If It Doesn’t Work

• Consider switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy, especially cognitive behavioral psychotherapy

• Consider presence of concomitant substance abuse

• Consider presence of chlordiazepoxide abuse

• Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

• Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

• Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

• Not generally rational to combine with other benzodiazepines

• Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

• In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

CHLORDIAZEPOXIDE: SIDE EFFECTS

How Drug Causes Side Effects

• Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

• Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

• Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects

✽ Sedation, fatigue, depression

✽ Dizziness, ataxia, slurred speech, weakness

✽ Forgetfulness, confusion

✽ Hyper-excitability, nervousness

✽ Pain at injection site

• Rare hallucinations, mania

• Rare hypotension

• Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

• Reported but not expected

Sedation

• Many experience and/or can be significant in amount

• Especially at initiation of treatment or when dose increases

• Tolerance often develops over time

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

• Take largest dose at bedtime to avoid sedative effects during the day

• Switch to another agent

• Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

CHLORDIAZEPOXIDE: DOSING AND USE

Usual Dosage Range

• Oral: mild to moderate anxiety: 15–40 mg/day in 3–4 doses

• Oral: severe anxiety: 60–100 mg/day in 3–4 doses

Dosage Forms

• Capsule 5 mg, 10 mg, 25 mg

• Injectable 100 mg/5 mL

How to Dose

• Injectable: acute/severe anxiety: initial 50–100 mg; 25–50 mg 3–4 times/day if necessary

• Injectable: alcohol withdrawal: initial 50–100 mg; repeat after 2 hours if necessary

• Injectable: preoperative: 50–100 mg 1 hour before surgery

• Patients who receive injectable chlordiazepoxide should be observed for up to 3 hours

Dosing Tips

✽ One of the few benzodiazepines available in an injectable formulation

• Chlordiazepoxide injection is intended for acute use; patients who require longer treatment should be switched to the oral formulation

• Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

• Assess need for continued treatment regularly

• Risk of dependence may increase with dose and duration of treatment

• For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

• Can also use an as-needed occasional “top up” dose for interdose anxiety

• Because anxiety disorders can require higher doses, the risk of dependence may be greater in these patients

• Some severely ill patients may require doses higher than the generally recommended maximum dose

• Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

Overdose

• Fatalities can occur; hypotension, tiredness, ataxia, confusion, coma

Long-Term Use

• Evidence of efficacy for up to 16 weeks

• Risk of dependence, particularly for treatment periods longer than 12 weeks, and especially in patients with past or current polysubstance abuse

Habit Forming

• Chlordiazepoxide is a Schedule IV drug

• Patients may develop dependence and/or tolerance with long-term use

How to Stop

• Patients with history of seizure may seize upon withdrawal, especially if withdrawal is abrupt

• Taper by 10 mg every 3 days to reduce chances of withdrawal effects

• For difficult to taper patients, consider reducing dose much more slowly after reaching 20 mg/day, perhaps by as little as 5 mg per week or less

• For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL while drinking the rest; 3–7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

• Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

• Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge