Long-Term Use Of Benzodiazepine Drugs For Anxiety And Sleep Disorders Linked To Increased Alzheimer’s Risk

A new Open Access study published in the prestigious BMJ journal finds indication that use of benzodiazepines, widely prescribed drugs for treatment of anxiety and insomnia, is associated with an increased risk of developing Alzheimer’s disease, particularly for long-term users.

These drugs, medically referred to as benzodiazepine receptor agonists, work by increasing the effectiveness of a neurotransmitter called gama-amniobutryic acid (GABA) that impedes sending alert fullness signals to other nerve cells. This action has the complimentary effects of reducing anxiety, increased sedation and muscle relaxation, and benzodiazepines are commonly prescribed to treat general anxiety, panic attacks, insomnia, seizures (including status epilepticus), muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, opiate withdrawal syndrome, withdrawal from benzodiazepines themselves, and Ménière’s disease. They may also be used for sedation in certain medical procedures such as endoscopies to reduce tension and anxiety, and impart pain tolerance, and in some surgical procedures to induce amnesia or to reduce anesthesia dose requirements or as the sole agent when IV anesthesia is not available or is contraindicated.

However, a Wikipedia entry notes that concerns about long-term effects of benzodiazepines have been raised since at least 1980, and remain to be fully answered, and cites a 2006 metanalysis of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics, concluding that more research is needed to evaluate long-term effects of hypnotic drugs. The majority of benzodiazepine problems have been related to long-term as opposed to short-term use, and the article says there is a growing body of evidence of harm resulting form long-term use (ie: longer than 2-4 weeks to three months depending on whose definition of “long term”) of benzodiazepines, especially at higher doses.

The article says long-term effects of benzodiazepine use are very similar to long-term effects of alcohol abuse (with the exception of organ toxicity with the latter) and of other sedative-hypnotics, and that withdrawal effects and dependence are almost identical, citing a 1987 report by the Royal College of Psychiatrists in Great Britain determining that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. Nevertheless, benzodiazepines continue to be widely prescribed, and use of these drugs for treatment of anxiety has been found to significantly increase healthcare costs due to accidents and other adverse effects associated with their long-term use.

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When they first came on the market in 1961, benzodiazepines were initially regarded as safe and beneficial drugs. For a time, Valium (diazepam) was reportedly the highest-selling drug worldwide, and The New York Times Magazine’s Robin Marantz Henig reports that Xanax, the leading successor product to Valium, outsells every other psychiatric drug on the market (48.7 million prescriptions in 2011), with Valium itself still selling briskly to the tune of 14.7 million prescriptions written in 2011.

An astonishingly prolific range of benzodiazepine drugs are available in many forms, including tablet, capsule and liquid as well as injectable types. The most common variants include: Klonopin (clonazepam), Xanax (alprazolam), Librium (chlordiazepoxide),Valium (diazepam), Ativan (lorazepam), Doral (quazepam), Halcion (triazolam), and Rohypnol (flunitrazepam).

Adverse effects of benzodiazepines have been associated with anterograde amnesia and confusion (especially pronounced in higher doses) and sedation, with the elderly in particular being more prone to adverse effects of these drugs, such as confusion, amnesia, ataxia, and hangover effects, and falls.

In a 1984 study (Poulos CX, Zack M (November 2004). “Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers.” Behavioural Pharmacology 15 (7): 503–12. doi:10.1097/00008877-200411000-00006. PMID 15472572) 20 patients who had been on long-term benzodiazepines were submitted to brain CT scan examinations, with some scans appearing abnormal, although there was no significant relationship between CT scan appearances and benzodiazepine therapy duration., and clinical significance of the findings was unclear.

In 1986, it was indicated that permanent brain damage may result from chronic benzodiazepine use similar to alcohol-related brain damage.(Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI (2005). “Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence.” Substance Use & Misuse 40 (4): 499–510. doi:10.1081/JA-200052433. PMID 15830732)

A 1987 study (“Diazepam: overdose” Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10) of 17 high-dose inpatient benzodiazepine abusers anecdotally showed enlarged cerebrospinal fluid spaces with associated brain shrinkage, which reportedly appeared to be dose dependent with low-dose users having less brain shrinkage than higher-dose users. However, However, a 1987 CT study (Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0-19-515130-5) found no evidence of brain shrinkage in prescribed benzodiazepine users.

In 1989, a 4- to 6-year follow-up study of 30 inpatient benzodiazepine abusers (Lai SH, Yao YJ, Lo DS (October 2006). “A survey of buprenorphine related deaths in Singapore”. Forensic Science International 162 (1–3): 80–6. doi:10.1016/j.forsciint.2006.03.037) found neuropsychological function permanently affected in particularly those who were chronic high-dose abusers, and brain damage similar to alcoholic brain damage was also observed. However, unlike alcoholics, sedative hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in sedative hypnotic benzodiazepine abusers, it is often permanent.

A Committee on Safety of Medicines and the Royal College of Psychiatrists in the UK concluded in various statements (1988 and 1992) that benzodiazepines are unsuitable for long-term use and that they should in general be prescribed for periods of 2-4 weeks only.

