Day # 75: Benzodiazepines

At this point in our current theme of anxiety disorders we are going to transition to a discussion of anxiolytic medications. We already outlined the treatment of anxiety disorders on day # 65, and during our depressive theme we covered SSRI's and SNRI's in depth which are first-line meds for anxiety disorders. Now we will take a few days to discuss anxiolytics. We will start today with benzodiazepines and later discuss buspirone, gabapentin/pregabalin, and hydroxyzine.

Today's content level: Intermediate

INTRODUCTION AND MECHANISM OF ACTION

•Benzodiazepines = BDZs. Examples include alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and more.

•Benzodiazepines are considered "anxiolytics" and "hypnotics" thus their primary indication is the treatment of anxiety disorders and sleep disorders. There are, however, many other uses and they have anti-convulsive, sedative, muscle relaxant, and amnestic properties.

The major mechanism of action of benzodiazepines include:

• Activation/potentiation of GABA receptors (via allosteric modulation).

• GABA receptors are the most common inhibitory neurotransmitter in the nervous system.

• All BDZs are lipid-soluble which allows them to cross the blood brain barrier.

Other Properties:

• Benzodiazepines are normally divided into groups based on their half-life.

• Frequent or long-term use poses risk of physical dependence, tolerance, and addiction (although some believe risk is over-estimated). There is also potential for abuse.

• The most addictive BDZs are highly lipophilic with a short onset of action.

• Potential benefits should be viewed in the context of the known risks associated with benzodiazepine use.

Metabolism:

• Benzodiazepines are metabolized by the liver via the cytochrome P450 system. Most are metabolized by CYP3A4.

• In chronic alcoholics or liver disease, use BDZs that have no active metabolites. Remember these. Hint: there are a LOT of them.

  • Lorazepam (Ativan)

  • Oxazepam (Serax)

  • Temazepam (Restoril)

INDICATIONS

FDA approved indications:

• Anxiety Disorders (GAD, Panic, SAD): Provide rapid symptomatic relief. According to Maudsley, "all guidelines and consensus statements recommend that this group of drugs should be used only to treat anxiety that is severe, disabling or subjecting the individual to extreme distress". Preferably for short-term use only (1-4 weeks) for the management of anxiety and panic while a long-term agent is initializing (such as a SSRI or SNRI). A small number of patients with very disabling anxiety may benefit from long-term treatment. PRNs can be utilized as rapid treatment of panic attacks although panic symptoms return quickly if the drug is withdrawn. Many providers prefer not to prescribe PRNs since this can limit the psychotherapeutic focus on not avoiding the anxious stimulus. Chronic use must be monitored closely and generally a benzodiazepine with a long half-life and gradual onset of action (such as Clonazepam) are less likely to be abused. 1

• Sleep disorders: FDA approved for short-term management of insomnia (temazepam [Restoril], triazolam [Halcion], estazolam), however non-pharmacologic treatments (CBT for insomnia) or non-benzodiazepine hypnotics (eszopiclone [Lunesta], zolpidem [Ambien]) are preferred. BDZs inhibit REM sleep and there is a rebound increase when discontinued. The clinical significance is debated. Also used off-label in sleep walking disorder and REM sleep behavior disorders. 2

• Seizures and status epilepticus: Benzodiazepines are some of the most effective drugs in the treatment of acute seizures and status epilepticus. The BDZs most commonly used to treat status epilepticus are diazepam (Valium), lorazepam (Ativan), and midazolam (Versed). 3

• Anesthesia induction: Primarily used for premedication and sedation and also for induction of general anesthesia in high doses. They do not have analgesic properties.

Other off-label indications:

• Alcohol withdrawal: Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. They can be prescribed as a scheduled taper, PRN during a CIWA protocol, or a combination of both. Commonly used BDZs for this indication are diazepam (Valium), lorazepam (Ativan), and chlordiazepoxide (Librium). 4

• Acute mania / psychosis: BDZs can be useful during acute psychosis or mania particularly when associated with agitation or violent behavior. It is typically used in combination with antipsychotics and/or mood stabilizers for this outcome. 5 There is no evidence to support long-term benzodiazepine augmentation to antipsychotics in schizophrenia and should be reserved for the short-term management of acutely agitated patients. 6

• Agitation: Often used to treat agitated patients in the hospital that do not respond to verbal de-escalation and other non-pharmacological techniques. They are either used alone or in combination with antipsychotics. Midazolam (Versed) and lorazepam (Ativan) are considered drugs of choice for management of agitation because of their rapid onset of action, short half-life, and ability to give IM or IV.

