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Benzodiazepines
General information
The benzodiazepines typically share hypnotic, anxiolytic, myorelaxant, and anticonvulsant activity. Because their efficacy and tolerability are generally good, especially in the short term, they have been used extensively and are likely to continue to be used for many years to come. However, their less specific use in the medically or psychiatrically ill, and in healthy individuals experiencing the stresses of life or non-specific symptoms has often been inappropriate and sometimes dangerous [ , ]. The pharmacoepidemiology of benzodiazepine use has been carefully studied in various countries [ ], including the USA [ ] and France, where 7% of the adult population (17% of those over 65 years) are regular users [ ]. In Italy, consumption of benzodiazepines remained stable (50 defined daily doses per 1000 population) from 1995 to 2003, while expenditure increased by 43% to €565M per annum [ ]. The need to limit spending on pharmaceutical products, as well as the very real likelihood of inducing iatrogenic disease (for example cognitive impairment, accidents, drug dependence, withdrawal syndromes), has prompted many reviews and policy statements aimed at discouraging inappropriate use. Despite this, the available evidence suggests that there continues to be expensive and inappropriate use in several countries [ ].
A comprehensive review of manufacture, distribution, and use has described the marked international variation in use of the drugs and the role of the International Narcotics Control Board, a United Nations agency, in the restriction of these drugs [ ]. Most countries are signatories to the UN Convention on Psychotropic Substances 1971, and are thus obliged to implement controls on the international trade in abusable drugs, including benzodiazepines. Some countries, such as Australia and New Zealand, have imposed further stringent controls on certain drugs, such as flunitrazepam, which are thought to have particular abuse liability [ ]. A wide-ranging discussion of benzodiazepine regulation has pointed out both the potential merits of the approach and the fact that some restrictions in the past have turned out to be counterproductive [ ].
A comprehensive review of benzodiazepine-induced adverse effects and liability to abuse and dependence, in which it was concluded that most benzodiazepine use is both appropriate and helpful [ ], was subsequently challenged [ ]. Balanced clinical reviews of benzodiazepine use [ , ] include sets of recommendations on appropriate prescribing and avoiding adverse effects, including tolerance/dependence. Similarly, guidelines for the management of insomnia and the judicious use of hypnotics have been reviewed [ , ]. Benzodiazepines are often over-prescribed in hospital [ ], and their continued prescription after discharge constitutes a significant source of long-term users. Anxiety symptoms and insomnia are common in the medically ill population and can be due to specific physical causes, a reaction to illness, or a co-morbid psychiatric illness, such as depression. Moreover, caffeine, alcohol, nicotine, and a variety of medications can cause insomnia [ ]. Accordingly, the systematic assessment of such patients allows remediable causes to be identified and the use of hypnosedatives to be minimized. Elderly people and medically ill patients are susceptible to the adverse effects of benzodiazepines, and alternatives are worth considering [ , ], particularly given evidence that behavioral therapies can be more effective and more durable than drug therapy [ ].
The important advantages of the benzodiazepines over their predecessors are that they cause relatively less psychomotor impairment, drowsiness, and respiratory inhibition, and are consequently relatively safe in overdose. However, it must be emphasized that these advantages are relative, and that the low toxicity potential does not apply when they are combined with other agents, particularly alcohol [ ] and opioids [ ].
As well as the added toxicity seen in co-administration with other CNS depressants, benzodiazepines facilitate self-injurious behavior by disinhibiting reckless or suicidal impulses [ ]. Benzodiazepines are commonly used in both attempted and completed suicide [ ]. A German study has suggested that hypnosedatives are the commonest drugs used in self-poisoning, that most are prescribed by physicians, and that in nearly half of those taking them chronically, adverse effects were considered to be a possible cause of self-poisoning [ ]. Before prescribing any drugs of this class, clinicians are exhorted to assess both suicidality and alcohol problems; there is a quick screen for the latter, the Alcohol Use Disorders Identification Test (AUDIT), which consists of a 10-item questionnaire and an 8-item clinical procedure [ ].
