What are the long-term side effects of benzodiazepines?

From the Guidelines

Benzodiazepines should be avoided for long-term use due to their significant risks of dependency, cognitive impairment, falls, and other adverse effects, as evidenced by recent guidelines 1. The long-term side effects of benzodiazepines are a major concern, particularly when used beyond 2-4 weeks. Some of the common long-term effects include:

• Cognitive impairment, such as memory problems, confusion, and difficulty concentrating
• Physical dependence and tolerance, requiring increasing doses for the same effect
• Withdrawal symptoms, which can be severe and potentially life-threatening, including seizures, psychosis, and rebound anxiety
• Increased risk of falls and fractures, particularly in older adults
• Possible links to dementia with prolonged use, although causality remains debated
• Emotional blunting, depression, or paradoxical reactions like increased aggression or anxiety
• Sleep architecture disruption, reducing restorative deep sleep

According to the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guidelines, the benefits of benzodiazepines do not outweigh their potential harms, and their use is advised against for the treatment of chronic insomnia disorder 1. The U.S. Food and Drug Administration has also released safety announcements on the risk of serious injuries caused by sleep behaviors associated with benzodiazepines 1.

To minimize the incidence of adverse events, it is recommended that benzodiazepines be administered at the lowest effective dose and for the shortest possible duration, with all patients counseled on the potential risks 1. Given the significant risks associated with long-term benzodiazepine use, alternative treatments for insomnia and other conditions should be considered, and patients should be closely monitored for signs of dependency and other adverse effects.

From the FDA Drug Label

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets (see WARNINGS)

Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia and galactorrhea

The long-term side effects of benzodiazepines include:

• Cognitive impairment: concentration difficulties, transient amnesia or memory impairment
• Mood changes: irritability, depression, anxiety
• Physical dependence: withdrawal seizures upon rapid decrease or abrupt discontinuation
• Other adverse events: dystonia, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention 2
• Rare but serious events: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia and galactorrhea 2

From the Research

Long-term Side Effects of Benzodiazepines

The long-term side effects of benzodiazepines have been a subject of concern and study in the medical community. Some of the key findings include:

• Increased risk of dependence and addiction, which can occur when doses within the clinical range are taken regularly over about 6 months 3
• Development of tolerance, leading to the need for higher doses to achieve the same therapeutic effect 4
• Memory problems, constipation, and dry mouth are common side effects associated with benzodiazepine use 5
• Long-term use of benzodiazepines has been linked to an increased risk of mood and substance use disorders, including depressive disorders, bipolar disorders, and substance use disorders 6

Prevalence of Long-term Benzodiazepine Use

Studies have shown that long-term benzodiazepine use is a common phenomenon, with estimates suggesting that about 3% of the general population uses benzodiazepines long-term 4. The prevalence of long-term use is higher in elderly patients, with one study finding that 47% of adult benzodiazepine users were long-term users 4.

Characteristics of Long-term Benzodiazepine Use

Long-term benzodiazepine use is often characterized by steady treatment with low doses 4. However, in elderly patients, long-term use and exceeding recommended doses is relatively common 4. Factors associated with long-term use include older age, higher doses, and longer treatment duration 4.

Comparison with Other Medications

Studies have compared the side effects of benzodiazepines with those of selective serotonin reuptake inhibitors (SSRIs), another commonly used medication for anxiety disorders. One study found that SSRIs cause more adverse events than benzodiazepines in short-term treatment, including diaphoresis, fatigue, nausea, diarrhea, and insomnia 5. However, benzodiazepines were associated with memory problems, constipation, and dry mouth 5.

Clinical Implications

The findings of these studies have important implications for clinical practice. They suggest that benzodiazepines should be used with caution, particularly in elderly patients and those with a history of substance use disorders 6, 7. Additionally, the use of benzodiazepines should be regularly reviewed and monitored to minimize the risk of dependence and other adverse effects 3, 4.