• Catatonia: Gold standard treatment for akinetic and excited catatonia.

• Akathisia (short-term management): Akathisia is the most common form of EPS. Benzodiazepines as well as beta blockers and benztropine are effective for the treatment of akathisia.

• Muscle spasms: Valium (Diazepam) is sometimes used as a second line option for muscle spasms.

• Restless Leg Syndrome: Can be useful in mild intermittent cases of RLS. Most studied BDZ is clonazepam (Klonopin).

SIDE EFFECTS

Common side effects include:

• Sedation / Fatigue

• Ataxia / Dizziness / Falls

• Slurred Speech

• Confusion / Forgetfulness / Impaired cognition

• Worsened depression (mixed data)

• Rare hypotension

• Rare paradoxical hyper-excitability or nervousness

Serious side effects include:

• Respiratory depression: Rare in oral therapy but is possible when IV route is used. Mostly in overdose particularly when co-ingested with other CNS depressants (ex: alcohol, opioids). Also increased risk in patients with COPD and sleep apnea.

• Tolerance / Dependence / Withdrawals / Risk of Abuse: As mentioned above, frequent or long-term use poses risk of tolerance, dependence, and risk of abuse particularly those with shorter half-lives and highly lipophilic. Withdrawal is similar to alcohol withdrawal and can be fatal if not treated (anxiety, tremor, hallucinations, seizures, potential death).

• Falls / Fractures: 50% increased risk of hip fractures in the elderly. New prescriptions and high doses have the highest risk.

• Use in Pregnancy: Use in the third trimester can result in withdrawal symptoms, decreased APGARS, and poor feeding in the newborn.

• Dementia: Conflicting evidence regarding increased risk of development of dementia. 6

• Overdose: Can be lethal in overdose (cardiopulmonary depression) particularly in combination with other CNS depressants (alcohol, opioids, z-drugs, and clozapine). Flumazenil, a benzodiazepine antagonist, can be used to reverse the effects of BDZ intoxication, however caution must be exercised as it can precipitate withdrawal and seizures. BDZs are relatively safer in overdose than barbiturates.

SPECIFIC DRUG CHARACTERISTICS

•Benzodiazepines are normally divided into groups based on their half-life. Choice of BDZ is based on time to onset of action, duration of action, and method of metabolism.

Long-Acting (Half-life > 20 hours)

• Diazepam (Valium)

  • Rapid onset with long half-life 20-80 hours.

  • Common uses: alcohol detox and muscle spasms.

  • Less commonly prescribed for anxiety due to euphoria.

• Clonazepam (Klonopin)

  • Half-life 18-50 hours.

  • Common uses: anxiety disorders (GAD and panic disorder) and REM sleep behaviors.

• Chlordiazepoxide (Librium)

  • Half-life 5-30 hours.

  • Common uses: alcohol detox. Easy dosing schedule.

Intermediate Acting (Half-life: 6–20 Hours)

• Alprazolam (Xanax)

  • Rapid onset with half-life 6-27 hours.

  • Common uses: anxiety disorders (GAD and panic disorder).

  • High levels of euphoria / potential for abuse.

  • In my experience it is often prescribed by PCPs but avoided by psychiatrists.

• Lorazepam (Ativan)

  • Relatively quick onset with half-life 10-20 hours.

  • Common uses: alcohol detox, panic attacks, agitation, and catatonia.

  • Safe in chronic alcoholics and liver disease.

• Oxazepam (Serax)

  • Half-life 5-15 hours.

  • Common uses: alcohol detox.

  • Safe in chronic alcoholics and liver disease.

• Temazepam (Restoril)

  • Half-life 7-11 hours.

  • Common uses: insomnia (although less commonly used now since the z-drugs were developed)

  • Safe in chronic alcoholics and liver disease.

Short Acting (Half-life: <6 Hours)

• Midazolam (Versed)

  • Half-life 1-6 hours.

  • Common uses: acute agitation, also used in medical and surgical settings such as anesthesia induction.

• Triazolam (Halcion)

  • Half-life 2-5 hours.

  • Common uses: insomnia (although less commonly used now since the z-drugs were developed)

  • Elevated risk of anterograde amnesia and sleep-related activities such as sleep-walking, eating, driving, etc.

CONCLUSION

Great work today. In our next post we will discuss buspirone.

Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.

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