However, a 1993 CT study (Holt, Gary A. (1998). Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press. pp. 90–91. ISBN 0-944496-59-8) investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group, and a study in 2000 (Zácková P, Kvtina J, Nmec J, Nmcová J (December 1982). “Cardiovascular effects of diazepam and nitrazepam in combination with ethanol”. Die Pharmazie 37 (12): 853–6. PMID 7163374 )found that long-term benzodiazepine therapy does not result in brain abnormalities.

Notwithstanding conflicting findings, with various forms of dementia now affecting some 36 million people worldwide and rapidly growing, with incidence projected to double every 20 years, reaching 115 million in 2050, increased risk of dementia has been identified in benzodiazepine users, although the nature of this association, whether causal or not, remains unclear.

To investigate the relationship between the risk of Alzheimer’s disease and benzodiazepine exposure over at least five years, as well as a potential dose-response relationship possibly linked with treatment, a team of researchers based in France and Canada used data from the Quebec, Canada health insurance program database (RAMQ) track development of Alzheimer’s disease in a sample of elderly residents living in the province who had been prescribed benzodiazepines. They note that prevalence of benzodiazepine use among elderly patients is consistently high in developed countries, ranging from 7 percent to 43percent.

Over a period of at least six years the scientists identified 1,796 cases of Alzheimer’s disease, which they individually compared with 7,184 healthy people matched for age, sex, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09. Association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis, and was assessed by using multivariable conditional logistic regression.

The investigation’s results show past use of benzodiazepines for three months or more associated with an increased risk (up to an alarming 51 percent) of Alzheimer’s disease. The strength of association increased with longer exposure and with use of long-acting benzodiazepines rather than short-acting ones. Moreover, further adjustment for symptoms that might indicate the start of dementia, such as anxiety, depression or sleep disorders, did not meaningfully alter the results.

The researchers conclude that In this large case-control study, benzodiazepine use was associated with an increased risk of Alzheimer’s disease, and the stronger association observed for long term exposures reinforces suspicion of a possible direct association, although they emphasise that the nature of the link is still not definitive but say the stronger association seen with long-term exposures. Nevertheless, their findings reinforce suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of other conditions associated with increased risk of dementia. They suggest that unwarranted long-term use of these drugs should be considered a public health concern.

The study published this week in BMJ, entitled “Benzodiazepine use and risk of Alzheimers disease: case-control study” (BMJ 2014; 349 doi: https://dx.doi.org/10.1136/bmj.g5205 (Published 09 September 2014), is coauthored by Sophie Billioti de Gage, PhD student, Yola Moride, professor, Thierry Ducruet, researcher, Tobias Kurth, director of research, Hlne Verdoux, professor, Marie Tournier, associate professor, Antoine Pariente, associate professor, and Bernard Bgaud, professor, variously of INSERM, U657-Pharmacoepidemiology, College of Health Sciences, and Inserm Research Center for Epidemiology and Biostatistics, Université de Bordeaux,, Bordeaux, France; the University of Montreal Hospital Center Faculty of Pharmacy and Research Center, Montreal, Canada; and the Centre Hospitalier Charles Perrens, Bordeaux, France.

The coauthors observe that while acute deleterious effects of benzodiazepines on memory and cognition are well documented, possibility of an increased risk of dementia is still a matter of debate. They note that frequency of symptoms highly correlated with prescription of benzodiazepines (anxiety, insomnia, and depressive disorders) increases in the years before a diagnosis of dementia, hence it is possible that benzodiazepines might not cause the disease but rather be prescribed to treat conditions associated with Alzheimer’s development, but that adjustment for such a reverse causality bias is not easy in observational studies. Moreover, they point out that few studies published on the topic have had sufficient power to investigate a cumulative dose relation, which makes a compelling argument for further assessment of potentially drug induced outcomes.

The scientists evaluated association between past benzodiazepine use and risk of Alzheimers disease using an administrative claims database with a long follow-up period, and investigated potential dose-effect relationships. They found use of benzodiazepines at any time was significantly associated with an increased risk of Alzheimers disease, with no difference observed for cumulative exposures of up to three months. In longer term use, they report that Alzheimer’s risk increased with cumulative exposures, and association with Alzheimer’s was stronger for long acting benzodiazepines than for short acting ones.

However, with their study finding risk of Alzheimer’s disease increased by 43-51% among those who had used benzodiazepines in the past, the researchers say it reinforces suspicion of an increased risk of Alzheimer type dementia among benzodiazepine users, particularly long term users, and provides arguments for carefully evaluating the indications for use of this drug class — especially considering the prevalence and chronicity of benzodiazepine use in older people. They contend that with no preventive or curative treatment having been shown to be satisfactorily effective for Alzheimer’s disease, identification of putative alterable risk factors should be prioritized, and with increasing incidence of dementia in developed countries, greater likelihood of Alzheimer’s development in 43-51% of benzodiazepine users would generate a huge number of excess cases.

The scientists conclude that in light of evidence they’ve compiled, it is crucial to encourage physicians to carefully balance benefits and risks, with a bias toward shortest duration of treatment and a preference for formulations with a short half life when initiating or renewing a treatment with benzodiazepines and related products in older patients. Moreover, notwithstanding the lack of data in younger adults, the precautionary principle would also support extending that recommendation to them, and that further study is somewhat urgently warranted.

Sources:
BMJ
Wikipedia
British Journal of Clinical Pharmacology
The New York Times Magazine
Allsleep.com
benzo.org.uk