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Benzodiazepines

Published 24.8.2017

Benzodiazepines are the most commonly used sedative medicinal substances that are used for the treatment of anxiety and phobia symptoms as well as sleeping disorders. The medicinal substances of this group are also used for epilepsy and muscle tension treatment as well as psychiatric treatment, but this article mostly focuses on the former uses. The ‘Sleeping medication’ article also discusses their use as sleeping medication.

Benzodiazepines can quickly alleviate sudden anxieties and phobias. They are prescribed CNS (central nervous system impacting) medications, which are typically prescribed for short-term treatment lasting from a few weeks to a few months. Benzodiazepines are not suitable for long-term and regular treatment as they lose their effectiveness in frequent use and may cause medicine addiction. Medicinal treatment aims towards as low doses as possible. The basic principle is that the medication dose is too large if it causes tiredness during the day.

Benzodiazepines test positive in most drug screening tests. 

Medicinal products and dosing

Based on their half-life, benzodiazepines are divided into short-acting, medium-acting and long-acting products. The table below presents some products on the Finnish market with their possible daily doses.

Medicinal substance Trade names Half-life (hours)

Dose
(mg/24 hours)

Long-acting
Diazepam Diapam, Medipam, Stesolid 30-50 2-40
Chlordiazepoxide Risolid 20-100 10-100
Clonazepam Rivatril 30-40 2-4
Nitrazepam Insomin 20-48 5-10 (sleeping medicine)
Medium-acting
Alprazolam Xanor, Alprox, Alprazolam 12-15 0,5-6
Lorazepam Temesta, Lorazepam 10-20 0,5-8
Oxazepam Opamox, Oxamin 6-20 30-120
Temazepam Tenox 8-20 10-30
Short-acting
Midazolam Dormicum, Midazolam 1,5-3 3,75-15 (for the night)
Triazolam Halcion 2-4 0,125-0,25 (for the night)

Diazepam is the most long-acting benzodiazepine and it used to treat anxiety, stress and restlessness, insomnia, epilepsy, muscle tension and alcohol withdrawal symptoms as well as premedication before medical procedures. Other long-acting benzodiazepines include chlordiazepoxide, clonazepam and nitrazepam. Like diazepam, chlordiazepoxide is commonly used for similar purposes. The official indication of clonazepam is the treatment of epilepsy, but it is also used to treat panic disorder. The use of nitrazepam is mostly limited to the treatment of sleeping disorders of adults or the treatment of epilepsy in adult and children.

Alprazolam, lorazepam, oxazepam and temazepam are medium-acting benzodiazepines. Alprazolam is used for treating the panic and anxiety disorders of adults especially in cases where SSRI medication does not result in the desired treatment response. The indications of oxazepam are anxiety, stress and phobias and insomnia. Lorazepam is used to treat severe depression if other treatment methods do not alleviate the symptoms. Temazepam is primarily used to only treat sleeping disorders, but it can also be prescribed for the alleviation of temporary day-time anxiety symptoms.

The short-acting midazolam and triazolam can be used for the short-term treatment of severe insomnia. Midazolam is also used as premedication before medical procedures. Short-acting benzodiazepines are not used for treating anxiety symptoms and they are not suitable for long-term use. They are also not the first option for treating insomnia and their use is, in fact, mostly limited to hospital use.

Absorption into the body

All benzodiazepines absorb well when taken orally, but the time it takes from them to take effect varies. Diazepam and temazepam, which are the most fat-soluble, are absorbed the quickest and thus take effect the fastest. The quick response increases the risk of the substance's abuse for intoxication purposes compared to other benzodiazepines that are absorbed slower. Chlordiazepoxide and clonazepam are absorbed slightly slower than diazepam, which means that their misuse potential is smaller. Oxazepam is also more water-soluble than diazepam, which is why its effect starts slower.

Mechanism of action

Gamma-Aminobutyric acid (GABA) is a natural transmitter substance of the brain, the purpose of which is to control and pacify the actions of nerve cells. All benzodiazepines strengthen the effect of GABA naturally present in the brain, which results in the desired therapeutic effects.

Detrimental effects

In short-term uses and with low doses, the detrimental effects of benzodiazepines are minor. Common detrimental effects include tiredness, sleepiness, inertia, muscle weakness as well as poorer performance and alertness, which may cause issues in traffic and at work and increases the risk of accidents. Detrimental effects are usual in the beginning of the treatment, but as it continues, they are alleviated and a tolerance against them develops quickly.

The short-acting benzodiazepines, in particular, may cause memory issues but also other products, especially in long-term use, may weaken the memory. Long-term use can also cause dullness of emotions or expose the user to depression symptoms. In some cases, benzodiazepines may trigger a paradoxical reaction, the symptoms of which are agitated and aggressive behaviour and worsening anxiety.

