Benzodiazepines and Dementia - Is There A Connection?

In our last blog, we discussed the concerns that accompany the use, and misuse, of a class of medications known as anticholinergics. In this blog, we are going to look at benzodiazepines or "benzos".

To be clear, there currently exists no evidence that benzodiazepines cause dementia, however researchers at the Cleveland Clinic Akron General in Akron, Ohio state that there is growing evidence of a link between this drug and Alzheimers disease in older adults.

“Despite the lack of evidence proving causality, the association between benzodiazepine use and the development of dementia is a major cause for concern given the prevalence of benzodiazepine use among older adults,” contend Rajesh R. Tampi, M.D., and Adriane Bennett, Ph.D., in an article published in Psychiatric Times.

According to them, prescribing benzodiazepines to older adults, "must be carefully reviewed given the lack of data regarding their long-term efficacy and their significant adverse effects including the risk for developing dementia.” Although we want to focus on dementia, there are so many issues with this class of medications that we need to look at in order to tell the whole story.

During my years of working as a clinician and administrator in the field of addiction, I cannot stress enough my own concerns about the overuse of benzodiazepines among older adults and seniors and the problems they develop as a result, with the side effects that occur often attributed to the "aging process". Even more concerning are the prolonged withdrawal symptoms many seniors experience called post-acute withdrawal syndrome (PAWS), which we will discuss later.

The Problems with Benzodiazepines

Overdoses and addiction

Let’s start this conversation by looking at the benzodiazepine problem. When it comes to all demographic groups, benzodiazepines are implicated in over 30% of drug overdose rates in the United States, according to the Centers for Disease Control (CDC). Now when I say implicated, it is important to note that by themselves, benzodiazepines can be relatively safe when taken as directed, even though they are highly addictive. But when used with any number of other medications and alcohol, their effects are magnified (a process called synergy) and can lead to rapid death -- hence their implication in overdose deaths.

Seniors appear to be more adversely affected by this class of drugs than any other group. This is due to two factors - synergy, as previously discussed, and falls, in which benzodiazepines are strongly implicated in the senior population.

High Prescription Rates

One long-term study by the National Institutes of Health raised serious concerns about the use of these medications in senior citizens. The study found that among all adults 18 to 80 years old, about 1 in 20 received a benzodiazepine prescription in 2008, the period covered by this study.

This number rose substantially with age, from 2.6 percent among those 18 to 35, to 8.7 percent in those 65 to 80, the oldest group studied. Long-term use — a supply of the medication for more than 120 days — also increased markedly with age. Of people ages 65 to 80 who used benzodiazepines, 31.4 percent received prescriptions for long-term use vs.14.7 percent of users 18 to 35.

In all age groups, women were about twice as likely as men to receive benzodiazepines. Among women 65 to 80 years old, 1 in 10 was prescribed one of these medications, with almost a third of those receiving long-term prescriptions. More current numbers suggest that the number of prescriptions being written for benzodiazepines has not slowed down.

Again, why? I believe stereotypes are at work here. The view that women are more “prone” to anxiety disorders and the fact that men don't usually speak about their levels of anxiety -- which they usually treat with alcohol -- may be responsible for this.

So, just what are benzodiazepines and why have they managed to stay under the radar screen? Let's look at our history.

America's Love Affair With Drugs

Help From a Bottle

America began to rapidly change after World War II. As our nation transitioned from a war economy and faced with millions of people returning home from military jobs, all areas of manufacturing began to slow down. This was accompanied by a rise in inflation and an increase in unemployment, which created massive anxiety in the country (and the world, for that matter) and the public clamored for help. And the help they sought was in a medication bottle -- drugs called tranquilizers (barbiturates).

The tranquilizers of the day were extremely addictive and way too powerful for an adult to use daily and continue to function responsibly. Something else was needed to address the day to day stress without zoning out millions of Americans. Then came a breakthrough. In the mid-50s, a drug called Miltown hit the market (named after the town in New Jersey where it was manufactured) and was considered to be a “mild tranquilizer” and joined similar drugs like Equanil and Reserpine. Soon, they became the most prescribed drugs in history up to that point.