Hypersensitivity reactions are rare. A few cases of anaphylaxis have been described, although usually these have been with the injectable forms and may have involved the stabilizing agents [ ]. Serious skin reactions to clobazam [ ] and tetrazepam [ ] have been reported. Lesser reactions have also been reported with diazepam, clorazepate (via N -methyldiazepam) [ ], and midazolam [ ].
Tumor-inducing effects have been observed in animals [ ], but human reports are essentially negative.
First-trimester exposure appears to confer a small but definite increased risk (from a baseline of 0.06% up to 0.7%) of oral cleft in infants [ ]. However, second-generation effects are infrequent and usually reversible [ ], although some doubt remains about the extent of developmental delay in children who have been exposed in utero [ ]. A review has emphasized that concerns about second-generation effects are mainly theoretical, and has concluded that some agents (for example chlordiazepoxide) are probably safe during pregnancy and lactation and that others (for example alprazolam) are best avoided [ ].
Pharmacokinetics
As far as is currently known, benzodiazepines and similar drugs (zopiclone, zolpidem) act by a single mechanism, interacting at the GABA receptor complex to enhance the ability of GABA to open a chloride ion channel and thereby hyperpolarize the neuronal membrane. It is usual, therefore, to classify benzodiazepines, and recommend their clinical use, on the basis of their duration of action or their half-life. While this is without doubt a useful classification, it is simplistic and does not take into account other important pharmacokinetic factors.
The first factor that is considered significant is the metabolism of benzodiazepines to pharmacologically active metabolites. Many newer benzodiazepines intended for use as long-acting anxiolytic or sedative agents were in fact intended to be so metabolized to ensure stable blood concentrations over prolonged periods. Drugs with long durations of effect, attributable at least in part to the formation of active metabolites, are listed in Table 1 . Individuals vary considerably in their metabolism of benzodiazepines, and interpatient variation in concentrations of the parent compounds and of (generally active) metabolites is usual. In addition, ethnicity plays a major role in determining the frequency of poor and extensive metabolizers, with notable differences between Caucasians and East Asians [ ].
Table 1
Benzodiazepines with active metabolites that have long half-lives; metabolism and predominant metabolite half-lives
| To desmethyldiazepam * | t 1/2 (hours) | To other metabolites | t 1/2 (hours) |
|---|---|---|---|
| Lorazepate | 40–100 | Chlordiazepoxide | 40–100 |
| Diazepam | 36 | Clobazam | 30–150 |
| Halazepam | 20 | Flurazepam | 40–120 |
| Medazepam | 2 | Quazepam | 40–75 |
| Prazepam | 120 + |
Another, often neglected, aspect of the pharmacokinetics of benzodiazepines is their rate of onset of action, since their properties and therapeutic benefits depend to a considerable degree on the rapidity of onset of their perceived effects. Within a given drug class, the more rapidly the hypnotic effect occurs, the greater the abuse potential. For most drugs of abuse, it is the affective and behavioral changes associated with a rapid rise in drug blood concentration that is sought, whether the drug is abused by intravenous injection, nasal or bronchial absorption, or (as with alcohol) rapid oral absorption from an empty stomach [ ]. Diazepam and flunitrazepam are effective hypnotics because they are rapidly absorbed and there is a quick rise in blood concentrations, even though after tissue redistribution and loss of their immediate effects they have long half-lives. It also explains the preference, and so the increased liability for abuse, for drugs like diazepam [ ] and flunitrazepam, especially when the latter is snorted [ ]. In general, polar molecules, such as lorazepam, oxazepam, and temazepam (all of which have a hydroxyl group), gain access to the CNS more slowly than their more lipophilic cousins. Since temazepam is much more quickly absorbed from a soft gelatin liquid-containing capsule than from a hard capsule or tablet, it is the preferred form for both hypnotic use ( Table 2 ) and recreational use (and for this reason is restricted in some countries). Kinetic differences between drugs and between formulations partially explain why comparing equipotent doses of benzodiazepines is difficult.
