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According to the Cleveland Clinic, "Benzodiazepines tell your brain to release a neurotransmitter, gamma-aminobutyric acid (GABA). This neurotransmitter has a specific job: It makes your nervous system less active." This is what would cause the "high."

Benzodiazepines: What They Are, Uses, Side Effects & Risks (clevelandclinic.org)

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What are benzodiazepines?

Benzodiazepines are medications that make your nervous system less active. The decrease in nervous system activity makes these medications helpful for a variety of symptoms and conditions.

Many countries, including the U.S., classify benzodiazepines (sometimes known by the slang term "benzos") as controlled substances. That means you need a prescription to get them. It's illegal to have or obtain them (depending on the laws where you are) if you don't have a prescription.

IMPORTANT: Benzodiazepines are controlled because they can have dangerous effects, especially when misused. They can also be habit-forming. Because of these factors, healthcare providers use benzodiazepines cautiously. If your nervous system's activity drops too low, it can have dangerous or even deadly effects.

How do benzodiazepines work?

Your nervous system uses chemical and electrical signals to send and relay messages throughout your body. The chemical signals, known as neurotransmitters, can attach to cells with the right receptors. Neurotransmitters and receptors work much like your car keys. Neurotransmitters (your car key) can only fit into the right receptor (your car ignition). If it fits, the neurotransmitter can activate a process within the cell (starting your car).

Benzodiazepines tell your brain to release a neurotransmitter, gamma-aminobutyric acid (GABA). This neurotransmitter has a specific job: It makes your nervous system less active. The slowed activity can have the following effects:

Amnestic: This word comes from a Greek word that means "forgetfulness." Benzodiazepines temporarily block the formation of new memories (known as anterograde amnesia).

Anxiolytic: This term is a combination of two Greek root words, "anxio" for "anxiety" and "lytic," meaning "to loosen." While active, medications with this effect "loosen'' anxiety's hold on you.

Hypnotic: While many people associate "hypnotic'' with the practice of hypnosis, this word actually comes from the name Hypnos, the Greek god of sleep. Just like their namesake, hypnotic medications make you sleepy.

Sedative: This term comes from a Latin word that means "to settle." In this context, benzodiazepines help your nervous system "settle down" and have a quieting effect.

Other ways to classify benzodiazepines

There are two main ways that experts classify benzodiazepines:

Strength: Some benzodiazepines are stronger than others (though potency can vary from person to person for varying reasons). For example, 15 milligrams (mg) to 30 mg of flurazepam is generally equivalent to 0.25 mg to 0.5 mg of clonazepam.

Duration of action: Some benzodiazepines are short-acting and last only several hours. Some are long-acting and last several days. Most long-acting benzodiazepines aren't as strong.

The strength and duration of action of benzodiazepines are important in what conditions they treat. Short-term or emergency conditions usually merit the use of stronger, short-acting benzodiazepines. Chronic, non-emergency conditions are usually treatable with lower-strength, longer-acting benzodiazepines.

What conditions do benzodiazepines treat?

These medications treat conditions based on which effect they cause. While there are separate types because they have different primary effects, there's a lot of overlap between them. For example, most benzodiazepines have a sedative effect in addition to their primary effect.

Amnestic: These are common for beginning general anesthesia before surgeries and other medical procedures.

Anxiolytic: These treat anxiety disorders, such as social anxiety disorder and panic disorder.

Hypnotic: These treat insomnia and related sleep disorders.

Sedative: This effect has many uses. It can treat conditions and symptoms related to muscle control, such as muscle spasms. It can also treat more severe issues like catatonia (which often happens with mental health conditions like schizophrenia or bipolar disorder). These benzodiazepines are also very important in treating seizures (including those due to epilepsy) and status epilepticus, a seizure-related medical emergency.

What are nonbenzodiazepines?

A few medications mimic the hypnotic effects and work similarly to benzodiazepines, but they aren't the same. Experts call these nonbenzodiazepines. These drugs also activate the same receptors as benzodiazepines and cause GABA release. Because of how they work, these drugs are most effective in treating insomnia and related sleep disorders. They include:

Are benzodiazepines commonly prescribed?

Yes, benzodiazepines are commonly prescribed and see widespread use. In a 12-month period spanning 2014 and 2015, experts estimate that at least 30.5 million people in the U.S. took benzodiazepines prescribed by a healthcare provider.

What are the most commonly prescribed benzodiazepines?

The most common benzodiazepines approved in the United States include (but aren't limited to):

Alprazolam (Xanax®): Approved for treating anxiety disorders, panic disorder and premenstrual dysphoric disorder.

Chlordiazepoxide (Librium®; brand name is no longer available in the U.S.): Approved for treating alcohol withdrawal and anxiety-related conditions.

Clobazam (Onfi®, Sympazan®): Approved for treating seizures and certain forms of epilepsy.

Clonazepam (Klonopin®): Approved to treat agitation, anxiety and seizures.

Clorazepate (Tranxene®): Approved for treating anxiety and seizures.

Diazepam (Diastat®, Valium®, Valtoco®): Approved to treat alcohol withdrawal, seizures and muscle spasms. Also approved for use as pre-anesthesia for surgery and procedures. These can also treat toxic effects on the heart from chloroquine and hydroxychloroquine.

Estazolam (ProSom®; brand name is no longer available in the U.S.): Approved to treat insomnia.

