The benzodiazepines (pronounced [ˌbɛnzəʊdaɪˈæzəpiːnz], or "benzos" for short) are a
class of psychoactive drugs considered minor tranquilizers with varying
hypnotic, sedative, anxiolytic, anticonvulsant, muscle
relaxant and amnesic properties, which are mediated by slowing down the
central nervous system.[1] Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol
withdrawal. They can also be used before certain medical procedures such as endoscopies
or dental work where tension and anxiety are present, and prior to some unpleasant medical
procedures in order to induce sedation and amnesia for the
procedure. Another use is to counteract anxiety-related symptoms upon initial use of
SSRIs and other antidepressants, or as an adjunctive treatment. Recreational stimulant
users often use benzodiazepines as a means of "coming down" (see: Drug abuse).
All benzodiazepines have an addictive potential. Use of benzodiazepines should only
commence after medical consultation, and benzodiazepines should be prescribed the smallest dosage possible to provide an
acceptable level of symptom relief. Dependence varies with the benzodiazepine used
and with the user, with some reporting alprazolam dependence in as little as three days.
Common benzodiazepines
For various benzodiazepines and their respective generic and non-US brand-names, half-lives, and primary
uses, see
list of benzodiazepines.
The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the
5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (see figure to the above
right).
Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, or as a
suppository. When used as a recreational drug, pills are often crushed and
snorted.[citation needed] Well-known benzodiazepines and
their primary trade names include:
A related class of drugs which also work on the benzodiazepine receptors, the nonbenzodiazepines, has recently been introduced.[2] Nonbenzodiazepines are molecularly distinct from benzodiazepines and have less addictive
potential, while still offering benefits very similar to benzodiazepines.
Pharmacology
Duration of action
Benzodiazepines are commonly divided into three groups by their half-lives:
Short-acting compounds have a half life of less than 12 hours and have few residual effects if taken before bedtime, but
rebound insomnia may occur and they might cause wake-time anxiety. Intermediate-acting
compounds have a half life of 12–24 hours, may have residual effects in the first half of the day. Rebound insomnia however is
more common upon discontinuation of short acting benzodiazepines. Day time withdrawal symptoms is also a problem with prolonged
usage of short acting benzodiazepines, including day time anxiety. Long-acting compounds have a half life greater than 24
hours.[3][4] Strong sedative effects typically persist throughout the next day
if long acting preparations are used for insomnia. Accumulation of the compounds in the body may occur. The elimination half-life
may greatly vary between individuals, especially the elderly. Shorter-acting compounds are usually best for their
hypnotic effects, whilst longer-acting compounds are usually better for their anxiolytic effects. Benzodiazepines with shorter half-lives tend to be able to produce tolerance and
addiction quicker as the drug does not last in the system for as long, with resultant interdose withdrawal phenomenon and next
dose craving. Although short acting drugs are more commonly prescribed for insomnia there are exceptions to the rules, such as
alprazolam being prescribed as an anxiolytic more than a
hypnotic, despite possessing a short half-life.
Mechanism of action
Benzodiazepines produce a range of effects from depressing to stimulating the central
nervous system via modulating the GABAA receptor, the most prolific
inhibitory receptor within the brain. The GABAA receptor is made up from 5 subunits out of a possible 19, and
GABAA receptors made up of different combinations of subunits have different properties, different locations within
the brain and importantly, different activities in regards to pharmacological and clinical effects.
Benzodiazepines bind only to alpha subunits which contain a histidine amino acid residue,
(i.e., α1, α2, α3 and α5 containing GABAA receptors). For this
reason benzodiazepines show no affinity for α4 and α6 subunits containing GABAA receptors, which
contain an arginine instead of a histidine residue. Other sites on the GABAA
receptor also bind neurosteroids, barbiturates
and certain anesthetics.[5]
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ
subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation
where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening
of the associated chloride ion channel and hyperpolarizing the neuron. This potentiates the inhibitory effect of
the available GABA leading to sedatory and anxiolytic effects. As mentioned above, different benzodiazepines can have different
affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high
activity at the α1 are associated with sedation whereas those with higher affinity for GABAA receptors
containing α2 and/or α3 subunits have good anti-anxiety activity.[6]
Clinically used benzodiazepines are full agonists at the benzodiazepine receptor producing
anxiolytic and sedating properties. However, with regular or chronic use the risk of physical dependence increases with
demonstratable withdrawal symptoms upon discontinuation or dosage reduction. Benzodiazepines also have abuse potential. The
benzodiazepine receptor is a modulatory site for the GABA receptor.
Compounds which bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor
agonists and display sedative/hypnotic properties. Compounds which in the absence of agonist have no apparent activity but which
competitively inhibit the binding of agonists to the receptor are called benzodiazepine receptor antagonists. Finally ligands which decrease GABA function are termed benzodiazepine receptor
inverse agonists. Full inverse agonists have potent convulsant activities.