Table 2
Rates of absorption and half-lives of benzodiazepines
| Benzodiazepine | t max (hours) | t ½ (hours) |
|---|---|---|
| Slow absorption | ||
| Clonazepam | 2–4 | 20–40 |
| Loprazolam | 2–5 | 5–15 |
| Lorazepam | 2 | 10–20 |
| Oxazepam | 2 | 5–15 |
| Temazepam (hard capsules) | 3 | 8–20 |
| Intermediate absorption and elimination | ||
| Alprazolam | 1–2 | 12–15 |
| Bromazepam | 1–4 | 10–25 |
| Chlordiazepoxide | 1–2 | 10–25 |
| Intermediate absorption, slow elimination (with active metabolites) | ||
| Flurazepam | 1.5 | 40–120 |
| Clobazam | 1–2 | 20–40 |
| Chlorazepate | 1 | 40–100 |
| Quazepam | 1.5 | 15–35 |
| Rapid absorption, slow elimination, but rapid redistribution | ||
| Diazepam | 1 | 20–70 |
| Flunitrazepam | 1 | 10–40 |
| Nitrazepam | 1 | 20–30 |
| Rapid absorption, rapid elimination, rapid redistribution | ||
| Lormetazepam (soft capsules) | 1 | 8–20 |
| Temazepam (soft capsules) | 1 | 8–20 |
| Rapid absorption, rapid elimination | ||
| Brotizolam | 1 | 4–7 |
| Zolpidem | 1.5 | 2–5 |
| Zopiclone | 1.5 | 5–8 |
| Rapid absorption, very rapid elimination | ||
| Midazolam | 0.3 | 1–4 |
| Triazolam | 1 | 2–5 |
The route of metabolism can also be significant, particularly in those with liver disease or who are taking concomitant hepatic enzyme inhibitors, such as erythromycin [ ]. The complex interaction between hepatic dysfunction and benzodiazepines has been reviewed [ ]; these drugs more readily affect liver function in individuals with liver disease and may also directly contribute to hepatic encephalopathy, as shown by the ability of benzodiazepine antagonists to reverse coma transiently in such patients [ ]. Elderly people appear to be at increased risk only if they are physically unwell, and particularly if they are taking many medications.
Rapid absorption, often followed by rapid redistribution to tissue stores with consequent falls in brain and blood drug concentrations, plays a significant role in the quick onset and cessation of perceived effects, but long-term actions, for example mild sedative and antianxiety effects, are a consequence of slow hepatic clearance, either by hydroxylation and subsequent conjugation to a glucuronide or by microsomal metabolism to other possibly pharmacologically active metabolites. Agents that are subject to microsomal metabolism and/or oxidation accumulate more rapidly in patients with reduced liver function (for example frail elderly people); only the metabolism of drugs such as oxazepam, lorazepam, and temazepam, which predominantly undergo glucuronidation, is not affected by liver function ( Table 3 ) nor suffer from interference by drugs, such as cimetidine, estrogens, or erythromycin, which compete for the enzyme pathways (see Drug–Drug Interactions ).
Table 3
Predominant metabolic pathways for benzodiazepines and related agonists
| Via CYP3A oxidation | |||
| Alprazolam | Clonazepam | Halazepam | Prazepam |
| Anidazolam | Chlorazepate | Loprazolam | Quazepam |
| Bromazepam | Diazepam (also CYP2C19) | Lormetazepam | Triazolam |
| Brotizolam | Estazolam | Medazepam | Zaleplon |
| Chlordiazepoxide | Flunitrazepam | Midazolam | Zolpidem |
| Clobazam (also CYP2C19) | Flurazepam | Nitrazepam | Zopiclone |
| Via glucuronidation | |||
| Lorazepam | Oxazepam | Temazepam | |
NB: Drugs other than diazepam and clobazam, in particular the so-called “Z drugs” (zaleplon, zolpidem, zopiclone) (34), are also likely to have multiple oxidative pathways.