Flurazepam (Dalmane®; brand name is no longer available in the U.S.): Approved to treat insomnia.

Lorazepam (Ativan®, Loreev®): Approved for treating seizures, chemotherapy-related nausea and vomiting, anxiety, pre-anesthesia for surgery and procedures, and phobias.

Midazolam (Nayzilam®, Seizalam®, Versed®; brand name Versed is no longer available in the U.S.): Approved to treat seizures, sedate people on a ventilator, and as pre-anesthesia for surgery and procedures.

Oxazepam (Serax®; brand name is no longer available in the U.S.): Approved as a treatment for alcohol withdrawal syndrome, anxiety and agitation.

Quazepam (Doral®): Approved to treat insomnia and sleep problems.

Remimazolam (Byfavo®): Approved for pre-anesthesia before surgeries and procedures.

Temazepam (Restoril®): Approved for treating insomnia.

Triazolam (Halcion®): Approved for treating insomnia.

Unapproved benzodiazepines

Many benzodiazepines aren't approved for use in the United States. Some of these have approval in other countries, and some don't have approval anywhere.

One benzodiazepine that's noteworthy - even though it's not approved (and illegal) in the United States - is flunitrazepam. This drug is best known as Rohypnol (or by the slang term "roofies"), and it's infamous for its use as a " date rape " drug. As a result, flunitrazepam is a well-studied drug in the U.S. (and in many places worldwide). Healthcare providers can test for it and treat people under its influence (see below under "What are the disadvantages, side effects and complications that are possible with benzodiazepines?").

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Benzodiazepines: What They Are, Uses, Side Effects & Risks

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Benzodiazepines are medications that slow down activity in your brain and nervous system. These medications are controlled substances, but still see widespread use.

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If you are experiencing extreme drowsiness, confusion, impaired coordination, decreased reflexes and respiratory depressions while taking Benzodiazepines you may be experiencing an overdose.

Overdosing on Benzodiazepines can be very dangerous and may cause coma and death.

https://www.dea.gov/factsheets/benzodiazepines#:~:text=What%20are%20Benzodiazepines%3F,Ativan%C2%AE%2C%20and%20Klonopin%C2%AE.

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Weaning the person of benzos over time seems to be the best treatment. According to the National Library of Medicine, "The current treatment of choice is to switch the current short-acting BZD for a long-acting alternative then gradually taper the dose to wean the individual off BZD completely. Clonazepam has been used in the outpatient setting as a medication for taping the use of BZD."

Benzodiazepines: Uses, Dangers, and Clinical Considerations - PMC (nih.gov)

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Marcello Moccia, Academic Editor

Abstract

Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood-brain barrier to affect the inhibitory neurotransmitter GABA and exert sedative effects. Related to their rapid onset and immediate symptom relief, BZDs are used for those struggling with sleep, anxiety, spasticity due to CNS pathology, muscle relaxation, and epilepsy. One of the debilitating side effects of BZDs is their addictive potential. The dependence on BZDs generally leads to withdrawal symptoms, requiring careful tapering of the medication when prescribed. Regular use of BZDs has been shown to cause severe, harmful psychological and physical dependence, leading to withdrawal symptoms similar to that of alcohol withdrawal. Some of these withdrawal symptoms can be life threatening. The current treatment for withdrawal is through tapering with clonazepam. Many drugs have been tested as a treatment for withdrawal, with few proving efficacious in randomized control trials. Future research is warranted for further exploration into alternative methods of treating BZD withdrawal. This call to action proves especially relevant, as those seeking treatment for BZD dependence and withdrawal are on the rise in the United States.

Keywords: benzodiazepines, GABA, withdrawal, cognitive decline

1. Introduction

Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood-brain barrier to affect the inhibitory neurotransmitter GABA and exert sedative effects. GABA is the most common neurotransmitter in the CNS, and BZDs primarily work on the GABA-A receptor subunit [ 1]. The GABA-A receptor has various subunits, and the most important in this case is the alpha (A) submit unit. The alpha subunit has various isoforms, which dictate a BZD's effects on the CNS. The A1 subunit is believed to be responsible for the sedative effects and anterograde amnesia, and some of the anticonvulsive impacts of diazepam [ 1]. The A2 subunit isoform mediates the anxiolytic and myorelaxant effects [ 1]. In total, there are six isoforms of the GABA-A subunit. To be specific in terms of binding sites and actions, BZD binds between the alpha and the gamma subunit. It enhances the effect of GABA at the GABA-A receptor, allowing it to exert a more significant effect [ 2].

Chronic users of the drug class often exhibit reliance with a high risk for abuse. This should provide pause, as BZD discontinuation after chronic use leads to withdrawal symptoms, with heavy users at risk for seizure activity [ 8]. Short-acting BZDs appear to carry more significant risks of adverse effects on abrupt cessation and usually exhibit greater dependence [ 9]. Several factors determine the rate and severity of withdrawal from the hypnotic. These are (1) the duration of use, (2) elimination half-life (short- or long-acting), (3) daily dosage, (4) rate of the taper and (5) the potency of the BZD itself [ 10]. One study found a withdrawal rate of approximately 40% in those using for six or more months with abrupt cessation of long-acting BZDs [ 10]. BZDs should especially be cautioned for use in the elderly, as the medication can lower the seizure threshold, cause gait instability, and balance problems [ 11]. Currently, the number of individuals seeking treatment for complications related to BZD use dependence is rising [ 5]. Therefore, the aim of this review is to highlight the indications for BZD use, the dangers of withdrawal from BZD, concerns regarding the cognitive decline associated with BZD use, and the clinical studies regarding this cognitive decline and treatment of withdrawal symptoms.

