# FDA-Approved Medications for Alcohol Use Disorder -- APA 2018

## Statement 9: Naltrexone or Acamprosate (1B)

APA recommends (1B) that naltrexone or acamprosate be offered to patients with moderate to severe alcohol use disorder who:

- Have a goal of reducing alcohol consumption or achieving abstinence
- Prefer pharmacotherapy or have not responded to nonpharmacological treatments alone
- Have no contraindications to the use of these medications

This is the **highest-rated pharmacotherapy recommendation** in the guideline.

## Naltrexone

### Mechanism of Action

Naltrexone is an opioid receptor antagonist (primarily mu-opioid receptor) that reduces the rewarding effects of alcohol and diminishes craving.

### Oral Naltrexone

| Parameter | Detail |
|---|---|
| **Starting dose** | 25 mg/day for the first 1-2 days to assess tolerability |
| **Target dose** | 50 mg/day (single tablet, once daily) |
| **Route** | Oral |
| **Frequency** | Once daily |
| **FDA-approved indication** | Alcohol dependence |

- Titration from 25 mg to 50 mg helps minimize initial nausea.
- Can be initiated while the patient is still drinking; abstinence is not a prerequisite for starting treatment.

### Injectable Extended-Release Naltrexone (XR-NTX, Vivitrol)

| Parameter | Detail |
|---|---|
| **Dose** | 380 mg |
| **Route** | Intramuscular injection (gluteal) |
| **Frequency** | Every 4 weeks (28 days) |
| **FDA-approved indication** | Alcohol dependence |

- Eliminates daily adherence burden.
- Particularly useful for patients with poor oral medication adherence.
- Requires opioid-free period of 7-10 days prior to initiation (to avoid precipitated withdrawal in patients with co-occurring opioid use).

### Naltrexone Efficacy Data

- Oral naltrexone: NNT (number needed to treat) of approximately 12 to prevent return to any drinking, 20 to prevent return to heavy drinking (based on COMBINE trial and meta-analyses).
- Injectable naltrexone: demonstrated significant reduction in heavy drinking days in RCTs; may have advantages in adherence-dependent populations.

### Naltrexone Adverse Effects

- **Nausea** (most common; usually transient)
- Headache, dizziness, fatigue
- Hepatotoxicity risk at high doses (> 300 mg/day); generally safe at 50 mg/day
- Injection site reactions (injectable form)

### Naltrexone Contraindications (Statements 17-18)

**Statement 17 (1C):** APA recommends that naltrexone not be used by patients who have **acute hepatitis or hepatic failure**.

- Naltrexone is hepatically metabolized; baseline liver function tests (LFTs) should be obtained before initiation.
- Mild-to-moderate elevations in transaminases (common in heavy drinkers) are NOT a contraindication.
- Monitor LFTs periodically during treatment.

**Statement 18 (1C):** APA recommends that naltrexone not be used as a treatment for AUD by individuals who **use opioids or who have an anticipated need for opioids**.

- Naltrexone will block the analgesic effects of opioid medications.
- Can precipitate acute opioid withdrawal in opioid-dependent individuals.
- Patients must be opioid-free for a minimum of 7-10 days before starting naltrexone (7 days for short-acting opioids, 10-14 days for long-acting opioids).
- Patients should carry a medical alert card indicating naltrexone use to inform emergency providers.

**Statement 19 (1C):** APA recommends that in patients with AUD and **co-occurring opioid use disorder**, naltrexone be prescribed to individuals who are able to abstain from opioid use for a clinically appropriate time prior to naltrexone initiation.

## Acamprosate

### Mechanism of Action

Acamprosate modulates glutamatergic neurotransmission and is thought to restore the balance between excitatory and inhibitory neurotransmission disrupted by chronic alcohol use.

### Dosing

| Parameter | Detail |
|---|---|
| **Target dose** | 666 mg (two 333 mg tablets) three times daily; total 1,998 mg/day |
| **Route** | Oral |
| **Frequency** | Three times daily |
| **FDA-approved indication** | Maintenance of abstinence from alcohol |

- Should be initiated as soon as possible after alcohol withdrawal is complete and abstinence is achieved.
- Can be started while the patient is still in withdrawal treatment.
- Does not require dose titration.
- No hepatic metabolism (renally excreted); preferred in patients with hepatic impairment.

### Acamprosate Efficacy Data

- NNT of approximately 12 to prevent return to any drinking (European meta-analyses).
- More effective in patients whose goal is **complete abstinence** rather than reduced drinking.
- The COMBINE trial (U.S.) did not show a significant benefit of acamprosate over placebo; however, European trials consistently demonstrated efficacy.

### Acamprosate Adverse Effects

- **Diarrhea** (most common)
- Flatulence, nausea
- Generally well tolerated; no hepatotoxicity risk

### Acamprosate Contraindications (Statements 15-16)

**Statement 15 (1C):** APA recommends that acamprosate **not be used by patients who have severe renal impairment** (CrCl <= 30 mL/min).