Marketed as “miracle drugs”, they were used to treat the anxiety and stress of the “everyday housewife” (it was considered a “weakness” for men to take them, as they treated their anxiety with alcohol as we discussed before). Their use was so widespread, it was not uncommon to see signs posted in neighborhood pharmacies proclaiming that they were out of Miltown but with a promise that “more will be here tomorrow”. Doctors, pressured by the pharmaceutical companies as well as their patients, wrote out prescriptions in record numbers.

But the wonders of this class of drugs were short-lived. It turned out that Miltown and the other “mild” barbiturates were just as addictive as their more powerful predecessors, creating a rapid dependence in its users and increased the dangers of overdosing. Pharma had to find a new medication to address America’s hunger for a ‘feel-good’ drug. Enter benzodiazepines, discovered accidentally while researching an alternative for barbiturates.

Once Called a Wonder Drug

When benzodiazepines hit the market in the mid-1960s, they were touted as safer than barbiturates and were embraced by the medical profession as the next “wonder-drug” to treat the “nervousness and anxiety” of the American people.

By the mid-1970s, benzodiazepines had become one of the most prescribed drugs in the United States and in most developed countries around the world. As these medications reached their height of popularity, the initial euphoria exhibited by medical professionals began to wane for the general population – but continued to be used liberally for their senior patients.

As the 1980s rolled around, warnings on the negative effects of long-term benzodiazepine use were issued with seniors being one of the groups targeted. Despite this concern, benzodiazepines continued to be a hugely popular class of drugs.

And now, in the 21st Century, benzodiazepines are still prescribed at relatively high rates. Now to be fair, this class of drugs is still safer than barbiturates as their main danger occurs, as discussed earlier when used with other medications or substances that cause respiratory depression, whereas barbiturates can cause respiratory depression on their own and directly cause death and overdose.

However, in seniors, benzodiazepines – by themselves – have serious and sometimes deadly consequences. In fact, benzodiazepines are considered to be so dangerous for seniors that a group of physician geriatric experts has indicated that there exists no safe level of use in elderly patients.

Black Box Warning

Based on these concerns, the Food and Drug Administration (FDA) has issued a black box warning for them and their use with other CNS depressants. This is the strictest warning put on the labeling of prescription drugs or drug products by the FDA when there exists reasonable evidence of serious hazards with a drug. Even so, benzodiazepines continue to be prescribed for the elderly to treat anxiety and sleep problems at alarmingly high rates.

Some of the direct effects of benzodiazepines on seniors include drowsiness, confusion, mental clouding, lethargy, and the inability to concentrate. Other side effects include blurred vision, night wandering, incontinence, nightmares, and appetite changes.

Secondary dangers of these drugs include cognitive difficulties, falls, and fractures due to impaired balance and automobile accidents – and as mentioned earlier, statistics indicate that benzodiazepines are the number one drug implicated in falls caused by medications.

These drugs are also problematic due to the physiological changes that we experience as we grow older. The process of aging tends to slow nearly all body functions, including the liver, which means it takes longer for a senior’s body to process this medication. In addition, an aging body also tends to store this drug in fat cells. Given this, the level of benzodiazepines in the body of a senior tends to be higher than that of a younger person using the same amount and can approach toxic levels even when taken as directed.

As the body stores benzodiazepines, the accumulation of this drug continues as the body is unable to effectively eliminate it. Because of this dangerous cycle, the side effects become atypical and can lead to a misdiagnosis of conditions of aging, including dementia and Alzheimer’s disease.

Benzos and Addiction

Why Benzos Are So Addicting

The National Institute on Drug Abuse (NIDA) considers benzodiazepines to be one the most addictive substances known to man, behind heroin, cocaine, and nicotine. This is because benzodiazepines affect dopamine production within the brain. Dopamine is a neurotransmitter associated with pleasure, reward, and motivation. When any activity – sex, eating, substance abuse – causes excessive dopamine levels (rewarding, pleasurable activities), the brain is “trained” to repeat that behavior.

Addiction to benzos can occur rather quickly, both psychologically and physically. Using them for a period as small as three weeks can cause withdrawal symptoms when use stops. Using them for prolonged periods increases the likelihood of severe withdrawal symptoms.

Benzo Withdrawal

The most serious withdrawal symptom of benzos is the risk of Tonic-Clonic (also known as Grand Mal, a term no longer used) seizures. According to medical professionals, these occur in nearly one-third of users who do not seek treatment for withdrawal from these drugs.

