Data Show Cognitive Consequences of Benzodiazepine Use

Benzodiazepines are a commonly prescribed class of medications used to manage conditions such as anxiety, insomnia, alcohol withdrawal, muscle spasms, and seizures. Because of the potential for dependence, withdrawal, and long-term adverse effects (AEs), they are only intended for short-term use. However, benzodiazepines are frequently used to manage disease states for the long term, despite labeling recommendations that the duration of use for these medications remains no more than 2 to 4 weeks.¹

In one meta-analysis of 13 studies, the average duration of benzodiazepine use was 9.9 years, with some patients using benzodiazepines for as long as 34 years.² This is concerning because, as health care professionals, it is our responsibility to provide care that is not only effective but also safe for patients, and the safety and efficacy of long-term benzodiazepine use beyond the recommended time frame are not well understood.³

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One of the primary concerns of longterm benzodiazepine use is its impact on cognitive function.⁴ Although much remains unknown, some prescribers believe that cognitive impairment resulting from benzodiazepine use is a transient effect related to peak plasma levels and time since last dose.² However, many studies have shown otherwise.

Several studies have demonstrated that long-term use of benzodiazepines can cause impairment in numerous dimensions of cognitive function.² In current longterm users, benzodiazepines have been shown to cause impairment in the domains of motor coordination, psychomotor speed, verbal reasoning and learning, executive function, sensory processing, episodic memory, and concentration.^2,5 Benzodiazepines have also been shown to decrease IQ, processing speed, and visuospatial and visuomotor abilities.^2,4

The experience of this cognitive impairment in patients can also result in delayed response time and altered perceptions of self, environment, and interpersonal relationships in addition to causing deficits in expressive language, working memory, visuoconstruction, and divided attention.^2,6 In a meta-analysis including 13 studies in which the average length of benzodiazepine use was 10 years, cognitive impairment was found in all domains studied, including sensory processing, visuospatial abilities, and motor performance.² Another study analyzing the impact of long-term benzodiazepine use on cognition found that about 21% of subjects had cognitive impairment in all domains investigated.⁵ All of these studies further corroborate the detrimental impact benzodiazepines can have on patients’ cognitive abilities.

In addition, multiple studies have implicated the inappropriate use of benzodiazepines as a risk factor for dementia-related illnesses. In a meta-analysis including clinical and observational studies, Ettcheto et al supported the theory that long-term use of benzodiazepines, especially in older patients, increases the risk of Alzheimer disease and dementia, with the increased risk of dementia compounded when patients take high cumulative doses.⁷ Another study by Islam et al concluded that long-term exposure to benzodiazepines increases the risk of dementia as much as 78% compared with individuals who do not use benzodiazepines.⁸

Although the exact mechanism by which benzodiazepines increase the risk of dementia disorders is unknown, potential causes include the drug’s ability to prevent the creation of new memories by inhibiting brain activity and synaptic plasticity, to decrease metabolic activity in the brain, and to encourage the formation of neurofibrillary tangles.⁷ Although studies have supported that benzodiazepines can lead to dementia, other studies have presented conflicting evidence showing that long-term use does not lead to an increased risk for Alzheimer disease or dementia.^7,9 One study stated that benzodiazepines may have a beneficial impact on preventing these diseases; however, this could be because disease states treated by benzodiazepines include insomnia and anxiety, which are themselves implicated as increasing the risk of dementia.⁹ A major hindrance to knowledge in this area is that a majority of studies are observational, which means a causal relationship cannot be determined from the data.⁸ This, in turn, means more research is needed to further knowledge on the relationship between benzodiazepine use and dementia risk.

Because the effects of long-term benzodiazepine use are not well understood, many prescribers believe the more pernicious effects of benzodiazepines on cognition are temporary. However, studies have demonstrated that cognitive dysfunction attributed to benzodiazepines can be long lasting and can persist after discontinuation. Fortunately, some prior long-term benzodiazepine users have experienced some degree of improvement in cognitive function.⁴ On the other hand, this improvement is not always enough to allow these users to return to their baseline functioning.

One study indicated that although patients improve after cessation of benzodiazepines, they never reattain the level of cognitive function of controls in the study who did not previously use benzodiazepines.² Impairments have been determined to persist in domains including speed of processing, working memory, and divided and sustained attention.⁶

In a study following previous benzodiazepine users for 6 months after withdrawal, it was observed that they continued to show dysfunction in multiple cognitive domains compared with controls. Another study followed previous benzodiazepine users and saw impairments in cognitive function even at 10 months post discontinuation.⁴ These studies support continued impairment at 6 and 10 months after discontinuation of benzodiazepines but it is unknown if or when cognitive function will return to baseline levels.⁵

A potential confounding factor around whether patients return to normal cognitive function is that benzodiazepines are often used to manage mental health disorders such as anxiety and insomnia, which in and of themselves can lead to some degree of cognitive impairment; if patients discontinue treatment, symptoms of these diseases may return. However, in studies comparing cognitive function in previous benzodiazepine users with controls and anxious controls, previous benzodiazepine users still performed worse in multiple cognitive categories.^4,6

Knowing that using benzodiazepines beyond the recommended duration can have such detrimental lasting effects on patients, it is important that providers take the time to educate themselves to make the best decisions for their patients’ health. Many patients trust their providers to make decisions in their best interest, so it is crucial that providers ensure that when benzodiazepines are used as a treatment, they are the best available option based on a thorough risk-benefit assessment. It is also essential that prior to being prescribed benzodiazepines, patients are educated on the potential harms of this class of medications so they can be involved in making a decision they feel most comfortable with.

