# Off-Label Medications and Medications Not Recommended -- APA 2018

## Statement 11: Topiramate or Gabapentin (2C)

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

- Have a goal of reducing alcohol consumption or achieving abstinence
- Prefer topiramate or gabapentin or are intolerant to or have not responded to naltrexone and acamprosate
- Have no contraindications to the use of these medications

These medications are **not FDA-approved** for the treatment of AUD. They are considered **second-line** agents, typically used after trials of naltrexone and acamprosate, though patient preference may lead to earlier use.

## Topiramate

### Mechanism of Action

Topiramate has multiple mechanisms relevant to AUD: antagonism of glutamate at AMPA/kainate receptors, facilitation of GABA-A receptor activity, and inhibition of dopamine release in the mesocorticolimbic pathway.

### Dosing

| Parameter | Detail |
|---|---|
| **Starting dose** | 25 mg/day (or 25 mg twice daily) |
| **Titration** | Increase by 25-50 mg/week |
| **Target dose** | 200-300 mg/day in divided doses |
| **Maximum dose** | 300 mg/day (based on AUD trials) |
| **Route** | Oral |
| **Frequency** | Twice daily |

- **Slow titration is essential** to minimize cognitive side effects and reduce dropout rates.
- In key RCTs (Johnson et al., JAMA 2007), topiramate was titrated to 300 mg/day over 8 weeks.

### Efficacy Data

- Multiple RCTs have demonstrated that topiramate reduces heavy drinking days, drinks per drinking day, and percentage of heavy drinking days compared to placebo.
- NNT approximately 8 for reduction in heavy drinking (Johnson et al., JAMA 2007).
- Topiramate was effective in patients who were **actively drinking** at treatment initiation (abstinence not required).

### Adverse Effects

- **Cognitive impairment** ("word-finding difficulty," reduced concentration) -- most common reason for discontinuation
- Paresthesias (tingling in extremities)
- Weight loss (may be advantageous in obese patients)
- Metabolic acidosis
- Nephrolithiasis (kidney stones)
- Taste disturbance
- Teratogenic: FDA Pregnancy Category D; effective contraception required in women of childbearing potential

### Contraindications

- Hypersensitivity to topiramate
- Pregnancy or planned pregnancy (teratogenic: associated with cleft lip/palate)
- Severe hepatic impairment (use with caution)
- History of nephrolithiasis (relative contraindication)
- Conditions where metabolic acidosis would be dangerous (use with caution)

## Gabapentin

### Mechanism of Action

Gabapentin binds to the alpha-2-delta subunit of voltage-gated calcium channels, modulating neurotransmitter release. It may address the hyperexcitable glutamatergic state associated with protracted alcohol withdrawal.

### Dosing

| Parameter | Detail |
|---|---|
| **Starting dose** | 300 mg on day 1 |
| **Titration** | Increase by 300 mg every 1-2 days |
| **Target dose** | 900-1,800 mg/day in divided doses |
| **Route** | Oral |
| **Frequency** | Three times daily |

- In key trials (Mason et al., JAMA Intern Med 2014), gabapentin 1,800 mg/day was more effective than 900 mg/day.
- Dose reduction required in renal impairment (gabapentin is renally excreted).

### Efficacy Data

- Mason et al. (2014) demonstrated that gabapentin 1,800 mg/day significantly increased the rate of total abstinence (NNT approximately 8) and no heavy drinking days compared to placebo.
- Gabapentin 900 mg/day showed intermediate efficacy.
- Gabapentin may be particularly beneficial in patients with co-occurring **insomnia, anxiety, or protracted withdrawal symptoms**, as it addresses these symptoms directly.

### Adverse Effects

- **Somnolence** and dizziness (most common)
- Fatigue
- Peripheral edema
- Ataxia at higher doses
- Potential for **misuse/diversion**, particularly in populations with polysubstance use disorder
- Respiratory depression risk when combined with opioids or other CNS depressants

### Contraindications

- Hypersensitivity to gabapentin
- Use with caution in patients with a history of substance use disorders involving sedatives/hypnotics (misuse potential)
- Dose adjustment required in renal impairment:

| CrCl (mL/min) | Recommended Maximum Daily Dose |
|---|---|
| >= 60 | 1,800 mg/day (or higher per clinical judgment) |
| 30-59 | 600-900 mg/day |
| 15-29 | 300-600 mg/day |
| < 15 | 100-300 mg/day |

## Medications NOT Recommended for AUD

### Statement 12: Antidepressants (1B)

APA recommends (1B) that antidepressant medications **not be used for the treatment of alcohol use disorder** unless there is evidence of a co-occurring disorder for which an antidepressant is an indicated treatment.

- SSRIs (e.g., sertraline, fluoxetine) have not demonstrated efficacy for reducing alcohol consumption in patients without co-occurring depression.
- If a patient has co-occurring major depressive disorder AND AUD, antidepressants should be used for the depression, with the understanding that they do not independently treat the AUD.
- Alcohol-induced depressive symptoms frequently improve with abstinence; reassessment of mood after 2-4 weeks of abstinence is recommended before initiating antidepressant therapy.

### Statement 13: Benzodiazepines (1C)

APA recommends (1C) that in individuals with alcohol use disorder, benzodiazepines **not be used** unless:

- Treating **acute alcohol withdrawal** (for which benzodiazepines remain the standard of care)
- A co-occurring disorder exists for which a benzodiazepine is an indicated treatment

- Benzodiazepines carry significant risks of cross-dependence, respiratory depression, and overdose in patients with AUD.
- Long-term benzodiazepine use is associated with worsened AUD outcomes.

## Off-Label Medication Selection Algorithm

```
Patient with moderate to severe AUD who has:
  - Failed or is intolerant to naltrexone AND acamprosate
  - OR prefers topiramate or gabapentin
      -> Assess co-occurring symptoms
          -> Prominent insomnia, anxiety, protracted withdrawal?
              -> Gabapentin may be preferred
              -> Start 300 mg/day, titrate to 900-1,800 mg/day
              -> Monitor for misuse in polysubstance use populations
          -> Obesity or metabolic syndrome co-occurring?
              -> Topiramate may be preferred (weight-loss effect)
              -> Start 25 mg/day, slow titrate over 8 weeks
              -> Monitor for cognitive side effects
          -> Renal impairment?
              -> Gabapentin: reduce dose per CrCl
              -> Topiramate: use with caution
          -> Pregnancy or planned pregnancy?
              -> Neither topiramate nor gabapentin should be used
              -> Topiramate is Category D (teratogenic)
```

## Limitations

- Topiramate and gabapentin are supported by fewer and smaller RCTs compared to naltrexone and acamprosate.
- The evidence rating (2C -- suggesting rather than recommending) reflects more uncertainty in the balance of benefits and harms.
- Optimal dosing for both agents in AUD remains under investigation; doses in clinical trials may differ from those used in clinical practice.
- Gabapentin's misuse potential is a growing concern, and several U.S. states have classified it as a controlled substance, which may affect prescribing practices.
- Neither topiramate nor gabapentin has been studied extensively in combination with FDA-approved AUD medications.