Some compounds lie somewhere between being full agonists or full antagonists and are termed either partial agonists or partial
antagonists. There has been interest in partial agonists for the benzodiazepine receptor with evidence that complete tolerance
may not occur with chronic use, with partial agonists demonstrating continued anxiolytic properties with reduced sedation,
dependence and withdrawal problems.[7]
The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium
channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of
slowing recovery of sodium channels from inactivation.[8]
Therapeutic uses
Benzodiazepines have a number of therapeutic uses, are well tolerated, and are very safe and effective drugs in the short term
for a wide range of conditions.
Use as anticonvulsants
Benzodiazepines are potent anticonvulsants and have life-saving properties in the
acute management of status epilepticus. The most commonly used benzodiazepines for
seizure control are lorazepam and diazepam. A
meta-analysis of 11 clinical trials concluded that lorazepam was superior to diazepam in
treating persistent seizures.[9] Although diazepam is much
longer-acting than lorazepam, lorazepam has a more prolonged anticonvulsant effect. This is because diazepam is very lipid
soluble and highly protein-bound and has a very large distribution of unbound drug and this results in diazepam having only a
20–30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of
unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be
considered superior to diazepam, at least in the initial stages of treatment of status epilepticus.[10]
Use as anxiolytics
Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety.
Benzodiazepines are usually administered orally for the treatment of anxiety; however, occasionally lorazepam or diazepam may be
given intravenously for the treatment of panic attacks.[1]
Use for insomnia
Hypnotic benzodiazepines have strong sedative effects and certain benzodiazepines therefore are often prescribed for the
management of insomnia. Longer-acting benzodiazepines such as nitrazepam have side effects which may persist into the next day
whereas the more intermediate-acting benzodiazepines (for example temazepam) may have less
"hangover" effects the next day.[2] Benzodiazepine hypnotics should be reserved for short-term courses to treat acute conditions as tolerance and
dependence may occur if these benzodiazepines are taken regularly for more than a few weeks.
Use as a premedication before procedures
Benzodiazepines can be very beneficial as premedication before surgery, especially in those who are anxious. Usually
administered a couple of hours before surgery, benzodiazepines will bring about anxiety relief and also produce amnesia. Amnesia
can be useful in this situation as patients will not be able to remember any unpleasant memories from surgery.[3] Lorazepam can be utilized in patients
who are particularly anxious about dental procedures.[4] Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, fast onset of action and its extremely short
duration of action.
Use in intensive care
Benzodiazepines can be very useful in intensive care to sedate patients receiving mechanical ventilation or those in extreme distress or severe pain. Caution should be exercised
in this situation due to the occasional scenario of respiratory depression, and benzodiazepine overdose treatment facilities
should be available.[5]
Use in alcohol dependence
In the management of alcohol withdrawal benzodiazepines can have potentially life-saving effects by ameliorating the alcohol
withdrawal syndrome. Delirium tremens, which can be potentially fatal, can be
effectively treated by benzodiazepines and often prevented from occurring in the first place. The usual benzodiazepines used in
the management of alcohol withdrawal are Chlordiazepoxide (Librium) or diazepam (Valium). Chlormethiazole is an alternative but is not as well
tolerated as benzodiazepines and may have more risks associated with it and should only generally be used in an inpatient
setting.[6]
Use in muscular disorders
Benzodiazepines are well known for their strong muscular relaxing properties and can be useful in the treatment of muscular
spasms, for example Tetanus or spastic disorders [7] and Restless legs syndrome.
Use in acute mania
Mania, a mood disorder, is a state of extreme mood elevation and is a diagnosable serious
psychiatric disorder. Benzodiazepines can be very useful in the short term treatment of
acute mania, until the effects of Lithium or neuroleptics
take effect. Benzodiazepines bring about rapid tranquillisation and sedation of the manic individual, therefore benzodiazepines
are a very important tool in the management of mania. Both clonazepam and lorazepam are used for the treatment with some evidence that clonazepam may be superior in the treatment of
acute mania.[11][12]
Therapeutic uses in veterinary practice
As in humans, benzodiazepines have a wide range of uses in veterinary practice in
the treatment of various disorders and scenarios involving animals.