1.1. Indications for Benzodiazepines

BZDs are most commonly used for panic disorder and generalized anxiety disorder (GAD) regarding its indications for anxiety. Specifically, temazepam is commonly used for insomnia, clonazepam is commonly used for anxiety and seizures, lorazepam is commonly used for catatonia and seizure abortion when used intramuscularly or intravascularly, and diazepam is commonly used for anxiety, muscle spasms and rectally for seizures. In terms of anxiety, BZDs are used as a bridge when starting another medication or as abortive therapy for panic attacks. Given concerns for use dependence and withdrawal, SSRIs and antidepressants have been made mainstay therapy for these conditions. However, given their delayed onset of action, BZDs continue to be widely prescribed for these illnesses [ 12].

Other important indications for the use of BZDs include the treatment of catatonia, seizure disorders, and alcohol and BZD withdrawal. The drug class is the mainstay of treatment for catatonia, which is characterized by postural rigidity, immobility, purposeless activity, and disturbances in one's consciousness [ 10]. Catatonia presents in populations suffering from bipolar disorder, schizophrenia, or a variety of medical conditions. BZDs act on the CNS to exert anxiolytic and sedative effects and, together with electroconvulsive therapy, are the mainstay therapy for catatonia [ 13].

BZDs are also used in urgent seizure emergencies, including status epilepticus, acute seizures, cluster seizures, and seizures due to alcohol and BZD withdrawal. Neuronal damage may begin as soon as five min of seizure activity, so abortion with BZDs or other CNS sedatives is imperative [ 14]. Diazepam, lorazepam, and midazolam are most widely used for abortion of prolonged seizures, as they all exert anticonvulsive effects when bound to the alpha 1, 2, and 5 subunits of the GABA-A receptor in the CNS. Alcohol withdrawal abruptly removes the previous, chronic sedative effect of alcohol on the CNS due to prolonged stimulation of GABA receptors, resulting in unchecked autonomic activity and increased sympathetic stimulation. This mechanism results in symptoms and signs of psychomotor agitation such as diaphoresis, anxiety, nausea, vomiting, tremors, and possibly seizures and delirium. BZDs bind to the effect of the inhibitory neurotransmitter GABA to slow the firing of the autonomic nervous system, preventing hyperstimulation and associated sequelae of withdrawal.

Long-acting BZDs are also used to taper, and eventually discontinue, short-acting, chronic BZD usage. Like alcohol, abrupt withdrawal of the sedative action of BZDs on GABA causes hyperstimulation of the autonomic nervous system with similar associated symptoms and signs. Long-acting BZDs are a component of mainstay therapy to prevent BZD withdrawals seizures [ 15].

1.2. Duration of Treatment

2. Benzodiazepine Overuse Pathology, Misuses, and Complications

2.1. The Effects of Benzodiazepine on Cognition

Many studies have examined the effects of benzodiazepines on cognition with varied results. Some of the variations in results may be attributed to cognitive criteria in which each study followed. In a prospective longitudinal study on the effects of psychotropic drugs in the cognition of the elderly, Allard et al. [ 19] found no significant long-term effect of BZD use on cognition. This is supported in a similar study of elderly adults on a BZD for six months with drug discontinuation one month later. The study found no significant cognitive impairment in adults with long-term use of BZD [ 20]. A study of over 2000 older adults assessed the effects of chronic BZD use on cognition [ 21]. Chronic use of BZD leads to a small but significant change in fluid intelligence, while long-term use of BZD correlates with worse cognitive decline when compared to the effects of using a high dosage [ 21].

2.2. Side Effects of Benzodiazepine Use

2.3. Misuse of Benzodiazepine

There has been a steady increase in the number of prescribed BZDs in the US [ 27]. Bachhuber et al. 2016 reported an increase in ED visits for overdose and increased overdose death due to BZD use [ 28]. Women are more susceptible to BZD overuse because they are more likely to be prescribed than men [ 29]. Mclean et al. 2011 reported that the diagnosis of anxiety and stress disorders has a higher prevalence in women, which can explain the discrepancies in the prescription for men vs. women [ 30].

It has been shown that patients diagnosed with substance use disorder have increased tendencies to misuse BZD compared to the general population [ 31]. Although women are prescribed BZDs more commonly than men, Mchugh et al., 2021 reported no gender-based misuse of BZD in adults with substance abuse disorder [ 32]. Most of the participants in the study reported coping as a reason for their misuse of BZD prescriptions. Cook et al. also supported the conclusion that there is no gender-based difference in BZD misuse, although their study found that white race is more likely than other races (Black, Hispanic and Asians) to misuse BZD due to the prevalence of more prescriptions given to white patients than others [ 33]. An additional study on BZD misuse in adolescents found that factors such as white race, lower family income, older age and delinquencies are associated with BZD misuse. At the same time, it also found a correlation between misuse and depression [ 34].

