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What Are Benzodiazepines?

Benzodiazepines are a class of medications that work in the central nervous system and are used for a variety of medical conditions. As a class, benzodiazepines are similar in how they work in the brain but have different potencies, durations of actions, and receptor site affinities. Because of this, some benzodiazepines work better than others in the treatment of particular conditions.

Benzodiazepine Uses:

• Sedative-hypnotics for sleep
• Adjuncts to anesthesia to induce relaxation and amnesia (procedural memory loss)
• To reduce anxiety (anxiolytic)
• Panic disorders
• To treat or prevent seizures
• For alcohol withdrawal
• Muscle relaxant

Benzodiazepines are a large drug class and have a long history of development, starting with the first FDA-approvals in the 1960s, chloridiazepoxide (Librium) and diazepam (Valium). There are many options available within the class, and most benzodiazepines are now available generically, making them very affordable.

All benzodiazepines are listed as DEA schedule IV controlled substances. As controlled substances, all benzodiazepines have the potential for abuse, addiction and diversion.

In the past, benzodiazepines, especially when used as a sedative-hypnotic for sleep, were touted as safer alternatives to the older barbiturates, which could lead to fatal overdose, particularly when combined with alcohol. Traditional benzodiazepines taken alone are rarely associated with lethal overdoses, but when combined with other sedatives or alcohol, the risk greatly increases. Flumazenil is a benzodiazepine antagonist antidote that can be given intravenously in the emergency setting to reverse the effects of a benzodiazepine overdose, although some controversy exists over its use.

Table 1 lists U.S. generic and brand name benzodiazepines, their common uses and duration of action. Many of the brand name products have been discontinued by their manufacturers; however, equivalent, lower-cost generics are available for these brands.

Some benzodiazepines (diazepam, chlordiazepoxide) have active metabolites that remain in the system (long acting), and this can be problematic for patients – especially older patients. Elderly patients may have liver impairment and trouble eliminating the drugs from their system. Side effects, such as dizziness, confusion or unsteadiness may persist in the elderly who are prescribed long-acting benzodiazepines. On the other hand, short-acting benzodiazepines are often preferred for insomnia because they theoretically produce less next-day drowsiness, although many patients still experience these effects.

Table 1: Common Benzodiazepines Available in the U.S.

*The half-life is the amount of time it takes for half of the drug to be eliminated from the body. The shorter the half-life, the quicker the drug is eliminated.

How Do Benzodiazepines Work?

GABA is the main inhibitory neurotransmitter in the brain. There are three types of GABA (gamma-aminobutyric) receptors in the brain: GABA-A, GABA-B, and GABA-C. Benzodiazepines work in the central nervous system, selectively occupying certain protein areas in the brain called GABA-A receptors. Benzodiazepines enhance responses to the inhibitory neurotransmitter GABA by opening GABA-activated chloride channels and allowing chloride ions to enter the neuron. This action allows the neuron to become negatively charged and resistant to excitation, which leads to the various anti-anxiety, sedative, or anti-seizure activity seen with these drugs. The a2 subunit of GABA-A appears to be responsible for the anti-anxiety effects of benzodiazepines; other subunits modulate the amnesic and sedative properties of benzodiazepines. Benzodiazepines that target specific subunits of the GABA receptors have more selective pharmacologic actions.

Common Uses for Benzodiazepines

Alcohol Withdrawal

Alcohol withdrawal is diagnosed in a patient with a history of heavy and prolonged alcohol use and a sudden reduction or complete abstinence from alcohol. Alcohol withdrawal produces changes in the body, such as:

• Shakes,
• Sleeping difficulties
• Confusion
• Anxiety
• Hallucination
• Seizures
• Delirium tremens

The use of medications such as benzodiazepines is a first-line treatment for alcohol withdrawal. Benzodiazepines reduce symptoms and may be life-saving for the patient. Commonly used medicines in this group include chlordiazepoxide (Librium), diazepam (Valium), and lorazepam (Ativan). Lorazepam may be preferred in patients with liver impairment. Chlordiazepoxide, diazepam, and lorazepam can be given orally, intravenously, or intramuscularly. Oxazepam (Serax) may be useful but is only available orally.

A 2010 Cochrane Review (Amato, et al) from sixty-four randomised controlled trials compared benzodiazepine use versus other drugs for alcohol withdrawal. In the review, there was a trend in favor of benzodiazepines for seizure and delirium control, severe life-threatening side effects, dropouts, dropouts due to side effects and patient’s global assessment score. However, when different benzodiazepines were compared among themselves for effectiveness, results never reached statistical significance; however, chlordiazepoxide showed a trend toward better performance. The authors concluded that benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, especially seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with other drugs. However, the studies were varied with different interventions and outcomes, and the authors could not reach definite conclusions about the overall safety or efficacy of benzodiazepines.

Anxiety

Anxiety and worry is a common problem in adults; however, when chronic, unwarranted worry lasts for a period of six months or longer and interferes with normal daily activities, this may be diagnosed as Generalized Anxiety Disorder (GAD). GAD is the most frequent anxiety disorder, affecting about 5% of adults in the primary care setting. The occurrence of three out of six symptoms listed below constitutes a diagnosis of GAD.

• Excessive anxiety for at least six months not due to another mental condition, medication, or substance abuse
• Sleep disturbances, insomnia
• Fatigue
• Restlessness
• Difficulty concentrating
• Irritability
• Muscle tension

Drug treatment will depend upon the level of anxiety, patient characteristics such as age and organ function, and patient preference. For patients who do not want to use medications, cognitive behavioral therapy and relaxation therapy have been shown to be effective. Antidepressants (SSRIs/SNRIs) are considered first-line therapy for most patients, and benzodiazepines may play an adjunctive role in the treatment of GAD to address acute symptoms while the antidepressant takes effect. Short-term use of benzodiazepines(2-6 weeks) is recommended.

Common benzodiazepines used for GAD include alprazolam, diazepam, and lorazepam. Benzodiazepines should be used with extreme caution in the elderly due to the risk for excessive sedation, confusion, and risk for falls and fractures. Mirtazapine and buspirone are also effective in GAD for patients who do not respond to at least two trials of SSRIs or SNRIs. Long-term use of benzodiazepines for GAD should be avoided, when possible.

Insomnia

The benzodiazepine hypnotics shorten the time it takes to fall asleep and prolong the sleeping period. The main differences exist in how long they might remain in the body, possibly leading to prolonged side effects. For example, triazolam has a much shorter duration than diazepam, allowing quicker clearance of the drug and theoretically less side effects. On the other hand, diazepam can remain in the system for days, and especially in the elderly, this can boost the risk for long-term side effects.

Benzodiazepines should be used for a short period of time (usually 2-4 weeks) for insomnia. In general, patients should reassess their sleep habits – avoiding caffeine late in the day, limit electronics (TV, computer, tablets) in the bedroom, and avoiding alcohol late in the evening. Exercise early in the can often help to promote a more restful sleep.

The benzodiazepines that were initially FDA-approved for insomnia, such as temazepam (Restoril) or triazolam (Halcion), are not used as frequently today due to the availability of the newer nonbenzodiazepine drugs, such as eszopiclone (Lunesta), zolpidem (Ambien), or zaleplon (Sonata). All of the nonbenzodiazepine agents are approved only for treatment of insomnia.

Muscle Relaxant

The skeletal muscle relaxant class, which includes agents such as baclofen, carisoprodol, methocarbamol, metaxalone, and cyclobenzaprine, are typically used first-line when a muscle relaxing therapeutic effect is needed. Benzodiazepines such as diazepam may be used short-term as muscle relaxants reducing the tone of skeletal muscle. These are generally used to relieve painful skeletal muscle spasms.

Panic Disorders

Panic disorder is a specific type of anxiety disorder. A person with panic disorder has panic attacks which are repeated episodes of intense fear which may be expected or unexpected. These symptoms may be accompanied by physical symptoms that are similar to the body’s normal response to danger – the fight or flight phenomenon. Panic attacks may accompany other mood, anxiety or substance abuse conditions. The symptoms that a person may experience include:

• Rapid heart rate
• Trembling or tingling sensation
• Flushing, redness and sweating
• Shortness of breath
• Fear and heightened awareness of surroundings, even if no danger is present
• Worry about death or losing control
• Avoidance of crowds or other public spaces due to fear of impending attack (agoraphobia)

Panic disorder can be a prolonged, chronic disorder, but it is very treatable with medications that lessen symptoms. Behavioral therapy and treatment with the antidepressants such as selective serotonin-reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or behavioral therapy are first-line treatments. The older tricyclic antidepressants, such as nortriptyline (Aventyl, Pamelor) and imipramine (Tofranil) are effective, too, but may be hindered by side effects. In patients without comorbid conditions such as depression benzodiazepines may be used cautiously for a short period.

Benzodiazepines may be used at the beginning of therapy to lessen symptoms while the antidepressants take effect, which may take 4 to 6 weeks. Benzodiazepines such as clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium) and alprazolam (Xanax) are useful for panic attacks. They are safe when used as directed and often bring quick relief from panic symptoms. When discontinued, benzodiazepines should be slowly tapered to help avoid withdrawal symptoms like rebound insomnia and anxiety.

Conscious Sedation

Conscious sedation is the use of a combination of medications to help the patient relax (a sedative) and to block pain (an anesthetic) during a medical or dental procedure. A combination of a benzodiazepine and an opiate analgesic for pain relief is typically used. This method of sedation is often used for patients receiving an outpatient surgery or procedure that allows the patient to return home the same day, for example, endoscopy or colonoscopy procedures, wisdom tooth extractions, biopsies, and uncomplicated surgical procedures lasting less than one hour.

The benzodiazepines most commonly used for conscious sedation are classified by their length of action: diazepam is considered the longest acting, lorazepam is the intermediate acting and midazolam is short acting. Midazolam is frequently used for procedures expected to last less than one hour, and is often combined with the opiate fentanyl for pain control.

The patient may remain awake but sedated, and usually there is no recollection of the procedure. In conscious sedation, most patients can respond to verbal cues or tactile commands. Conscious sedation allows the patient to recover more quickly from anesthesia, but they will need someone to drive them home and are usually drowsy until the next day. There is normally no need to aid breathing in conscious sedation; however, a deeper level of sedation may rarely occur, therefore respiratory and resuscitative equipment should be available to healthcare providers.

Contraindications to conscious sedation include:

• Pregnancy
• Known allergy to any of the medication
• Alcohol intoxication or other substance abuse
• CNS depression
• Some instances of glaucoma

Seizures

Benzodiazepines are often used in the treatment of seizures; examples include:

• Clobazam
• Clonazepam
• Clorazepate
• Diazepam
• Lorazepam
• Midazolam

For most types of acute or prolonged seizures or status epilepticus, an intravenous (IV) or rectal benzodiazepine would be the treatment of first choice. Status epilepticus is considered a medical emergency in which there is either more than 30 minutes of continuous seizure activity; or there are two or more sequential seizures without recovery of full consciousness between two seizures. Intravenous lorazepam is considered to be the first treatment of choice by many clinicians; diazepam is available as a rectal gel for patients without access to an IV line.

Buccolam is a specific form of midazolam available in the U.K. It is available as an ‘oromucosal solution’ (a solution given in the side of the mouth, into the space between the gum and the cheek) in prefilled syringes. Buccolam is used for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from three months to less than 18 years). Buccolam is not available in the U.S.

Clonazepam is the benzodiazepine most frequently used for long-term control and prevention of chronic seizure disorders; however, in general benzodiazepines are not usually the first choice for seizure prevention. Benzodiazepines are not appropriate for the long-term control of epilepsy because of the development of tolerance in a high proportion of patients. More traditional types of seizure treatments (for example: carbamazepine, oxcarbazepine, levetiracetam, phenytoin, valproic acid, topiramate, lamotrigine) might be used first line, dependent upon patient characteristics and specific epilepsy diagnosis.

Lennox-Gastaut syndrome is a severe form of epilepsy that usually begins in early childhood. This form of epilepsy may involve seizures of multiple types, mental impairment, and a particular brain wave pattern. Clobazam is used as an additional (adjunct) benzodiazepine anticonvulsive treatment with other seizures medications in the treatment of Lennox-Gastaut syndrome.

Adverse Effects of Benzodiazepines

Unusual sleep behaviors and anterograde amnesia may occur with traditional benzodiazepines; this effect is especially a risk with triazolam use. Next day drowsiness and “hangover effect” is a concern with benzodiazepines that have long duration, for example, with diazepam or flurazepam. The sedative side effects can carry into the next day and impair driving and other daily activities; this is a particularly concerning risk in the elderly. More recent research is focusing on the possible adverse effects on cognition (thinking and reasoning ability) in patients using benzodiazepines for long periods of time. In some patients, severe allergies like anaphylaxis and angioedema have been reported with benzodiazepines. There are many other side effects of benzodiazepines; check with your physician or pharmacist for specific questions.

Overall, benzodiazepines should be used short-term as they can lead to tolerance, dependence (addiction) and abuse. Potent benzodiazepines with shorter elimination half-lives (triazolam, alprazolam, lorazepam) may be the most prone to causing problems with tolerance and dependence. Withdrawal reactions can also occur if the drug is stopped suddenly, especially those that are shorter-acting. Sudden discontinuation can also lead to rebound insomnia, making sleep difficult, and perpetuating continued use and higher doses of benzodiazepines. Discontinuation of a benzodiazepine should be done gradually under a doctor’s direction.

Intravenous (IV) benzodiazepines can be associated with cardiac and/or respiratory arrest if they are given too rapidly. Other reactions due to IV administration may include:

• hypotension
• cardiac arrhythmias
• slow heart rate
• apnea
• respiratory depression
• nausea/vomiting
• blurred vision or double vision
• skin rash
• injection site reactions

In the elderly, benzodiazepines should be avoided. The 2012 Beers Criteria, an expert opinion-developed guideline addressing safe drug use in the elderly, specific states that benzodiazepine use should be avoided in the elderly. Older adults have increased sensitivity and lowered metabolism of this class. If there is a documented need, low doses and drugs with shorter durations (half-lives) will help to minimize side effects like dizziness, weakness, and falls that may lead to hip fractures. Under the care of a clinician, there may be appropriate uses for benzodiazepines in the elderly, such as for seizure disorders, certain sleep disorders, benzodiazepine or alcohol withdrawal, severe GAD, procedural anesthesia, and end-of-life care.

Drug and Herbal Interactions with Benzodiazepines

Important: Many drug interactions can occur with benzodiazepines; therefore, a drug interaction screen completed by a healthcare provider is an important step each time a new drug is added or discontinued in any treatment regimen.

Traditional benzodiazepines can be associated with overdoses and fatal consequences when combined with alcohol, other sedatives, or illicit drugs. While it is rare that an overdose of benzodiazepines by itself would be fatal, when combined with other drugs that depress the central nervous system, the risk greatly increases. Examples of other drugs that may be additive to the central nervous system depression if combined with benzodiazepine include:

• Phenothiazines
• Opiates
• Barbiturates
• MAO inhibitors
• Antidepressants
• Alcohol
• Illicit Drugs

Like the nonbenzodiazepines, many traditional benzodiazepines are broken down in the liver and when combined with drugs that block this action, blood levels can rise. Lorazepam, oxazepam and temazepam are less likely to have this risk. Rifampin, which can boost metabolism, may reduce the effectiveness of benzodiazepines, and the proton pump inhibitors omeprazole and esomeprazole can elevate diazepam levels. Patients should not stop using any medications, including benzodiazepines, without first talking to their doctor. Abrupt discontinuation of benzodiazepines may lead to severe withdrawal symptoms.

Herbal supplements and grapefruit can have significant interactions with certain benzodiazepines. Examples of some of the more common interactions include:

• Kava: Combined use of kava and benzodiazepines is not recommended. A case report suggests that kava may increase the central nervous system adverse effects of benzodiazepines. In the report, a 54-year-old man treated with alprazolam became semicomatose with lethargy and disorientation following self-medication with kava for 3 days. The exact mechanism of interaction is unknown, but an additive or synergistic CNS effect is suspected. Patients on benzodiazepines should be advised to consult their caregiver before using any alternative medicines.
• St. John’s Wort: Combined use of St. John’s wort with benzodiazepines may increase side effects such as dizziness, drowsiness, impaired thinking and difficulty concentrating. You should avoid or limit the use of alcohol while being treated with these medications. Avoid driving or operating hazardous machinery until you know how the medications affect you. It is important to tell your doctor about all other medications you use, including vitamins and herbs.
• Grapefruit/grapefruit juice: Grapefruit and grapefruit juice may interact with ertain benzodiazepines such as midazolam, triazolam, and alprazolam. Blood levels of these drugs may be increased if taken after drinking grapefruit juice and lead to potentially dangerous side effects. The proposed mechanism is CYP450 3A4 enzyme inhibition. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor. Orange juice does not appear to interact with benzodiazepines.

Many benzodiazepines are broken down in the liver and may interact with drugs that also have action in the liver.

• 3A4 inhibitors/CYP2C19 inhibitors: Some benzodiazepines such as alprazolam, chlordiazepoxide, clonazepam, and diazepam are full or partial CYP3A4 or CYP2C19 substrates, meaning they are metabolized (broken down) to some degree by one or both of these liver enzymes. If benzodiazepines that are CYP3A4 or CYP2C19 substrates are used with another drug that inhibits these enzymes, drug levels of the benzodiazepine may rise due to decreased metabolism and excretion. Either these types of drugs should be avoided with certain benzodiazepines or the benzodiazepine should be given in smaller doses; check with your doctor or pharmacist.

Benzodiazepine Use in Pregnancy and Breastfeeding

Pregnancy

In general, benzodiazepines should NOT be used in pregnancy.

Benzodiazepines are in FDA Pregnancy Category D, meaning there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Under the direction of a physician, certain benzodiazepines may be given in very serious and life-threatening situations like status epilepticus.

