transient, asymp- Baclofen. Although findings are con- tomatic, hepatic elevations flicting, baclofen is the only agent that has have been observed in patients who receive been specifically studied for treating AUD naltrexone. Because of the absence of first- in patients with ALD. A GABA B recep- pass metabolism, long-acting IM naltrexone tor antagonist, baclofen is currently FDA- may produce less hepatotoxicity than the approved for treating spasticity. In a series oral formulation. When the FDA approved of open-label and double-blind studies, both formulations of naltrexone, a “black- baclofen has been shown to effectively box” warning was issued concerning the reduce alcohol intake, promote abstinence, risk of liver damage; however, these warn- and prevent relapse.5,6 Further studies ings have since been removed from their identified a possible dose-related response, respective prescribing information. noting that 20 mg taken 3 times daily may Disulfiram inhibits dehydro- confer additional response over 10 mg taken genase, resulting in elevated acetaldehyde 3 times daily.5,6 Conversely, the ALPADIR concentrations after consuming alcohol. In study failed to demonstrate superiority of theory, this medication reduces a person’s baclofen vs placebo in the maintenance of desire to drink due to the negative physi- abstinence from alcohol despite dosing at ological and physical effects associated with 180 mg/d.9 This study did, however, find a increased acetaldehyde, including hypo- significant reduction in alcohol craving in tension, flushing, , and vomiting. favor of baclofen.9 Further, in a randomized Although most of these reactions are short- controlled trial (RCT) conducted in veter- lived, disulfiram can induce hepatotoxic- ans with chronic , baclofen 30 ity and that may prove fatal. mg/d failed to show superiority over pla- Disulfiram should be avoided in patients cebo with regard to increasing abstinence or Current Psychiatry with advanced ALD. reducing alcohol use.10 Vol. 20, No. 1 27 continued Savvy Psychopharmacology

Table 3 Medications for treating alcohol use disorder Appropriate in alcoholic Medication Dosing information liver disease? FDA-approved medications Acamprosate 666 mg 3 times daily Yes CrCl 30 to 50 mL/min: 333 mg 3 times daily CrCl ≤30 mL/min: contraindicated Naltrexone, oral 50 mg/d Not recommended for use in Naltrexone suspension, 380 mg once every 4 weeks patients with acute hepatitis or intramuscular hepatic failure Disulfiram 125 to 500 mg/d Avoid use in patients with Clinical Point advanced ALD Off-label medications Of the 3 medications Baclofen 10 mg 3 times daily; Yes FDA-approved for maximum dose: 15 mg 3 times daily Topiramate 75 to 300 mg/d Yes, clearance may be alcohol use disorder, reduced in hepatic impairment only acamprosate is Use with caution in hepatic considered safe encephalopathy Gabapentin 900 to 1,800 mg/d Yes for use in patients Ondansetron 4 mcg/kg twice daily Yes, use with caution because with severe ALD liver toxicity has been reported ALD: alcoholic liver disease; CrCl: clearance Source: References 5-8

Topiramate. A recent meta-analysis found of abuse in other high-risk populations (ie, that topiramate use may result in fewer drink- those with , incarcerated ing days, heavy drinking days, and number persons, and those who misuse prescrip- of drinks per drinking day.7 Additionally, tions recreationally).8 topiramate has demonstrated a statistically Ondansetron is speculated to decrease the significant reduction in alcohol craving as reward from alcohol via the down-regula- well as the ability to decrease all liver function tion of dopaminergic . Studies exam- test values.5 This agent should be used with ining ondansetron for patients with AUD caution in patients with hepatic encepha- have found that it decreases alcohol cravings lopathy because the adverse cognitive effects in those with early-onset (initial associated with topiramate may confound the onset at age ≤25), but not in late-onset alco- clinical course and treatment of such. holism (initial onset at age >25).5 However, Gabapentin. The use of gabapentin to the ondansetron doses used in these trials treat patients with AUD is supported by were very low (4 mcg/kg), and those doses multiple RCTs. In studies that evaluated are not available commercially.5 dose-related response, higher doses of gab- apentin (up to 1,800 mg/d) showed greater CASE CONTINUED efficacy than lower doses (ie, 900 mg/d).8 Following a discussion of available pharma­ Because gabapentin does not undergo cotherapeutic options for AUD, Mr. S is started hepatic metabolism, its use in patients with on baclofen, 10 mg 3 times daily, with plans for ALD is considered safe. Although the abuse dose titration. At a 2-week follow-up appoint- potential of gabapentin is less defined in ment, Mr. S reports that he had not been tak- Current Psychiatry 28 January 2021 patients with AUD, there have been reports ing baclofen as often as instructed; however, Savvy Psychopharmacology

he denies further alcohol consumption and re- Related Resources commits to baclofen treatment. Unfortunately, • Crabb DW, Im GY, Szabo G, et al. Diagnosis and treatment of alcohol-related liver diseases: 2019 practice guidance from Mr. S is soon admitted to hospice care due to con- the American Association for the Study of Liver Diseases. tinued decompensation and is unable to attend . 2020;71(1):306-333. any additional outpatient follow-up appoint- • Murail AR, Carey WD. Disease management. Liver test interpretation - approach to the patient with ments. Three months after his initial outpatient liver disease: a guide to commonly used liver tests. contact, Mr. S dies due to alcoholic cirrhosis. Cleveland Clinic Center for Continuing Education. Updated August 2017. www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/hepatology/ References guide-to-common-liver-tests/ 1. Agrawal S, Dhiman RK, Limdi JK. Evaluation of abnormal liver function tests. Postgrad Med J. 2016;92(1086):223-234. Drug Brand Names 2. World Health Organization. Global status report on alcohol Acamprosate • Campral Naltrexone • Revia, Vivitrol and health 2018. Published 2018. Accessed November 5, 2020. https://www.who.int/substance_abuse/publications/global_ Baclofen • Lioresal Ondansetron • Zofran alcohol_report/gsr_2018/en/ Disulfiram • Antabuse Topiramate • Topamax Gabapentin • Neurontin Clinical Point 3. Osna NA, Donohue TM, Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res. 2017;38(2):147-161. Baclofen may 4. Leggio L, Lee MR. Treatment of alcohol use disorder in patients with alcoholic liver disease. Am J Med. 2017;130(2):124-134. 8. Mason BJ, Quello S, Shadan F. Gabapentin for the treatment promote abstinence of alcohol use disorder. Expert Opin Investig Drugs. 2018; 5. Addolorato G, Mirijello A, Leggio L, et al. Management of 27(1):113-124. and reduce return in patients with liver disease. CNS Drugs. 2013;27(4):287-299. 9. Reynaud M, Aubin HJ, Trinquet F, et al. A randomized, placebo- controlled study of high-dose baclofen in alcohol-dependent to alcohol use 6. Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for patients-the ALPADIR study. Alcohol Alcohol. 2017;52(4): alcoholic patients with alcoholic liver disease. Am J Health Syst 439-446. in patients with Pharm. 2014;71(15):1265-1276. 10. Hauser P, Fuller B, Ho S, et al. The safety and efficacy of 7. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for baclofen to reduce alcohol use in veterans with chronic advanced ALD adults with alcohol use disorders in outpatient settings. JAMA. hepatitis C: a randomized controlled trial. . 2014;311(18):1889-1900. 2017;112(7):1173-1183.