2.4. Complications of Benzodiazepine Abuse

One of the main categories of people with BZD prescriptions is those with insomnia. Manconi et al. explored the effects of long-term BZD use on sleep architecture and microstructure in those with insomnia. They found significant changes in sleep microstructure in chronic insomnia with high dosage abuse of BZD, but sleep architecture changes were not significant. Long-term use of BZD leads to negative changes in sleep microstructure in patients with insomnia [ 35].

A study of patients undergoing total knee arthroplasty reported that patients who have filled a BZD prescription within 6 months before their surgery are at a high risk of revision of the surgery and femur fracture fixation [ 36]. BZD use is associated with an increased risk of falls, which may explain the revisions. The study also found a correlation between patients who use BZD preoperatively and those who have postoperative delirium [ 36].

Several case reports have also linked tapering of different BZD with Takotsubo cardiomyopathy (TCM). Hashm et al. reported a case of TCM 2-3 days after starting the tapering of alprazolam in a 63-year-old Caucasian female which resolved after the previous dosage was restarted [ 37]. TCM has also been associated with the tapering of other BZD such as clonazepam and lorazepam [ 38, 39].

2.5. Issues with Clinical Use of Benzodiazepine

In 2018, between 8.3% and 12.8% of BZD users in Switzerland have prescriptions from multiple physicians which resulted in the inability to track the number of prescriptions a patient is given yearly [ 40]. In a survey of British general practitioners, many reported pressures in prescribing BZD to patients and a lack of adequate knowledge on alternative psychological treatment for insomnia [ 41].

BZDs are classified either by their duration of action or potency. The difference in these characteristics dictates the clinical applicability of the drugs. Oxazepam, temazepam, and chlordiazepoxide which are low potency benzodiazepines are well tolerated with low toxicity levels. Alprazolam, lorazepam and clonazepam are high potently clinically used to treat panic disorders and serve as adjuncts for treating many other diseases [ 1]. Due to their toxic effect on the central nervous system, appropriate care is necessary with BZD. BZDs lead to long-lasting impairment of episodic implicit memory while it only impairs implicit memory transiently [ 1]. They also lead to disinhibition, impairing the user's ability to appropriately assess the risky actions or behaviors. Elderly patients in intensive care can develop delirium if they are on a BZD [ 1].

Researchers studied the neuroplastic effects of diazepam on mice. Results showed that, compared to wild-type mice, mice on diazepam experienced longer uninterrupted sleep [ 42]. It also reduces the expression of mRNA transcripts such as CaMKIIa, BDNF, GIF, c-fos, NGFIa which are necessary for regulating synapses and plasticity [ 42]. The suppression of CaMKIIa by diazepam has a long-lasting effect leading to a limited neuronal response to changes in intracellular calcium and decreased response by GABA-A receptors [ 42].

3. Benzodiazepine Use Dangers

Researchers investigating the correlation between anxiolytic and hypnotic drugs with mortality hazards examined over 100,000 patients in a retrospective cohort study. They found that the hazard of death was doubled in patients prescribed BZD compared to control patients [ 47]. The result was statistically significant. There was an association between the prescription of anxiolytic drugs and mortality, resulting in 4 excess deaths in the anxiolytic drug group within an average of 7.6 years [ 47]. The relationship between hypnotics and cancer was expanded upon by Kripke et al. They found a 35% increased chance of developing a new non-melanoma cancer in users of hypnotics [ 48]. In agreeing with some of the studies above, there was also a 4.6-fold increase in the hazard of death in patients on hypnotics over 2.5 years [ 48]. This is more significant than the study by Weich et al. [ 47] which found a 2-fold increased hazard of death in 7 years. It was also reported that the risk of death in patients using less than 18 pills per year is increased by 3.6-fold [ 48].

In a literature review exploring the relationship between BZD and suicide risk, it stated that although anxiety and insomnia which are often treated with a BZD, it can increase the risk of suicide; several studies in the literature have suggested that BZD use is also involved in increased suicide risk in its users [ 51]. The use and discontinuation of alprazolam within 2 weeks disrupt sleep onset and quality, increasing suicide risks [ 51].

4. Withdrawal

4.1. Symptoms of Withdrawal

Regular use of BZDs has been shown to cause serious, harmful psychological and physical dependence, leading to withdrawal symptoms similar to that of alcohol withdrawal. Regular use of BZDs can lead to tolerance, which is the physiologic dependence on the presence of BZDs in the body's system. This can be linked to addiction as the patient is not just psychologically addicted to the substance, which can be seen with cravings, and physical addiction. Withdrawal, like with alcohol since they exert their effects on similar receptors, can be life threatening. Withdrawal occurs as the BZD concentration in blood and tissue declines, generally causing symptoms opposite to that of the drug's therapeutic effects. Psychological symptoms include increased excitability, nightmares, anxiety, insomnia, panic attacks, depression, hallucinations, irritability, paranoid thoughts, social phobia, poor memory, poor concentration, delirium, and even psychosis. Physical symptoms include headache, seizures, pain or stiffness in the head and neck region, an altered sensation of limbs, weakness and fatigue, tingling and numbness, muscle twitches, tremors, gastrointestinal symptoms (abdominal distension, nausea, diarrhea, constipation, etc.), appetite and weight changes, unusual smell, and others have been documented [ 52]. These symptoms may last for one to a few weeks after cessation, with duration and severity largely depending upon the amount of time spent chronically taking the BZD, the half-life of the specific BZD, and the daily dose consumed [ 26].