Pharmacodynamics
The use of techniques of molecular biology to clone the benzodiazepine receptor and the other components of the GABA receptor/chloride channel complex has shown that there are likely to be many variant forms of the receptor, owing to the multiplicity of protein subunits that constitute it. This has given rise to the hope that more selective agonist drugs, for example the “Z drugs” (zaleplon, zolpidem, and zopiclone), may produce fewer adverse effects [ , ]; however, this hope appears to have been over-optimistic [ ]. There are also many ways in which different drugs interact with receptor sites to produce their effects, including agonism, partial agonism, antagonism, inverse agonism (contragonism), and even partial inverse agonism; this increases the complexity considerably. The suggestion that partial agonists (such as alpidem and abecarnil) have greater anxiolytic than sedative potency [ ], or that they will be less likely to give rise to abuse [ ] or dependence [ ], is yet to be established.
Medicolegal considerations
Medicolegal problems, especially with the use of triazolam, have been discussed [ ]; debate continues on the interpretation of evidence that points to an increased incidence of adverse behavioral effects with triazolam [ ], flunitrazepam, and other short-acting high-potency agents [ ]. A review has highlighted a substantial rate (0.3–0.7%) of aggressive reactions to benzodiazepines, and the fact that a majority so affected may have intended a disinhibitory effect, with clear forensic implications [ ]. High rates of benzodiazepine consumption, much of it illicit, continue in prison populations.
Efforts to restrict benzodiazepines in New York State [ , ] and to ban triazolam (Halcion) in the UK [ , ] and the Netherlands [ ] have likewise been fraught with controversy. For example, the requirement to use triplicate prescription forms in New York has been effective in reducing prescription volumes, including arguably necessary and appropriate prescriptions [ ]. A 1979 suspension of triazolam availability in the Netherlands was overturned in 1990, while a 1993 formal ban in the UK has remained in force [ ]. Two extensive reports have included recommendations for resolving the special problems posed by the Halcion controversy [ , ].
General adverse effects and adverse reactions
Benzodiazepines have a high therapeutic index of safety, with little effect on most systems (other than the CNS) in high doses. However, their toxicity increases markedly when they are combined with other CNS depressant drugs, such as alcohol or opioid analgesics. Medically ill and brain injured patients are particularly susceptible to adverse neurological or behavioral effects [ , , ].
The most frequent adverse effect which occurs in at least one-third of patients is drowsiness, often accompanied by incoordination or ataxia. Problems with driving, operating machinery, or falls can result, particularly in the elderly, and can be an important source of morbidity, loss of physical function, and mortality [ , ]. Memory impairment, loss of insight, and transient euphoria are common; “paradoxical” reactions of irritability or aggressive behavior have been well documented [ ] and appear to occur more often in individuals with a history of impulsiveness or a personality disorder [ ], and in the context of interpersonal stress and frustration [ ]. Tolerance to the sedative and hypnotic effects generally occurs more rapidly than to the anxiolytic or amnestic effects [ ].
Physical dependence on benzodiazepines is recognized as a major problem, and occurs after relatively short periods of treatment [ , ], particularly in patients with a history of benzodiazepine or alcohol problems. Abrupt withdrawal can cause severe anxiety, perceptual changes, convulsions, or delirium. It can masquerade as a return of the original symptoms in a more severe form (rebound), or present with additional features [ , ]. Up to 90% of regular benzodiazepine users have adverse symptoms on withdrawal. The differences between rebound, withdrawal syndrome, and recurrence have been reviewed in detail [ ].
Rebound insomnia or heightened daytime anxiety can occur, particularly after short-acting benzodiazepine hypnotics [ , , ], and constitute a major reason for continuing or resuming drug use [ ].
The use of intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus has been evaluated in a double-blind, randomized trial in 205 adults [ ]. The patients presented either with seizures lasting 5 minutes or more or with repetitive generalized convulsive seizures, and were randomized to receive intravenous diazepam 5 mg, lorazepam 2 mg, or placebo. Status epilepticus was controlled on arrival at the hospital in significantly more patients taking benzodiazepines than placebo (lorazepam 59%, diazepam 43%, placebo 21%). The rates of respiratory or circulatory complications related to drug treatment were 11% with lorazepam, 10% with diazepam, and 23% with placebo, but these differences were not significant.
Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.3 mg/kg have been compared in a prospective randomized study in 47 children (aged 6 months to 5 years) with prolonged (over 10 minutes) febrile seizures [ ]. Intranasal midazolam controlled seizures significantly earlier than intravenous diazepam. None of the children had respiratory distress, bradycardia, or other adverse effects. Electrocardiography, blood pressure, and pulse oximetry were normal in all children during seizure activity and after cessation of seizures.
Organs and systems
Cardiovascular
Hypotension follows the intravenous injection of benzodiazepines, but is usually mild and transient [ ], except in neonates who are particularly sensitive to this effect [ ]. Local reactions to injected diazepam are quite common and can progress to compartment syndrome [ ]. In one study [ ], two-thirds of the patients had some problem, and most eventually progressed to thrombophlebitis. Flunitrazepam is similar to diazepam in this regard [ ]. Altering the formulation by changing the solvent or using an emulsion did not greatly affect the outcome [ ]. Midazolam, being water-soluble, might be expected to produce fewer problems; in five separate studies there were no cases of thrombophlebitis, and in two others the incidence was 8–10%, less than with diazepam but similar to thiopental and saline [ ].
Respiratory
Respiratory depression has been reported as the commonest adverse effect of intravenous diazepam [ ], especially at the extremes of age. Midazolam has similar effects [ ]. All benzodiazepines can cause respiratory depression, particularly in bronchitic patients, through drowsiness and reduction in exercise tolerance [ ]. Rectal administration of, for example, diazepam can offer advantages in unconscious or uncooperative patients, and is less likely than parenteral administration to produce respiratory depression.
In a prospective study of children admitted to an accident and emergency department because of seizures, there were 122 episodes in which diazepam was administered rectally and/or intravenously; there was respiratory depression in 11 children, of whom 8 required ventilation [ ]. The authors questioned the use of rectal or intravenous diazepam as first-line therapy for children with acute seizures. This report has been challenged [ , ]. The authors of the second comment stated that this complication does not occur when rectal diazepam gel is used without other benzodiazepines; they also recommended that during long-term therapy families should be instructed not to give rectal diazepam more than once every 5 days or five times in 1 month.
In a case-control study in 2434 patients with chronic obstructive pulmonary disease (COPD) and respiratory failure and 2434 age- and sex-matched patients without respiratory failure, exposure to benzodiazepines during the 180 days before the index date was associated with an increased risk of respiratory failure (adjusted OR = 1.56; 95% CI = 1.14, 2.13) [ ]. There was a greater than 2-fold increase in risk in those who used two or more kinds of benzodiazepines and in those using combinations of benzodiazepines and non-benzodiazepine medications.
Nervous system
Falls
The role of different types of benzodiazepines in the risk of falls in a hospitalized geriatric population has been examined in a prospective study of 7908 patients, consecutively admitted to 58 clinical centers during 8 months [ ]. Over 70% of the patients were older than 65 years, 50% were women, and 24% had a benzodiazepine prescription during the hospital stay. The findings suggested that the use of benzodiazepines with short and very short half-lives is an important and independent risk factor for falls. Their prescription for older hospitalized patients should be carefully evaluated.
In a case–control study using the Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE) database, the records of 9752 patients hospitalized for fracture of the femur during the period 1992–1996 were extracted and matched by age, sex, state, and index date to the records of 38 564 control patients [ ]. Among older individuals, the use of benzodiazepines slightly increased the risk of fracture of the femur. Overall, non-oxidative benzodiazepines do not seem to confer a lower risk than oxidative agents. However, the latter may be more dangerous among very old individuals (85 years of age or older), especially if used in high dosages.
In a similar case–control study, 245 elderly patients were matched with 817 controls [ ]. Benzodiazepines as a group were not associated with a higher risk of hip fracture, but patients who used lorazepam or two or more benzodiazepines had a significantly higher risk.
