What is benzodiazepine?

Benzodiazepine is a chemical compound commonly used to treat anxiety, to produce sedation, or as a muscle relaxant.

Benzodiazepine Description:

Benzodiazepines are a class of drugs with sedative, hypnotic, anxiolytic, anticonvulsant, amnestic and muscle relaxant properties. They are often used for short-term relief of severe, disabling anxiety or insomnia. Long-term use can be problematic due to the development of tolerance and dependency.

Benzodiazepines began to be widely prescribed for stress-related ailments in the 1960s and 1970s. They are commonly divided into three groups:

  • Short-acting compounds act for less than six hours and exhibit few residual effects if taken prior to sleep, but rebound insomnia is possible and may cause wake-time anxiety.
  • Intermediate-acting compounds have an effect for 6-10 hours, may have mild residual effects but rebound insomnia is not common.
  • Long-acting compounds have strong sedative effects and persist. Accumulation of these compounds may occur.

The first benzodiazepine, chlordiazepoxide (Librium®) was discovered quite by accident in 1954 by the Austrian scientist Dr. Leo Sternbach while working for the Hoffmann-La Roche pharmaceutical company. He initially discontinued his work on the compound Ro-5-0690, but “rediscovered” it 3 years later when an assistant was cleaning the laboratory. Though he initially discouraged by his employer, Sternbach conducted further research which revealed the compound was an effective tranquilizer.

In 1963, approval was given to diazepam (Valium®) – a simplified version of Librium – mainly to counteract symptoms of anxiety. Sleep-related difficulties were treated with nitrazepam (Mogadon®), introduced in 1965 and flurazepam (Dalmane®), introduced in 1973.

Almost all medically-used benzodiazepines are Schedule IV controlled drugs under the US’s Federal Controlled Substances Act.

Flunitrazepam (Rohypnol) is treated more severely under Federal law than other benzodiazepines. For example, despite being Schedule IV like any other benzodiazepine, it is not commercially available in America. Federal penalties are much tougher for trafficking and possession than other Schedule IV substances. With the exception of 5 grams or more of crack cocaine, flunitrazepam is the only controlled substance in which first-offense simple possession is a Federal felony. Several other countries limit the availability of benzodiazepines legally. Though they are commonly prescribed drugs, the Medicare Prescription Drug, Improvement, and Modernization Act specifically states that insurance carriers that provide Medicare Part D coverage are not required to cover benzodiazepines.

Benzodiazepine Treatment and usage:

Benzodiazepines are employed in many situations, depending on the pharmacokinetics of each of the constituent drugs. The main use of the short-acting compounds is insomnia, while anxiety responds better to medium- or long-acting forms of the drugs.

Benzodiazepine Method of action:

The full complex actions of benzodiazepines are currently beyond the understanding of neuroscientists. The Physicians Desk Reference lists their exact method of action as “unknown.”

What is known, however, is that benzodiazepines work in conjunction with gamma-amino butyric acid (GABA), a neurotransmitter. Neurotransmitters are the messengers that move between neurons (nerve cells) allowing them to communicate. They are divided into excitory (exciting) and inhibitory (calming) based on their effects on the nerve cell. GABA is one of the main inhibitory neurotransmitters that occurs in over 40% of all neurons. This accounts for the broad range of adverse reactions possible when the medication is discontinued.

Warnings or dangers associated with benzodiazepines:

Tolerance to many of the therapeutic effects of benzodiazepines can develop rather rapidly with daily or frequent use. Unlike tolerance to other drugs like opioids, nicotine or stimulants, tolerance to benzodiazepines can put the patient at risk for experiencing an iatrogenic syndrome, consisting of a range of side effects that can be worse than the original condition.

For this reason, current established guidelines restrict benzodiazepine treatment to a maximum of 2-4 weeks in use. It is typical for tolerance to the hypnotic effects to occur within days and the anxiolytic effects normally do not last for more than a few months. After that, the dose may need to be increased on a regular basis to minimize the numerous unpleasant symptoms that can emerge during long-term (more than 4 weeks) use.