4.2. Mechanism of Withdrawal

Symptoms associated with withdrawal occur due to the chronic effect on the GABA-A receptors in the CNS to BZDs. Over time, this causes a neuroadaptive process of both desensitization of the inhibitory function of GABA, sensitization of excitatory glutamine receptors, and possibly sensitization of N-methyl-D-aspartate (NMDA) receptors, along with other receptors. These changes contribute to tolerance to specific BZD and dosage, mediating dependence and later withdrawal [ 53].

4.3. Alprazolam

One of the most well-studied BZDs in the setting of withdrawal is alprazolam. Due to its short half-life, and rapid absorption, alprazolam is distinguished as one of the most rapid-acting BZD with fastest relief of symptomology, increasing its abuse liability [ 54]. Alprazolam is widely used as monotherapy for panic disorder and anxiety and was found superior to other forms of monotherapy for these conditions including other BZD, non-SSRI antidepressants, and buspirone. This superior effect is thought to be due to its unique alpha-2 adrenergic activity, enhancing its potency for relieving panic and anxiety disorders. This same mechanism is also thought to be the cause behind alprazolam's strong rebound hyperadrenergic effects with cessation [ 54, 55]. Many drug therapies have been suggested as treatment for alprazolam withdrawal with few rendered effective. These treatments will be discussed briefly below.

4.4. Special Populations and Withdrawal

4.4.1. The Elderly

Withdrawal has potential to be ubiquitously dangerous, but there are four main populations susceptible to the potentially life-threatening dangers of BZD dependence. First, the elderly (over 65 years old) are of extremely high risk due to their predisposition for falls, confusion, insomnia, memory loss, and other psychiatric problems regardless of BZD use. As the brain changes with age, the regions of the brain responsible for various sleep patterns and behaviors shrink, often resulting in less restful sleep, inability to sleep for longer durations, and fewer sleep spindles generation during non-REM sleep, a process necessary for memory consolidation and new information retention [ 56]. Because of these sleep changes and their predisposition for insomnia, the elderly may more often have chronic BZD use for sleep relief. However, given BZD's potential side effects of psychomotor retardation, amnesia, and increased forgetfulness, their use in the elderly is incredibly dangerous. Cessation after long-term usage (greater than two weeks) has even shown in some individual's the inability to return to cognitive baseline. It has been associated with increased risk for dementia [ 57, 58]. The elderly also have a decreased body water concentration, causing usual doses to elevate to potentially toxic levels quickly, exacerbating all effects, negative and otherwise, of BZDs. Rarely, catatonia and delirium can develop as part of the withdrawal syndrome. Given this picture, withdrawal symptoms should be carefully treated with BZD long-acting taper, with decreasing doses slowly over time, along with psychotherapeutic interventions such as motivational enhancement and cognitive behavioral therapy (CBT) with psychoeducation [ 59].

4.4.2. Children

Secondly, approximately 20% of the children in the intensive care unit given BZD during sedation, more specifically midazolam, have been shown to exhibit withdrawal effects. The severity of the withdrawal sequelae depends on the total dose and duration of infusion and usually presents as agitation, tremors, difficulty sleeping, and inconsolable crying [ 60].

4.4.3. Pregnant Women and the Fetus

Pregnant women and fetuses are at increased risk for adverse effects of withdrawal; they both metabolize BZD slowly, and the drug can cross the placenta to cause concentrations to build up to significant levels in the neonate [ 18]. While a therapeutic dose has not been proven teratogenic, use during pregnancy has been linked to low birth weight, preterm labor, and intrauterine growth restriction. The unborn fetus is at high risk for "floppy infant syndrome," characterized by muscle laxity, failure to suckle, and oversedation. Approximately two weeks after birth, the infant experiences withdrawal consisting of continued difficulty feeding, high pitched cries, hyperexcitability, and consequently possible failure to thrive. The ultimate concern is that such fetuses will later be susceptible to autism, learning difficulties, attention deficit disorder, and general hyperactivity [ 24].

4.5. Treatment for Benzodiazepine Withdrawal

There are pharmacological options for treatment in those suffering from withdrawal or wishing to discontinue their chronic BZD use. Many alternate drug therapies have been proposed to reduce the severity of withdrawal, including alpha-blockers (propranolol and clonidine), anticonvulsants (valproic acid, lamotrigine, carbamazepine, and phenobarbital), progesterone, baclofen, and trazodone. Each of these studies received mixed results, with no statistically significant advantage to BZD therapy. The current treatment of choice is to switch the current short-acting BZD for a long-acting alternative then gradually taper the dose to wean the individual off BZD completely [ 8]. Clonazepam has been used in the outpatient setting as a medication for taping the use of BZD. However, no set schedule for a taper has been validated in the current literature.

5. Clinical Studies

Many clinical studies have been conducted to assess the severity and treatment of withdrawal systems, while others assess more long-term effects of chronic BZD use. The mainstay of BZD withdrawal treatment at this time is a slow taper off the drug to prevent severe withdrawal symptoms; however, many patients cannot tolerate this taper without experiencing rebound anxiety and other symptoms. Current studies are aimed to decrease this rebound anxiety effect while also decreasing relapse into BZD use using different medications, counseling, BZD dosing strategies, or different tapering techniques.