In addition, education on the potential harms of benzodiazepine use is an area that pharmacists are particularly able to support as members of the health care team. Pharmacists truly are the medication experts, so they can play an integral role in helping to make informed patient care decisions, such as determining if there are better alternatives or whether a medication is the best choice for a patient, and finding ways to minimize the risk of certain AEs.

Some important things to consider regarding the reduction of harm to patients caused by long-term benzodiazepine use are risk factors. Certain patient populations are at a higher risk of experiencing lasting AEs on cognition, including those taking higher doses; older patients; and those using benzodiazepines concomitantly with drugs, alcohol, or anticholinergic psychotropic medications.² With age as a risk factor, older patients are at a higher risk of experiencing reduced recovery of cognition after discontinuation of benzodiazepines.⁴ This is because as patients get older, they have fewer neurons and receptors to which benzodiazepines can bind, meaning more receptors are occupied at the same dose, making them more susceptible to the AEs of benzodiazepines.³

Pharmacokinetic properties of benzodiazepines also play a role in the probability of patients experiencing cognitive dysfunction after withdrawal from long-term benzodiazepine use. For example, agents with shorter half-lives tend to have a lower risk of cognitive impairment whereas those with intermediate-to-long half-lives have an increased risk.⁶ Another potential risk factor for experiencing cognitive impairment after long-term benzodiazepine use is sex; however, there is conflicting evidence on whether men or women are at higher risk. One study stated that men were at increased risk; however, another supported that women are at higher risk. In 1 study, women were found to have a significantly lower compound cognitive score than men, and sex was undetermined to be an important predictor of cognitive dysfunction.⁵ Although a worse performance of cognitive function in women was found, it was determined to be due to state anxiety, and when this was accounted for, sex was no longer found to be a predictor of worse cognitive function. Instead, it was determined that state anxiety itself was the predictor.⁵ This conflicting evidence on sex as a risk factor indicates that more research is needed to increase our knowledge on the long-term effects of benzodiazepines not only on cognition, but on overall health. Further, it is important for providers to assess for these risk factors before prescribing benzodiazepines to patients because those at increased risk may not be the best candidates for benzodiazepines, especially in the long term, and it may be an important time to consider alternatives.

Because of inadequate knowledge on the impact of long-term benzodiazepine use on cognition, health care professionals must become educated on the potential harmful effects of long-term use. This is even more important because labeling for the recommended duration of use of benzodiazepines was only recently updated; for this reason, disseminating this information to providers is crucial. However, with pharmacists on the health care team, they can counsel patients and other providers in this area, as pharmacists’ expertise in the safe and effective use of medications cannot only save lives but improve the quality of life.

Reference

1. Kennedy KM, O’Riordan J. Prescribing benzodiazepines in general practice. Br J Gen Pract. 2019;69(680):152-153. doi:10.3399/bjgp19X701753

2. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry. 2005;66(suppl 2):9-13.

3. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol. 2014;77(2):295-301. doi:10.1111/j.1365-2125.2012.04418.x

4. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc. 2005;11(3):281-289. doi:10.1017/S1355617705050332

5. Zetsen SPG, Schellekens AFA, Paling EP, Kan CC, Kessels RPC. Cognitive functioning in long-term benzodiazepine users. Eur Addict Res. 2022;28(5):377-381. doi:10.1159/000525988

6. Crowe SF, Stranks EK. The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis. Arch Clin Neuropsychol. 2018;33(7):901-911. doi:10.1093/arclin/acx120

7. Ettcheto M, Olloquequi J, Sánchez-López E, et al. Benzodiazepines and related drugs as a risk factor in Alzheimer’s disease dementia. Front Aging Neurosci. 2020;11:344. doi:10.3389/fnagi.2019.00344

8. Islam MM, Iqbal U, Walther B, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2016;47(3-4):181-191. doi:10.1159/000454881

9. Pariente A, de Gage SB, Moore N, Bégaud B. The benzodiazepinedementia disorders link: current state of knowledge. CNS Drugs. 2016;30(1):1-7. doi:10.1007/s40263-015-0305-4

About the Authors

Deja Neal is a class of 2024 PharmD candidate at the Wegmans School of Pharmacy at St John Fisher University in Rochester, New York.

Jolene Bressi, PharmD, PMP, BCMAS, is an adjunct professor at Ancora Education and a member of the board of directors at The Alliance for Benzodiazepine Best Practices.