Medication for alcohol use disorder: Which agents work best?

We consider acamprosate an effective option for patients who do not respond to naltrexone or have a contraindication. Dosages of 333 mg to 666 mg, 3 times a day, are recommended, although dosages up to 3 g/d have been studied; titration is not required.^2,7,28 We recommend advising patients to continue treatment even if they relapse, because these medications may mitigate relapse severity. Adherence to multiple daily doses can be problematic for some patients, but pairing medications with meals or bedtime may improve adherence.

Diarrhea is the most common side effect of acamprosate; nervousness, fatigue, insomnia, and depression have been reported with high dosages.^2,3,7,28 Acamprosate is excreted through the kidney and is safe for patients with liver disorders such as acute hepatitis or cirrhosis. The drug is contraindicated in patients with acute or chronic renal failure with creatinine clearance <30 mL/min; those with less severe renal insufficiency might need a lower dosage. Obtain baseline renal function before starting acamprosate; women of childbearing age should undergo a pregnancy test.

Disulfiram inhibits alcohol metabolism, resulting in acetaldehyde accumulation, which causes unpleasant physical effects such as nausea, vomiting, and hypotension. This creates a negative rather than a positive experience with drinking. A US Veterans Administration Cooperative Study randomized 605 participants to riboflavin, disulfiram, 1 mg/d (an inactive dose), or disulfiram, 250 mg/d (standard dose). There was no difference in percentage of patients remaining abstinent or time to first drink.⁸ Participants receiving disulfiram, 250 mg/d, had fewer drinking days after relapse compared with the other groups.⁸

Adverse physical effects produced when disulfiram and alcohol interact include tremor, diaphoresis, unstable blood pressure, and severe diarrhea and vomiting. Disulfiram can cause medically serious reactions in a small percentage of patients, especially those with significant medical comorbidity or advanced age. Patients with severe hypertension, diabetes mellitus, heart disease, a history of stroke, peripheral neuropathy, epilepsy, or renal or hepatic insufficiency should not use disulfiram.³ Patients taking disulfiram should avoid casual exposures to food, aftershave, mouthwash, and hand sanitizer that might contain alcohol. Disulfiram has no significant effect on alcohol craving. Social support to help oversee dosing may enhance adherence.⁷

Off-label medications

Topiramate is FDA-approved to treat migraine headaches and some seizure disorders. Topiramate facilitates GABA-mediated neuronal inhibition and antagonizes certain glutamate receptor subtypes. In an RCT (N = 150), topiramate, up to 300 mg/d, was more effective than placebo at reducing heavy drinking days and number of drinks per day, increasing days abstinent, and alleviating cravings.⁹ In a 12-week, double-blind RCT (N = 150), topiramate increased “safe drinking”—defined as ≤1 standard drink per day for women and ≤2 per day for men—vs placebo.¹⁰ Dosages were 75 mg to 300 mg/d in twice daily divided doses. Dosing starts at 25 mg/d and increases by 25 to 50 mg a day at weekly intervals. We recommend reserving topiramate for persons who do not respond to or cannot tolerate naltrexone and acamprosate because of the slow titration needed to prevent side effects. Although not studied, it may seem that topiramate’s antiepileptic actions could prevent seizures during alcohol withdrawal, but the protracted titration would limit its utility.

Side effects of topiramate include impaired memory and concentration, paresthesia, and anorexia and are more likely to present during rapid titration or with a high dosage.^7,8 Rare reports of spontaneous myopia, angle-closure glaucoma, increased intraocular pressure, ocular pain, and blurry vision have been reported, but these complications often resolve with discontinuation of topiramate.^7,8

Topiramate primarily is excreted through the kidney, and its action in the renal tubules can lead to metabolic acidosis or nephrolithiasis.⁸ Relative contraindications include acute or chronic kidney disease, including kidney stones. Consider slower titration and a 50% reduction in dosing if creatinine clearance is <70 mL/min. Obtain renal function tests before starting topiramate and consider monitoring serum bicarbonate for metabolic acidosis (we test at 3 and 6 months, then every 6 months). Because of teratogenic effects of topiramate (eg, cleft lip and palate), rule out pregnancy in all women of childbearing age.

Baclofen is a GABA_b receptor agonist that is FDA approved for treating spasticity. Because GABA transmission is down-regulated in chronic AUD, it is a commonly targeted neurotransmitter when developing medications for AUD. GABA_a receptors are fast-acting inhibitory ion channels, and its agonists (eg, benzodiazepines) have a significant abuse and cross-addiction liability. GABA_b receptors, however, are slow-acting through a complex cascade of intracellular signals, and therefore GABA_b agonists such as baclofen have been studied for treating addiction.

In a randomized double-blind, placebo-controlled trial (N = 39), baclofen was superior to placebo in suppressing obsessive aspects of cravings and decreasing state anxiety.¹¹ Baclofen, 10 mg 3 times daily, in another randomized double-blind, placebo-controlled trial (n = 42) reduced the number of drinks per day by 53% vs placebo; 20 mg 3 times a day resulted in a 68% reduction in drinks per day vs placebo.¹² However, a placebo-controlled RCT (n = 80) reported that baclofen, 10 mg 3 times daily, was not superior to placebo for primary outcomes related to alcohol consumption, although it did significantly decrease cravings and anxiety among persons with AUD.¹³ Evidence suggests that baclofen might be effective for promoting abstinence, reducing the risk of relapse, and alleviating cravings and anxiety in persons with AUD, although further investigation is needed.