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Benzodiazepines, (pronounced ‘ben-zoh-die-AZ-a-peens’) or “Benzos” are a class of central nervous system depressants used primarily to treat anxiety and insomnia.

They do this by inducing a general feeling of calm, relaxation, and sedation. This process of removing anxiety is called anxiolysis.

The mechanism of action or the specific way in which benzodiazepines bring about their sedating, calming effect is through their action on the brain chemical or neurotransmitter GABA (gamma-aminobutyric acid) at the GABA receptors (benzodiazepine receptors) in the brain.

GABA plays a very important role in mammalian central nervous system physiology and chemistry.

It is the chief inhibitory chemical responsible for tamping down neuronal excitability and regulating muscle tone in humans.

In other words, when your nervous system goes into overdrive and gets over-stimulated with anxiety, panic, etc., GABA effectively puts the “brakes” on your “runaway train,” quickly calming you down.

GABA sends its inhibitory message to its specific target sites on the GABA-A receptors located on the outside of the neuron that is receiving the message.

So, benzodiazepines decrease the activity of the neurons that are responsible for triggering stress and anxiety reactions.

What conditions do Benzodiazepines treat?

Benzodiazepines are approved to treat the following medical conditions:

• Anxiety Disorders (short-term only, as a bridge while a prescribed SSRI begins to work)
• Panic Disorder
• Insomnia
• Seizure disorders
• Social anxiety disorder
• Agitation from alcohol withdrawal or substance abuse
• General anesthesia or sedation prior to surgery

Off-label use

• Other sleep disorders (REM sleep disorder, Restless Legs Syndrome, etc)
• Tic/Movement disorders (tremors, tardive dyskinesia, etc)
• Depression
• Traumatic brain injury (TBI)
• Muscle spasms (sometimes given with muscle relaxants)
• Agitation
• Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD)
• Eating disorders

Differences between benzodiazepines

Not all benzodiazepines are the same. Some are longer acting and some are shorter acting (their half life). They also differ in how quickly they start working, and the medical conditions for which they are prescribed.

Many variables factor into proper dosing of the benzodiazepine for you.

The drug’s chemical structure and the manner in which it is metabolized (broken down) by your liver and eliminated by your kidneys play an important role in how long the medication stays in your system.

These factors can determine whether the drug is exerting its intended therapeutic effect, or an overdose or toxicity is more likely.

All benzodiazepines undergo either a Phase 1 or Phase 2 reaction when they are being metabolized and eliminated by the body.

Phase 1 Reaction Pathway Explained

In simplest terms, the liver processes certain benzodiazepines through the Phase 1 pathway, and in so doing, another pharmacologically active benzo is produced, in addition to the parent benzo.

To illustrate this concept, let’s take a look at how a commonly prescribed benzo, Valium (diazepam), is metabolized by the liver. Valium undergoes Phase 1 reaction, resulting in an active metabolite called desmethyldiazepam.

Looking at the image below, we see two graphs; the one on the left depicts blood levels of the drug and the number of hours taken to eliminate it in a younger person.

The blue line represents the parent drug, diazepam, while the red line represents the active metabolite.

The graph on the right relays the same information, this time in an older adult.

See the huge difference between both individuals?

In the older adult, the active metabolite’s blood levels are still being steadily maintained past 192 hours (8 days) with just one dose of the benzo! And, this medication is usually dosed 3 or 4 times daily!

And, this is why older adults are so sensitive to and at incredibly high risk for adverse events from benzodiazepine use!

Which benzodiazepines are preferred for older adults?

Phase 2 Reaction Pathway Explained

Not all benzodiazepines undergo Phase 1 reactions. Some go through the Phase 2 reaction pathway. When these drugs are broken down, no active metabolites are produced.

So, the overall duration of action and half-life of these benzos are not long. Reduced drug levels and less time in the body translate to fewer adverse effects and toxicity.

Some Phase 2 pathway benzodiazepine examples are Lorazepam, Oxazepam, and Temazepam (Remember the acronym “LOT“).

As a drug class, benzodiazepines are potentially inappropriate for older adults. However, there are certain situations where there may be a clear medical need for a benzo to be prescribed for an older adult.

For example, a one-time dose to calm someone down prior to invasive pre-dental surgery, or a panic attack may be appropriate.

