Bromazepam

Bromazepam — sold commercially as Lexotan — is a prescription benzodiazepine medication used to treat anxiety-related symptoms and disorders.

First patented in 1961 and then approved for medical use in 1974, bromazepam is a traditional 1,4 benzodiazepine similar to diazepam. This means the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.

Bromazepam is classified as a high-potency benzodiazepine with comparable potency to drugs like lorazepam and triazolam. It’s also notoriously long-lasting because several of its metabolites are active too.

Like most other benzodiazepines, in high doses, bromazepam exhibits sedative and muscle-relaxant properties. This drug has a high risk for addiction and abuse.

IUPAC Name: 7-bromo-5-pyridin-2-yl-1,3-dihydro-1,4-benzodiazepin-2-one

Other Names: Brozam, Lectopam, Lexomil, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexatin, Calmepam, Zepam, & Lexotanil.

Metabolism: According to its manufacturer, the specific enzymes involved in the metabolism of bromazepam have not been fully elucidated. There is evidence to suggest that CYP2D6 does inhibit its metabolism, but more research is needed [9].

Duration of Effects: Intermediate-Acting (20–40 hours). The onset of action with bromazepam occurs in 15-30 minutes.

How Does Bromazepam Work?

By and large, benzodiazepines all share the same basic mechanism of action, which produces their signature anxiolytic, hypnotic, anti-seizure, and muscle relaxant properties through an inhibitory effect on the brain and central nervous system (CNS.)

A couple of benzodiazepines have novel and distinct ways to go about this. Still, the majority of them exert their actions through the gamma-aminobutyric acid neurotransmitter, also known as GABA. GABA receptors are the chief inhibitory compound in the mature vertebrate central nervous system.

As a traditional benzodiazepine, bromazepam is known to bind with the α1, α2, α3, and α5 GABA-A subunits but not with α4 and α6. What is less understood, though, are the reasons for this specificity and the exact way each subunit triggers a different effect [3].

Out of the two types of GABA receptors, benzodiazepines bind to GABA-A at a different site where GABA-A binds and produce an allosteric effect. In other words, they potentiate the natural inhibitory mechanism of the GABA-A compounds. This is an important point of difference: unlike barbiturates, benzodiazepines are not GABA receptor activators; they work by increasing the natural activity of the GABA neurotransmitter [1].

GABA-A receptors have a complicated structure, and there still is a lot we don’t know about the way benzodiazepines exert their effects. However, we do know the GABA-A receptors are made up of a total of 19 different subunits. And we also know that differences in the activation of these distinct subunits accounts for the variations in the effects profile of benzodiazepines. In other words, which subunits a benzodiazepine binds to has a major role in determining its effects [2].

Once a benzodiazepine binds to a GABA-A molecule, the passage of negatively charged chloride ions into the neurons increases. This causes the neuron to become hyperpolarized and thus less likely to fire off an action potential: the electrical signals that are used by the body’s neurons communicate.

With the neurons in the brain and CNS now less likely to send an action potential, total brain activity is reduced, and the effects of the benzodiazepines are achieved. Also, long-lasting benzodiazepines are generally more attuned to use as anxiolytic agents, while shorter-acting benzodiazepines are more used as hypnotics.

Is Bromazepam Safe? Risks & Side-Effects

It’s important to understand the general situation regarding benzodiazepine misuse in the United States before we look at the specific situation of bromazepam.

Benzodiazepine Misuse Statistics

The National Institute on Drug Abuse (NIDA) has documented how drug overdose deaths involving benzodiazepines have steadily risen since 1999. The deaths plateaued for a while in 2010 but started rising again in 2014. An important point to note is that after 2014, deaths involving both benzodiazepines and opioids account for a much larger percentage of fatalities.

Recently, a 2020 survey by the CDC showed that benzodiazepines were involved in 12.290 deaths in the US. Additionally, the NIDA published another study that claims 16% of overdose deaths involving opioids also had the presence of benzodiazepines.

In response to these worrying trends, in 2016, the FDA issued a black box warning to deter users from the potentially fatal dangers of concomitant opioid and benzodiazepine use. In general, combining any two nervous system depressants is a bad idea as it increases the risk of respiratory depression, the leading cause of drug overdose deaths.

Bromazepam Misuse

Under the Controlled Substances Act, bromazepam is currently listed as a Schedule IV compound. This means that bromazepam has widely accepted medical uses but is still capable of causing physical dependence and has the potential for misuse. In general, the consensus among experts is that deaths stemming from single-drug benzodiazepine use are rare but do happen.

As a benzodiazepine, bromazepam has largely fallen out of use in recent years and is no longer available in the United States. Consequently, almost no figures can tell us how it fits in among other benzodiazepines in terms of toxicity. However, there are some things we can reasonably infer.

As a high-potency benzodiazepine with pharmacologically active metabolites, it could be reasoned that bromazepam is among the more dangerous in its class. Also, acute bromazepam poisoning can cause a prolonged coma [4]. A 2015 study conducted over a two-year time period pointed to bromazepam as the leading benzodiazepine in drug poisoning among the elderly [5].

Side Effects of Bromazepam

According to its manufacturer (Roche Pharmaceuticals), the following adverse effects have been identified with bromazepam usage:

• Allergic directions and anaphylaxis (rare)
• Anterograde amnesia
• Anxiety
• Ataxia
• Blurred vision
• Cardiac failure, including cardiac arrest, hypotension, palpitations, and tachycardia
• Decreased alertness
• Decreased hemoglobin and hematocrit, increased and decreased WBC
• Depression
• Diplopia
• Dizziness
• Drowsiness
• Elevations of alkaline phosphatase, bilirubin, SGOT, and SGPT
• Emotional and mood disturbances
• Falling
• Fatigue
• Incontinence
• Increased and decreased blood sugar levels
• Muscle weakness and muscle spasms
• Pruritus
• Seizures

Roche states that adverse effects are more common when starting bromazepam treatment and usually disappear with repeated administration.

Benzodiazepine Withdrawal & Dependence

Benzodiazepine dependence and withdrawal are very serious matters. Doctors consider benzodiazepines, alcohol, and opioids as having the most dangerous withdrawal symptoms; in rare cases, they can even be deadly.

The schedule IV classification of benzodiazepines really doesn’t portray how dangerous they can be in this regard. Multiple studies show how benzodiazepine dependence and withdrawal symptoms tend to develop in a significant proportion of users who have a prescription. In one study, one-third of individuals who used benzodiazepines for longer than four weeks became physically dependent after concluding treatment [6].

Since the immediate cessation of benzodiazepines can be quite dangerous, users who develop withdrawal symptoms must engage in a slow drug-tapering process to safely get off the drug. This process can take as long as 24 weeks, and complications can always develop, even though it is generally safe.