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Benzodiazepines Linked to Increased Alzheimer’s Risk

Benzodiazepines Linked to Increased Alzheimer’s Risk

BenzodiazepinesBenzodiazepines include some anti-seizure medications such as in a hospital environment, intravenous clonazepam, lorazepam, and diazepam are first-line choices, clonazepam due to its stronger and more potent anticonvulsant action, lorazepam due to its faster onset and diazepam for its longer duration of action. In the community, intravenous administration is not practical and so rectal diazepam or (more recently) buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.

When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy.  Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France.   It was approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy. Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy. Discontinuation after long term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.

Use of benzodiazepines to treat insomnia or anxiety may increase the risk for Alzheimer’s disease (AD), new research suggests.

The association was even stronger in participants who had been prescribed benzodiazepines for 6 months or longer ― and in those who used long-acting versions of the medications.A case-control study of nearly 9000 older individuals showed that risk for AD was increased by 43% to 51% in those who had “ever used” benzodiazepines in the previous 5 years.

Lead author Sophie Billioti de Gage, PharmD, who is also a PhD student and researcher at INSERM Unit 657–Pharmacoepidemiology at the University of Bordeaux, France, told Medscape Medical News that the overall results were not a surprise because the short-term deleterious effects of these medications on memory are well documented. A study published by the same researchers last year showed a 50% increased risk for dementia in patients using benzodiazepines.

“The nature of the link (causal or not) is still not definitive, but these conclusions reinforce the suspicion of a possible direct association,” said Dr. Billioti de Gage.

The investigators note that although these medications are important treatment options, clinicians should “comply with good practice guidelines” and prescribe benzodiazepines for as short a time as possible. In addition, use should not exceed 3 months.

“For people needing or using benzodiazepines, it seems crucial to encourage physicians to carefully balance the benefits and risks when initiating or renewing a treatment,” added Dr. Billioti de Gage.

The study was published online September 9 in BMJ.

Public Health Implications

The researchers examined data from the Quebec, Canada, health insurance program database for 1796 individuals with a first diagnosis of AD who were older than 66 years (67% women) and who had exposure to benzodiazepines at least 5 years prior.

These patients were compared with 7184 sex- and age-matched healthy individuals; 6-year follow-up data were assessed for all participants.

Cumulative use of the medications was grouped into 3 subcategories of prescribed daily doses: 1 to 90, 91 to 180, and more than 180.

In addition, there were 2 subcategories based on “drug elimination half-life” ― those who used short-acting (<20 hours) benzodizepines, and those who used long-acting (≥20 hours).

Results showed a significantly increased risk for AD for those who had ever used benzodiazepines (adjusted odds ratio [OR], 1.51; 95% confidence interval [CI], 1.36 – 1.69).

After adjusting for anxiety, depression, and insomnia, the results did not change markedly (OR, 1.43; 95% CI, 1.28 – 1.60).

“The strength of association increased with exposure density,” report the investigators.

The ORs for AD were 1.32 (95% CI, 1.01 – 1.74) for those prescribed 91 to 180 daily doses, and 1.84 (95% CI, 1.62 – 2.08) for those prescribed more than 180 daily doses. There was no significant association for AD for cumulative exposures of up to 3 months.

The association strength also increased with the drug half-life. There was an OR for AD of 1.43 (95% CI, 1.27 – 1.61) for short-acting versions of the drugs vs an OR of 1.70 (95% CI, 1.46 – 1.98) for long-acting ones.

“Our findings are of major importance for public health, especially considering the prevalence and chronicity of benzodiazepine use in elderly populations and the high and increasing incidence of dementia in developed countries,” write the researchers.

Although she noted that these treatments should be of short duration, Dr. Billioti de Gage added that patients should not abruptly discontinue long-term use because of the risk for withdrawal effects. Instead, they should first talk with their clinician.

Better Monitoring Needed

Kristine Yaffe, MD, endowed chair and professor of psychiatry at the University of California, San Francisco, and Malaz Boustani, MD, professor at the Indiana University Center for Aging Research in Indianapolis, write in an accompanying editorial that the investigators “extend the pharmacoepidemiological research” that shows adverse cognitive effects from use of these medications, while also showing a link to AD.

“Their results suggest that long term exposure…might be a modifiable risk factor for this condition,” they write, adding that the findings are strengthened by the researchers’ rigorous methods.

The editorialists note that in 2012, the American Geriatrics Society updated their list of drugs that were inappropriate for elderly patients because of the drugs’ treatment-related adverse events to include benzodiazepines.

However, “a review of published literature indicates that up to half of older adults continue to use these,” they write. And dedicated monitoring of cognitive function is often not found in routine hospital and clinical care.

“To fill this gap, we support the development of a structured reproducible approach to the identification and accurate monitoring…of all drug treatments used by older adults with multiple chronic conditions,” write Dr. Yaffe and Dr. Boustani.

“Better surveillance for cognitive side effects could improve therapeutic decisions among doctors treating high risk older adults…and hopefully, eventually, help to reduce the burden of cognitive impairment worldwide.”

A full list of disclosures from the study authors and editorialists can be found in the original article.

BMJ. Published online September 9, 2014

Written by and source: Deb Brauser, Medscape.com

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