Benzodiazepines were first introduced to the United States in 1960 and became instantly popular because of their desirable safety profiles, particularly with regard to respiratory depression, which was much lower compared to their predecessors, especially barbiturates.1,2 Benzodiazepines promote binding of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) to the GABA-A receptor, increasing ionic currents through ligand-gated chloride channels, which decreases neuronal excitability of neurons and thus increases central nervous system inhibitory tone.3 In the 2 decades after their introduction, while their mechanism of action was being studied by researchers, many clinicians started observing dependence and abuse in patients using them.1
Anxiety disorders are the most prevalent mental illness in the United States, affecting up to 40 million adults.4 The lifetime prevalence of anxiety disorders among the general population in the US is about 30%.4 Historically, benzodiazepines were considered the mainstay of treatment for anxiety disorders.5 They also have a role in the treatment of many nonpsychiatric conditions. Currently 4% to 5% of the US population uses benzodiazepines.6 Use of benzodiazepines tends to increase with age, and women tend to be prescribed these medications twice as often as men.7 Tolerance to the effects of the medications develops if they are used over an extended period of time, resulting in dosage escalation and potential abuse.8 An estimated 2.3% to 18% of Americans have abused sedatives or tranquillizers for nonmedical purposes in their lifetime, and nearly 10% of these people meet the criteria for abuse or dependence.9 Emergency departments have seen a 139% increase in benzodiazepine-related visits since 2010.10 The total number of admissions into substance abuse treatment programs for benzodiazepines tripled from 1988 to 2008; however, during this same time period, the number of admissions to substance abuse treatment programs only increased by 11%.11
Several countries have developed guidelines that suggest short-term use of these medications with small doses;12 however, these are commonly ignored and benzodiazepines are prescribed for long-term use, particularly in the elderly and those on concessionary benefits.13 In addition, in most undeveloped countries and in many emerging countries as well, these medications are available over the counter without a prescription, leading to rampant overuse and abuse.14 Incidentally, most of the adverse effects of benzodiazepines are not the markedly visible ones that might cause premature removal of the drug from the market, such as hepatic or skin reactions or death.15
In this article, we explore the physiological and pharmacological effects of these medications, examine the problems that patients can encounter with their use, and suggest some solutions for clinicians.
Clinical Uses of Benzodiazepines
Benzodiazepines have anxiolytic, sedative-hypnotic, anticonvulsant, and muscle-relaxant activity16 and are used in both acute and chronic management of multiple conditions (Table 1). Anxiety disorders are common in the general populations, with separation anxiety disorder, phobias, social anxiety disorder, panic disorders, generalized anxiety disorder, and substance-induced anxiety disorders being the most common anxiety disorders included in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).17 Currently, benzodiazepines are recommended as second-line agents for anxiety disorders due to their long-term side effects, including abuse and dependence.18 Nonetheless, many clinicians still consider benzodiazepines as effective treatment options for acute and chronic episodes of anxiety disorders.19 A recent study documented that 60.2% of psychiatrists still use benzodiazepines either as combination or monotherapy in generalized anxiety disorder because of their rapid onset of action and efficacy.20 Benzodiazepines are also commonly used for the treatment of panic disorder, and lorazepam, an intermediate-acting benzodiazepine, is a widely used agent along with haloperidol for the management of acute agitation.21 Single-dose administration of a benzodiazepine is a preferred treatment for certain phobias such as fear of flying, and they are one of the most frequently prescribed medications for insomnia.22,23 They can also be used as a muscle relaxant, for treatment of acute psychosis with agitation, for alcohol withdrawal, and for sedation for office procedures. Diazepam, clonazepam, and lorazepam are used for the treatment of acute seizures and status epilepticus.24
Commonly Used Benzodiazepines
Side Effects of Benzodiazepines
Although benzodiazepines have a wide range of uses as outlined above, they are by no means easy to use. All benzodiazepines have a few common side effects such as fatigue, drowsiness, and lethargy. Higher doses commonly cause dizziness, coordination impairment, vertigo, blurred vision, slurred speech, euphoria, and mood changes. Hostile and erratic behavior can also occur in some circumstances.25
Regarding individual benzodiazepines (and in addition to the above), midazolam is a relatively safe sedative agent for use in emergency departments. Cough, hiccups, nausea, and vomiting are commonly reported adverse effects.26 Alprazolam use results in greater adverse reactions such as depression, enuresis, aggression, and disinhibition.27 Clonazepam, a long-acting benzodiazepine, is thought to be just as efficacious as the shorter-acting ones with slightly fewer side effects, although its very long half-life (30–40 hours) can result in accumulation and possible adverse effects, especially in the elderly.28
Benzodiazepine Abuse and Dependence
The prevalence of benzodiazepine use in the general population is 4% to 5% and increases with age.7 Women are twice as likely to be prescribed benzodiazepines as compared to men. Most people take benzodiazepines as prescribed; less than 2% misuse them.7 Those at greatest risk for abuse or dependence are those with a family history or personal history of substance use disorders. Abuse of benzodiazepines is likely to be higher in countries where they are easily obtainable and there are fewer controls (eg, parts of Asia and South America),14 but much of the literature about abuse relates to the US and European nations, where misuse often results from diverted prescriptions. Some experts divide abuse into two groups: deliberate/recreational abuse with the goal of getting high versus patients who unintentionally misuse benzodiazepines over time, leading to dose escalation and dependence.7
“Addiction” is defined as compulsive drug-seeking behavior(s) or an intense desire to take a drug despite negative consequences.17,29 According to the International Classification of Diseases, tenth edition (ICD-10),30 dependence is diagnosed if three or more of the following criteria are met in the previous 12 months: strong desire or compulsion to take the drug, difficulties in controlling drug use, withdrawal symptoms, tolerance, neglect of other interests, and persistent use of the drug despite negative consequences. The DSM-517 favors a more dimensional approach, specifying 11 criteria for substance use disorders that range from mild to severe with key elements being dose escalations, tolerance, and loss of control. Substance misuse generally presents as strong family or personal history of substance use, a chaotic life environment, frequent emergency department visits, “losing” medications, frequent mental illness relapses, psychiatric treatment resistance, signs of withdrawal, and family concern.31
Mechanism of Benzodiazepine Dependence
All benzodiazepines bind to specific sites on the GABA-A receptor, which increases affinity for GABA, an inhibitory neurotransmitter. With long-term benzodiazepine use, the efficiency of the GABA-A receptor decreases through tolerance. When benzodiazepines are abruptly stopped, this down-regulated state of inhibitory neurotransmission is unmasked.2
Differences in abuse potential within the benzodiazepine class relate to pharmokinetic differences. Lipophilicity is the chemical property responsible for how quickly the drug takes effect. Drugs with higher lipophilicity and shorter half-lives are at greater risk for abuse potential. Diazepam, alprazolam, and lorazepam have the highest abuse potential due to these properties, whereas oxazepam, clorazepate, and chlordiazepoxide have the lowest.7
Benzodiazepines cause a decrease in norepinephrine, serotonin, acetylcholine, and dopamine, which are neurotransmitters needed for normal mood, memory, muscle tone, emotional responses, and heart rate and blood pressure control. Tolerance develops to these effects in chronic benzodiazepine use. When benzodiazepines are abruptly stopped, neurotransmitter systems go into overdrive due to the lack of GABA-ergic inhibitory activity. Withdrawal symptoms then emerge and persist until the central nervous system reverses this adoption.32 Withdrawal symptoms typically mirror the drug's pharmacological effects. The sedative effects can turn into insomnia and nightmares, anxiolytic effects generate panic and anxiety, muscle relaxant effects turn into cramping or spasms, and anticonvulsant effects can morph into seizures.33
Withdrawal symptoms can be mild and transient or prolonged, and they can be divided into physical, psychological, and sensory symptoms. Rebound insomnia is common if using benzodiazepines for sleep disorders. The most common physical symptoms are muscle tension, spasms, pain, weakness, and generalized malaise. Common psychological withdrawal symptoms include anxiety and panic, restlessness, agitation, depression, mood lability, impaired concentration, depression, and sleep changes. Perceptual changes such as hyperacusis and photophobia may occur and seizures can happen, especially if discontinued abruptly. Severe withdrawal symptoms include paranoia, psychosis, and withdrawal delirium.34
Treatment of Benzodiazepine Use Disorder
Patients with benzodiazepine use disorder can be broadly divided into three categories.
Patients with Chronic Use of Benzodiazepines Without Withdrawal Symptoms
The main question that most outpatient psychiatrists will ask themselves when evaluating a new patient with chronic use of benzodiazepines is whether they should attempt to discontinue the benzodiazepine. The first step is to clarify the diagnosis and original indication for the use of these drugs and also to gather a history of previous trials of different treatment strategies, both pharmacological (eg, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, buspirone, hydroxyzine) and psychotherapeutic (eg, cognitive-behavioral therapy).35
Patient preference plays an important role in the negotiating process to enhance the therapeutic alliance. Patients will likely feel defensive and fearful of considering alternative medications or a taper. Psychoeducation can clarify misconceptions, short-term benefits, alternatives, long-term adverse effects, and potential dependence issues. Patient compliance and misuse of benzodiazepines can be checked through a state's prescribing monitoring program website.
Continuation of benzodiazepines is contingent upon a clear indication followed by close monitoring. It is also important to create a transition plan to alternative and safer evidence-based treatment modalities.36 Gradual discontinuation or complete avoidance of this class of medication is warranted when there is no convincing indication, when there are contraindications or other evidence of side effects including but not limited to oversedation, episodes of altered mental status, falls, and other proofs of misuse. Elderly patients, in particular, should be warned about the risk of adverse effects such as falls with subsequent fractures and possible memory impairment.
Benzodiazepines should be avoided completely in certain conditions like neurocognitive disorders, other substance use disorders, sleep apnea, chronic respiratory insufficiency, cerebellar ataxia, Parkinson's disease, closed-angle glaucoma, and myasthenia gravis.37
Many nonpharmacological interventions have a strong evidence base in conditions in which benzodiazepines are frequently used. For example, insomnia responds well to cognitive-behavioral therapy, sleep hygiene, relaxation techniques, and sleep restriction.38 Benzodiazepines can actually inhibit the therapeutic effects of psychotherapy by promoting avoidance, inhibiting cognitive processing, and inhibiting fear extinction upon exposure.16
Patients with Chronic Use of Benzodiazepines with Withdrawal Symptoms
Benzodiazepine withdrawal can potentially be life-threatening, so its accurate recognition and treatment is critical to improving clinical outcomes. As outlined above, withdrawal symptoms can include muscle tension, weakness, spasms, pain, sweating, shivering, anxiety, restlessness, agitation, mood swings, tremors, tachycardia, blurred vision, tinnitus, drowsiness, derealization, seizures, psychosis, and delirium.34 High-potency, short-acting benzodiazepines have a higher risk of abuse and dependence and usually cause earlier and more severe withdrawal symptoms. A gradual taper over 2 to 3 months is recommended to facilitate the process.19 The process is not easy, and there is a 50% risk of relapse after discontinuation.39 Elderly patients, those with brain injury, and those with comorbid substance use disorders are at higher risk of developing more severe withdrawal symptoms.35 The onset of withdrawal symptoms may be delayed up to 2 weeks with long-acting benzodiazepines (clonazepam, diazepam, chlordiazepoxide) or it may appear as early as 24 to 72 hours after discontinuation of shorter-acting benzodiazepines (eg, alprazolam). Long-acting benzodiazepines are the preferred treatment in managing withdrawal symptoms, and some experts recommend reducing the initial benzodiazepine dose by 50% every week or to reduce the daily dose by 10% to 25% every 2 weeks.40
Some benzodiazepines (lorazepam, oxazepam, temazepam) are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney, so they are preferred choices if hepatic impairment is present.
Patients with Acute Intoxication or Overdose of Benzodiazepines
Overdose of isolated benzodiazepines can cause slurred speech, ataxia, and altered mental status but generally does not cause more serious clinical complications unless combined with other substances (eg, alcohol).41 Regardless, the first step in management remains the same, which is to protect the patient's airway, breathing, and circulation. In most cases of isolated benzodiazepine overdose, clinical observation is sufficient with close monitoring and management of possible withdrawal symptoms. Flumazenil is a nonspecific competitive antagonist of the benzodiazepine/GABA receptor, but its administration can lead to withdrawal seizures, so its use remains controversial.42 Consultation with a medical toxicologist is highly recommended.42
Benzodiazepines have historically been widely used for a number of conditions. They remain useful tools in a clinician's armamentarium but abuse and dependence remain ongoing risks.
In psychiatry, their most common use has been for anxiety disorders where they are rapidly efficacious, but they have been increasingly supplanted by newer, safer alternatives with less risk of dependence.
If used, close monitoring is essential. Abuse and dependence can develop rapidly, especially in those already at risk (eg, people with a personal or family history of substance abuse). Red flags that can indicate abuse and/or dependence include frequent emergency department visits, “losing” medications, frequent mental illness relapses, psychiatric treatment resistance, signs of withdrawal, and family concern.
Treatment is usually multifaceted, and long-acting benzodiazepines are still a mainstay of detoxification. Withdrawal symptoms generally mirror the pharmacological effects of the drugs. Acute benzodiazepine overdoses or severe withdrawal symptoms may require inpatient detoxification followed by prolonged outpatient rehabilitation. Mild withdrawal can be managed on an outpatient basis but requires both pharmacological and psychotherapeutic treatment strategies as well as strict monitoring for compliance.
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Commonly Used Benzodiazepines
||Elimination Half-Life (h)
||Common Clinical Uses
||Anxiety, panic disorder
||Anxiety, alcohol withdrawal
||Anxiety, seizure, alcohol withdrawal
||Seizure, alcohol withdrawal