Introduction
In medicine, the benzodiazepine groups of psychotropics are amongst the most widely prescribed drugs (Blackwell, 1973). The first true benzodiazepine was chlordiazepoxide and was marketed as Librium in 1960. Valium (diazepam) was developed and marketed around the same time.
Due to the wide margin of safety of benzodiazepines, they became very popular as sedatives and hypnotics (Hanson, Venturelli, Fleckenstein, 2006). In Australia, at least 4% of all prescriptions made by general practitioners include the benzodiazepines diazepam, temazepam, and oxazepam (Britt et al., 2007.)
This essay describes the mechanism of action, clinical uses, side effects, problems, and controversies associated with benzodiazepines.
Mechanism of Action
In the process of experiencing anxiety, the central nervous system inhibitory neurotransmitter, Gamma-aminobutyric acid (GABA), plays a major role. The GABA receptor complex has several subunits (Roy-Byrne, 2005).
GABA is an inhibitory transmitter in areas of the brain like the limbic system, reticular activating system, and the motor cortex (Hanson, Venturelli, Fleckenstein, 2006.)
Whenever the GABA–benzodiazepine receptor complex is activated, chloride ions move into the neurons. This leads to an increase in membrane polarization and inhibition of neurons (Roy-Byrne, 2005.)
Benzodiazepines act by amplifying the frequency of ion channel openings, thereby enhancing the function of GABA. By this process, benzodiazepines cause CNS depression (Roy-Byrne, 2005), and results in clinically observable muscle relaxation, decreased agitation, along an antiseizure effect (Pary & Lewis, 2008). Thus, depression of specific CNS areas explains the actions of benzodiazepines like mood alteration (limbic function), drowsiness (reticular activating system function), and muscle relaxation (motor cortex function) (Hanson, Venturelli, Fleckenstein, 2006). In addition, the brain may have specific ‘Valium receptors’ with which benzodiazepines may be interacting (Young & Kuhar, 1979.)
Side effects
The side effects of benzodiazepines correlate with their relative half-lives. Diazepam, chlordiazepoxide, flurazepam, and clonazepam, which are longer-acting compounds, tend to pile up active metabolites. This results in impaired cognition, retarded psychomotor performance, and sedation (Reus, 1998). Alprazolam and oxazepam, which are shorter-acting compounds, produce side effects like early morning insomnia, daytime anxiety, and when discontinued, cause insomnia and rebound anxiety (Reus, 1998.)
Other side effects of benzodiazepines include: lethargy, nausea, skin rashes, decreased libido, irregular menstrual cycles, blood cell abnormalities, and increased sensitivity to alcohol and other CNS depressants (Hanson, Venturelli, Fleckenstein, 2006.)
Withdrawal from the longer half-life benzodiazepines can be accomplished through gradual, stepwise dose reduction (by 10% every 1–2 weeks) over 6–12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines (Reus, 1998.)
Clinical applications of benzodiazepines
Some of the clinical applications of benzodiazepines include the use in anesthesia and intensive care as a sedative and inducing agent, in psychiatric emergencies like acute arousal, acute alcohol withdrawal, acute insomnia, in anxiety disorders as an adjunct to other psychological interventions and pharmacotherapy, and epilepsy (Sim, Khong, Wain, 2007). Other uses include: posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, and social phobia (Pary & Lewis, 2008.)
Generalized anxiety disorder
When compared to other drugs used for moderate-to-severe anxiety disorders, benzodiazepines have been found to have greater efficacy and provide faster relief from anxiety; a favorable outcome has also been reported in the long term (Ballenger et al., 2001). In particular, somatic symptoms are responsive to benzodiazepines (Saletu et al., 1997).
Posttraumatic stress disorder and obsessive-compulsive disorder
Although benzodiazepines are useful for posttraumatic stress disorder and obsessive-compulsive disorder, monotherapy with benzodiazepines alone is not indicated (Pary & Lewis, 2008.)
Panic disorder
Benzodiazepines have been recommended for panic disorder, with or without agoraphobia (American Psychiatric Association, 1998). In cases where it is crucial to control early symptoms, for example, a stressful event with recent onset, benzodiazepines are beneficial (American Psychiatric Association, 1998).
Accelerated therapeutic response and a reduction in early anxiety have been noted in patients with panic disorder when benzodiazepines are combined with antidepressants in the early stages (Goddard et al, 2001.)