Effects on performance
All benzodiazepines can cause drowsiness and sedation, and can affect motor and mental performance. Driving is one motor and mental task that is particularly likely to be impaired [ , ], with dangerous consequences; hypnosedatives, like alcohol, impair both actual driving performance [ ] and laboratory psychomotor tests [ ], and are over-represented in blood samples from delinquent drivers [ , ]. As with alcohol, the maximal impairment occurs while the drug blood concentrations are rising [ ], rather than when they have peaked, are stable, or are falling. Somewhat surprisingly, zopiclone 7.5 mg, but not triazolam 0.25 mg, produced deficits in simulated aircraft flight performance 2 and 3 hours after the dose [ ]. The motor and mental performance reductions induced by hypnotics, especially in elderly people [ ], result in an increased incidence of falls [ ] which can cause hip fractures [ ]. Agents with short half-lives, including the “Z drugs”, were previously thought to carry a reduced risk or even none, but earlier reassuring data have been supplanted by convincing evidence of harm, particularly during the first 2 weeks of prescription [ , ].
Fit young subjects had no impairment of their exercise ability after temazepam or nitrazepam, although nitrazepam caused a subjective feeling of hangover [ ].
Seizures
Benzodiazepines can provoke seizures and occasionally precipitate status epilepticus.
-
A 28-year-old man with complex partial status, which lasted for 2 months, had a paradoxical worsening of seizure activity in response to diazepam and midazolam [ ].
Of 63 neonates receiving lorazepam, diazepam, or both in an intensive care unit, 10 had serious adverse events, including 6 with seizures [ ].
Psychological, psychiatric
Cognition
The amnestic effects of benzodiazepines are pervasive and appear to derive from disruption of the consolidation of short-term into long-term memory [ ]. Amnesia appears to underlie the tendency of regular hypnotic users to overestimate their time asleep, because they simply forget the wakeful intervals [ ]; in contrast, the same patients underestimate their time spent asleep when drug-free. This amnestic property [ , ] has been used to advantage in minor surgery, particularly with midazolam and other short-acting compounds (although male doctors and dentists are advised to have a chaperone present when performing benzodiazepine-assisted procedures with female patients). However, unwanted amnesia can occur, particularly with triazolam, when used as a hypnotic or as an aid for travelers [ , ]. The combination of a short half-life and high potency, especially when it was used in the higher doses that were recommended when the drug was initially launched, makes triazolam particularly likely to cause this problem. Studies of low-dose lorazepam (1 mg) in healthy young adults have shown specific deficits in episodic memory [ , ]. Flurazepam and temazepam have initiated relatively few reports of adverse effects on memory, although flurazepam did cause daytime sedation. Temazepam was uncommonly mentioned in adverse reaction reports, but was also reported more often as being without adequate hypnotic effect. Ironically, temazepam produces more, and oxazepam less, sedation than other benzodiazepines in overdose [ ].
The role of benzodiazepines in brain damage has been reviewed [ , ]. Cognitive impairment in long-term users can be detected in up to half of the subjects, compared with 16% of controls, but the issue of reversibility with prolonged abstinence is unresolved. Cognitive toxicity is more common with benzodiazepines than other anticonvulsants, with the possible exception of phenobarbital [ ].
Patients often have memory deficits after taking benzodiazepines and alcohol. In a study of hippocampal presynaptic glutamate transmission in conjunction with memory deficits induced by benzodiazepines and ethanol, reductions in hippocampal glutamate transmission closely correlated with the extent of impairment of spatial memory performance. The results strongly suggested that presynaptic dysfunction in dorsal hippocampal glutamatergic neurons would be critical for spatial memory deficits induced by benzodiazepines and ethanol [ ].
When the relation between benzodiazepine use and cognitive function was evaluated in a prospective study of 2765 elderly subjects, the authors concluded that current benzodiazepine use, especially in recommended or higher dosages, is associated with worse memory among community-dwelling elderly people [ ].
In a prospective study, 1389 people aged 60–70 years were recruited from the electoral rolls of the city of Nantes, France (Epidemiology of Vascular Aging Study) [ ]. A range of symptoms was examined, including cognitive functioning and symptoms of depressive anxiety, and data were also collected on psychotropic and other drugs, as well as tobacco use and alcohol consumption at baseline and thereafter at 2 and 4 years. Users of benzodiazepines were divided into episodic users, recurrent users, and chronic users. Chronic users of benzodiazepines had a significantly higher risk of cognitive decline in the global cognitive test and two attention tests than non-users. Overall, episodic and recurrent users had lower cognitive scores compared with non-users, but the differences were not statistically significant. These findings suggest that long-term use of benzodiazepines is a risk factor for increased cognitive decline in elderly people.