Midazolam and diazepam are utilized for their anesthetic properties in veterinary practice in combination with other general anesthetic drugs
such as ketamine.[13][14]
Midazolam or diazepam can also be used as a sedative
anxiolytic to quell anxiety and agitation experienced by animals in veterinary practice for example during transport. [15][16] Diazepam has also been found to have tranquillising effects on various animals tested with the
following properties; myorelaxation, stress reduction and aggression inhibition.[17]
Benzodiazepines are also commonly used for the control of muscular conditions in animals. Diazepam has been prescribed for the effective treatment and control of tremors by veterinarians in animals. Corticosteroids and or Diazepam have been
found to be effective for the control of tremors in veterinarian practice.[18][19] Diazepam has also been
used in to control muscle spasms that were the result of tetanus
in cats.[20]
Benzodiazepines, such as diazepam, are used in the treatment of various forms of epilepsy in dogs.[21] Benzodiazepines have potent anticonvulsant properties and are very effective in the short term in managing seizure disorders in
animals. However with prolonged usage benzodiazepines tend to lose their
anticonvulsant properties. Partial benzodiazepine receptor agonists have shown some promise with continued efficacy being demonstrated with benzodiazepine receptor partial agonists and
also displaying mild withdrawal symptoms upon discontinuation which may make them superior to benzodiazepines in the long-term
management of epilepsy in animals.[22] Phenobarbitol is the drug of choice and potassium
bromide is the drug of second choice in the treatment of epilepsy in dogs and diazepam is recommended for the treatment at
home of cluster seizures.[23]
Lorazepam has been found to be an effective premedication before general anesthesia in bringing about
adequate muscular relaxation for veterinary surgery.[24]
The benzodiazepine Zolazepam in combination with Tiletamine has been used in the tranquilization of wild animals such as gorillas and polar bears and has been
found to be in terms of reduced side effects superior to ketamine.[25][26]
Midazolam can also be used along with other drugs in the sedation and capture of wild
animals.[27]
Side effects
The side effects are predictable as they are intrinsic effects of the drug class of benzodiazepines. Knowing the relative
effects of benzodiazepine types will help clinicians prescribe the most appropriate type. For example, lorazepam may not be best treatment choice for the elderly due to its stronger amnesic effects and thus
greater potential for aggravating forgetfulness and confusion. But then lorazepam is a good choice for the acute treatment of
status epilepticus due to its potent anticonvulsant properties.
Benzodiazepines have largely replaced the barbiturates, mainly because benzodiazepines
are much safer in terms of overdose. Prior to the introduction of benzodiazepines, barbiturate overdose was of significant
concern to both the medical community and the general public. Still, drowsiness, ataxia,
confusion, vertigo, impaired judgement, and a number of other effects are common.
The concern is also that—even though they are relatively non-toxic in themselves—benzodiazepines may facilitate suicide by
other drugs or means, through disinhibition. However, benzodiazepines when combined with other central nervous system depressants
such as opiates or alcohol the risk of overdose and death increases significantly due to synergistic CNS, respiratory, and
cardiovascular system depression. The elderly, alcoholics, and those with underlying medical conditions, e.g., respiratory
disease or personality disorder, are at increased risk for both acute adverse reactions and problems arising from long-term use,
including dependence, confusion, memory impairment, or overdose.[28] Paradoxical reactions may occur in any individual on
commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal
thoughts.[29]
Benzodiazepines may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption
of alcohol, because both act as central nervous system depressants. The effects
of long-acting benzodiazepines can also linger to the following day.
Benzodiazepines can cause a wide range of significant behavioral disturbances and cognitive impairment. Cognitive deficits
including concentration and memory-processing problems is a well-known, adverse effect of benzodiazepines and occurs at
prescribed dose levels. The degree of cognitive impairment will depend on the dose used and individual tolerance level to the
drug, with the elderly being more vulnerable to cognitive impairments from benzodiazepines.
Amnesia can be a side effect of benzodiazepines and can be utilized in a therapeutic setting to reduce unpleasant memories
from investigatory medical procedures, e.g., endoscopies. In addition, the amnesic and sedating properties have found favor with
criminals as a date-rape drug. All benzodiazepines can be used as date-rape drugs, but
flunitrazepam (Rohypnol), clonazepam (Klonopin), midazolam (Versed), and temazepam (Restoril) are the most commonly used.[30]
For a full list of side effects pertaining to a specific drug, those in the United States should read the patient information,
prescriber guide, or manufacturer's information as published in the PDR or
other such manuals.
Paradoxical reactions
Severe behavioral changes resulting from benzodiazepines have been reported including mania,
schizophrenia, anger, impulsivity, and hypomania.[31] Individuals with
borderline personality disorder appear to have a greater risk of
experiencing severe behavioral or psychiatric disturbances from benzodiazepines. Aggression and violent outbursts can also occur
with benzodiazepines, particularly when they are combined with alcohol. Recreational abusers and patients on high-dosage regimes
may be at an even greater risk of experiencing paradoxical reactions to benzodiazepines.[32] Paradoxical reactions may occur
in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or
suicidal thoughts.[33]
When benzodiazepines are used as an adjunct in the treatment of seizures, an increase in dosage of the primary agent may be
required. The concomitant administration of benzodiazepines and anti-convulsants may precipitate an increase in certain seizure
activity, specifically tonic-clonic seizures.
