Some facts about benzodiazepines and their uses

Introduction

This guide describes how benzodiazepines act and provides evidence of the advantages and disadvantages associated with their use. The overall aim of the original report is to provide assistance to general practitioners in the appropriate prescribing of benzodiazepines.

What are benzodiazepines?

Benzodiazepines are a group of prescription-only pharmaceutical drugs that have sedating/hypnotic and calming effects. In this group, there is a variety of drugs, which are often more widely known by their trademarked names whereas they are no longer protected by patents and are also sold as generics. For instance diazepam and alprazolam are still known and available under their original trade name Valium^® and Xanax^®, respectively.

When they arrived into clinical practice in the 1960s, benzodiazepines responded to what was a pressing mental health need at that time, and appeared safe due to a paucity of side effects in comparison to barbiturates, chloral hydrate and other drugs, which were problematic due to reported toxicity and overdose. Benzodiazepines were then commonly used and prescribed short- and long-term, for anxiety, depression, insomnia, some mental illnesses and neuromuscular conditions. By the 1970s, they were among the most prescribed drugs in the world.

What are the pharmacological properties of benzodiazepines?

Benzodiazepines affect brain activity; they induce lower activity of the central nervous system by acting on a specific receptor of nervous cells. This results in four basic properties that give rise to their clinical use:

• reducing anxiety; 
• Sedative andhypnotic; 
• anticonvulsant; 
• muscle relaxant. 

On this basis, benzodiazepines are prescribed for a broad range of conditions including:

• insomnia;  
• anxiety disorders; 
• alcohol withdrawal; 
• mania and hypomania (a mood state characterized by persistent disinhibition and pervasive euphoric with or without irritable mood) ;  
• epilepsy;  
• musculo-skeletal disorders. 

In particular, benzodiazepines have been shown to be one of the most effective drugs class in the management of alcohol withdrawal syndrome.

The pharmacological effects are non-selective and benzodiazepines may be short, medium, or long acting, depending on the speed and mechanisms by which they are eliminated from the body. Benzodiazepines may have significant interactions with other drugs that are also eliminated by the liver.

Their properties, causing inhibitory effects throughout the brain, may also yield to drowsiness and cognitive impairment, dampening of emotions such as fear and anxiety, memory impairment, and impairment of balance, motor control, muscle tone and coordination.

Who should not use benzodiazepines?

Benzodiazepines should not be prescribed, or prescribed with extreme caution, to:

1. Women who are, or may be, pregnant; 
2. Patients with disorders related to other active substances use; 
3. Patients with medical or mental health conditions that may be worsened by benzodiazepines (e.g. fibromyalgia, chronic fatigue syndrome, depression, bipolar disorder or impulse control disorders); 
4. Patients being treated with opioids for chronic pain or addiction; 
5. Patients experiencing grief reactions, because benzodiazepines may suppress and prolong the grieving process.  
6. Also, benzodiazepines are generally not recommended for use in children and for the management of chronic pain. There is sparse evidence that they are clinically effective as muscle relaxants. 

Do people develop a tolerance to benzodiazepines?

Tolerance to all drugs of dependence develops with repeated use. At the start of a treatment, when the amount of the drug in the bloodstream reaches a steady concentration due to the balance between intake and elimination, patients may start experiencing a loss of effect to various degrees.

Tolerance develops differently for each effect of the drug. For instance, a high proportion of patients with epilepsy develop tolerance to the anticonvulsant effects within a few weeks, but tolerance to the anxiolytic and amnesic effects of benzodiazepines probably does not occur at all, even if there is some evidence that a slow tolerance may develop over years.

There is also a high degree of cross-tolerance between benzodiazepines and other sedative/ hypnotic medications and alcohol, which makes it difficult to calculate equivalence between various benzodiazepines.

What are the main side effects of benzodiazepines?

The main recognized side effects of benzodiazepine use are:

1. Cognitive impairment, which includes sedation, drowsiness, learning impairment, psychomotor slowing, and short-term amnesia. Benzodiazepines have especially been shown to also impair vision, attention, information processing, memory, motor coordination, and combined-skill tasks. A range of cognitive and psychomotor effects may persist after withdrawal. According to some studies, an increased risk of dementia may also appear.  
2. Anxiety that patients may experience when they take benzodiazepines over a long time, or after stopping long-term use (rebound anxiety); 
3. Depression which may be aggravated or that first appears during benzodiazepine use, possibly by reducing the output of neurotransmitters such as serotonin and noradrenaline; 
4. Paradoxical stimulation and disinhibition (especially at high doses), leading patients to behave out of character and potentially placing themselves in dangerous situations because of an impaired perception of inherent risk in particular in sexual behaviour, and reckless driving.  
5. Patients over 60 years of age seem to have the most significant risk of harm with benzodiazepine use relating to falls, fractures and cognitive decline.
6. More generally, the harmful effects of benzodiazepines, other than the risk of dependence with long-term use, have been associated (i.e. not proven cause and effect) with an increased risk of death from all causes, in particular when combined with other central nervous system depressants such as alcohol or opioids.  

Are benzodiazepines addictive?

Based on the available epidemiological data, the prevalence of benzodiazepine abuse is generally low when the drug is adequately medically prescribed.

Patients with a history of alcohol abuse, or even those with moderate alcohol consumption, appear to experience greater reinforcement effects with benzodiazepines. If a patient doesn’t have a substance use disorder, the risk of addiction to benzodiazepines during long-term treatment of anxiety and related disorders seems low. The pharmacological dependence that develops when long-term use of benzodiazepines does not create compulsive or uncontrollable behaviour (only noted in 0.9% excessive users after 3 years).

Slow discontinuation of benzodiazepines use is recommended.

What are the symptoms at withdrawal of a treatment with benzodiazepines?

Benzodiazepine withdrawal syndrome is highly variable and secondary to high dosage and long-term use. Withdrawal symptoms include irritability, paraesthesia (abnormal sensations), tinnitus, headaches, dizziness, poor memory, poor concentration, perceptual distortions, menstrual disturbances, and sensory hypersensitivity. The mildest form of withdrawal is rebound of the original symptoms, such as anxiety and insomnia, recurring transiently at a greater intensity.

Withdrawal symptoms can usually be minimised by gradual reduction of benzodiazepines use.

How should doctors and patients approach benzodiazepine use?

From the practitioner’s side:

1. Prescribing benzodiazepines should be based on a comprehensive medical assessment,  
2. Benzodiazepines should be prescribed at the lowest effective dose and for the shortest clinical time frame to minimise risks,
3. Supervised benzodiazepine treatment may remain an acceptable long-term therapeutic option if alternative treatments fail. 

From the patient’s side:

Any patient taking benzodiazepines should refer to one doctor at one practice for all its health needs and prescriptions, and disclose his medical history and the other medication he might be taking, including herbal remedies and illicit medication.

Patients have to agree from the start that the treatment is a trial and that if it has no clear effect, the treatment would stop.

They also have to understand that they should not consume alcohol or use illicit drugs along with benzodiazepines as the ratio between risks and benefits of benzodiazepines changes considerably when other psychoactive drugs are used or when the patient has a substance abuse problem.