**Statement 16 (1C):** APA recommends that for individuals with **mild to moderate renal impairment**:
- Acamprosate should not be used as a first-line treatment
- If used, the dose should be reduced compared with recommended doses in individuals with normal renal function
- Per FDA labeling: for moderate renal impairment (CrCl 30-50 mL/min), the recommended dose is 333 mg three times daily (half the standard dose)

## Disulfiram

### Statement 10 (2C)

APA suggests (2C) that disulfiram be offered to patients with moderate to severe alcohol use disorder who:

- Have a goal of **achieving abstinence** (NOT suitable for reduction/moderation goals)
- Prefer disulfiram or are intolerant to or have not responded to naltrexone and acamprosate
- Have no contraindications to the use of disulfiram

### Mechanism of Action

Disulfiram inhibits aldehyde dehydrogenase, causing accumulation of acetaldehyde when alcohol is consumed, producing a highly aversive reaction (disulfiram-ethanol reaction).

### Dosing

| Parameter | Detail |
|---|---|
| **Starting dose** | 250 mg/day |
| **Dose range** | 125-500 mg/day |
| **Route** | Oral |
| **Frequency** | Once daily |
| **FDA-approved indication** | Alcohol dependence (adjunct to supportive and psychotherapeutic treatment) |

- Should NOT be administered until patient has abstained from alcohol for at least 12 hours.
- Supervised administration (by a spouse, family member, pharmacist, or clinic) increases efficacy.
- The disulfiram-ethanol reaction can occur for up to 2 weeks after the last disulfiram dose.

### Disulfiram-Ethanol Reaction

Symptoms include: flushing, nausea, vomiting, headache, diaphoresis, chest pain, palpitations, dyspnea, hypotension. Severe reactions can include cardiovascular collapse, respiratory depression, and death.

### Disulfiram Contraindications

- **Concomitant alcohol use** or inability to abstain
- **Severe myocardial disease** or coronary occlusion
- **Psychosis** (can exacerbate psychotic symptoms)
- **Known hypersensitivity** to disulfiram or thiuram derivatives (rubber vulcanization)
- **Metronidazole** use (interaction risk)
- **Pregnancy** (teratogenic potential)
- Use with caution in hepatic disease; obtain baseline LFTs and monitor

### Disulfiram Efficacy

- Evidence for disulfiram is less robust than for naltrexone and acamprosate; efficacy is primarily demonstrated in open-label trials and supervised administration settings.
- Effectiveness depends on adherence, which is why supervised administration is recommended.

## Medication Selection Algorithm

```
Patient with moderate to severe AUD
  -> Assess contraindications for each medication
  -> Assess treatment goals
      -> Goal: Abstinence OR Reduction?
          -> Naltrexone (oral or injectable): Suitable for both goals (1B)
          -> Acamprosate: Primarily for abstinence maintenance (1B)
          -> Disulfiram: Abstinence only (2C)
      -> Hepatic impairment (acute hepatitis/hepatic failure)?
          -> Yes -> Do NOT use naltrexone; consider acamprosate
          -> Mild elevations in LFTs -> Naltrexone is acceptable
      -> Renal impairment?
          -> Severe (CrCl <= 30) -> Do NOT use acamprosate
          -> Moderate (CrCl 30-50) -> Reduce acamprosate dose to 333 mg TID
          -> Consider naltrexone instead
      -> Concomitant opioid use or anticipated need?
          -> Yes -> Do NOT use naltrexone; consider acamprosate
      -> Poor oral medication adherence?
          -> Consider injectable naltrexone (380 mg IM every 4 weeks)
      -> Patient prefers abstinence-based aversive approach?
          -> Consider disulfiram (with supervised administration)
```

## Statement 14: Pregnancy and Breastfeeding (1C)

APA recommends (1C) that for pregnant or breastfeeding women with alcohol use disorder, pharmacological treatments **not be used** unless:

- Treating acute alcohol withdrawal with benzodiazepines
- A co-occurring disorder exists that warrants pharmacological treatment

- None of the FDA-approved AUD medications (naltrexone, acamprosate, disulfiram) have established safety in pregnancy.
- The primary intervention for pregnant women with AUD is psychosocial treatment and behavioral support.
- Brief interventions to reduce alcohol use during pregnancy have demonstrated efficacy.

## Limitations

- The COMBINE trial, the largest U.S. RCT of AUD pharmacotherapy, showed naltrexone efficacy but did not confirm acamprosate benefit in the U.S. population, creating uncertainty about its generalizability.
- Head-to-head comparisons between naltrexone and acamprosate are limited; the choice between these agents is often guided by clinical factors (hepatic vs. renal function, treatment goals) rather than comparative efficacy data.
- Disulfiram efficacy evidence relies heavily on supervised administration paradigms, limiting generalizability to real-world settings.
- Optimal treatment duration is not well established for any AUD medication; clinical practice generally recommends at least 3-12 months of pharmacotherapy.