A detailed review has confirmed a relation between impaired memory and benzodiazepine use [ ]. Different drugs had a similar profile in relation to memory impairment and this was independent of sedation. The benzodiazepines produced anterograde amnesia but not retrograde amnesia, and retrieval processes remained intact.
Delirium
Excessive anxiety and tremulousness, hyperexcitability, confusion, and hallucinations were all reported more often with triazolam than with temazepam or flurazepam, when spontaneous reporting was analysed [ ]. Whether this is dose-related, and perhaps related to the rapid changes in blood concentration with triazolam, is not clear. Delirium is common, particularly in elderly people, who may have impaired drug clearance, and must always be regarded as possibly drug-induced. Of considerable relevance to hospital practice is the finding of a three-fold increased risk of postoperative delirium in patients given a benzodiazepine [ ]. Dose- and age-related increases in adverse cognitive and other central nervous effects from benzodiazepines [ ] are well documented. The use of these drugs in elderly people has been reviewed, with recommendations about maximizing the benefit-to-harm balance in this group of individuals who are susceptible to cognitive and other adverse effects [ , ].
Sleep
The benzodiazepines typically suppress REM sleep, with consequent rebound dreaming and restlessness on withdrawal, leading to poorer sleep patterns [ , ].
The use of benzodiazepines, particularly the short-acting compounds such as triazolam, for the induction of sleep has provoked much discussion [ ]. The debate rages over the risks and benefits of short-acting compounds, in inducing bizarre behavior or rapid withdrawal with daytime anxiety, compared with the possibility of hangover sedation and performance deficits with longer-acting compounds [ ]. The treatment of sleep disorders is multifaceted, because of the complex nature of sleep and the variety of factors that can give rise to sleep disorders [ ]. Consequently, such treatment should be selected and proffered carefully, with due regard for all the factors, not treated cavalierly with the latest flavor-of-the-month benzodiazepine receptor agonist. Non-drug treatments are effective [ ] and should be considered first; pharmacological treatment should take into consideration any pre-existing factors, for example anxiety, depression, the duration and nature of medical problems (including any painful condition), concomitant medications, and other substance use [ ].
Psychoses
Depression is commonly seen [ ], either during benzodiazepine treatment or as a complication of withdrawal [ ]. Relief of anxiety symptoms can uncover pre-existing depression, rather than causing depression per se. In addition to their euphoriant effects in some individuals, benzodiazepines can directly increase irritability and depression and, less commonly, lead to full-blown manic episodes [ , ].
Review of a Canadian adverse drug reactions database showed several cases of previously unreported benzodiazepine-induced adverse effects, including hallucinations and encephalopathy [ ], although whether benzodiazepines alone were responsible is difficult to confirm. Visual hallucinations have also been reported in association with zolpidem [ ].
Benzodiazepine withdrawal, like alcohol withdrawal, can cause schizophreniform auditory hallucinations [ ].
Behavior
While they are generally regarded as being tranquillizers, benzodiazepines and related hypnosedatives can release aggression and induce antisocial behavior [ ], particularly in combination with alcohol [ ] and in the presence of frustration [ ]. Aggression can occur during benzodiazepine intoxication and withdrawal [ ]. Non-medical use of flunitrazepam [ ] seems particularly likely to reveal paradoxical rage and aggression, with consequent forensic problems. The combination of abnormal disinhibited behavior and amnesia produced by benzodiazepines can be singularly dangerous. Anecdotal cases suggest that hypnosedatives can also disinhibit violent behavior in individuals taking antidepressants. A literature review of behavioral adverse effects associated with benzodiazepines (clonazepam, diazepam, and lorazepam) has shown that 11–25% of patients with mental retardation have these adverse effects [ ]. In two controlled studies, lorazepam was more likely to provoke aggression than oxazepam [ , ].
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