Risk of addiction

The most important and most severe detrimental effect of benzodiazepines is the potential drug addiction, which will cause withdrawal symptoms when use of the medicine is stopped. All benzodiazepines are medicinal substances that may easily cause both mental and physical addiction. In short-term, controlled use, the risk of addiction is fairly low.

Repeated, long-term use often accustoms the body to the substance, due to which the same treatment dose no longer results in the desired effect (tolerance grows). Because of this, the dose of the medicine needs to be increased to achieve the desired results. A psychologically addicted person also sees the use of benzodiazepines as vital, which means that quitting their use or situations where the medicine runs out cause the person a great deal of anxiety.

The risk of medicine addition is increased by long-term, regular use and large doses. Additionally, the person’s propensity of using other intoxicants also increases the risk of benzodiazepine addiction. Addiction can be a low-dose addiction, in which regular doses are used in accordance with the treatment recommendations, but quitting the use is difficult due to the withdrawal symptoms.

A more difficult form of addiction is high-dose addiction, which means that benzodiazepines are used in high doses that the user also increases independently due to their rising tolerance. Sudden quitting after long-term use of large doses will cause severe, sometimes even life-threatening withdrawal symptoms. High-dose use is often linked to use of other intoxicants.

Overdosing

If used separately, benzodiazepines are not usually fatally toxic even in large doses. Overdosing often manifests itself as excessive nervous system depression, during which the sedative effects become more obvious. Large doses may lead to a state similar to stupor, which can, at worst, lead to respiratory depression or coma, but rarely to death. Used intravenously, the risk of respiratory depression is significantly larger than when using the medicine orally. The effect of benzodiazepines can be cancelled with flumazenil, which is an effective antidote in the case of an overdose.

Combined use

Benzodiazepines are sometimes used together with other central nervous system depressants, alcohol and intoxicants. In such cases, the users usually attempt to strengthen the effects of the other substances or benzodiazepines. Misuse or use as an intoxicant increase the risk of life-threatening overdose or accidents.

All benzodiazepines strengthen the effects of other central nervous system drugs and alcohol. They strengthen the effects of, for example, certain depression medications (e.g. amitriptyline, doxepin), epilepsy medication (e.g. phenobarbital, phenytoin, carbamazepine), calming antihistamines (e.g. diphenhydramines, promatsin) and opiates (such as morphine).

Used together, alcohol and benzodiazepines may cause unpredictable and dangerous detrimental effects, so alcohol should not be used during the treatment. Using benzodiazepines together with alcohol strengthen the effects of both, and also incoherency and aggressiveness may occur.

Combined use with other substances that affect the central nervous system exposes to excessive CNS depression, which may cause respiratory depression and, therefore, become life-threatening.

Withdrawal symptoms

Quitting regular use of benzodiazepines completely may cause withdrawal symptoms even with the instructed dosage. Withdrawal symptoms are the body’s natural reaction to ending the regular use of the substance and they are not a sign that the symptoms treated with the medicine have returned or worsened. Common withdrawal symptoms include anxiety, irritableness, sleeping disorders, heart palpitations, sweating, tremors, memory and attention issues and general nausea. The withdrawal symptoms will feel uncomfortable and disconcerting, but they are only temporary. If benzodiazepines have been in regular use for a long time, their use should not be stopped suddenly, but instead the dose should be lowered gradually according to a doctor’s instructions.

Long-acting products usually keep the medicine substance content of the body more even than short- or medium acting products, which means that the withdrawal symptoms are usually milder. The content of long-acting benzodiazepines decreases slowly, so it remains in the body for a long time even after quitting its use. The withdrawal symptoms after quitting can also manifest themselves after several days.

Pregnancy and nursing

The use of benzodiazepines is not recommended during pregnancy and nursing. Benzodiazepines penetrate the placenta and are carried into the foetus. Using the substances during early pregnancy does not cause a significant risk of deformation, but developmental delays have been observed in some studies. Using the substances during late pregnancy exposes the infant to withdrawal symptoms and typical detrimental effects of benzodiazepines (sleepiness, respiratory depression, inertia.

Oxazepam can be used during nursing, as it does not get into the breastmilk in large quantities. With usual treatment doses, oxazepam is not expected to harm a nursing infant. In repeated use as anxiety or sleeping medication, the dose should be taken before the longest break in nursing, e.g. right after the final feeding in the evening, so that the nursing child’s exposure to the medicinal substance is as minimal as possible.

Miia Kallio
Pharmacist student, University of Eastern Finland

Niina Karttunen
Pharmacist, Doctor of Pharmacy, University of Eastern Finland

 

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