An increased risk of congenital malformations in humans has been suggested with use of some benzodiazepines. Withdrawal syndrome has been described in neonates whose mothers took benzodiazepines during pregnancy. Withdrawal symptoms such as intrauterine growth retardation, tremors, irritability, hypertonicity, diarrhea/vomiting, and vigorous sucking have been described. Floppy infant syndrome, which presents as hypotonia, lethargy, and sucking difficulties, has also been reported with the use of certain benzodiazepines, such as diazepam or lorazepam.

Breast Feeding

Women who are breastfeeding their infant should not use benzodiazepines unless directed to do so by their physician. Benzodiazepines may accumulate in breast milk and in breastfed infants. Some benzodiazepines may be appropriate therapy in women who are breastfeeding, but only under the direction of a physician. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines. Infants of lactating mothers should be observed for pharmacological effects (including sedation and irritability). Patients should not stop using any medications without first talking to their doctor.

Flumazenil Use for Benzodiazepine Reversal

Flumazenil (Romazicon), is indicated for the reversal of the sedative benzodiazepine effect and for treatment in a benzodiazepine overdose. Flumazenil blocks the central effect of benzodiazepines by competitive interaction at the benzodiazepine receptor site. A patient experiencing a benzodiazepine overdose may have the following signs and symptoms:

• Dizziness
• Inability to talk or respond
• Confusion
• Drowsiness
• Blurred vision or nystagmus
• Agitation
• Weakness
• Low blood pressure
• Respiratory depression
• Hallucinations
• Coma

The use of flumazenil in benzodiazepine overdose is controversial and the risks may outweigh any possible benefit. Flumazenil may be effective in reversing the sedation that occurs in a benzodiazepine overdose, but its effects on reversal of depressed breathing is less predictable. In addition, but due to its short half-life, sedation and respiratory depression may recur. The patient should be observed by a healthcare provider with resuscitative equipment for recurrence of sedation or respiratory depression for at least 2 hours after flumazenil administration or until the patient is stable.

In addition, in patients who are tolerant or dependent to the effects of benzodiazepines, the use of flumazenil may precipitate severe withdrawal symptoms and seizures; therefore, its use is contraindicated in these patients.

Benzodiazepine Withdrawal

Physical dependence on benzodiazepines, can occur after prolonged use of therapeutic doses, or even after a short treatment period in some patients. In general, benzodiazepines should be discontinued slowly to minimize symptoms such as:

• Sleep disturbances and rebound insomnia
• Restlessness
• Irritability
• Elevated anxiety
• Weakness
• Blurred vision
• Panic attacks
• Tremors
• Sweating/flushing
• Nausea/vomiting
• Headache
• Seizures
• Psychosis
• Hallucinations

Shorter-acting drugs produce a brief and more intense withdrawal reaction that usually begins within 24 hours of discontinuation. Longer-acting benzodiazepines have a slower development of withdrawal symptoms that typically begin several days after discontinuation, but peak at about 7 days.

The length of time required to complete a benzodiazepine withdrawal depends upon individual patient characteristics, type of benzodiazepine, ability to handle stress involved with withdrawal, and original reason for benzodiazepine use. Benzodiazepine withdrawal periods generally range from 4 weeks to 6 months, but can exceed a year in some circumstances.

Rapid withdrawal can lead to a syndrome of severe withdrawal symptoms in many patients. A taper of the benzodiazepine may be accomplished by reducing the dose to no more than one quarter of the daily dose per week, with a minimum taper time of 4 weeks. Withdrawal can also be managed by transferring the patient to an equivalent dose of diazepam or chlordiazepoxide, as these benzodiazepines have long half-lives and long-acting active metabolites, allowing for a smoother withdrawal process. At all times, benzodiazepines should be discontinued under the care of a physician.

Costs of Benzodiazepines

Many oral benzodiazepines are available in a generic form which can lead to cost-savings for patients. In general, benzodiazepines are usually used for short-term (2-4 weeks) of treatment, which will also cut down on expenses. The following oral benzodiazepines are available in generic formulations in the U.S., others may be available.

• Alprazolam
• Chlordiazepoxide
• Clonazepam
• Clorazepate
• Diazepam
• Estazolam
• Flurazepam
• Lorazepam
• Oxazepam
• Temazepam
• Triazolam

If cost is a concern for any medication treatments, be sure to speak to your physician when prescriptions are being written and discuss options with your pharmacist, as well. You may be able to save money on certain medications by splitting your tablets in half. Remember that drug prices are subject to change at any time and may differ among pharmacies. Always check with your local pharmacy for exact pricing.