Understanding Benzodiazepines: Important Considerations for Safe Use and Potential Risks

Understanding Benzodiazepines: Important Considerations for Safe Use and Potential Risks.

What Are Benzodiazepines?

Benzodiazepines (BZDs) are among the most commonly prescribed medications in the US. This family of psychoactive drugs is well-known for its ability to depress the central nervous system (CNS). They have sedative effects and quickly penetrate the blood-brain barrier, influencing the inhibitory neurotransmitter GABA. The GABA-A receptor subunit is the primary target of BZDs, making GABA the most prevalent neurotransmitter in the central nervous system.

Understanding GABA-A Receptors

The GABA-A receptor consists of several subunits, with the alpha (A) subunit being the most significant. Different isoforms of the alpha subunit determine how a BZD affects the CNS. For example, the A1 subunit is responsible for the sedative effects, anterograde amnesia, and some anticonvulsive actions of diazepam. Meanwhile, the A2 subunit mediates myorelaxant and anxiolytic actions. BZDs bind between the alpha and gamma subunits, enhancing the effects of GABA. Due to their lipid solubility, BZDs distribute widely throughout the body, resulting in higher tissue concentrations than in the blood.

Caution in Use

BZDs should be used cautiously, especially in older adults, smokers, and individuals with liver disease. The liver metabolizes these medications after they exert their effects, excreting them through conjugation. BZDs are often prescribed for insomnia, anxiety, muscle relaxation, and epilepsy due to their quick onset and immediate symptom relief. Their sedative action helps reduce sleep onset latency, benefiting those with insomnia. Additionally, BZDs effectively prevent acute panic and anxiety episodes, significantly alleviating anxiety. They are also useful in quickly stopping convulsive activity in individuals with epilepsy or seizure disorders.

The Rise of Benzodiazepines

In the 1960s and 1970s, BZDs gained fame through popular culture, with artists like The Rolling Stones and Hollywood films sensationalizing Valium (diazepam). This led to widespread societal acceptance, as BZDs were marketed to anyone seeking relaxation and better sleep. Today, their use continues to rise in the US, driven by increasing anxiety and sleep-related issues. However, this ongoing usage brings the grim reality of BZD dependency. Long-term users often exhibit signs of dependence and a significant risk of misuse. Stopping BZDs after prolonged use can lead to withdrawal symptoms and puts heavy users at risk for seizures.

Common Indications for Benzodiazepines

BZDs are frequently prescribed for panic disorder and generalized anxiety disorder (GAD). For instance, temazepam is commonly used for insomnia, clonazepam for anxiety and seizures, lorazepam for catatonia and seizure abortion, and diazepam for anxiety, muscle spasms, and seizures. While SSRIs and antidepressants are established as standard treatments for anxiety disorders due to concerns about withdrawal and dependency, BZDs are still often recommended despite their delayed onset of action.

Other Uses of Benzodiazepines

BZDs are also indicated for treating seizures, alcohol withdrawal, and catatonia. Catatonia, characterized by postural stiffness and immobility, is primarily treated with this class of drugs. They work alongside electroconvulsive therapy to provide sedative and anxiolytic effects on the CNS. BZDs are effective in treating acute seizures, cluster seizures, status epilepticus, and seizures caused by alcohol and BZD withdrawal.

The Mechanism Behind Alcohol Withdrawal

Alcohol withdrawal leads to prolonged activation of GABA receptors, resulting in unregulated autonomic activity and increased sympathetic stimulation. This quickly diminishes alcohol's previous sedative effects on the CNS. Symptoms of psychomotor agitation, such as tremors, nausea, vomiting, anxiety, and potentially seizures and delirium, arise from this mechanism. BZDs bind to the inhibitory neurotransmitter GABA to slow down the autonomic nervous system's firing, preventing hyperstimulation and associated withdrawal symptoms. Short-acting BZDs are tapered and eventually stopped with long-acting BZDs. Similar to alcohol, abrupt cessation of BZDs can lead to hyperstimulation of the autonomic nervous system, causing similar symptoms. Long-acting BZDs are the primary treatment for BZD withdrawal seizures.

Efficacy and Risks of Benzodiazepines

While BZDs are effective for their designated disorders, guidelines recommend limited usage to a few weeks due to the serious risk of dependency and potentially fatal withdrawal symptoms. Despite this, many users continue taking them for months or even years. Studies indicate that BZD use increases with age, particularly among those aged 65 and older. Long-term usage, defined as two or more months at a therapeutic dosage, can lead to adverse side effects. Older adults are especially vulnerable to psychomotor impairment, cognitive decline, and anterograde amnesia, which can affect short-term memory and increase forgetfulness. Between 1% and 20% of users may experience violent behavior and resentment, along with other concerning side effects. Tolerance is the primary cause of dependency, leading users to require higher dosages for the same level of symptom relief.

Side Effects of Benzodiazepine Use

Understanding the side effects of benzodiazepine use.

Several notable adverse effects are associated with BZDs. Elderly users over 80 years old face a significantly higher risk of falls resulting in injury. A study found that older hospitalized patients given short-acting BZDs had an increased chance of falling. Pregnant women who take BZDs are at risk for premature delivery and low birth weight. Although some studies indicate teratogenic effects on fetuses, these findings are not statistically significant, and other drugs, such as antidepressants, may contribute to observed abnormalities. The addictive potential of BZDs is one of their most concerning adverse effects. Their relative safety compared to barbiturates has led to increased prescriptions, but careful tapering is essential to avoid withdrawal symptoms.