According to the Epilepsy Foundation, this type of seizure (also called a convulsion) is what most people think of when they hear the word "seizure." As implied by the name, they combine the characteristics of tonic and clonic seizures. Tonic means stiffening, and clonic means rhythmical jerking. This type of seizure involves both sides of the brain.

Seizures are dangerous for a number of reasons, first, if they occur in an uncontrolled setting, like driving a car, it can be potentially fatal. Vomiting and aspiration can occur and a lack of oxygen can also cause damage.

Other withdrawal symptoms include delirium (an abrupt change in the brain that causes mental confusion and emotional disruption) and paranoia (intense anxious or fearful feelings and thoughts often related to persecution, threat, or conspiracy). These symptoms lead to erratic and sometimes violent behaviors, hallucinations, and delusions.

Withdrawal from benzos has an acute phase that can last for days or weeks, given the type of benzo used and the half-life of that drug. However, many states that withdrawal symptoms have lasted for months and even years. Such protracted withdrawal symptoms are called post-acute withdrawal syndrome (PAWS), which can occur with any drug that has a toxic effect on the brain.

Benzodiazepine withdrawal typically has an acute phase that might last several days to a few weeks, depending on the half-life of the benzodiazepine. Given the complex and potentially fatal withdrawal syndromes, medical management of benzodiazepine detoxification is recommended.

Women Are Over-Represented - A Cause for Concern

Why women?

A recent Athena Health report continues to show that those over the age of 65 are prescribed benzodiazepines more than any other age group. Ten percent of women over the age of 65 are prescribed one of these drugs compared to just six percent of men, nearly twice the rate.

According to Dr. Robert Roca, the chair of the American Psychiatric Association's Council of Geriatric Psychiatry, “women are more likely to express distress” while men tend to hold their feelings. The problem with this, as we discussed before, men tend to use alcohol to deal with anxiety, which is a problem to be discussed in the future.

...In Alzheimer's Cases as Well

But it's not just with scripts of benzos where women are over-represented, it is also with the incidence of Alzheimer's disease. Nearly two-thirds of the more than 5 million Americans living with Alzheimer’s are also women. Why?

According to the Alzheimer's Association, the easiest explanation is that women generally live longer than men, making them more likely to reach the ages of greater risk. But according to their website, "there is emerging evidence that suggests there may be unique biological reasons for these differences beyond longevity alone. These biological underpinnings may contribute to the underlying brain changes, progression, and symptom manifestation in Alzheimer’s disease."

"There is evidence that biological sex differences may affect mortality in men differently than women, but how that affects Alzheimer’s disease and related dementia incidence is not clear. Do hormones play a role? What about our genes? Do lifestyle components such as sleep patterns, stress, and depression influence sex differences in Alzheimer’s disease?"

And, are the lifestyle components of Alzheimer's disease also a reason for the over-representation of benzodiazepine use by women? There is so much work to be done here.

Dangerous and Deadly Combinations

So now let’s look at the dangers of combining these drugs with other medications. When it comes to overdose risk, the combination of benzodiazepines and opioids are indeed the most dangerous, a concern that prompted a Black Box warning by the Food and Drug Administration regarding the use of these two classes of medications together.

Opioids and Benzos

A study examined data from more than 71,000 Medicare Part D beneficiaries to find out how simultaneous use of opioids and benzos influence overdose risk over time. Patients were divided based on whether they had only taken opioids prior to overdose or had a supply of both opioids and a benzo drug. For those in the group with a supply of both, the researchers subdivided by the cumulative number of days the patients had taken an opioid with a benzo.

The analysis showed that overdose risk was five times higher for patients taking both drugs during the first 90 days compared to those only taking just an opioid. The risk was doubled for those taking both drugs during the next 90 days. After 180 days, the risk of overdose was roughly the same as taking only opioids.

There are a number of reasons for this, including the patient's lack of understanding of the side-effects and when to report them as well as how the patient takes them. In any case, it is important to know that based on this study, if an overdose is to occur, it will be in the first three to six months, something caretakers should be aware of.

But opioids are not the only drug when taken together with benzodiazepines that can cause serious side-effects. Let's look at three classes of medication that need to be monitored.

Insomnia Drugs (Z-drugs) and Benzos

Known as “Z-drugs” and prescribed to help battle insomnia, many medical providers are unaware that they have a similar mechanism of action as benzodiazepines. These drugs include Ambien, Lunesta, and Sonata.

