Benzodiazepines: Caught between patient needs and guidelines

EVOLUTION OF CONCERNS

In 1990, a task force established by the American Psychiatric Association to assess the risks associated with benzodiazepines identified several concerns, primarily the potential for addiction and dependence with long-term use.⁴ Addiction involves intense cravings, loss of control, and continued use despite harm; physiologic dependence is a normal adaptation to long-term use, even at therapeutic doses. Benzodiazepines are mildly reinforcing, meaning their effects on the brain’s reward system are subtle or weak compared with the effects of drugs like opioids or cocaine. Benzodiazepines are not typically abused as standalone substances; abuse usually occurs in conjunction with other addictions.³

The American Psychiatric Association task force noted that withdrawal symptoms could occur upon discontinuation even when benzodiazepines are used as prescribed. Consequently, dose reduction can lead to physiologic withdrawal, relapse, or rebound anxiety, and abrupt cessation of benzodiazepines can be life-threatening.⁴

The physiologic withdrawal that occurs even with prescribed use raised concerns about the safety of long-term benzodiazepine use.⁴ In response, Z-drugs (eg, zolpidem, zaleplon, eszopiclone) were developed with the hope of reducing the risks of dependence and withdrawal. However, Z-drugs have pharmacologic effects similar to those of benzodiazepines and have proven to be equally problematic.⁵

Recently, negative sentiment about benzodiazepines has intensified given the association of benzodiazepines with opioid-related deaths.⁶ This prompted the US Food and Drug Administration 2016 warning against prescribing opioids and benzodiazepines together, followed in 2020 by black-box warnings on the risk of coprescribing as well as the risks of addiction and dependence. Two years later, 1 in 6 opioid overdose deaths involved benzodiazepines⁶ and, consequently, benzodiazepines are no longer considered first-line treatments for anxiety or insomnia. Further, there is increasing emphasis on deprescribing even for people who have experienced no ill effects.⁷

Accordingly, many countries have restricted the prescription of all benzodiazepine receptor agonists incorporating both benzodiazepines and Z-drugs. Current guidelines recommend only short-term treatment, recognizing that long-term treatment may result in tolerance and risk of dependence.^6,7 The guidelines recommend avoiding benzodiazepine receptor agonists altogether in older patients based on data showing cumulative adverse effects such as cognitive decline, dependence, and increased falls.⁵ It remains unclear whether strict regulations and guidelines are genuinely evidence based and, if so, whether they can realistically be implemented in real-world settings.⁸

WHAT IS THE ROLE FOR BENZODIAZEPINES?

Despite the challenges associated with their use, benzodiazepines have a place in the therapeutic armamentarium. They are considered first-line treatment for preventing seizures and delirium tremens in the context of alcohol withdrawal.⁹ Although benzodiazepines are primarily indicated for conditions such as status epilepticus and catatonia, insomnia and anxiety are the most commonly reported indications for their use in patients.¹⁰ Caution is advised when considering benzodiazepines for tardive dyskinesia and muscle spasms; although frequently prescribed, benzodiazepines are generally not recommended for these and related conditions. Table 1 offers a guide to prescribing benzodiazepines.^7,9,11

BEST PRACTICES: MINIMIZING RISK, JOINT DECISION-MAKING

We lack clear guidelines on how to safely deprescribe benzodiazepines, and only a limited number of clinical trials have explored effective tapering strategies. Modesto-Lowe et al⁷ recommend minimizing benzodiazepine risks through a 3-tiered prevention strategy:

Primary prevention requires careful patient selection and education, reserving benzodiazepines for severe and disabling symptoms. If benzodiazepines are used, it is crucial to set expectations that they are a short-term, crisis-oriented solution; patients should be aware of the long-term risks, including tolerance and dependence.

Secondary prevention limits the duration of benzodiazepine prescriptions to ideally no more than 4 weeks. If extended use is necessary, patients must be continuously educated about the risks and benefits and encouraged to explore alternative treatments.

Tertiary prevention involves collaborating with long-term users to gradually taper the medication. This process should use shared decision-making to discuss the pros and cons of continued use vs tapering.

EMPOWER (Eliminating Medications Through Patient Ownership of End Results),¹⁰ a randomized trial conducted in Canadian adults age 65 and older, showed the efficacy of patient education and shared decision-making to decrease overuse of benzodiazepines. After face-to-face discussions and receiving informational pamphlets, 27% of participants in the intervention arm stopped using benzodiazepines within 6 months compared with just 5% in the control group.