5.1. Factors Influencing Withdrawal Symptoms

Certain factors play a role in the severity of withdrawal symptoms, such as dosage, duration of action of the BZD duration of treatment with the drug, and severity of psychiatric symptoms pre-treatment. Studies have shown that treatment for longer periods with high-dosage, short-acting BZD contribute to more severe withdrawal effects [ 61]. Milder effects are seen with longer-acting BZD that are used for shorter periods [ 61]. Those who have never experienced withdrawal symptoms from BZD discontinuation could quit using BZD more easily [ 62]. Baseline anxiety is an important indicator of withdrawal symptoms [ 63]. People with severe anxiety before starting treatment with BZD typically have more severe withdrawal symptoms, and thus have a harder time fully discontinuing the drug [ 63]. Psychiatric diagnoses have also been linked to one's ability to discontinue treatment with BZD. One study showed a high co-occurrence with BZD dependence and all psychiatric disorders in general [ 64, 65]. Specifically, those with cluster B personality disorders have the worst prognosis in regard to discontinuing BZD. In one study, not a single subject diagnosed with a cluster B personality disorder successfully discontinued BZD use [ 63]. They also had a higher dropout rate from the study [ 63]. Additionally, younger patients tend to have a decreased success rate of discontinuing BZD use than older patients [ 66]. Interestingly, those who used alcohol while taking BZD experienced no difference in discontinuation rate from those who did not use alcohol [ 64].

5.2. Pharmacologic Management of Withdrawal Symptoms

Many medications have been tested to alleviate withdrawal symptoms and make it easier for patients to discontinue BZD since a gradual taper does not always lead to successful discontinuation of the drug. Currently, a gradual taper with clonazepam is used as maintenance therapy for BZD-dependent patients. However, it still carries the risk for abuse and dependence since this is also a BZD, albeit a slow-acting one [ 67].

One medication that is not a BZD that has been used to treat BZD withdrawals is flumazenil. This medication is currently FDA approved for BZD overdose. Flumazenil is a BZD antagonist, which works by displacing BZD from its binding site without having an effect on GABA itself. IV infusion of this medication has been shown to decrease aggression during BZD withdrawals by self-report in one study [ 68]. One study showed that a 7 day IV infusion of flumazenil during withdrawal in patients stabilized with clonazepam or antidepressants led to abstinence in over half of their subjects [ 67]. However, in the same study, for those with polysubstance abuse, flumazenil did not reduce cravings for other drugs and did not restore BZD receptors' sensitivity [ 67]. This study was limited by the small sample size, a lack of double-blinding, multiple parallel treatments, and had the potential for subjects to fail to report relapse in drug use [ 67]. More careful research will need to be performed in this area. Some researchers are even looking into long-term subcutaneous administration of flumazenil for BZD-dependent patients. This could be a feasible alternative to IV infusion of flumazenil because patients can be mobile when given medications subcutaneously, so they are more likely to return for repeat treatments and recommend treatment to friends [ 64]. It has been shown that the efficacy of withdrawal treatment might be more associated with levels of flumazenil in cerebral spinal fluid rather than plasma levels of the drug [ 64]. Clinical Institute Withdrawal Assessment Alcohol Scale (CIWA) symptoms peaked at day 1 and decreased significantly during days 2 and 3, leading researchers to this conclusion in one study [ 64]. However, Flumazenil carries a high risk of seizures, so one must be cautious when administering this drug [ 68]. Flumazenil is continuously shown to be a viable option for BZD withdrawal treatment; however, other medications currently on the market might be more efficacious.

The antiepileptic oxcarbazepine has also shown potential to ameliorate withdrawal symptoms more than older-generation antiepileptics such as carbamazepine [ 71]. Oxcarbazepine has a better side effect profile and is a more tolerable anticonvulsant than older antiepileptic drugs [ 71]. One case series showed that not only did oxcarbazepine provide more tolerability than the current mainstay of treatment, but it also shortened the withdrawal time frame for patients to just 11 to 19 days, even for patients previously taking high doses of BZD [ 71]. It is important to note that this study was uncontrolled, so further randomized controlled studies need to be performed to increase the validity of these results [ 71].

5.3. Educational Approaches to Benzodiazepine Withdrawal

5.4. Long-Term Effects of Benzodiazepine Use

Some studies in the past have shown that there is a correlation between chronic BZD use and a decline in cognitive function, including the development of dementia and dementia-like diseases. One study showed a potential for cognitive decline after BZD use in the elderly, but at the same time did not find a link between their use and the development of Alzheimer's dementia [ 73]. The researchers in the study cautioned the prescription of BZD in the elderly due to the potential for cognitive decline [ 73].

So, while some more recent studies have shown that BZDs do not affect cognitive function, prescribers should proceed with caution when prescribing these drugs to elderly patients and dementia patients because of the risk of delirium and falls in this patient population. Table 1 summarizes the studies discussed in this section.