In these cases, when absolutely necessary, Phase 2 reaction pathway benzodiazepines are preferred for use in older adults (again, remember “LOT”).

If possible, Phase 1 pathway benzos should be avoided.

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Lorazepam vs Temazepam – Uses and Differences

Lorazepam may be used off-label to manage insomnia, while temazepam is a sedative-hypnotic benzodiazepine that has a specific FDA indication to treat it.

Lorazepam is also used to treat anxiety, panic disorders, and alcohol withdrawal.

Side effects of lorazepam that are different from temazepam

lorazepam

• Fatigue
• Insomnia
• Difficulty concentrating
• Constipation
• Appetite changes
• Skin rash

Side effects of temazepam that are different from lorazepam

• Dry mouth
• Depression
• Daytime sleepiness
• Increased thirst
• Numbness
• Burning
• Pain
• Tingly feeling

Serious side effects of benzodiazepines as a drug class

• Increased sedation (sleepiness/drowsiness)
• Confusion
• Delirium (serious disturbance in cognition resulting in confusion and reduced awareness of surroundings)
• Impaired coordination, increasing risk of falls and fractures
• Impaired thinking and memory loss (worsened in older adults with dementia or cognitive impairment)
• Dizziness
• Double or blurred vision
• Slurred speech
• Muscle weakness
• Nausea/loss of appetite
• Dry mouth

Symptoms of benzodiazepine overdose

• Unconsciousness
• Low blood pressure
• Overdose deaths (when taken with another nervous system depressant such as alcohol or opioid)
• slowed, shallow breathing
• Oversedation/sleepiness

If you observe your loved one exhibiting any of the above symptoms, treat it as a medical emergency and call emergency services IMMEDIATELY! (They could have taken it with another central nervous system depressant, the combination of which can be life-threatening, and you never want to assume otherwise).

Benzodiazepine withdrawal symptoms (Benzodiazepine Withdrawal Syndrome – BZWS)

Benzodiazepines are only meant to be taken for the short term.

Taking them for as little as three weeks (on average, as each person’s body chemistry and tolerance varies) can lead to physical dependence on the drugs.

Physical dependency means that your body resets to a new biochemical “normal” that requires continued use of the drug to function normally.

The longer you are taking the benzo and the higher the dose, the more difficult it will be for you to wean yourself off of the medication.

If you stop taking the drug suddenly, or if you decrease the dose too suddenly in your attempt to do so, you will experience withdrawal symptoms, some of which can be very severe and life-threatening.

In my own practice, I have seen patients who have been on a benzo for years, struggle to come off the drug.

Even with a very slow taper (dose decrease) of the medication, some of my patients experience withdrawal symptoms that force them to return to the original dose they were taking.

In some cases, it has taken my patients many months or over a year to successfully remove themselves from the vice-like grip of the benzo.

The bullet list below lists some of the withdrawal symptoms you may experience:

• Rebound anxiety
• Restlessness
• Delirium
• Seizures (because benzos reduce the seizure threshold in your brain)
• Sleep problems or disturbances
• Irritability
• Panic attacks
• Hand tremor
• Sweating
• Confusion/cognitive difficulty
• Hallucinations/psychosis
• Heart palpitations
• Weight loss
• Nausea
• Suicidal ideations

Furthermore, these withdrawal symptoms are not consistent and come and go in waves on a daily or weekly basis.

Mental health experts refer to the nature of these symptoms as “waves” and “windows.”

It is important to note that a small subset of people may experience protracted withdrawal syndrome, in which symptoms can persist for months or years after cessation of the offending benzo!

As you can imagine, physical dependence on benzodiazepines can lead to very serious and life-threatening outcomes in the elderly, especially those with cognitive impairment or dementia.

FDA warning for benzodiazepines

Due to their potency and potential to cause abuse, addiction, physical dependence, and withdrawal reactions, the FDA required on September 23, 2020, that the US boxed warning be updated for all benzodiazepines:

• Taking benzodiazepines together with opioid drugs (oxycodone, morphine, etc) can cause profound sedation, respiratory depression, coma, and death
• Physical dependence can occur, even if taken as prescribed, with continued use. Abrupt dose changes or discontinuation can result in severe, life-threatening withdrawal
• Always follow medical advice – only take your benzodiazepine as prescribed by your healthcare provider and for the shortest duration possible. Misuse and addiction can result when taking a benzodiazepine, resulting in overdose and death

Benzodiazepine use in the elderly with dementia

I am well aware of the dangers of long-term benzodiazepine use in the elderly. I have seen this time and again in my clinical experience.