When these medications are used in combination with benzodiazepines, they can cause blackout spells. In another 2017 study of emergency room visits for adverse events involving benzodiazepines or “Z-drugs”, it found a 4-fold increase in risk for serious events when the two medications were combined.

There are growing evidence and research studies underway that implicate the use of anticholinergics, benzodiazepines, and z-drugs may lead to long-term cognitive decline and dementia.

Stomach Meds and Benzos

Known as proton pump inhibitors (PPIs) used to treat acid reflux, medications such as Prilosec, Nexium, Prevacid, and Protonix have been shown to increase the blood levels of benzodiazepines by interfering with the way the liver clears them from the body.

As a result, the side effects of benzodiazepines are magnified causing increased confusion, sedation, dizziness, falls, and driving mishaps. The most common PPIs associated with these side effects are Prilosec and Nexium.

Fluoroquinolone Antibiotics and Benzos

Fluoroquinolones are antibiotics that are commonly used to treat a variety of illnesses such as respiratory and urinary tract infections. These medications include Cipro, Levaquin, and Avelox. Since they compete for the same binding site as benzos, the antibiotics actually block the benzos leading to acute withdrawal symptoms in those who have been taking them long term (similar to what Narcan does with an opioid overdose victim). Benzo withdrawal can be life-threatening resulting in seizures, high fevers, and psychosis.

The FDA has issued a Black Box Warning for benzodiazepines and these medications stating that they can cause serious or even deadly side effects when used together.

Here are some other issues associated with benzodiazepine use.

Other Concerns

Memory Impairment and Benzos

In the majority of studies, benzodiazepines have been shown to block a person's ability to learn new information. Research seems to indicate that this results from the brain's inability to transfer short-term memory to long-term memory. Elderly patients are more sensitive than younger ones to the effects of benzodiazepines and memory problems. As a result, family and friends may be willing to chalk this up to aging issues or even the onset of dementia rather than looking at benzodiazepines as the cause.

Cognitive and Psychomotor Effects and Benzos

Both short term and long term use of benzodiazepines have been shown to have an effect on cognitive and psychomotor functioning. These include sedation, drowsiness, coordination issues, vertigo, and dizziness.

Accidents and Benzos

Benzodiazepine use has been shown to affect driving skills, especially in seniors. Even some of the less strong benzodiazepines have been associated with increased falls resulting in hip fractures.

The Association Between Benzos and Alzheimer's

The biology...

To repeat an earlier point, the association between benzos and Alzheimer's does not indicate causation, however, researchers are finding more and more links that continue to raise suspicions. Researchers have identified three possible biological connections between benzos and the development of dementia.

First, there are indications that benzos decrease the activity of the amyloid precursor enzyme 1 (BACE-1) and c-secretase activity resulting in amyloid accumulation in the brain. The second, astrocytes that are in close proximity to the amyloid accumulation in the brain secrete GABA (aminobutyric acid), leading to cognitive decline. Lastly, benzos appear to reduce the cognitive reserves by decreasing brain activation levels.

Benzos, dementia and mortality

In articles published in 2017 and 2020, benzo and related drug use were associated with a 40 percent increase in mortality among individuals with Alzheimer's disease. These findings were printed in the International Journal of Geriatric Psychiatry. According to the study, the deaths, which were traced back to day one of use, were the result of adverse events such as falls, hip fractures, pneumonia, and stroke.

Stroke risk

There appears to be a significant stroke risk among those with Alzheimer's disease who use benzos. Researchers have found a 20 percent increase in the risk of stroke among this group. As a result, they strongly advise against the use of benzos and benzo like drugs since stroke is one of the leading causes of death among this group.

Pneumonia and Benzos

One theory put forward by the researchers, based at several institutions across Finland, is that the sedative effects of benzodiazepines may increase the risk of pneumonia by boosting the likelihood of aspiration of saliva or food into the lungs. This theory correlates with the study’s finding that pneumonia risk is highest at the start of benzodiazepine use, as the sedative effect is more pronounced initially before tolerance is built up, according to researchers.

At this point, there exists evidence that a positive association does exist between benzos and the development of dementia, but no causality. Despite this, medical professionals need to heed the associative evidence when prescribing this class of drugs to older adults.

In our next blog, we'll look at "Z-drugs", opiates, antipsychotics, and mood stabilizers.