Table 1

Treatment

Studies

Flumazenil

IV infusion of flumazenil over 7 days during withdrawal period, patients stabilized with clonazepam or antidepressants. An improvement in abstinence was found
Self-reported effects of flumazenil on aggression during withdrawals. A self-reported decrease in aggression in patients was found
Comparison of IV infusion to subcutaneous administration of flumazenil. Subcutaneous administration was found to be more tolerable for patients

Propranolol

Abrupt discontinuation of benzodiazepines in severely dependent patients and administration of propranolol rather than a slow taper. Researchers found no difference from mainstay treatment [ 66]
Propranolol administration to patients after abrupt discontinuation of diazepam and lorazepam. Researchers found some difference from mainstay treatment

Captodiamine

Administration of captodiamine to benzodiazepine-dependent patients for 45 days after abrupt cessation of benzodiazepines. Researchers found no withdrawal symptoms present after discontinuation of captodiamine

Anticonvulsants

A case series on patients taking oxcarbazepine after cessation of benzodiazepines. A shorter withdrawal period was noted

Antipsychotics

A comparison of cyamemazine to bromazepam after 3 month treatment with benzodiazepines. Cyamemazine was found to be as effective as bromazepam in treating withdrawal symptoms

Standardized counselling protocols

Comparison of a slow taper to counselling on the dangers of benzodiazepines and alternatives to treatment. Researchers found no difference in treatments
Comparison of a slow taper to a standardized interview and education protocol alongside a slow taper. Researchers found a significant improvement in symptoms and success rate in benzodiazepine discontinuation in the experimental group

6. Conclusions

BZDs show an increased risk for abuse and dependence. Over time, the inhibitory function of GABA may be desensitized with a corresponding sensitization of excitatory glutamine receptors. This neuroadaptive process builds tolerance, causing many chronic users to need increasing dosages for similar effects. As the drug concentration in blood and tissue decline, the sympathetic nervous system, possible seizures, and generally symptoms opposite that of its intended, therapeutic effect. This is of chief concern in four main populations: the elderly, children, pregnant women, and their neonates, given their sensitivity to BZD effects. One study further showed that the risk of dying is doubled in patients prescribed BZD compared with controls [ 47].

Current treatment for withdrawal is through tapering with clonazepam, and overdose should be treated with flumazenil [ 67]. Many drugs have been tested as a treatment for withdrawal, with few proving efficacious in randomized control trials. There is room in the research body for further exploration into alternative methods of treating withdrawal that does not include the BZD itself. This call to action proves especially relevant, as those seeking treatment for BZD dependence and withdrawal are on the rise in the United States [ 3].

Author Contributions

Conceptualization, A.N.E., C.E.S., B.M.D. and T.A. were involved in the writing of the manuscript; A.N.E., C.A.N., J.H., E.M.C., A.D.K. and A.M.K. were involved in manuscript editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to no human subjects being involved.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data supporting the results above can be found on PubMed.

Conflicts of Interest

None of the authors have any conflict of interest to report in this project.

Footnotes

Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Griffin C.E., Kaye A.M., Bueno F.R., Kaye A.D. Benzodiazepine Pharmacology and Central Nervous System-Mediated Effects. Ochsner J. 2013;13:214-223. [[ PMC free article] [ PubMed] Google Scholar]

18. Authier N., Balayssac D., Sautereau M., Zangarelli A., Courty P., Somogyi A.A., Vennat B., Llorca P.M., Eschalier A. Annales Pharmaceutiques Francaises. Elsevier Masson; Paris, France: 2009. Benzodiazepine dependence: Focus on withdrawal syndrome; pp. 408-413. [[ PubMed] [ CrossRef] Google Scholar]

26. O'Brien C.P. Benzodiazepine Use, Abuse, and Dependence. Prim. Care Companion CNS Disord. 2005;66((Suppl. 2)):28-33. [ Google Scholar]

71. Vicens C., Fiol F., Llobera J., Campoamor F., Mateu C., Alegret S., Socías I. Withdrawal from long-term benzodiazepine use: Randomised trial in family practice. Br. J. Gen. Pract. J. R. Coll. Gen. Pract. 2006;56:958-963. [[ PMC free article] [ PubMed] Google Scholar]

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Benzodiazepines: Uses, Dangers, and Clinical Considerations

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Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood-brain ...

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Tranquilizers aren't meant for long term use as they have a high risk of causing the brain to become physically and psychologically dependent on them.

Physical symptoms include nausea, diarrhea, vomiting, sweating, muscle pain, headaches and heart palpitations. More serious symptoms such as seizures and tremors are possible as well.

Psychological symptoms include anxiety, panic attacks and disrupted sleep patterns.

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Benzo Withdrawal Symptoms
Benzodiazepines (benzos) are not intended to be taken long-term, as prolonged use or abuse can cause the brain to become both physically and psychologically dependent on them.
Withdrawal symptoms, ranging from a return of uncomfortable psychological symptoms to physical manifestations such as nausea and diarrhea, may occur when the drugs are removed from the bloodstream.

Withdrawal side effects are not generally lethal, although they are best managed with professional medical attention and supervision.

Benzo withdrawal symptoms may include:

Benzodiazepines are all designed as central nervous system depressants; however, they each may work slightly differently at targeting certain symptoms. For example, Restoril, Dalmane (flurazepam), and Halcion (triazolam) are considered primarily hypnotic benzodiazepines prescribed for insomnia, while Xanax, Ativan, Librium (chlordiazepoxide), and Valium are classified as anxiolytics used to treat anxiety symptoms. Klonopin is considered primarily an anticonvulsant. Different metabolites of these medications make them slightly different, which may also affect how quickly they leave the bloodstream. Withdrawal from different benzodiazepines is generally thought to bring the same general symptoms; however, it is possible that an individual withdrawing from a hypnotic may have more disrupted sleep patterns while withdrawal from an anxiolytic may include higher levels of anxiety.