Usually, my patients were started on the benzo in their 20s, 30s, or 40s for managing their anxiety or insomnia.

Now, they are in their 60s, 70s, or 80s, and are experiencing adverse effects due to the physical and body chemistry changes that accompany advancing age.

My patients are now much more sensitive to the effects of the drug and the risks that come with its use, such as oversedation, falls, fractures, memory problems or impaired cognition, and worsening of underlying dementia.

The prevalence of benzodiazepine use among older people in the United States is around 8.7%. On the surface, this metric does not seem too concerning.

However, what is truly alarming is that out of this number, approximately 44% of these prescriptions are potentially inappropriate.

In fact, the 2019 American Geriatrics Society Beers Criteria lists the benzodiazepine drug class as potentially inappropriate medications (PIMs) for older adults.

Negative consequences of benzodiazepine use

There is ample evidence in the medical literature, supported by expert opinion, that draws a clear association between benzodiazepine use and poor medical, personal, social, and financial outcomes.

Dione and colleagues were able to link benzodiazepine use to an increased risk for falls, outpatient visits, emergency room visits, hospitalizations, and higher health care costs.

Bachhuber and colleagues were able to link benzodiazepine use to an increase in the overdose death rate.

An increased risk of falls among older adults with benzo use was shown by Díaz-Gutiérrez and colleagues.

Dassanayake and fellow investigators were able to link benzodiazepine use to a 60% to 80% increase in the risk of traffic accidents.

Deeply concerning is the emergence of recent data that suggests benzodiazepine use may be associated with an increased risk of developing dementia among the elderly (see medical references below).

Drug interactions with benzodiazepines

Benzodiazepines do interact with many medications. The most significant interactions are those that amplify the central nervous system depressive effects of the benzodiazepines.

This happens when you combine the benzo with alcohol, opioids, sedative-hypnotic drugs such as Ambien or Lunesta, or when you take another medication that interferes with the liver’s ability to metabolize the benzo in question.

Examples of medications that interfere with the liver’s metabolism of certain benzodiazepines are ketoconazole, valproic acid, phenytoin, cimetidine, and fluoxetine.

This is not an all-inclusive list and there are many other drugs that also interact with benzos.

I highly encourage you to consult with your doctor or pharmacist to make sure they have reviewed your current medication list and determined that there are no interactions before you start taking your prescribed benzo.

The table below provides a nice overview of the commonly used benzodiazepines:

List of Benzodiazepines and their Pharmacology

Summary:

• Benzodiazepines are potentially inappropriate for use in older adults
• Benzodiazepines are associated with an increased risk of falls, fractures, impaired memory, confusion, delirium, and muscle weakness
• Benzodiazepines must be used for the shortest duration of time and at the lowest effective dose
• Extended duration of benzodiazepine use can lead to physical dependence and worse outcomes
• Lorazepam, Oxazepam, and Temazepam are relatively safer to use in older adults than the other benzodiazepines because they do not have active metabolites

References

1. Dionne PA, Vasiliadis HM, Latimer E, Berbiche D, Preville M. Economic impact of inappropriate benzodiazepine prescribing and related drug interactions among elderly persons. Psychiatr Serv. 2013;64(4):331-8.
2. Bachhuber MA, Hennessy S, Cunningham CO, Starrels JL. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013. Am J Public Health. 2016;106(4):686-8.
3. Díaz-Gutiérrez MJ, Martínez-Cengotitabengoa M, Sáez de Adana E, et al. Relationship between the use of benzodiazepines and falls in older adults: a systematic review. Maturitas. 2017;101:17-22.
4. Dassanayake T, Michie P, Carter G, Jones A. Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf. 2011;34(2):125-56.
5. Verdoux H, Lagnaoui R, Begaud B. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol Med. 2005;35(3):307-15.
6. Yaffe K, Boustani M. Benzodiazepines and risk of Alzheimer disease. BMJ. 2014;349:g5312.
7. Bocti C, Roy-Desruisseaux J, Hudon C, Roberge P. Benzodiazepine and dementia: a time for reflection. Maturitas. 2013;75(2):105-6.