Trials like EMPOWER¹⁰ have given momentum to the benzodiazepine deprescription movement, but implementing similar strategies in real-world clinical settings may be difficult given variable resources and patient adherence. Further, like our patients, all benzodiazepines are not the same and their risk profiles differ. For example, compared with other benzodiazepines, alprazolam is associated with higher toxicity risks in overdose situations and a more intense withdrawal experience, leading to quicker physiologic dependence.¹²

In response to these challenges, the American Society of Addiction Medicine has issued new guidelines on tapering benzodiazepines.¹² The guidelines emphasize the importance of patient-centered approaches, allowing for flexibility in diverse clinical circumstances. Due to lack of high-quality evidence specifically addressing benzodiazepine tapering strategies, however, the recommendations are based largely on clinical consensus and low-quality evidence from 10 studies. Further, developing tapering strategies collaboratively with patients can be a challenge in practice. Table 2 suggests strategies for tapering.^7,9,12

CLINICAL REALITIES

A recent study highlights an increase in benzodiazepine prescriptions in young adults in the United Kingdom, where new prescriptions to manage anxiety in people age 18 to 34 increased nearly 50% between 2008 and 2018, and 44% of benzodiazepine prescriptions were for more than 4 weeks.¹³ A subsequent qualitative study explored why clinicians might prescribe benzodiazepines despite guidelines advising caution.¹⁴ Some patients insist on the prescriptions, believing benzodiazepines are the only effective option. They also have concerns about the effectiveness and delayed onset of alternatives like psychotherapy and selective serotonin reuptake inhibitors. Primary care clinicians feel uneasy when declining to prescribe benzodiazepines and have seen more treatment-seeking in young adults who are already dependent on these drugs. Most clinicians try to avoid prescribing benzodiazepines but find it a challenge to deny them in situations such as acute anxiety, patients starting selective serotonin reuptake inhibitors, or crises when mental health services are not immediately available.

This trend is also observed in the United States, where benzodiazepine prescription rates have increased significantly; about 65.9 million office visits occur annually for this purpose.⁶ Although it has been observed that “[q]uietly, we have become a nation on benzodiazepines,”⁶ this widespread use is not without controversy.² An analysis of 8 studies across 7 countries revealed that primary care clinicians often find the process of prescribing benzodiazepines to be complex, uncomfortable, and demanding.¹⁵ Meanwhile, concerns persist about patients remaining on these medications indefinitely and the potential for dose escalation.

LONG-TERM USE AND DOSE ESCALATION: DO THE DATA SUPPORT CONCERNS?

In 2017, the US Food and Drug Administration updated its original statement advising against coprescription of opioids and benzodiazepines, stating instead that buprenorphine should not be withheld from patients taking benzodiazepines.¹⁶ This was one of the first publications to at least tacitly recognize that while benzodiazepine use is problematic in the substance-using population, the goal of benzodiazepine abstinence is outweighed by the need to provide treatment for opioid use disorder.

Subsequent studies have looked more closely at the potential long-term risks of benzodiazepine use. A study done in Denmark from 2000 to 2020 analyzed long-term use and dose escalation of benzodiazepines and benzodiazepine-related drugs among 4.3 million adults age 20 to 80.¹⁷ In 950,767 new benzodiazepine-related drug users, only 15% used them for more than a year, and only 3% for more than 7 years, with the highest rates among those starting with Z-drugs. In users with at least 3 years of continuous use, dose escalation above recommended doses occurred in only 7%. Further, the risks of long-term use and dose escalation were higher in patients with psychiatric comorbidity, especially substance use. This study challenges the belief that starting benzodiazepine-related drugs inevitably leads to prolonged use or dose escalation. Rather, it found that overall risk was low and risk was highest in patients with comorbidity.

Benzodiazepines can become problematic in high-risk populations, but this does not rule out their safe use for appropriate patients.^7,8 Critics of benzodiazepine guidelines argue that they do not align with clinical realities; they particularly question the blanket approach of discontinuing these medications for all long-term users.⁸ A 2023 study by Maust et al¹⁸ indicates that deprescribing benzodiazepines in patients on long-term stable treatment led to increased mortality along with increases in nonfatal overdoses, suicidal ideation, and emergency department visits, compared with those who continued treatment. This surprising finding gives pause to the current push to rid our patients’ cabinets of these medications across the board.

The Rosenqvist et al¹⁷ and Maust et al¹⁸ studies call into question the widespread notions that long-term use of benzodiazepine is de facto harmful and that deprescribing is always beneficial. The Archer et al¹⁴ study shows us that withholding benzodiazepines in certain situations can be very difficult. While we await further research to clarify under what circumstances long-term use of benzodiazepines is appropriate, it behooves us to take a more measured approach rather than simply advocating for the discontinuation of all benzodiazepine use.

DISCLOSURES

The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.