Clinical Aspects of Benzodiazepine Use

BZDs are categorized based on their potency or duration of effect. These differences determine their clinical usefulness. Low-potency BZDs include oxazepam, temazepam, and chlordiazepoxide. Benzodiazepines are generally well-tolerated and have minimal toxicity. They are effective therapeutic medications for treating panic disorders and are often used as adjuncts for various other conditions. However, proper care is necessary due to their harmful effects on the CNS. While BZDs temporarily impair implicit memory, they can cause long-term impairment of episodic implicit memory. Disinhibition may also occur, making it harder for users to recognize dangerous behaviors. Elderly patients in critical care on BZDs may experience delirium.

Risks Associated with Benzodiazepine Use

Research shows that BZDs are among the most misused substances, especially among individuals using multiple drugs. A study examining over 1,000 drug addiction fatalities linked to oxycodone found that diazepam was commonly used alongside it. Further data indicated that 54% of oxycodone abusers also depended on a BZD. Additionally, 64% of heroin users abuse BZDs. A retrospective cohort analysis involving nearly 100,000 patients revealed that those administered BZDs had twice the mortality risk compared to control patients.

Researchers also investigated the connection between overdose fatalities and non-overdose mortality from hypnotic drugs in patients receiving opioid maintenance medication. They found that benzodiazepines increased the rate of non-overdose deaths, likely due to their effects on motor, sensory, and cognitive abilities, as well as an increased risk of falls. Less than 13% of non-overdose fatalities were trauma-related. Veterans prescribed both BZDs and opioids simultaneously face a higher risk of overdose death, with a significant correlation between BZD dosage and overdose fatality.

Withdrawal Symptoms

Common symptoms of benzodiazepine withdrawal.

Frequent BZD use can lead to severe physical and psychological dependency, with withdrawal symptoms resembling those of alcohol withdrawal. Tolerance, or physiological reliance on BZDs, can develop with regular use, leading to both physical and psychological addiction. Withdrawal can be fatal, similar to alcohol withdrawal. It occurs as blood and tissue BZD concentrations decrease, resulting in symptoms that are the opposite of the drug's therapeutic benefits.

Psychological Withdrawal Symptoms

• Increased excitability
• Nightmares
• Anxiety
• Sleeplessness
• Panic attacks
• Depression
• Hallucinations
• Irritability
• Social anxiety
• Paranoid thoughts
• Impaired memory
• Delirium
• Psychosis
  
  

Physical Withdrawal Symptoms

• Headache
• Seizures
• Neck pain or stiffness
• Altered limb sensation
• Weakness and exhaustion
• Tingling and numbness
• Muscle twitches
• Tremors
• Gastrointestinal symptoms (abdominal distension, nausea, diarrhea, constipation, etc.)
• Changes in appetite and weight
• An unusual odor
  
  

The severity and duration of these symptoms depend on several factors, including the length of time taking the BZD, the specific BZD's half-life, and the daily dose used. Symptoms can last anywhere from one to several weeks after stopping.

Vulnerable Populations

While withdrawal can be hazardous for anyone, four major groups are particularly vulnerable to the risks associated with BZD dependency. First, older adults (over 65) are at high risk due to their propensity for falls, disorientation, sleeplessness, memory loss, and other mental health issues. Aging leads to changes in brain areas linked to sleep patterns, often resulting in less restful sleep and difficulties in memory consolidation.

Second, studies show that 20% of children in critical care units receiving BZDs during sedation—specifically midazolam—exhibit signs of withdrawal. The intensity of withdrawal symptoms, such as agitation and tremors, depends on the overall dosage and duration of infusion.

Pregnant women and fetuses are also more susceptible to withdrawal effects. BZDs metabolize slowly and can cross the placenta, leading to dangerous concentrations in neonates. Use during pregnancy has been associated with low birth weight, premature labor, and intrauterine growth restriction. While therapeutic dosages are not teratogenic, "floppy infant syndrome" can occur, characterized by muscle laxity and excessive drowsiness in the newborn. Withdrawal symptoms may appear about two weeks after delivery, including feeding difficulties and high-pitched crying.

The dose, duration of BZD effect, and intensity of mental symptoms before therapy all influence the severity of withdrawal symptoms. Research indicates that prolonged use of high-dose, short-acting BZDs can lead to more severe withdrawal symptoms, while short-term use of longer-acting BZDs results in milder side effects. Individuals who have never experienced withdrawal symptoms may find it easier to stop taking BZDs. Baseline anxiety is a key predictor of withdrawal symptoms; those with extreme anxiety before starting BZD therapy often experience more severe withdrawal symptoms, complicating cessation.

Conclusion: Awareness and Support

In general, this blog aims to create awareness about BZDs and the importance of seeking help. In Australia, there is a drug checking service called 'CanTest' where you can verify your substances if you are unsure about their purity. Please consult your healthcare professional before taking this medication, and ensure that someone is present when you use it. Additionally, the Canberra Alliance for Harm Minimisation and Advocacy can provide support and training for take-home naloxone and other harm reduction education.

To your health,

Nwabekeehealth

Reference

Edinoff, A. N., Nix, C. A., Hollier, J., Sagrera, C. E., Delacroix, B. M., Abubakar, T., Cornett, E. M., Kaye, A. M., & Kaye, A. D. (2021). Benzodiazepines: Uses, dangers, and clinical considerations. Neurology International, 13(4), 594–607. https://doi.org/10.3390/neurolint13040059