In a letter to the British Medical Journal, it was reported that a
high proportion of parents referred for actual or threatened child abuse were taking drugs
at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling
less anxious or depressed, they became more hostile and openly aggressive towards the child as
well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as
difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event.[34]
Paradoxical rage reactions from benzodiazepines are thought to be due to partial deterioration from consciousness, generating
automatic behaviors, fixation amnesia, and aggressiveness from disinhibition with a possible serotonergic mechanism playing a
role.[35]
Tolerance
Tolerance develops to many of the therapeutic effects of benzodiazepines rapidly with daily or frequent use. Generally,
tolerance to the hypnotic and sedative effects occurs within days; however, tolerance to the anxiolytic effects of
benzodiazepines takes longer to develop. According to a 1988 report published by the Committee on Safety of Medicines, there is little evidence of continued
anxiolytic properties from benzodiazepines after four months of continuous use other than the
suppression of withdrawal signs and recommended that prescriptions of benzodiazepines be limited to 2–4 weeks only.[36][37] There is also evidence that long-term use may actually worsen anxiety in some people with or without prior psychiatric history as was found in a study of 50 patients.[38] A possible explanation for increased anxiety from chronic
use of benzodiazepines is that it is a side effect of tolerance with increasing doses required to suppress withdrawal effects.
However, patients should be aware that this could lead to a cycle of increasing doses and worsening side effects. In addition, as
dosage is increased, the potential for addiction becomes greater.
Cross tolerance
Benzodiazepines share a similar mechanism of action with various sedative compounds which act by enhancing the
GABAA receptor. Cross tolerance typically means that one drug will alleviate the withdrawal effects of another. It
also means that tolerance of one drug will result in of another similarly acting drug. Benzodiazepines are often used for this
reason to detoxify alcohol dependent patients and can have life-saving properties in preventing and/or treating severe
life-threatening withdrawal syndromes from alcohol such as delirium tremens. However,
although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as
positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to
significantly increase the level of alcohol consumed in alcoholics.[39] However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very
slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic which is well known
for being a relapse risk factor in alcoholics. See (benzodiazepine
withdrawal syndrome).
There is also cross tolerance between alcohol, the benzodiazepines, the
barbiturates, and the nonbenzodiazepine drugs
which all also act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the
GABAA receptor.[40][41][42][43]
Dependence and withdrawal
-
Long-term benzodiazepine usage generally leads to some form of tolerance and/or
dependence. Regular use of benzodiazepines at prescribed levels for six weeks was
found to produce a significant risk of dependence with resultant withdrawal symptoms appearing on abrupt discontinuation in a
study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone no withdrawal
symptoms developed.[44] Various studies have shown
between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will
experience withdrawal symptoms.[45]
Benzodiazepine dependence is a frequent complication when they are prescribed for or taken for longer than four weeks with
physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug seeking behavior.
Withdrawal symptoms include: anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and in rare cases,
psychosis and epileptic seizures. The risk factors for benzodiazepine dependence are as follows: long-term use beyond four weeks,
use of high doses, use of potent short-acting benzodiazepines or those with certain pre-existing personality characteristics such
as dependent personalities and those prone to drug abuse.[46]
Previously, physical dependence on benzodiazepines was largely thought to only occur in people on high-therapeutic-dose ranges
and low- or normal-dose dependence wasn't suspected until the 1970s, and it wasn't until the early 1980s that it was
confirmed.[47] However, low-dose dependence is now a
recognized clinical disadvantage of benzodiazepines and severe withdrawal syndromes can occur
from these low doses of benzodiazepines even after gradual dose reduction.[48][49] Low dose dependence has
now been clearly demonstrated in both animal studies and human studies.[50][51]
In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four
baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment.
Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because
low-dose benzodiazepine therapy was continued over a period of 6–10 months suggesting rapid onset of dependence with
benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine
treatment.[52] In another animal study, physical
dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment and
withdrawal signs appeared after only three days after high-dose treatment which demonstrated the extremely rapid development of
tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines
sensitized baboons to the development of physical dependence.[53]
In humans, chronic, low-therapeutic-dose dependence was clearly demonstrated using flumazenil
to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects
included increased ratings of dizziness, blurred vision, heart pounding, feelings of
unreality, pins and needles, nausea, sweatiness, noises
louder than usual, jitteriness, things moving, sensitivity to touch.[54] In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who
received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on
low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to
flumazenil precipitated benzodiazepine withdrawal.[55] It
has been estimated that 30–45% of chronic low dose benzodiazepine users are dependent and it has been recommended that
benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days maximum to avoid dependence.[56]
Some