Problems associated with benzodiazepines
Both fatal and nonfatal opioid overdose has been noted with the use of benzodiazepines in heroin addicts (Zador, Sunjic, Darke, 1996). In the elderly, the use of benzodiazepines has been associated with confusion and accidental falls (Panneman et al., 2003). Even with low doses of benzodiazepines, there is a danger of physiological dependence (Sim, Khong, Wain, 2007.)
Pharmacologic dependence, which is “the physiologic adaptation accompanying sustained drug use” (Rickels et al, 1990) is seen when benzodiazepines are used at therapeutic doses for at least 1 year (Rickels et al, 1990.)
An increased risk for benzodiazepine dependence is seen in patients with the following 4 characteristics (American Psychiatric Association, 1990): chronic insomnia, chronic medical or psychiatric illnesses, history of dependence on sedative-hypnotics or alcohol, chronic dysphoria, and borderline or dependent personality disorders.
Tolerance, which means, “increased dosages are necessary to maintain symptom remission”(O’Brien, 2005) also develops with long-term use of benzodiazepines. Tolerance mainly develops to the sedative and psychomotor effects of benzodiazepines and not to the acute short-term memory effects (O’Brien, 2005.)
The occurrence of withdrawal symptoms, which occur within 2-3 days of stopping treatment, is also a significant problem with benzodiazepines. In general, benzodiazepines with a shorter half-life cause more withdrawal symptoms and more chances for abuse (Pary & Lewis, 2008). Withdrawal symptoms include insomnia, agitation, perceptual disturbances, dysphoria, and increased awareness of sensory stimuli (Bogunovic & Greenfield, 2004). Medical inpatients may display symptoms like delirium and seizures and abnormal vital signs (Pary & Lewis, 2008.)
Rarely, benzodiazepines can cause paradoxical effects like nightmares, anxiety, sweating, irritability, and restlessness. Bizarre behavior, paranoia, rage, agitation, and hostility might also be seen (Hanson, Venturelli, Fleckenstein, 2006.)
Controversies
The controversies about benzodiazepines involve three main areas: the potential for abuse, the appropriateness of long-term use (due to the risk of developing dependence and withdrawal symptoms), and the side effects of benzodiazepines, especially cognitive impairment (Salzman, n.d)
In recent years, a lot of concern has been raised about the overprescription of benzodiazepines due to their apparent safety. However, many physicians have cautioned against this complacent attitude and warn that prolonged and unsupervised intake of benzodiazepines can be very harmful.
In 1990, Xanax (alprazolam), which was widely being used for panic disorder, was reported to cause severe withdrawal symptoms and strong dependency on the drug (Hanson, Venturelli, Fleckenstein, 2006). One case has been reported about a 63-year-old patient who was on Halcion (a short-acting benzodiazepine) who murdered his mother due to the paradoxical effects (paranoia, rage, agitation, and hostility) of the drug (Hanson, Venturelli, Fleckenstein, 2006.)
The use of benzodiazepines involves clinical, ethical, and legal dilemmas. While at times it may be unethical to prescribe benzodiazepines, it may also be unethical to withhold them. For example, in patients with chronic, serious medical illnesses like heart disease, it would be unethical to withhold the relief obtained from benzodiazepines (Bursztajn & Brodsky, 1997.)
In the prescription of benzodiazepines, caution is advised when treating special categories of patients like pregnant patients, and institutionalized patients (like geriatric residents of nursing homes and inmates in correctional settings), patients under stress like exams or those testifying in court, etc (Bursztajn & Brodsky, 1997.)
Conclusion
Benzodiazepines are one of the most widely prescribed psychotropic agents. They are useful in the treatment of insomnia, anxiety disorders, alcohol withdrawal, anesthesia, and intensive care. Benzodiazepines are not recommended as monotherapy for patients with PTSD and obsessive-compulsive disorder.
Benzodiazepines act by enhancing the function of GABA and thus cause CNS depression. Some of the common side effects include impaired cognition, retarded psychomotor performance, sedation, early morning insomnia, daytime anxiety, nausea, etc. They can produce withdrawal symptoms and cause dependence and tolerance. In the elderly, benzodiazepines can lead to falls, while in heroin addicts, opioid overdose has been noted.
Benzodiazepines should be prescribed carefully at the lowest dose and for a short time. The controversies about benzodiazepines involve three main areas: the potential for abuse, the appropriateness of long-term use, and the side effects of benzodiazepines. The use of benzodiazepines involves clinical, ethical, and legal dilemmas. A careful judgment and adherence to established guidelines are recommended. Their overprescription should be avoided.
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