Eventually the patient may reach a point where increasing the dose is no longer effective in relieve the drug’s side effects. This is why it is important for physicians to adhere to the established guidelines of 2-4 weeks maximum. Tolerance can cause a wide range of symptoms related to nervous system dysfunction to emerge, many identical to benzodiazepine withdrawal symptoms.

Long term use of benzodiazepines generally leads to some for of tolerance and/or dependence. As a Schedule IV controlled drug, benzodiazepines are considered moderately addictive.

Benzodiazepine Side effects:

Benzodiazepine side effects are predictable as they are intrinsic effects of this drug class. Knowing the relative effects of the drugs will help physicians prescribe the most appropriate type. For example, lorazepam may not be the best option for longer term treatment in the elderly due to its stronger amnesic effects, potentially worsening forgetfulness and confusion. However, it may be an appropriate choice for short-term treatment of a younger, non-drinking patient as it is relatively less sedating.

Benzodiazepines have replaced barbiturates due to the fact that they have a lower potential for abuse and relatively lower adverse reactions (death, for example, is relatively common in barbiturate overdose) and interactions. Even still, ataxia (unsteady or clumsy coordination), confusion, vertigo, impaired judgment, drowsiness, and a number of other effects are common.

Benzodiazepines may interfere with a person’s ability to operate vehicles or machinery. The impairment is heightened by alcohol consumption, because both act as central nervous system (CNS) depressants. The effects of long-lasting formulations of the drugs may linger over to the following day.

Some patients experience the sedative effects of drowsiness or lethargy, decreased mental sharpness, less occupational efficiency or productivity, slurring of speech, somewhat decreased coordination and occasionally, headache.
These may continue for the first few weeks, but tend to disappear, especially when the dose is increased gradually.

Benzodiazepine Overdose and withdrawal:

Overdoses of benzodiazepines can, especially when in combination with alcohol, may lead to coma, but does not cause severe biochemical disturbances and therefore usally carries a relatively good prognosis. The antidote for all benzodiazepines is flumazenil (Annexate®), which is sometimes used empirically in individuals present with unexplained loss of consciousness in an emergency room setting.

Withdrawal symptoms can include anxiety, panic attacks, tachycardia, depression, suicidality (thought and behavior), insomnia, hypertension, tremor, dysphoria, loss of appetite, sweating and delusions.

Abruptly discontinuing these medications may result in a severe and very unpleasant withdrawal syndrome that may additionally result in confusion, psychosis, convulsions and effects similar to delirium tremens (sometimes called the DTs, “the horrors”, “the shakes” or “rum fits” – a condition usually associated with complete alcohol withdrawal).

As such, anyone on long-term or high dosage of any benzodiazepine should be carefully weaned off the drug. It is important to note that the withdrawal syndrome from long-term benzodiazepine use, even at low dosage, can be severely debilitating, lasting months to years. This can normally be avoided or minimized by very gradual tapering of the drug over a period of several months.

Precautions with benzodiazepines in children and the elderly:

Benzodiazepine use among older patients is common, especially among women, but it has been associated with negative consequences, including risk of falling, depression, hip fractures and cognitive decline.

As well, older people are more sensitive to the drugs’ CNS depressant effects than younger patients. Benzodiazepines can cause confusion, amnesia, ataxia, hangover effects, pseudo-dementia and night wandering in the elderly.
Increased sensitivity to benzodiazepines in older people is partially due to the fact that elderly people metabolize drugs less efficiently than young people, and thus the drug effects last longer and accumulation may occur with regular use.

Side effects of benzodiazepines in children have yet to be properly established, but hallucinations, light sensitivity, insomnia, impaired coordination and feelings of fear have been reported in children given benzodiazepines.

Benzodiazepines are generally not recommended for persons under the age of 18, and should not be given to children under 6 months.

Types of benzodiazepines:

Common benzodiazepines include Xanax (alprazolam), Librium (Chlordiazepoxide), Klonopin (clonazepam), Valium (diazepam), Ativan (lorazepam), Rohypnol (flunitrazepam), Halcion (triazolam) and numerous other lesser-known versions and derivatives.

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