Benzodiazepine Withdrawal Timeline

Most benzodiazepine (benzo) withdrawal symptoms start within 24 hours and can last from a few days to several months, depending on the length of the abuse and the strength of the benzo used. Prolonged withdrawal isn't uncommon, however. About 10 percent of people who abuse benzos still feel withdrawal symptoms years after they have stopped taking the drugs.

Each benzodiazepine medication has a specific half-life that influences the length of time it takes for the drug to leave the bloodstream. If an individual is dependent on a benzo, once the drug is purged from the body, withdrawal may begin. For shorter-acting benzos like Xanax, withdrawal may start within 10-12 hours of stopping the drug. With a longer-acting benzodiazepine such as Valium, it may take a few days for symptoms to appear.

Some short-acting benzodiazepines, like Xanax, are thought to be more potent than some of the longer-acting ones, such as Valium, as well. While withdrawal will be similar for both, users of short-acting benzos may experience withdrawal symptoms sooner and with more intensity, as benzos with longer half-lives will stay in the body longer, therefore slowing the onset of withdrawal.

Benzo Withdrawal Phases

Benzodiazepine withdrawal may occur in three main phases: early withdrawal, acute withdrawal, and protracted withdrawal.
The early withdrawal phase usually starts within a few hours to a few days of stopping the medication and may last a few days. During early withdrawal, an individual may experience a return of anxiety and insomnia symptoms as the brain rebounds without the drugs. Symptoms the benzos worked to suppress may come flooding back. The tapering process frequently used in medical detox may help dampen this rebound effect.

After a few days of stopping a benzodiazepine, acute withdrawal may begin. This phase constitutes the bulk of withdrawal. Symptoms may include anxiety, panic, insomnia, muscle spasms or tension, nausea and/or vomiting, diarrhea, blurred vision, seizures, hallucinations, short-term memory impairment, trouble concentrating, clouded thinking, mood swings, agitation, drug cravings, twitching and weight loss due to a decreased appetite. It is during this phase that specific medications may be most beneficial at targeting some of the certain symptoms. Suicidal thoughts and actions may occur during acute withdrawal from a benzodiazepine as well, and therapy and support groups may help diffuse these complicated emotions. Acute withdrawal may last between two weeks and several months.

Some people, around 10 percent according to a study published by , may experience protracted withdrawal syndrome that can extend several months or even years after stopping use of a benzodiazepine.

Individuals may experience tingling in their arms and legs, muscle twitches, prolonged anxiety and insomnia, and cognitive deficits as well as depression and mood swings that may be difficult to manage. These symptoms may appear randomly and without warning. Mental health services and support beyond medical detox include therapy and counseling to manage protracted withdrawal symptoms. When a mental health disorder is also present, called co-occurring disorders, specialized treatment that caters to dual diagnoses may be beneficial during recovery.

While there is no hard and fast timeframe for the withdrawal period from a benzodiazepine, medical and mental health professionals can help to greatly reduce the intensity and duration of symptoms that occur during detox. Again, benzo withdrawal should not be attempted without medical supervision. Medical detox can aid in the safe removal of benzodiazepines from the body and brain, and following up with therapy and family support services promotes a smooth recovery.

Benzo Withdrawal Risk Factors
There is no specific timeline dictating exactly how long withdrawal from a benzo, or benzodiazepine, medication will last.
While each individual may experience withdrawal differently, certain estimations can be made. Benzodiazepine withdrawal duration and intensity depend on several factors, including:

Length of time taking benzodiazepines

Dosage amount

Type of drug used/abused

Method used to take or abuse benzodiazepines

Underlying medical or mental health issues

Abuse of other drugs or alcohol concurrently

Family history of drug dependency or previous issues with substance abuse and/or dependency may increase the likelihood of developing a dependency on a benzodiazepine and may potentially add to the withdrawal timeline duration as well.

Benzodiazepines are Schedule IV controlled substances per the Drug Enforcement Administration (DEA). They are sedatives and tranquilizers prescribed to treat symptoms of insomnia, anxiety, panic, seizure disorders, and muscle tensions or spasms. Common benzodiazepines include Xanax ( alprazolam), Klonopin ( clonazepam), Restoril (temazepam), Ativan ( lorazepam), and Valium ( diazepam). Alprazolam, the generic name for Xanax, was the 13th most prescribed medication in the country in 2012, according to a survey done by IMS Health.

Individuals taking benzos for several months or more and in high doses are likely to experience more withdrawal symptoms that last longer than those taking smaller doses for a shorter length of time. For example, the U.S. Food and Drug Administration (FDA) reported that patients taking doses of 4 mg/day or higher of Xanax for longer than three months were more likely to become dependent on the drug and therefore more likely to experience more uncomfortable withdrawal symptoms than those taking smaller doses for less time.

The method of ingestion is also related to the onset of withdrawal. For instance, snorting or injecting benzos sends the drugs straight into the bloodstream to take almost instant effect. Ingesting a pill requires that it be digested through the digestive tract, which creates a less intense high and slower onset of withdrawal symptoms.

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Benzo Withdrawal Symptoms, Timeline & Detox Treatment

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Read on to learn more about benzodiazepine withdrawal, the common symptoms, benzo withdrawal timeline, and benzodazepine withdrawal treatment.